Conditions: Acute Lymphoblastic Leukemia
Keywords: Leukemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 600
Healthy volunteers: no

Brief summary:
The primary objective of this study (TOTXVI) is to compare the clinical benefit, the pharmacokinetics, and the pharmacodynamics of polyethylene glycol-conjugated (PEG) asparaginase given in higher dose (HD PEG) versus those of PEG-asparaginase given in conventional dose (CD PEG) during the continuation phase.

This study has several secondary objectives:

Therapeutic Objectives:

To estimate the event-free survival and overall survival of children with ALL who are treated with risk-directed therapy.

To study whether intensifying induction, including fractionated cyclophosphamide and thioguanine, in patients with day 15 MRD \> 5%, will result in improved leukemia cytoreduction in this subgroup compared to TOTXV.

To assess whether intensification of central nervous system (CNS)-directed intrathecal and systemic chemotherapy will improve outcome in patients at high risk of CNS relapse.

Exploratory Pharmacologic Objectives:

To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol.

To compare the pharmacokinetics and pharmacodynamics of PEG-asparaginase given in higher dose (3,500 or 3,000 units/m2) versus those of PEG-asparaginase given in conventional dose (2,500 units/m2) in the continuation phase.

Exploratory Biologic Objectives:

To determine the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of remission induction.

To validate new markers and methods for MRD detection. To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and before reinduction, and to associate these features with treatment outcome.

To identify new prognostic factors by applying new technologies to study patient material (e.g., stored plasma, serum, cerebrospinal fluid, and normal and leukemic cells).

Exploratory Neuroimaging Objectives:

To use quantitative MR measures (Diffusion Tensor Imaging and high resolution volumetric imaging) to assess differences in myelin and cortical thickness development in patients treated for ALL relative to healthy controls matched for age and gender.

To assess the impact of folate pathway genetic polymorphisms on myelin and cortical thickness development and neurocognitive performance.

To assess the impact of frontal-parietal lobe myelin and cortical thickness development on neurocognitive performance in attention, working memory, fluency, visual-spatial reasoning and processing speed.

Detailed description:
Details of the Treatment Plan:

Treatment will consist of three main phases: Remission Induction, Consolidation, and Continuation.

1. Remission Induction

   * Intrathecal Treatment during Induction

   Frequency and total number of triple intrathecal treatments for Remission Induction is based on the patient's risk of CNS relapse.All patients will receive triple intrathecal treatment on days 1 and 15. Patients with high risk features may receive additional triple intrathecal treatment on days 4, 8, 11, and 22.\[t(1;19)/E2A-PBX1.

   Induction treatment will begin with prednisone, vincristine, daunorubicin, PEG-asparaginase and triple intrathecal treatment, followed by cyclophosphamide plus cytarabine plus thioguanine.

   Remission Induction Chemotherapy (6-7 weeks) Prednisone 40 mg/m2/day PO (divided t.i.d.) Days 1 - 28 Dexamethasone will be substituted for prednisone in patients with early T-cell precursor (ETP) immunophenotype.

   Mercaptopurine will be substituted for thiopurine in TPMT HET/deficient patients Dexamethasone (for ETP immunophenotype only) 10 mg/m2/day PO (divided t.i.d.)Days 1-21; 4 mg/m2/day PO (divided t.i.d) Days 22-24; 2 mg/m2/day PO(divided t.i.d) Days 25-28 Vincristine 1.5 mg/m2 IV (max 2 mg) Days 1, 8, 15, 22 Daunorubicin 25 mg/m2 IV Days 1 and 8 PEG-asparaginase 3,000 Units/m2 IV Day 3

   \- Participants with Day 15 MRD greater than or equal to 1%: PEG-asparaginase 3,000 Units/m2 IV Day 15

   \- Participants with Day 15 MRD less than 5% (excluding MLL positive infants): Cyclophosphamide 1000 mg/m2 IV Day 22 Cytarabine 75 mg/m2/dose IV Days 23-26, 30-33 Thioguanine \[Mercaptopurine (TPMT HET/deficient patients only)\]60 mg/m2/dose PO Days 22-35 Dasatinib (Ph+ participants only) 40 mg/m2 b.i.d starting Day 22 of induction to continue until end of treatment

   Day 15 MRD \> or equal to 5% (excluding MLL+ infants) Cyclophosphamide† 300 mg/m2 IV/ q12 hrs on Days 22-23 Cytarabine 75 mg/m2/dose IV Days 23-26, 30-33 Thioguanine \[Mercaptopurine (TPMT HET/deficient patients only) 60 mg/m2/dose PO Days 22-35 Dasatinib‡ (Ph+ participants only) 40 mg/m2 b.i.d Daily Starting Day 22 of induction to continue until end of treatment

   \- Infants with MLL positive rearrangement: Clofarabine 40 mg/m2/dose IV Days 22-26 Etoposide 100 mg/m2/dose IV Days 22-26 Cyclophosphamide 300 mg/m2/dose IV Days 22-26
2. Consolidation Treatment (8 weeks) High Dose Methotrexate (HDMTX) 2.5 gm/ (low risk), or targeted 65 μM (std/high-risk) days 1, 15, 29 and 43. Mercaptopurine 50 mg/m2/day Days 1 to 56. All patients will receive triple intrathecal therapy every other week for four doses on Days 1, 15, 29, and 43. Dose is age dependent.

   \- Reintensification

   Patients with high-risk leukemia may receive reintensification therapy and then will be offered the option of transplant. This treatment will attempt to maximize leukemic cell kill before allogeneic hematopoietic stem cell transplantation.

   Dexamethasone 20 mg/m2/day PO or IV Days 1-6.Cytarabine 2 grams/m2, 3-hour IV infusion every 12 hours Days 1-2. Etoposide 100 mg/m2, 1-hour IV infusion every 12 hours Days 3-5. Intrathecal methotrexate+hydrocortisone+cytarabine (ITMHA) Day 5; PEG-asparaginase 3,000 units/m2 IV Day 6

   Patients with suboptimal response to reintensification may receive one to two cycles of clofarabine/cyclophosphamide/etoposide/dexamethasone:

   Clofarabine 40 mg/m2/day, 2-hour IV infusion Days 1-5 Etoposide 100 mg/m2/day, 2-hour IV infusion Days 1-5 Cyclophosphamide 300 mg/m2/day, 30-60 minute IV infusion Days 1-5 Dexamethasone 8 mg/m2/day (divided t.i.d) Days 1-5
3. Continuation Treatment (120 weeks)

Abbreviations used below: DEX=dexamethasone; DOX=doxorubicin; VCR=vincristine; MP=mercaptopurine; PEG-ASP=polyethylene glycol-conjugated asparaginase; MTX=methotrexate; 6MP=mercaptopurine

Weeks 1 through 20 - treatment depends on risk assignment standard-high versus low-risk

Week Standard-/High-Risk Low-Risk

1. DEX+DOX+VCR+MP + PEG-ASP/MP + DEX + VCR
2. MP MP + MTX
3. MP + PEG-ASP/MP + MTX
4. DEX + DOX + VCR + MP/MP + DEX + VCR
5. MP + PEG-ASP MP + MTX
6. MP MP + MTX
7. Reinduction I
8. Reinduction I
9. Reinduction I
10. MP/MP + MTX
11. DOX + VCR +MP + PEG-ASP/MP + MTX
12. MP/MP + MTX
13. MP + PEG-ASP/MP + MTX
14. DEX + DOX + VCR +6MP/MP + DEX + VCR
15. MP + PEG-ASP/MP + MTX
16. MP/MP + MTX
17. Reinduction II
18. Reinduction II
19. Reinduction II
20. No chemotherapy/MP + MTX

    Drug Dosages, Schedules and Routes for Continuation Therapy Weeks 1 to 6 and 10 to 16:

    Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (divided t.i.d.) for 5 days, Days 1-5. Doxorubicin 30 mg/m2 IV, Day 1. Vincristine 2 mg/m2 IV push (max. 2 mg), Day 1 (0.05 mg/kg for patients \< 1 year of age or \< 10kg in weight). MP (mercaptopurine) 50 mg/m2 PO daily for 7 days (std/high risk), Days 1-7, 75 mg/m2 PO daily for 7 days (low risk), Days 1-7. PEG-ASP (PEG-asparaginase) 2,500 vs. 3,500 units/m2 IV randomization, Day 1. Methotrexate 40 mg/m2 IV Day 1.

    Dexamethasone, vincristine, and asparaginase will be given regardless of blood counts, provided that the patient is clinically well. Doxorubicin, mercaptopurine and methotrexate will be held if white blood count (WBC) \<1000/mm3 or absolute neutrophil count (ANC) \<300/mm3. Doxorubicin, mercaptopurine and methotrexate will be reduced for WBC \< 1500/mm3, or if WBC and ANC not increase by at least 2 folds a week after the start date of dexamethasone pulse.

    Reinduction Treatment - This phase of treatment is part of continuation and will be started at weeks 7 and 17 after bone marrow examination confirms complete remission. Doxorubicin and HD-cytarabine will be held if ANC \< or equal to 300/mm3 or WBC \< 1000/mm3.It is preferable to start HD-cytarabine when WBC \> or equal to 1800/mm3 and ANC \> 300/mm3 Reinduction treatment will be given twice: weeks 7 to 9 and weeks 17 to 19 for all patients. Intrathecal treatment will be followed by leucovorin rescue (5 mg/m2/dose PO, max 5 mg) at 24 and 30 hours only in patients with prior CNS toxicities or in patients with WBC \< 1500/mm3, or ANC \< 500/mm3.

    \- Reinduction I for Standard/High Risk ALL excluding MLL infants: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15 Doxorubicin 30 mg/m2 IV Days 1, 8. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15.

    Intrathecal chemotherapy, Methotrexate + hydrocortisone + Ara-C dose age dependent, Day 1.

    \- Reinduction II for Standard/High Risk ALL including MLL infants: Dexamethasone 8 mg/m2/day PO (t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. High-dose cytarabine 2 gm/m2 IV q 12 hr Days 15, 16. Intrathecal chemotherapy, dose age dependent, Day 1.

    \- Reinduction I for Low-Risk ALL: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. Doxorubicin 30 mg/m2/IV Day 1. Intrathecal chemotherapy, dose age dependent, Day 1.

    \- Reinduction II for Low-Risk ALL: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8, 15-21. Vincristine 1.5 mg/m2/week IV Days 1, 8, 15. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. Intrathecal chemotherapy, dose age dependent, Day 1.

    \- Reinduction I for MLL Infants: Dexamethasone 8 mg/m2/day PO (divided t.i.d.) Days 1-8 and 15-21. Clofarabine 40 mg/m2/day, -hour IV Days 1-5. Etoposide 100 mg/m2/day, 2-hour IV Days 1-5. cyclophosphamide 300 mg/m2/day, 1-hour IV Days 1-5. PEG-asparaginase 2,500 or 3,500 units/m2 IV Days 1, 15. Intrathecal chemotherapy, dose age dependent, on Day 1.

    \- Intrathecal Chemotherapy:
    * Triple intrathecal treatment will be given to low-risk cases with CNS-1 status (no identifiable blasts in CSF) on weeks 7, 12, 17, 25, 33, 41, and 49.
    * Triple intrathecal treatment will be given to low-risk cases with CNS-2, traumatic CSF with blasts status, or WBC \> 100 x 109/L on weeks 3, 7, 12, 17, 25, 29, 33, 37, 41, 45 and 49.
    * Triple intrathecal treatment will be given to standard/high-risk cases on weeks 7, 12, 17, 25, 29, 33, 37, 41, 45 and 49.
    * Triple intrathecal treatment will be given to other standard/high-risk cases with WBC \> or equal to 100 x 109/L, T-cell ALL, t (1;19)/E2A-PBX1, presence of Philadelphia chromosome, MLL rearrangement, hypodiploidy \<44, CNS-2 or CNS-3 status, or traumatic lumbar puncture with blasts on weeks 3, 7, 12, 17, 25, 29, 33, 37, 41, 45, 49, 57, 65, 73, 81, 89 and 97

    Treatment (weeks 21 to 29)

    Week Standard/High Risk Low Risk
21. MP + PEG-ASP+Dasatinib MP + MTX
22. MP +Dasatinib MP + MTX
23. MP + PEG-ASP + Dasatinib MP + MTX
24. Cyclo + Ara-C + Dasatinib MP + MTX
25. DEX + VCR + PEG-ASP + Dasatinib MP + DEX + VCR
26. MP + Dasatinib MP + MTX
27. MP + PEG-ASP+Dasatinib MP + MTX
28. Cyclo + Ara-C + Dasatinib MP + MTX
29. DEX + VCR +PEG-ASP + Dasatinib MP + DEX + VCR Dasatinib in Ph+ only

    Treatment (weeks 30 to end of therapy)

    Week Standard/High Risk Low Risk
30. MP + MTX + Dasatinib MP + MTX
31. MP + MTX + Dasatinib MP + MTX
32. Cyclo + Ara-C+Dasatinib MP + MTX
33. DEX + VCR + Dasatinib MP + DEX + VCR
34. MP + MTX + Dasatinib MP + MTX
35. MP + MTX + Dasatinib MP + MTX
36. Cyclo + Ara-C + Dasatinib/MP + MTX
37. DEX + VCR + Dasatinib /MP + DEX + VCR Dasatinib in Ph positive patients only

Drug Dosages, Schedules and Routes for Continuation Therapy from Week 21 to End of Therapy:

Mercaptopurine 75 mg/m2 PO daily for 7 days, Days 1-7. Methotrexate 40 mg/m2 IV or intramuscularly (IM) Day 1. Cyclophosphamide 300 mg/m2 IV, Day 1. Cytarabine 300 mg/m2 IV, Day 1. Dexamethasone 12 mg/m2 (std/high risk) or 8 mg/m2 (low risk) PO daily (divided t.i.d.) for 5 days, Day 1-5 (between week 21 and week 68).Decrease dexamethasone to 6 mg/m2 PO daily (divided t.i.d.) x 5 days,Day 1-5 between week 69 and week 101 for all risk groups.

Vincristine2 mg/m2 IV push (max 2 mg), Day 1 (0.05mg/kg for patients \< 1 year or \< 10 kg).

PEG-ASP 2,500 vs 3,500 units/m2 IV randomization (until week 30)

Dexamethasone, vincristine, and asparaginase will be given regardless of blood counts, provided that the patient is clinically well. Cyclophosphamide, cytarabine, mercaptopurine and methotrexate will be held if WBC \<1000/mm3 or ANC \<300/mm3. Mercaptopurine and methotrexate will be reduced for WBC \< 1500/mm3, or if WBC and ANC do not increase by at least 2 folds a week after the start date of dexamethasone pulse. Doses of cyclophosphamide and cytarabine may need to be reduced if patient misses 25% of chemotherapy and if the low counts deem to be related to this combination.

The same treatment (weeks 30-37) will be repeated for a total of 5 times, until week 69 (see Section 5.5.3 for intrathecal therapy). After week 69, all patients will receive daily mercaptopurine and weekly methotrexate interrupted with pulses of dexamethasone, vincristine, and mercaptopurine every 4 weeks. The dose of dexamethasone will be decreased to 6 mg/m2 between week 69 and week 101, after which only mercaptopurine and methotrexate will be given. Intrathecal treatment will be given every 8 weeks only to patients at risk of CNS relapse after week 49 and will be discontinued after week 97. Continuation therapy will be discontinued after 120 weeks.

Hematopoietic Stem Cell Transplantation (for patients who meet the criteria of high-risk ALL are candidates for allogeneic hematopoietic stem cell transplantation). However, if the option is declined by the patients or guardians, or the procedure is deemed unsuitable by the attending physician and the principal investigator, the patient will remain on study and continue to receive chemotherapy.

Arms:
arm 1: Participants randomized to receive higher dose PEG-asparaginase during the continuation phase.

Interventions:

* Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine
* Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib arm 2: Participants randomized to receive conventional dose PEG-asparaginase during the continuation phase..

Interventions:

* Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine
* Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib

Interventions: intervention 1: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine intervention 2: Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
Intervention descriptions: intervention 1: See Detailed Description section for details of treatment interventions. intervention 2: See Detailed Description section for details of treatment interventions.

Protocol document:
Prot_SAP_000.pdf: 
T O T X VI 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
IR B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D oc u me nt d ate d:  0 7- 1 7 -2 0 1 5  
SJ C R H 
T O T X VI C T G # - N C T 0 0 5 4 9 8 4 8
I nitial versi o n, date d: 0 6- 0 8 - 2 0 0 7, Res u b mitte d t o C P S R M C 0 7- 2 7 - 2 0 0 7 a n d 0 8-2 7 - 2 0 0 7 S u b mitte d t o I R B 9-1 7 -
2 0 0 7, Res u b mitte d t o I R B 9- 2 8 - 2 0 0 7 a n d 1 0-1 1 -2 0 0 7 .  (I R B a p pr o ve d: 1 0-2 3 -0 7) .  Acti vati o n Date: Oct o ber 2 6, 2 0 0 7 
Re visi o n 0. 1: Dece m ber 0 6, 2 0 0 7 (I R B A p pr o ve d: Dece m ber 1 4, 2 0 0 7) 
A me n d me nt 1. 0:  A pril 2 8, 2 0 0 8, Res u b mitte d t o C P S R M C Ma y 1 3, 2 0 0 8, Res u b mitte d t o I R B J u n e 2, 2 0 0 8 (I R B 
A p pr o ve d: J u n e 1 0, 2 0 0 8) 
Letter of A me n d me nt # 1 date d Marc h 1 1, 2 0 0 9 (I R B A p pr o ve d : A pril 1 4, 2 0 0 9) 
Re visi o n 1. 1 : A pril 2 0, 2 0 0 9 (I R B A p pr o ve d: A pril 2 3, 2 0 0 9). Acti vate d Ma y 8, 2 0 0 9 
A me n d me nt 2. 0:  A u g ust 2 0, 2 0 0 9, Res u b mitte d t o I R B o n 1 0/ 1 6/ 0 9 a n d 1 1/ 4/ 0 9 (I R B A p pr o ve d: N o ve m ber 5, 2 0 0 9) 
Res u b mitte d t o C P S R M C Oct o ber 5, 2 0 0 9. 
A me n d me nt 3. 0: J a n uar y 2 8, 2 0 1 0, R es u b mitte d t o C P S R M C Marc h 2 2, 2 0 1 0, Res u b mitt e d t o I R B A pril 2 1, 2 0 1 0 
I R B A p pr o ve d: A pril 2 2, 2 0 1 0) Acti vate d: Ma y 1 9, 2 0 1 0 
A me n d me nt 4. 0: J u n e 1 5, 2 0 1 0 (I R B A p pr o ve d: A u g ust 1 0, 2 0 1 0) 
A me n d me nt 5. 0: Se pte m ber 1 4, 2 0 1, Res u b mitte d t o I R B N o ve m ber 4, 2 0 1 1 
(I R B A p pr o ve d: Dece m ber 6, 2 0 1 1) Acti vate d: J a n uar y 1 8, 2 0 1 2 
Re visi o n 5. 1: Fe br uar y 2 7, 2 0 1 2 (I R B a p pr o ve d: A pril 3, 2 0 1 2) 
Acti vate d : A pril 1 8, 2 0 1 2 
Re visi o n 5. 2: J u n e 1 9, 2 0 1 2 (I R B a p pr o ve d: J u n e 2 5, 2 0 1 2) 
Acti vate d : A u g ust 2 1, 2 0 1 2 
Re visi o n 5. 3: J ul y 2 2, 2 0 1 3 (I R B a p pr o ve d: A u g ust 1 3, 2 0 1 3) 
Acti vate d: Se pte m ber 4, 2 0 1 3 
Re visi o n 5. 4: Oct o ber 2 1, 2 0 1 4. Res u b mitte d t o I R B Dece m ber 1 0, 2 0 1 4 a n d J a n uar y 1 4, 2 0 1 5.  
(I R B a p pr o ve d: J a n uar y 1 5, 2 0 1 5) Acti vate d: J a n uar y 2 9, 2 0 1 5 
Re visi o n 5. 5:  Marc h 2, 2 0 1 5 (I R B a p pr o ve d: A pril 1 4, 2 0 1 5) .  A cti vate d: J u ne 1 5 , 2 0 1 5. 
Re vi si o n 5. 6:  J ul y 1 7, 2 0 1 5 (I R B a p pr o ve d: J ul y 1 7, 2 0 1 5).  Acti vate d: J ul y 1 7, 2 0 1 5 
L O A, date d A pril 1 5, 2 0 1 6 (I R B a p pr o ve d: A pril 1 9, 2 0 1 6 Acti vate d : A u g ust 2 9, 2 0 1 6 
T O T A L T H E R A P Y S T U D Y X V I F O R N E W L Y DI A G N O S E D P A TI E N T S WI T H A C U T E 
L Y M P H O B L A S TI C L E U K E MI A 
Pri nci p al I n vesti g at or 
Si ma Je ha, M D 1 
C o - Pri nci p al I n vesti g at or 
C hi n g- H o n P ui, M D 1 
Secti o n C o or di n at ors 
P har mac o ki netics/ P har mac o ge n o mics  
Mar y V . Relli n g, P har m D2 
Willia m E. E va ns, P har m D
2 
Statistics  
C he n g C he n g, P h D 3 
Ja mes M. B o yett, P h D 3 
De p art me nts of 1O nc ol o gy, 2P h ar m ace utic al Scie nce s, 3Bi ost atistics 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
S u b-I n vesti g at ors 
 
J o h n K. C h oi, M D, P h D4 
Heat her C o n kli n, P h D 7 
Patricia Fl y n n, M D 5 
A dit ya Ga ur, M D 5 
Ta nja Gr u ber, M D, P h D 1 
Ha na Ha ki m, M D 5 
Ra n dall Ha y de n, M D 4 
Hir ot o I na ba, M D, P h D 1 
S ue C. Kaste, D O 6 
Ke vi n R. Kr ull, P h D 7 
Wi n g Le u n g, M D, P h D 8 
M o ni ka Metz ger, M D
1 
R o bert J. O g g, P h D 6 
De qi n g Pei, M S 3 
S usa na Rai m o n di, P h D 4 
Wil b ur n E. Re d dic k, P h D
6 
Ra ul Ri beir o, M D 1 
Jeffre y R u b nitz, M D, P h D 1 
J o h n T orre y Sa n dl u n d, M D 1 
Yi n mei Z h o u, M S 3 
 
 
 
 
De p art me nts of 1O nc ol o gy, 2P h ar m ace utic al Scie nces, 3Bi ost atistics 4P at h ol o gy, 5I nfecti o us 
Dise ases, 6R a di ol o gic al Scie nces, 7E pi de mi ol o gy a n d C a ncer C o ntr ol, 8B o ne M arr o w 
Tr a ns pl a nt ati o n & C ell ul ar T her a py 
 
 
St. J u de C hil dre n’s Researc h H os pital  2 6 2  Da n n y T h o mas Place 
Me m p his, T N  3 8 1 0 5 
Tele p h o ne ( 9 0 1) 5 9 5- 3 3 0 0 
 
 
C o nte nts of  t his d oc u me nt m ay n ot be  extr acte d wit h o ut per missi o n fr o m t he Pri nci p al I nvesti g at or. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


 
1  
 
 
 
 
 
 
 
 
 
T O:   
I R B a n d C T- S R C  
  
  
  
 
F R O M: 
Si m a Je h a, M D 
 
D A T E:   
A pril 1 5, 2 0 1 6 
 
R E:  
T O T X VI, T ot al T her a p y St u d y X VI f or Ne wl y Di a g n ose d P atie nts wit h Ac ute 
L y m p h o bl astic Le u ke mi a  
 
Re: Letter of A me n d me nt ( L O A) t o c o nti n ue e nr oll me nt 
 
 
 
A me n d me nt 6. 0 was s u b mitte d o n 4- 8- 2 0 1 6, a n d is sc he d ule d f or re vie w b y t he C T- S R C o n 4- 1 9- 2 0 1 6. 
T his a me n d me nt is t o c o nti n ue e nr oll me nt be y o n d t he c urre nt 5 3 1 tar gete d accr ual t o all o w sec o n dar y 
o bj ecti ves t o be c o m plete d.  Partici pa nts e nr olle d o n A me n d me nt 6. 0 will c o ntri b ute t o se veral sec o n dar y 
a n d e x pl orat or y o bj ecti ves; h o we ver t he y will n ot be ra n d o mize d f or t he pri mar y P E G-as para gi nase 
o bj ecti ve, a n d will n ot be offere d partici pati o n i n t he f oll o wi n g researc h st u dies : N K cell rece pt or, 
ne ur oi ma gi n g, a n d i ntesti nal micr o bi o me o bj ecti ves. 
 
T O T X VI e nr oll me nt is n o w at 5 3 1 partici pa nts.  Wit h t his letter of a me n d me nt, we are re q uesti n g t hat 
e nr oll me nt c o nti n ue wit h t he c urre ntl y a p pr o ve d pr ot oc ol u ntil t he ne w A me n d me nt 6 is a p pr o ve d a n d 
acti vate d n oti n g t he f oll o wi n g s pecificati o ns: 
 
1.  Ne w patie nts will n ot be ra n d o mize d t o sta n dar d- vers us hi g h- d ose P E G as para gi nase; t he y will 
recei ve sta n dar d d ose. 
 
2.  Ne w patie nts will n ot be offere d partici pati o n i n N K cell rece pt or, ne ur oi ma gi n g or i ntesti nal 
micr o bi o me researc h. 
 
3.  Patie nts e nr olle d via t he L O A will be re-c o nse nte d wit h A me n d me nt 6. 0 at t he ne xt cli nic visit 
after A me n d me nt 6. 0 is acti vate d. 
 
4.  T he a b o ve i nf or mati o n will be e x plai ne d t o t he patie nt/ L A R a n d d oc u me nte d i n t he me dical 
rec or d. 
 
T he tra nsiti o n bet wee n A me n d me nt 5 a n d A me n d me nt 6 will all o w partici pa nts t o c o nti n ue be nefiti n g 
fr o m pr ot oc olize d c o m ple x t hera p y a n d c o ntri b ute t o a ns weri n g i m p orta nt sec o n dar y o bj ecti ves. T ha n k 
y o u f or c o nsi deri n g t his re q uest. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
S Y N O P SI S 
 
A L L re gi me ns c o nsist of a c o m bi nati o n of m ulti ple a ge nts deli vere d o ver a peri o d of 2. 5 t o 3 
years i n 3 mai n p hases (re missi o n i n d ucti o n, c o ns oli dati o n, a n d c o nti n uati o n). See mi n gl y mi n or 
m o dificati o ns i n t he a d mi nistrati o n of dr u gs de v el o pe d o ver 3 0 years a g o (s uc h as 
merca pt o p uri n e, met h otr e x ate, vi ncristi ne, c ortic oster oi ds, a nt hrac ycli nes, a n d as para gi nase) ha ve 
ha d si g nifica nt i m pact o n o utc o me. F or e x a m ple, c ha n ges i n vi ncristi ne a n d as para gi n ase d osa ge 
f oll o wi n g i nte nsificati o n, a n d se q ue ntial es calati n g- d os e met h otre x ate f oll o we d b y as para gi nas e, 
si gnifica ntl y i m pr o ve d o utc o me of hi g h-ris k patie nts i n C C G trials 1. L o n ger e x p os ure t o 
as para gi n ase d uri n g earl y c o ns oli dati o n ha d a si g nifica nt i m pact o n o utc o me i n Da na Far ber 
st u dies2. Rece nt lar ge ra n d o mize d trials were de di cate d t o c o m pare merca pt o p uri ne t o 
t hi o g ua ni ne3, pre d nis o ne t o de x a met has o ne4; 5, si n gle t o tri ple i ntrat hecal t hera p y6 et c.  T he 
cu m ulati ve k n o wle d ge gat here d fr o m t hese a n d ot her trials f or m t he b asis of t he i m pressi ve c ure 
rates ac hie ve d i n c hil dr e n wit h A L L t o da y. 
 
T he pri mar y o bje cti ve of T O T X VI is t o c o m pare t he cli nical be nefit, t he p h ar mac o ki netics, a n d 
t he p har mac o d y n a mics of p ol yet h yle ne gl yc ol-c o nj u gate d ( P E G) as p ara gi nase gi ve n i n hi g h er 
d ose vers us t h ose of P E G-as para gi nase gi ve n i n c o n ve nti o nal d ose d uri n g t he c o nti n uati o n p hase. 
As para gi nas e is o ne of t h e ke y c o m p o ne nts of A L L t hera p y b ut its a d mi nistrati o n is c o m plicate d 
b y t he a vaila bilit y of differe nt pr e parati o ns, eac h wit h a differe nt p har mac o ki netic pr ofile 7. T he 
nati ve E. c oli as para gi nas e has bee n t h e m ost c o m m o nl y use d pre parati o n. P E G- as para gi nase, a 
l o n g-acti n g a n d less aller ge ni c f or m, is pr o gressi vel y re placi n g t he nati ve pr o d uct a n d is bei n g 
i ncreasi n gl y a d mi nistere d i ntra ve n o usl y i nstea d of i ntra m usc ularl y8.  M ost st u dies are e m piricall y 
ad o pti n g a P E G-as para gi nase d ose of 2, 5 0 0 u nits/ m 2, base d o n p u blis he d re p orts c o m pari n g t his 
d ose t o 6 d oses of 6, 0 0 0 u nits/ m 2 of nati ve E. c oli as para gi n ase.  H o we ver, t his d ose has faile d t o 
de plete C S F as para gi nas e i n s o me st u dies, s u g gesti n g it mi g ht be i na de q u ate f or C N S c o ntr ol.  
T his is of ut m ost i m p orta nce i n T O T X VI w here we rel y o n s yste mic c h e m ot hera p y i n a d diti o n t o 
i ntrat hecal t hera p y t o a v oi d cra nial irra diati o n.  I n a ra n d o mize d st u d y of 2, 5 0 0 u nits/ m2 P E G-
as para gi n ase i ntra m usc ul arl y e ver y ot her wee k f or 1 5 d oses vs. nati ve 2 5, 0 0 0 u nits/ m 2 E. c oli 
as para gi n ase i ntra m usc ul arl y e ver y wee k f or 3 0 d oses ( D F CI 9 1- 0 1), alt h o u g h t here was n o 
si gnifica nt differe nce i n E F S ( 8 4 % f or nati ve vs. 7 8 % f or P E G- as para gi nase, p = 0. 2 9), t h e tre n d 
is i n t he directi o n s u g gesti n g t hat 2, 5 0 0 u nits/ m2 of P E G-as para gi nase is sli g htl y less effecti ve 
t ha n t he 2 5, 0 0 0 u nits/ m2 of nati ve as para gi nas e.  As it is t he latter d ose of nati ve dr u g t hat has 
bee n use d o n T O T X V, we are c o mf orta bl e re pla ci n g t he m ore fre q ue ntl y a d mi nistere d 
i ntra m usc ular nati ve E. c oli as para gi nase wit h t he l o n ger acti n g, less i m m u n o ge ni c i ntra ve n o us 
P E G-as para gi nase, b ut w e pr o p ose t o test t he p ote ntial be nefits of a d mi nisteri n g P E G-
as para gi n ase at d oses hi g her t ha n t he 2, 5 0 0 u nits/ m 2 d uri n g c o nti n uati o n. 
 
Patie nts will be ra n d o mize d at t he c o m pleti o n of re missi o n i n d ucti o n i n T O T X VI t o c o m pare t he 
safet y, efficac y, a n d P K/ P D bet wee n t he “c o n ve nti o nal” a n d a hi g her d ose of P E G-as para gi nase. 
D uri n g t h e re missi o n i n d ucti o n p hase, T O T X V use d hi g h er d oses of nati ve E. c oli as para gi n ase 
( 1 0, 00 0 u nits/ m 2 per d ose) t ha n ot her p e diatric A L L pr ot o c ols ( 6, 0 0 0 u nits/ m2 per d ose) i nt o 
w hic h P E G-as para gi nas e has bee n s u bstit ute d at 2, 5 0 0 u nits/ m 2.  We ha ve c h ose n t o gi ve all 
chil dre n o n T O T X VI 3, 0 0 0 u nits/ m 2 i nstea d of t he “c o n ve nti o nal” d os e of 2 5 0 0 u nits/ m2 of P E G-
as para gi n ase, beca use we d o n ot wa nt t he i nte nsit y of as para gi nase i n t his St. J u de trial t o p ossi bl y 
be less t ha n t hat o n pri or St. J u de trials, all of w hic h use d 1 0, 0 0 0 u nits/ m 2 of nati ve E. c oli 
as para gi n ase. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
We ha ve bee n l ea ders i n re d uci n g pre ve nti ve cra ni al irra diati o n, a n d t he n eli mi nati n g it 
c o m pletel y i n T O T X V. T his is t he si n gle m ost i m p orta nt m o dificati o n t o decreas e l o n g-ter m 
a d verse effects a n d i m pr o ve q ualit y of life of s ur vi v ors. T his was ac hie ve d wit h t he i nte nsificati o n 
of C N S- directe d i ntrat h ecal a n d s yste mic c h e m ot hera p y. T h e ris k of C N S rela pse (a b o ut 3. 5 %) o n 
T O T X V c o m pares f a v ora bl y wit h t hat of re gi me ns still e m pl o yi n g pre v e nti ve cra ni al irra diati o n. 
M o re o ver, all patie nts wit h C N S rela pse are ali ve i n sec o n d re missi o n wit h retrie val t hera p y 
i ncl u di n g t hera pe utic C N S irra diati o n (as t he first c o urse of irra diati o n).  H o we ver a s u b gr o u p of 
pa tie nts wit h T-cell li nea ge, t( 1; 1 9)/E 2 A- P B X 1 , a n d t h ose wit h blasts i n t he C S F re mai n at hi g hest 
ris k of C N S rela pse; t hes e patie nts will recei ve 2 a d diti o nal i ntrat hecal treat me nts o n da y 4 a n d 1 1 
of i n d ucti o n o n T O T X VI t o re d uce t heir ris k of C N S rela pse. 
 
I n T O T X V w e c o nfir me d t hat t he prese n ce of mi ni mal resi d ual disease ( M R D) o n da y 1 9 is a 
si g nifica nt pr o g n ostic fact or. O ver 9 5 % p atie nts wit h ne gati ve M R D o n da y 1 9 re mai n i n 
re missi o n. I n T O T X VI, t hese patie nts will recei ve less i nte nsi ve Rei n d ucti o n II, a n d a re d uce d 
c u m ulati ve d ose of a nt hr ac ycli nes ( 8 0 m g/ m 2 i nstead of 1 1 0 m g/ m 2).  I n T O T X V, we o bs er ve d 
t hat patie nts wit h da y 1 9 M R D > 5 % ha d a dis mal o utc o me: 3 4. 5 % ha ve rel a pse d.  I n T O T X VI 
we will i nte nsif y i n d ucti o n t hera p y wit h fracti o nate d c ycl o p h os p ha mi de i n t hese patie nts t o 
ac hie ve m a xi mal c yt ore d ucti o n b y t he e n d of re missi o n i n d ucti o n (a critical e n d p oi nt t o ma xi mize 
t he c ha nces of d ura ble re missi o ns). 
 
T he maj orit y of patie nts will n o l o n ger ha v e s ur veilla nce marr o ws p ost re missi o n i n d ucti o n, as 
m o nit ori n g of M R D i n marr o w after re missi o n i n d ucti o n will o nl y b e perf or me d i n patie nts wit h 
p osi ti ve M R D o n da y 4 2 ( or w he n cli nicall y i n dicate d). I n T O T X V, we use d fl o w c yt o metr y a n d 
P C R i n ta n de m t o m o nit or M R D. Beca use of t he v er y hi g h c o nc or da nce bet wee n t he 2 met h o ds, 
i n T O T X VI w e will use pri maril y fl o w c yt o metr y, reser vi n g P C R f or cases w here le u ke mic cells 
d o n ot e x press s uita ble i m m u n o p he n ot y pes. 
 
I nfa nts wit h M L L rearra n ge m e nts ha ve a dis mal o utc o me des pite use of i nte nsi ve re gi me ns 
i ncl u di n g ste m cell tra ns pla ntati o n. T O T X VI will e x pl ore t he be nefit of a d di n g a pr o misi n g ne w 
t hera p y bl oc k de v el o pe d b y St J u de i n vesti gat ors9.  T he c urre nt dis mal o utc o me i n t his a ge gr o u p 
ma ke s t he dete cti o n of p ote ntial be nefit p ossi ble des pite t he e x pecte d s mall n u m ber of patie nts.   
 
Ot he r p har m ac ol o gic a dj ust me nts ha ve bee n ma de t o i m pr o ve q ualit y of life of o ur patie nts, 
decrease t he ris k of a d verse e ve nts, a n d mi ni mize i nc o n ve nie nce t o patie nts a n d staff.   
E x a m ples i ncl u de: 
 
a)  as para gi n ase will be a d mi nistere d i ntra ve n o usl y i nstea d of i ntra m usc ularl y; 
b)  t here is n o met h otre x ate wi n d o w i n T O T X VI as t he st u d y q u esti o n has bee n a ns were d o n 
T O T X V;  
c)  hi g h d ose met h otr e x ate will n ot be tar gete d i n l o w ris k patie nts (a b o ut half e nr olle d 
patie nts), e x ce pt w he n cli nicall y i n dicat e d;  
d)  c u m ulati ve a nt hrac ycli ne d ose will be re d uce d b y 3 0 m g/ m 2 i n half t he patie nts; 
e)  d urati o n of t hera p y h a d b ee n re d u ce d b y 2 6 wee ks i n b o ys; 
f) de x a met has o ne d ose has bee n re d u ce d after wee k 6 9 (f or a c u m ulati ve re d u cti o n of 8 0 
m g/ m 2 f or l o w-ris k patie nts a n d 2 4 0 m g/ m2 f or sta n dar d-ris k patie nts) 
 
All dia g n ostic sa m ples will be e x a mi ne d f or gl o bal ge n e e x pressi o n usi n g ge ne arra y c hi ps. T his 
will  c o nti n ue t o e nric h o ur u ni q ue data bas e o n t he ge n e e x pressi o n of A L L cells w hic h has 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
bec o me a n i n v al ua ble res o urce ( htt p:// w w w.stj u deresearc h. or g/ d ata/ A L L 1/i n de x. ht ml ) f or A L L 
i n vesti gat ors w orl d wi de. I n a d diti o n, t his will pr o vi de us wit h a n o p p ort u nit y t o vali date 
pr os pecti vel y t he ma n y retr os pecti ve o bser vati o ns ma de i n past c orrelati ve st u dies i ncl u di n g 
gl o bal ge n e e x pressi o n.  F or e x a m ple, t he e x pressi o n of se veral ge nes i n le u ke mic cells at 
dia g n osis was str o n gl y ass ociate d wit h da y 1 9 or d a y 4 6 (e n d of i n d u cti o n) M R D i n T O T X V, a n d 
was f o u n d t o be a n i n d e p e n de nt pre dict or of o verall treat m e nt o utc o me i n c orrelati ve st u dies of 
patie nts e nr olle d i n T otal XIII 1 0; 1 1.  T hese ge n es i ncl u de C A S P 8 A P 2 ( w hic h e nc o de a pr otei n t hat 
pr o m otes a p o pt osis a n d gl uc oc ortic oi d si g n ali n g) 1 0, a set of ge n es ass ociate d wit h i n vitro dr u g 
resista nce i n c hil d h o o d A L L1 1 -1 3 a n d ge nes e n c o di n g pr otei ns wit h k n o w n re g ul at or y f u ncti o ns i n 
cell c ycle pr o gressi o n 1 1.  I n T O T X VI, we will st u d y t he ass ociati o n of t hese ge n es’ e x pressi o n 
wit h M R D o n da ys 1 5 a n d 4 2, a n d wit h i nci de nce of rela pse. 
 
We will st u d y t he i n vitr o se nsiti vit y t o merca pt o p uri ne a n d t hi o g u a ni ne i n patie nts e nr olle d o n 
T O T X VI, a n d si m ulta ne o usl y deter mi ne t he se nsiti vit y of t h ese ne w cas es t o ot her a nti-le u ke mic 
a ge nts t hat we ha v e pre vi o usl y st u die d ( pre d nis o ne, vi ncristi ne, da u n or u bici n a n d as para gi nase). 
T his will per mit us t o el uci date ge n o mic det er mi n a nts of m ulti- dr u g cr oss resista nce t o all 6 a nti-
le u ke mic a ge nts. W e will als o use ot her ge n o me- wi de a p pr oac hes, i ncl u di n g S N P a n d ha pl ot y pe 
a nal ys es, t o i de ntif y ge nes a n d ge netic p ol y m or p his ms si g nifica ntl y li n ke d t o resista nce t o eac h of 
t hese me dicati o ns, a n d t o t he m ulti- dr u g cr oss resista nce p he n ot y pe. O ur pri or w or k f oc us e d 
pre d o mi na ntl y o n B-li nea ge A L L, a n d we ai m t o e xte n d t his w or k t o T- li nea ge A L L a n d 
i n vestigate cases st u die d i n T O T X V a n d T O X VI t o get h er. T his s u bset has a w orse pr o g n osis i n 
ma n y tr eat me nt pr ot oc ols, a n d t heref ore it is i m p orta nt t hat we u n dersta n d t he ge n o mic basis of 
dr u g resista nce i n t his s u bt y pe of c hil d h o o d A L L. 
 
We will st u d y t he ger mli ne ge n o mic deter mi na nts of ris k fact ors f or rela ps e, p o or res p o ns e ( M R D 
p ositi vit y), ac ute t o xicities, p har ma c ol o gi c p he n ot y pes a n d bi o mar kers a n d l o n g-ter m 
c o m plicati o ns of t hera p y as o utli ne d i n secti o n 2. 2. 1. T hese a n al ys es i n T O T X VI will be 
c o m pare d a n d i nter prete d i n t he c o nte xt of o n g oi n g a n d f ut ure ge n o mic a nal yses i n ot her A L L 
trials at St. J u de a n d else w here, wit h t h ose fi n di n gs re plicate d i n cli nical a n d la b orat or y setti n gs 
bec o mi n g ca n di dat es f or f ut ure use i n i n di vi d ualizi n g t hera p y. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Pr ot oc ol S u m m ar y 
T O T A L  T H E R A P Y  S T U D Y  X VI  F O R  N E W L Y  DI A G N O S E D  P A TI E N T S  WI T H  A C U T E  
L Y M P H O B L A S TI C  L E U K E MI A  
Pri nci p al I n ve sti g at or: Si ma J e ha, M. D.  
I N D h ol der: N ot a p plica ble, n o n -I N D/I D E st u d y 
B rief o ver vie w: Treat me nt will c o nsist of t hree mai n p hases: Re missi o n I n d ucti o n, C o ns oli dati o n, a n d 
C o nti n uati o n. T otal  d urati o n of t hera p y is 2 ½ t o 3 years.  
I nter v e nti o n: 
Re missi o n i n d ucti o n  
Dr u g: Pre d nis o ne  
Dr u g: Pre d nis ol o ne   
Dr u g: De xa met has o ne   
Dr u g: Vi ncristi ne   
Dr u g: Da u n or u bici n  
Dr u g: P E G -as para gi nase   
Dr u g: C ycl o p h os p ha mi de   
Dr u g: C ytara bi ne  
Dr u g: T hi o g ua ni ne   
Dr u g: Merca pt o p uri ne  
Dr u g: Dasati ni b ( P h + o nl y)  
Dr u g: Cl ofara bi n e ( M L L + i nfa nts o nl y)   
Dr u g: Et o p osi de ( M L L + i nfa nts o nl y)  
Dr u g: C ycl o p h os p ha mi de ( M L L + i nfa nts o nl y)   
Pr oce d ure: I ntrat hecal c he m ot hera p y  
 
C o ns oli dati o n treat me nt   
Dr u g: Met h otre xate   
Dr u g: Merca pt o p uri ne  
Pr oce d ure: I ntrat hecal c he m ot hera p y  
 
C o nti n uati o n treat me nt 
Ris k assi g n me nt Assi g ne d i nt er ve nti o n  
L o w risk   
Dr u g: Merca pt o p uri ne   
 
 
 
Dr u g: De xa met has o ne   
 
 
 
Dr u g: Vi ncristi ne   
 
 
 
Dr u g: Met h otre xate  
 
 
 
Dr u g: P e g -as para gi nase   
 
 
 
Dr u g: Met h otre xate   
 
 
 
Dr u g: D o x or u bici n  
 
 
 
Pr oce d ure: I ntrat hecal c he m ot hera p y  
 
St a n d ar d/ hi g h risk : 
Dr u g: Merca pt o p uri ne  
 
Dr u g: De xa met has o ne  
 
Dr u g: D o x or u bici n   
 
Dr u g: Vi ncristi ne   
 
Dr u g: Met h otre xate   
 
Dr u g: C ytara bi ne   
 
Dr u g: Et o p osi de  
 
 
 
Dr u g: P E G -as para gi nase   
 
 
 
Dr u g: C ycl o p h os p ha mi de  
 
 
 
Pr oce d ures i ntrat hecal c he m ot hera p y,  
 
 
 
Pr oce d ures ( hi g h ris k o nl y): e xter nal bea m R T ( C N S rela ps e) a n d H S C T  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
S a m ple size :  4 2 0 e val ua ble p artici pa nts i n 8. 6 years  
D at a m a n a ge me nt :  Data ma na ge me nt a n d statistical a nal ysis will be pr o vi de d l ocall y b y t he He mat ol o gical 
Mali g na ncies Pr o gra m c li nical researc h staff, Le u ke mia/ L y m p h o ma Di visi o n a n d Bi ostatistics De part me nt at St. 
J u de C hil dre n’s Researc h H os pital. 
 
H u m a n s u bjects : T he pri mar y ris k t o partici pa nts i n t his researc h st u d y is t o xicit y fr o m t he i nte nsi ve, m ulti- a ge nt 
c he m ot hera p y.  P artici pa nts ar e i nf or me d of t his a n d ot her p ote ntial si de effects d uri n g i nf or me d c o nse nt. A d verse 
e ve nts will be m o nit ore d, re p orte d a n d treate d a p pr o priatel y.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T a ble of c o nte nts 
 
1. 0  
O B J E C TI V E S .................................................................................................................. 1 
1. 1  
P ri mar y O bj ecti ve ........................................................................................................... 1 
1. 2  
S ec o n dar y T hera p e utic O bjecti ves .................................................................................. 1  
1. 3  
E x pl orat or y P har mac ol o gic O bj ecti ves .......................................................................... 1  
1. 4  
E x pl orat or y Bi ol o gic O bj ecti ves ..................................................................................... 1  
1. 5  
E x pl orat or y Ne ur oi ma gi n g O bjecti ves ........................................................................... 2  
1. 6  
E x pl orat or y I ntesti nal Micr o bi o me O bjecti ves ............................................................... 2  
2. 0  
B A C K G R O U N D A N D R A TI O N A L E ............................................................................ 2  
2. 1  
T he ra p y ........................................................................................................................... 2 
2. 2  
P har mac ol o gic St u dies .................................................................................................. 1 0  
2. 3  
B i ol o gi c St u dies ............................................................................................................ 1 4 
2. 4  
Ne ur oi ma gi n g St u dies ................................................................................................... 1 7  
2. 5  
P hila del p hia C hr o m os o me ( P h)- P ositi ve A L L ............................................................. 2 0  
2. 6  
Infa nt A L L .................................................................................................................... 2 2  
2. 7  
B ac k gr o u n d a n d R ati o nale f or I ntesti nal Micr o bi o me O bjecti ves ............................... 2 2  
2. 8  
In cl usi o n of W o me n a n d Mi n orities ............................................................................. 2 3  
3. 0  
E L I GI BI LI T Y C RI T E RI A A N D S T U D Y E N R O L L M E N T ......................................... 2 3 
3. 1  
In cl usi o n Criteria .......................................................................................................... 2 3  
3. 2  
E x cl usi o n Criteria ......................................................................................................... 2 4  
3. 3  
R esearc h Partici pa nt Recr uit me nt a n d Scree ni n g ......................................................... 2 4  
3. 4  
E nr oll me nt O n St u d y .................................................................................................... 2 4  
4. 0  
R I S K C L A S SI FI C A TI O N .............................................................................................. 2 4 
4. 1  
C riteria f or L o w- Ris k A L L (a p pr o xi matel y 4 8 % of patie nts) ...................................... 2 5 
4. 2  
C riteria f or Sta n dar d- Ris k A L L (a p pr o xi matel y 4 4 % of patie nts) ............................... 2 5 
4. 3  
C riteria f or Hi g h- Ris k A L L (a p pr o xi matel y 8 % of patie nts) ........................................ 2 5 
5. 0  
T R E A T M E N T P L A N .................................................................................................... 2 6  
5. 1  
Intrat hecal C he m ot hera p y ............................................................................................. 2 6  
5. 2  
R e missi o n I n d ucti o n C he m ot hera p y ( 6 t o 7 wee ks) ..................................................... 2 7  
5. 3  
C o ns oli dati o n Treat me nt ( 8 wee ks) .............................................................................. 2 9  
5. 4  
R ei nte nsificati o n Treat me nt (f or Hi g h- Ris k A L L) ....................................................... 3 2  
5. 5  
C o nti n uati o n Treat me nt ( 1 2 0 wee ks)............................................................................ 3 4  
5. 6  
He mat o p oietic Ste m Cell Tra ns pla ntati o n .................................................................... 4 1  
6. 0  
D R U G  I N F O R M A TI O N ................................................................................................ 4 1 
6. 1  
Dr u g S h orta ges a n d U n a vaila bilit y ............................................................................... 4 1  
7. 0  
T R E A T M E N T M O DI FI C A TI O N S ............................................................................... 4 2  
7. 1  
D o w n S y n dr o m e Partici p a nts ....................................................................................... 4 2  
7. 2  
R e nal D ysf u ncti o n ........................................................................................................ 4 3  
7. 3  
He patic D ysf u n cti o n ..................................................................................................... 4 3  
7. 4  
O be sit y .......................................................................................................................... 4 3 
7. 5  
Te stic ular Le u k e mia at Dia g n osis ................................................................................. 4 3 
7. 6  
Vi nc risti ne Ne ur ot o xicit y.............................................................................................. 4 4 
7. 7  
Ve n o us T hr o m b oe m b olis m ........................................................................................... 4 4  
7. 8  
A va sc ular Necr osis of B o ne .......................................................................................... 4 4 
7. 9  
P E G- As para gi n ase ........................................................................................................ 4 4  
7. 1 0  
T P M T Stat us a n d T hi o p uri ne D osa ge........................................................................... 4 5  
7. 1 1  
Pa ncreatitis .................................................................................................................... 4 6  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
7. 1 2  
P hila del p hia C hr o m os o me P ositi ve ( P h +) A L L ........................................................... 4 6  
8. 0  
D O S E M O DI FI C A TI O N S D U RI N G C O N TI N U A TI O N T H E R A P Y .......................... 4 7  
8. 1  
D ose  M o dificati o ns f or I na de q uate M yel os u p pressi o n ................................................ 4 7 
8. 2  
D ose  Decreases Base d o n Merca pt o p uri ne P har m ac ol o g y ........................................... 4 8 
8. 3  
Da sati ni b D osa ge A dj ust me nts ( P h + A L L Patie nts O nl y) ........................................... 4 8 
9. 0  
C O N TI N G E N C Y P L A N S F O R R E F R A C T O R Y DI S E A S E O R R E L A P S E ............... 4 9  
9. 1  
In d u cti o n Fail ures ......................................................................................................... 4 9  
9. 2  
He mat ol o gi c Rela pse .................................................................................................... 4 9  
9. 3  
E x tra me d ullar y Rela ps e ................................................................................................ 4 9 
9. 4  
E me r ge nce of C S F L y m p h o blasts d uri n g Re missi o n Re q uiri n g C N S Ra diati o n ......... 4 9 
1 0. 0  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C S T U DI E S ..................................... 5 0  
1 0. 1  
Hi g h- D ose Met h otre x ate ( H D M T X) ............................................................................ 5 0  
1 0. 2  
T hi o p uri nes ................................................................................................................... 5 0  
1 0. 3  
As para gi nas e, De x a met h as o ne a n d Bi o mar kers ........................................................... 5 0  
1 0. 4  
Plas ma H o m oc ystei n e ................................................................................................... 5 1  
1 1. 0  
E V A L U A TI O N S, T E S T S, A N D O B S E R V A TI O N S .................................................... 5 1  
1 1. 1  
Pretreat me nt E v al uati o n ................................................................................................ 5 1  
1 1. 2  
Data t o be O btai n e d Seri all y W hile O nst u d y ................................................................ 5 2  
1 1. 3  
Off- T h era p y E v al uati o ns .............................................................................................. 5 4  
1 2. 0  
E V A L U A TI O N C RI T E RI A ........................................................................................... 5 5  
1 2. 1  
Res p o nse Criteria .......................................................................................................... 5 5  
1 2. 2  
T o xicit y E val u ati o n Criteria ......................................................................................... 5 5  
1 2. 3  
F u ncti o nal M RI E val uati o n Criteria ............................................................................. 5 5  
1 3. 0  
S U P P O R TI V E C A R E .................................................................................................... 5 6  
1 3. 1  
Fe ver at Dia g n osis......................................................................................................... 5 6  
1 3. 2  
Meta b olic Dera n ge me nts .............................................................................................. 5 6  
1 3. 3  
H y p erle u k o c yt osis......................................................................................................... 5 6  
1 3. 4  
A vasc ular Necr osis of B o ne .......................................................................................... 5 6  
1 3. 5  
Pa nc yt o p e nias ............................................................................................................... 5 7  
1 3. 6  
N utriti o nal S u p ple me ntati o n ......................................................................................... 5 7  
1 3. 7  
Dr u g I nteracti o ns .......................................................................................................... 5 7  
1 3. 8  
D o w n S y n dr o m e ........................................................................................................... 5 7  
1 3. 9  
R S V Pr o p h yl a xis ........................................................................................................... 5 8  
1 3. 1 0  Pr o p h yla ctic A nti bi otics D uri n g Peri o ds of Pr ol o n ge d Ne utr o p e nia ............................ 5 8  
1 4. 0  
O F F- T R E A T M E N T A N D O F F- S T U D Y C RI T E RI A ................................................... 5 8  
1 4. 1  
Off Treat me nt Criteria .................................................................................................. 5 8  
1 4. 2  
Off St u d y Criteria ................................ ......................................................................... 5 8 
1 5. 0  
D A T A S A F E T Y M O NI T O RI N G B O A R D ................................................................... 5 9  
1 6. 0  
B I O L O GI C S T U DI E S ................................................................................................... 5 9 
1 6. 1  
Mi ni mal Resi d ual Disease ............................................................................................ 5 9  
1 6. 2  
Ge r mli ne D N A/ R N A .................................................................................................... 6 0 
1 6. 3  
De x a met has o ne/ As para gi nase Ser u m P har mac o d y na mic Bi o mar kers ........................ 6 0  
1 6. 4  
Deter mi nati o n of A L L Blast Se nsiti vit y t o A nti- Le u ke mic A ge nts, i n vitr o ............... 6 1 
1 6. 5  
N K Cell Rece pt or St u d y ............................................................................................... 6 1  
1 6. 6  
I nt esti nal Micr o bi o me Researc h ................................................................................... 6 1 
1 7. 0  
N E U R OI M A GI N G S T U DI E S ....................................................................................... 6 4  
1 7. 1  
M R I ma gi n g .................................................................................................................. 6 4  
1 7. 2  
Ge netic P ol y m or p his ms ................................................................................................ 6 5  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 7. 3  
Ps yc h ol o gical T esti n g ................................................................................................... 6 5  
1 7. 4  
F u ncti o nal M R I ma gi n g ................................................................................................ 6 6  
1 8. 0  
S T A T I S TI C A L C O N SI D E R A TI O N S ........................................................................... 6 7 
1 8. 1  
Safet y M o nit ori n g ......................................................................................................... 7 0  
1 8. 2  
Pri mar y O bj ecti ve ......................................................................................................... 8 0  
1 8. 3  
T hera p e utic O bjecti ves ................................................................................................. 8 9  
1 8. 4  
E x pl orat or y  P har mac ol o gic O bj ecti ves ........................................................................ 9 3  
1 8. 5  
E x pl orat or y Bi ol o gic al O bjecti ves ................................................................................ 9 3  
1 8. 6  
E x pl orat or y ne ur oi ma gi n g o bjecti ves ........................................................................... 9 6  
1 8. 7  
E x pl orat or y I ntesti nal Mi cr o bi o me O bjecti ve .............................................................. 9 8  
1 9. 0  
S A F E T Y A N D A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S ....................... 9 8  
1 9. 1  
Re p orti n g A d vers e E x perie nces ( A Es) a n d Deat hs ...................................................... 9 8  
2 0. 0  
IN F O R M E D C O N S E N T P R O C E S S ............................................................................ 1 0 0  
2 0. 1  
C o nse nt/asse nt at Re missi o n I n d ucti o n a n d P ost Re missi o n T hera pies ..................... 1 0 0 
2 0. 2  
C o nse nt at A ge of Maj orit y ......................................................................................... 1 0 1  
2 0. 3  
C o nse nt W he n E n glis h is N ot t he Pri mar y La n g ua ge ................................................. 1 0 2  
2 1. 0  
D A T A C O L L E C TI O N, M O NI T O RI N G A N D  C O N FI D E N TI A LI T Y ....................... 1 0 2 
2 1. 1  
Data C ollecti o n ........................................................................................................... 1 0 2  
2 1. 2  
St u d y M o nit ori n g ........................................................................................................ 1 0 2  
2 1. 3  
C o nfi de ntialit y ............................................................................................................ 1 0 3  
2 2. 0  
R E F E R E N C E S ............................................................................................................. 1 0 4  
 
A P P E N DI X I: 
Treat me nt Sc he mas a n d S pecial La b orat or y T ests  
A P P E N DI X II: Dr u g I nf or mati o n 
A P P E N DI X III:   Defi niti o ns Relate d t o I nfecti o us Diseases 
A P P E N DI X I V:  C o m m o n S u bstrates, I n hi bit ors a n d I n d ucers of  C Y P 3 A 4 
A P P E N DI X V:  Ra n d o mizati o n F or m 
A P P E N DI X VI:  Ps yc h ol o gical Test Batter y f or C hil dre n o ver T hree Years of A ge 
A P P E N DI X VII:  O verall Treat me nt Sc he ma 
A P P E N DI X VIII:  Tests Perf or me d f or G o o d Cli nical Care a n d f or Researc h 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1. 0  
O B J E C TI V E S  
 
T he  o verall ai m of t his st u d y is t o i m pr o ve t he c ure rate of c hil dre n wit h prec urs or B-cell 
an d prec urs or T-cell ac ute l y m p h o blastic le u ke mia ( A L L). 
 
1. 1  
Pri mar y O bj ecti ve 
 
T he  pri mar y o bje cti ve of t his st u d y is t o c o m pare t he distri b uti o ns of c o nti n u o us c o m plete 
remissi o n of patie nts ra n d o mize d o n t he first da y of t he c o nti n uati o n p hase t o recei ve a 
hi g her d ose of P E G-as para gi nase or t o recei ve t he c o n ve nti o nal d ose ( 2, 5 0 0 u nits/ m 2). 
 
1. 2  
Sec o n dar y T hera p e utic O bjecti ves 
 
1. 2 . 1 T o esti mate t he e ve nt-free s ur vi val a n d o verall s ur vi val of c hil dre n wit h 
A L L w h o are treate d wit h ris k- directe d t hera p y. 
1. 2. 2  T o st u d y w het her i nte nsif yi n g i n d ucti o n, i ncl u di n g fracti o nate d 
c ycl o p h os p ha mi de a n d t hi o g ua ni ne, i n patie nts wit h da y 1 5 M R D > 5 %, 
will res ult i n i m pr o ve d le u ke mia c yt ore d ucti o n i n t his s u b gr o u p c o m pare d 
t o T O T X V. 
1. 2. 3  T o assess w het her i nte nsificati o n of C N S- directe d i ntrat hecal a n d s yste mic 
che m ot hera p y will i m pr o ve o utc o me i n patie nts at hi g h ris k of C N S rela pse. 
 
1. 3  
E x pl orat or y P har mac ol o gic O bj ecti ves 
 
1. 3. 1  T o i de ntif y p har mac o ge netic, p har mac o ki netic a n d p har mac o d y na mic 
pre dict ors f or treat me nt-relate d o utc o mes i n t he c o nte xt of t he s yste mic 
t hera p y use d i n t he pr ot oc ol. 
1. 3. 2  T o c o m pare t he p har mac o ki netics a n d p har mac o d y na mics of P E G- 
as para gi nase gi ve n i n hi g her d ose ( 3, 5 0 0 or  3, 0 0 0 u nits/ m2) vers us t h ose of 
P E G-as para gi nase gi ve n i n c o n ve nti o nal d ose ( 2, 5 0 0 u nits/ m 2) i n t he 
c o nti n uati o n p hase. 
 
1. 4   
E x pl orat or y Bi ol o gic O bj ecti ves 
 
1. 4. 1 
T o deter mi ne t he pr o g n ostic val ue of le vels of mi ni mal resi d ual 
di sease i n peri p heral bl o o d at da y 8 of re missi o n i n d ucti o n. 
1. 4. 2  
T o vali date ne w mar kers a n d met h o ds f or M R D detecti o n. 
1. 4. 3 
T o ge n ot y pe nat ural killer ( N K) cell rece pt ors a n d meas ure t heir 
ex pressi o ns at dia g n osis a n d bef ore rei n d ucti o n, a n d t o ass ociate t hese 
feat ures wit h treat me nt o utc o me. 
1. 4. 4 
T o i de ntif y ne w pr o g n ostic fact ors b y  a p pl yi n g n e w tec h n ol o gies t o 
st u d y patie nt material (e. g., st ore d plas ma, ser u m, cere br os pi nal fl ui d, 
an d n or mal a n d le u ke mic cells). 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1. 5  
E x pl orat or y Ne ur oi ma gi n g O bjecti ves 
 
1. 5. 1  T o use  q ua ntitati ve M R meas ures ( Diff usi o n Te ns or I ma gi n g a n d hi g h 
res ol uti o n v ol u metric i ma gi n g) t o assess differe nces i n m yeli n a n d c ortical 
t hic k ness de vel o p me nt i n patie nts treate d f or A L L relati ve t o healt h y 
co ntr ols matc he d f or a ge a n d ge n der. 
1. 5. 2  T o assess t he i m pact of f olate pat h wa y ge netic p ol y m or p his ms o n m yeli n 
an d c ortical t hic k ness de vel o p me nt a n d ne ur oc o g niti ve perf or ma nce. 
1. 5. 3  T o assess t he i m pact of fr o ntal- parietal l o be m yeli n a n d c ortical t hic k ness 
de vel o p me nt o n ne ur oc o g niti ve perf or ma nce i n atte nti o n, w or ki n g 
me m or y, fl ue nc y, vis ual-s patial reas o ni n g a n d pr ocessi n g s pee d wit h b ot h 
ne ur oc o g niti ve testi n g a n d f u ncti o nal ma g netic res o na nce i ma gi n g. 
 
1. 6  
E x pl orat or y I ntesti nal Micr o bi o me O bjecti ves 
 
1. 6. 1  T o perf or m a c o m pre he nsi ve a nal ysis of t he i ntesti nal micr ofl ora i n 
patie nts wit h A L L pri or t o a n d s u bse q ue nt t o c he m ot hera p y usi n g ne xt 
g e nerati o n se q ue nci n g tec h n ol o gies as a n e x pl orat or y a p pr oac h. 
1. 6. 2  T o st u d y a n y alterati o n i n t he c o m p ositi o n a n d p o p ulati o n d y na mics of 
t he resi de nt i ntesti nal micr ofl ora i n patie nts wit h A L L after e x p os ure 
t o c he m ot hera p y c o m pare d t o pri or t o e x p os ure t o c he m ot hera p y. 
1. 6. 3  T o descri be t he fre q ue nc y a n d se verit y of gastr oi ntesti nal ill nesses 
d ur i n g i n d ucti o n c he m ot hera p y a n d o ver t he 6 m o nt h peri o d after 
co m pleti o n of i n d ucti o n i n patie nts w h o di d a n d t h ose w h o di d n ot 
ha ve c ha n ges i n i ntesti nal micr o bi ota. 
1. 6. 4  T o detect t he prese nce of pat h o ge ns f o u n d t o be a b u n da nt b y  t he 
micr o bi o me a nal ysis i n s u bse q ue nt st o ol sa m ples c ollecte d o ver t he 6 
m o nt h peri o d after c o m pleti o n of i n d ucti o n c he m ot hera p y. 
 
2. 0  
B A C K G R O U N D A N D  R A TI O N A L E 
 
2. 1  
T hera p y 
 
2. 1. 1  R is k assi g n me nt 
 
C hil d h o o d A L L c ure rat es e x cee d 8 0 % 1 4.  F urt her pr o gress r e q uires t he earl y i de ntificati o n 
of le u ke mia s u bt y pes t hat are resista nt or res p o nsi ve t o c urre nt c he m ot hera p y, s o t hat 
patie nts are n ot u n der- or o ver-treate d. T h e T O T X VI pr ot oc ol a p plies t he m ost 
c o m pre he nsi ve ris k classificati o n t o date, c o m bi ni n g blast cell i m m u n o p he n ot y pe a n d 
ge n ot y p e, wit h prese nti n g cli nical feat ur es a n d earl y tr eat me nt res p o ns e.  Acc or di n gl y, 
patie nts 1- 1 8 year- ol d are di vi de d i nt o t hree ris k gr o u ps: l o w -, sta n d ar d-, a n d hi g h-ris k 
(corres p o n di n g t o sta n d ar d-, hi g h -, a n d ver y hi g h-ris k cate g ories i n ot her pr ot oc ols)1 5.  
Infa nts c o nstit ute a se p arate ris k gr o u p 1 6; 1 7. 
 
B-cell prec urs or A L L cas es wit h a ge bet w ee n 1 a n d 1 0 years a n d prese nti n g le u k oc yt e 
c o u nt < 5 0 x 1 0 9/ L, le u ke mic cell D N A i n de x ≥1. 1 6 or T E L- A M L 1 f usi o n have a n o v erall 
e x celle nt pr o g n osis a n d are ge nerall y c o nsi dere d t o ha ve l o w-ris k le u ke mia.  H o we ver, as 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
ma n y as 1 5 % of t hes e cases still rela pse o n a nti meta b olite- base d t h era p y, f or u n k n o w n 
reas o ns1 8; 1 9.  Rece nt st u dies s h o we d t hat res p o ns e t o earl y treat me nt ca n i de ntif y patie nts 
w h o ha ve g o o d prese nti n g feat ur es b ut n o net heless ha ve a hi g h ris k of rela pse. I nteri m 
a nal ysis i n dicates t hat patie nts wit h n o detecta ble blasts o n da y 1 9 of re missi o n i n d ucti o n 
ha ve a n e x celle nt pr o g n osis i n T O T X V, i n a gree me nt wit h pre vi o us fi n di n gs wit h 
T O T XIII patie nts 2 0 T he ris k of rela pse i ncreas es i n patie nts wit h detecta ble blasts o n da y 
1 9 of i n d ucti o n: t h ose wit h 5 % or m ore blasts a m o n g b o ne m arr o w m o n o n uclear cells as 
meas ure d b y fl o w c yt o metr y h a ve a 5- year c u m ul ati ve ris k of rel a pse of 3 4 % + 2 2 %. P o or 
c yt or e d ucti o n o n da y 2 6 a n d detect a ble M R D ( ≥0. 0 1 %) at t he e n d of re missi o n i n d ucti o n 
( ~ da y 4 6) are a d diti o nal i n dicat ors of hi g h ris k of rela pse. He nce, patie nts wit h fa v ora ble 
prese nti n g feat ures b ut p o or earl y tr eat me nt res p o nse will be treate d as ha vi n g sta n dar d-
ris k AL L. T he re mai ni n g patie nts wit h fa v ora ble prese nti n g feat ures a n d g o o d res p o nse t o 
re missio n  i n d ucti o n t hera p y will be treate d o n t he l o w-ris k ar m. 
 
Beca use of t h eir ge n erall y p o or o ut c o me, cas es wit h C N S- 3 stat us ( ≥5 W B C/ μ L of 
cere br os pi nal fl ui d wit h i de ntifia ble blasts or cra ni al ner ve p als y), testic ular le u ke mia, or 
h y p o di pl oi d y ( < 4 4 c hr o m os o mes), will be treate d o n t he sta n dar d-ris k ar m 1 5; 2 1.  Patie nts 
wit h T -cell A L L, pre- B-cell A L L wit h t he t ( 1; 1 9) a n d E 2 A- P B X 1 f usi o n or M L L 
rearra n ge m e nt fare well pr o vi de d t hat t he y recei v e i nte nsi ve t hera p y2 2; 2 3.  He nce, t h e y are 
als o assi g n e d t o t he sta n d ar d-ris k gr o u p i n T O T X VI. 
 
Patie nts wit h P hila del p hia-c hr o m os o me ( B C R- A B L) - p ositi ve A L L h a ve a hi g h rel a pse 
hazar d. Se veral st u dies s h o we d t hat t heir pr o g n osis ca n be i m pr o ve d wit h all o ge n eic 
he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T) 2 4.  T yr osi n e ki nase i n hi bit ors ha ve latel y 
be e n i nc or p orate d i nt o fr o ntli ne re gi me ns f or P h + A L L.  T O T X V was a me n de d i n J u ne 
2 0 0 4 t o i nc or p orate i mati ni b. T he ne w t yr osi ne ki nase i n hi bit or dasati ni b has acti vit y i n 
B C R -A B L - p ositi ve le u ke mias t hat are resista nt t o i mati ni b2 5 -2 7.  T heref ore, dasati ni b will 
replace i mati ni b i n T O T X VI (secti o n 2. 5 ). 
 
Patie nts wit h > 1 % blasts at t he e n d of re missi o n i n d ucti o n a n d t h ose wit h > 0. 1 % at 1 6 
wee ks p ost re missi o n i n d ucti o n als o ha ve ver y p o or pr o g n osis.  T heref ore, t hese patie nts 
are c o nsi d ere d t o ha v e hi g h-ris k le u ke mia a n d are ca n di dates f or all o ge nei c H S C T d uri n g 
t heir first re missi o n. 
 
We rece ntl y i de ntifie d a s u bset ( 1 2 %- 1 5 %) of T- A L L c haracterize d b y a n at y pical 
i m m u n o p he n ot y pe c o nsisti n g of l o w e x pressi o n of T-cell mar kers ( C D 5, C D 1, C D 8) a n d 
e x pressi o n of m yel oi d- a n d ste m cell- ass ociat e d mar kers ( C D 1 3, C D 3 3, C D 1 1 b, C D 3 4, 
C D 1 1 7 a n d/ or C D 1 3 3). T his earl y T-cell prec urs or ( E T P) s u bt y p e has a disti nct ge ne 
e x pressi o n pr ofile, a hi g h pre vale nce of u n us u al kar y ot y pes, a n d a n i ncreas e i n ge n e c o p y 
n u m ber c ha n ges a n d lesi o ns 2 8.  T hese patie nts ha d a mar ke dl y i nf eri or cl eara nce of 
le u kemic blasts d uri n g re missi o n i n d ucti o n t hera p y a n d a dis mal o utc o me: 1 0- year o verall 
s ur vi val f or t he 1 7 patie nts wit h at y pical T- A L L was 1 6. 5 % + 1 0. 6 % v ers us 8 4. 7 % + 6. 8 % 
f or t he 1 22 patie nts wit h t y pical T- A L L ( P < 0. 0 0 0 1). T hese patie nts will als o be c o nsi dere d 
t o ha ve hi g h-ris k le u ke mia i n T O T X VI. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 1. 2  R e missi o n i n d ucti o n 
 
Re missi o n i n d ucti o n c o nsists of 3 wee ks of pre d nis o ne, vi ncristi ne, da u n or u bici n, a n d 
P E G-as para gi nase, f oll o we d b y 2 wee ks of c ycl o p h os p ha mi de, c yt ara bi ne, a n d 
t hi o g ua ni ne c o m bi nati o ns. T his re missi o n i n d ucti o n is si milar t o t hat use d i n T O T X V 
e x ce pt f or f oll o wi n g m o dificati o ns: 
 
(a) T he o pti o nal 4- da y met h otre x ate wi n d o w t hera p y will n ot be offere d a n d st a n dar d 
i n d ucti o n will start o n da y 1. 
( b) I ntr a m usc ular L- as para gi nase will be s u bstit ute d wit h i ntra ve n o us P E G- 
as para gi n ase w hic h h as b ee n safel y a n d s uccessf ull y use d i n t he Da na- Far ber 
Ca ncer I nstit ute ( D F CI) pr ot oc ols. Earl y res p o n d ers will recei ve a si n gle d ose of 
P E G-as para gi nase (s u bstit uti n g f or t he 6 i ntra m us c ular d oses of L-as p ara gi nase o n 
T O T X V), w h ereas patie nts wit h 1 % or m ore blasts o n da y 1 5 will recei v e a n 
a d diti o nal d ose of P E G-as para gi nase (s u bstit uti n g f or t he a d diti o nal 3 d oses of L-
as para gi n ase gi ve n o n T O T X V f or t his s u b gr o u p).  T he rati o nale f or t his d ose is 
i n dicate d i n t he S y n o psis f or T O T X VI. 
(c) T hi o g ua ni ne will be gi v e n o n da ys 2 2 t o 3 5 i nstea d of merca pt o p uri ne. T he 2 wee k 
bl oc k of c ycl o p h os p ha mi de, c ytara bi ne a n d t hi o g u a ni ne has bee n wi del y us e d i n 
t he C hil dre n’s Ca ncer Gr o u p ( C C G) re gi me ns. Ra n d o mize d st u dies ha ve s u g geste d 
t hat t hi o g ua ni ne is ass oci ate d wit h i m pr o ve d o utc o me. W hile i nter mitte nt p ulses of 
t hi o g ua ni ne h a ve bee n safel y us e d i n se veral re gi me ns, pr ol o n ge d use of 
t hi o g ua ni ne h as bee n ass ociate d wit h i ncrease d i n ci de nce of ve n o occl usi ve disease 
of t he li ver a n d p ort al h y perte nsi o n. He n ce we will n ot use t hi o g ua ni ne be y o n d t his 
1 4 da y  c o urse, a n d will c o nti n ue t o use merca pt o p uri ne f or pr ol o n ge d 
a d mi nistrati o n d uri n g c o ns oli dati o n a n d c o nti n uati o n. 
( d) C ycl o p h os p ha mi de t hera p y will be i nte nsifie d i n patie nts wit h 5 % or m ore blasts 
o n da y 1 5 of i n d ucti o n beca use of t he hi g h ris k of rela pse ( 3 4 %) i n t his gr o u p of 
patie nts. Fracti o nate d c ycl o p h os p ha mi de is wi del y use d i n a d ult A L L pr ot oc ols, 
a n d has pr o ve n s afe a n d effecti ve i n c hil dre n wit h B ur kitt le u ke mia/l y m p h o ma a n d 
rela pse d A L L. 
(e) T O T X V has pr o v e n t hat pre ve nti ve cra nial irra diati o n ca n be eli mi nate d, 
irres pecti ve of ris k gr o u p, wit h i nte nsificati o n of C N S- directe d a n d s yste mic 
che m ot hera p y. C u m ulati ve ris k of C N S rela pse ( ~ 3. 5 %) o n T O T X V c o m p ares 
fa v ora bl y wit h t hat of re gi me ns still e m pl o yi n g pre ve nti ve cra ni al irra diati o n. 
M ore o ver, all patie nts wit h C N S rela pse are ali ve i n sec o n d re missi o n wit h 
retrie val t hera p y i ncl u di n g t hera pe utic C N S irra diati o n (as t he first c o urse of 
irra diati o n). Patie nts wit h T-cell li nea ge, t( 1; 1 9)/E 2 A- P B X 1, a n d t h ose wit h blasts 
i n the C S F are at hi g hest ris k of C N S rela pse, a n d t hese patie nts will recei ve 2 
a d diti o nal i ntrat hecal treat me nts o n da y 4 a n d 1 1 of i n d ucti o n o n T O T X VI t o 
re d uce t h eir ris k of C N S rela pse. 
(f) Patie nts wit h E T P i m m u n o p he n ot y p e will recei ve de x a met has o ne ( 1 0 m g/ m 2 per 
da y) i nstea d of pre d nis o n e d uri n g re missi o n i n d ucti o n. T he use of de x a met h as o ne 
d uri n g i n d ucti o n t hera p y is ass ociate d wit h s u peri or o utc o me, b ut i ncrease d 
t o xicit y, i n patie nts wit h T- A L L treate d i n t he AI E O P- B F M A L L 2 0 0 0 tri al2 9.  We 
feel t hat t he p ote ntiall y i ncreas e d ris k of tr eat me nt-relate d t o xicit y is j ustifia ble i n 
patie nts wit h t he E T P i m m u n o p he n ot y pe, i n vie w of t heir p o or o utc o me w he n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
treate d wit h c o n v e nti o nal c he m ot hera p y. 
( g) Patie nts w h o are T P M T heter oz y g ote (a b o ut 1 0 % of all patie nts) will recei ve 
merca pt o p uri n e d uri n g i n d ucti o n i nstea d of t hi o p uri ne.  T otal 1 6 i n d ucti o n t hera p y 
was c o m plicate d wit h re versi ble he patic v e n o occl usi ve disease ( V O D) i n a patie nt 
w h o is T P M T heter oz y g ote. Ge netic p ol y m or p his ms t hat decrease T P M T acti vit y 
are c orrel ate d wit h i ncrease d se nsiti vit y a n d t o xicit y t o t hi o p uri ne. I n vie w of t he 
lac k of V O D o n t he B F M st u dies usi n g t hi o g ua ni ne a n d i n W T patie nts e nr olle d 
t o- date o n T otal 1 6, al o n g wit h t he c orrel ati o n bet wee n i nci de n ce of V O D a n d 
T P M T acti vit y, T otal 1 6 will be a me n de d t o ha ve T P M T H E T/ deficie nt patie nts 
(a b o ut 1 0 % of t otal) recei ve merca pt o p uri ne as per T otal 1 5 d uri n g i n d u cti o n 
i nstea d of t hi o g u a ni ne. N o c ha n ges will be ma de f or W T patie nts; h o we ver, 
vi gila nt m o nit ori n g is rec o m me n de d.   
 
2. 1. 3 
C o ns oli dati o n t hera p y 
 
C o ns oli dati o n t hera p y c o nsists of H D M T X (a vera ge of 5 g m/ m 2 o ver 2 4 h o urs i n 
sta n dar d-/ hi g h-ris k or a v era ge of 2. 5 g m/ m 2 o ver 2 4 h o urs i n l o w-ris k cases) gi ve n e ver y 
ot her wee k f or 4 d oses wit h le uc o v ori n resc u e, t o get her wit h i ntrat hecal treat me nt pl us 
c o nc o mita nt dail y merca pt o p uri ne ( 5 0 m g/ m 2).  T he feasi bilit y a n d effecti v e ness of 
H D M T X gi ve n at 5 g m/ m 2 ha ve bee n d oc u me nte d i n lar ge n u m bers of patie nts treate d i n 
T O T X V, t he Berli n- Fra n kf urt- M ü nster ( B F M) 3 0 a n d t he Ass ociazi o ne It alia na E mat ol o gia 
O nc ol o gi a Pe diatrica ( AI E O P) st u dies 3 1.  I n fact, t he i m pr o ve d treat me nt o utc o me of T-
cell A L L cases i n t he B F M st u dies a n d of i nter me diate-ris k B-li nea ge A L L cases i n t he 
AI E O P st u d y w as attri b ute d i n part t o t he use of H D M T X at 5 g m/ m 2. Res ults of T otal 
p har mac ol o gic st u dies s u g gest t hat w hile H D M T X at 2. 5 g m/ m 2 is s ufficie nt f or m ost B-
li nea ge A L L cases3 2; 3 3, n o n- h y p er di pl oi d B-li nea ge blasts acc u m ulat e m ore met h otre x ate 
p ol y gl uta mates wit h hi g h- d ose t ha n wit h l o w- d ose met h otre x ate.  I n a D F CI st u d y wit h 
va st maj orit y of cases of B-li nea ge p he n ot y pe, c hil dre n recei ve d a si n gle u p-fr o nt d ose of 
4 g m/ m 2 ha d better o verall le u ke mia-free s ur vi val t ha n t h ose recei vi n g 4 0 m g/ m 2.3 4  I n 
a d diti o n, i n o ur st u d y X, hi g her e x p os ure t o met h otre x ate was m ost i m p orta nt a m o n g t he 
hi g her-ris k B- li nea ge cases ( p = 0. 0 0 7) 3 5; 3 6.  He nce, i n T O T X VI, H D M T X will be gi ve n 
si milar t o d osi n g o n T O T X V. T he g oal is t o pr o vi de a vera ge s yste mic e x p os ure t hat is 
ac hie ve d at 5 g m/ m 2 f or T-cell a n d sta n d ar d-/ hi g h-ris k B-li nea ge A L L, a n d a vera ge 
ex p os ure ac hie ve d at 2. 5 g m/ m 2 f or l o w-ris k B-li nea ge A L L, f or a t otal n u m ber of 4 d oses 
H D M T X. 
 
Tar geti n g s yste mic e x p os ure i n T O T X V a p peare d t o be s o me w hat less i m p orta nt i n t he 
l o w-ris k ar m t ha n i n t he sta n dar d-/ hi g h-ris k ar m. I nter-c o urse tar geti n g i n t he l o w-ris k ar m 
res ulte d i n 1 2 %, 7 0 %, a n d 1 8 % of c o urses bei n g b el o w, i n, a n d a b o ve t h e 2 4 hr plas ma 
c once ntr ati o n tar get r a n ge of 3 3 μ M +/- 2 0 %. A d diti o nall y, t here was a n acce pta bl y l o w 
pr o p o rti o n of c o urs es ( 6 %) wit h “ dela ye d e x creti o n” ( 4 2 hr plas ma M T X c o nce ntr ati o n > 
1. 0 μ M). Tar geti n g t he l o w-ris k ar m di d n ot ha ve a s u bsta ntial i m pact o n a v oi di n g e xtre me 
e x p os ures relati ve t o si m ulate d c o n ve nti o nal d osi n g: 2 % vs. 3 % ste a d y-state-
co nce ntr ati o ns < 4 0 % of tar get a n d 5 % vs. 3 % wit h stea d y-state-c o nce ntrati o ns > 4 0 % of 
target wit h tar gete d vs. si m ulate d c o n ve nti o nal d osi n g res p ecti vel y. 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
I nter-c o urse tar geti n g i n t he sta n dar d-/ hi g h-ris k ar m res ulte d i n 2 3 %, 6 2 %, a n d 1 5 % of 
c o urses bei n g b el o w, i n, a n d a b o ve t he t ar get r a n ge of 6 5 u M +/- 2 0 %. A d diti o nall y, t here 
wa s a n acce pt a bl y l o w pr o p orti o n of c o urses ( 1 5 %) wit h “ dela ye d e x creti o n ” ( 4 2 hr 
plas ma M T X c o nce ntrati o n > 1. 0 u M). Tar geti n g t he sta n dar d-/ hi g h-ris k ar m a v oi de d 
e xtre me e x p os ures relati ve t o si m ulate d c o n ve nti o nal d osi n g: 3 % vs 0 % wit h stea d y-stat e 
c o nce ntr ati o ns < 4 0 % of tar get a n d 3 % vs. 1 0 % wit h stea d y-stat e-c o n ce ntr ati o ns > 4 0 % of 
target wit h tar gete d vs. si m ulate d c o n ve nti o nal d osi n g, res p ecti vel y. T he m e dia n 4 2 h o ur 
co nce ntr ati o n i n t he sta n dar d-/ hi g h-ris k ar m was 0. 5 4 u M, w hic h is q uite si milar t o t hat 
re p orte d ( 0. 4 3 u M) b y t h e B F M. M ore o v er, t he le uc o v ori n resc ue a d mi nistere d b y o ur 
gr o u ps was si milar, b ut t o xicit y was s u bsta ntiall y l o wer i n T O T X V t h a n t hat re p orte d b y 
B F M: ~ 4 % vs. 4 4 % gra d e 3 or 4 m uc ositis. T h us, it a p pears t hat t here ma y be m ore 
be nefit i n a v oi di n g t h e e xtre mes of e x p os ure i n t he sta n dar d/ hi g h t h a n i n t he l o w-ris k 
ar ms, alt h o u g h t ar get c o n ce ntrati o ns were better ac hie ve d i n t he l o w-ris k ar m. 
 
F or T O T X VI, o ur d ecisi o n is t o c o nti n ue tar geti n g H D M T X i n t he sta n dar d-/ hi g h- ris k 
ar m b ut n ot i n t he l o w-ris k ar m, u nless it is s pecificall y re q uest e d d ue t o cli nicia n c o ncer ns 
re gar di n g p atie nt i nsta bilit y.  T he reas o n f or t his is t hat t he d ose of 2. 5 g/ m2 g i ve n 
c o n ve nti o nall y t o t he T O T X V l o w-ris k gr o u p is ge nerall y a d e q uate: it res ults i n stea d y-
state c o nce ntrati o ns > 2 1 μ M i n 9 5 % of c o urses; t o xicit y was l o w, wit h i nfre q ue nt gra d e 3 
or 4 m uc ositis ( 1. 2 %); a n d usi n g a fi x e d 2. 5 g/ m 2 d ose, 9 5 % of t he ste a d y-state 
co nce ntr ati o ns w o ul d ha ve bee n < 4 6 μ M w hile t he hi g h est ste a d y-state c o nce ntrati o n 
w o ul d ha ve bee n 9 1 μ M. H o we ver, o n T O T X VI, if re nal d ysf u ncti o n, patie nt i nsta bilit y, or 
use of c o nc urre nt dr u gs lea ds t o c o ncer ns re gar di n g M T X cleara nce f or a n y partic ular 
co urse, t he cli nicia n ca n re q uest tar geti n g t o be perf or me d. 
 
We will c o nti n ue o ur tar geti n g a p pr oac h f or sta n d ar d-/ hi g h-ris k patie nts o n T O T X VI as 
we di d o n T O T X V. O ur g oals are t o c o nti n ue t o a v oi d u nacce pt a bl y l o w c o nce ntrati o ns 
(al beit i n a s mall % of c o urses), mi ni mize u nacce pta bl y hi g h c o n ce ntrati o ns, a v oi d GI 
t o xicit y, a n d mai ntai n t he maj orit y of c o urses i n t h e desire d tar get r a n ge.  Usi n g t his 
ap pr oac h, we ha d o nl y 5. 1 % of c o urses wit h gra de 3- 4 m uc ositis (c o m pare d t o as hi g h as 
4 4 % of c o urs es wit h B F M’s a d mi nistrati o n of 5 g/ m 2 wit h o ut tar geti n g). 
 
O ne of t he less o ns of t ar geti n g i nter-c o urse H D M T X was t hat we were n ot as s uccessf ul at 
ke e pi n g all c o urs es wit hi n + 2 0 % of t he tar get as w he n we p erf or me d i ntra-c o urse 
H D M T X tar geti n g 3 7.  We m o difie d T O T X V t o all o w i ntra-c o urse tar geti n g w he n p ossi ble 
b ut ha ve tar get e d o nl y a fe w cas es d ue t o t he m ore c o m plicate d l o gistics of nee di n g t o 
start H D M T X earl y e n o u g h i n t he da y t o all o w feasi ble i ntra-c o urse t ar geti n g. H o we ver, 
base d o n si m ulati o ns w hic h use d t he pre vi o us M T X cleara nce al o n g wit h a 2 h o ur M T X 
plas ma  c o nce ntrati o n t o tar get t he ste a d y-state c o n ce ntrati o n, 1 %, 9 1 %, a n d 8 % of c o urses 
w o ul d be bel o w, i n, a n d a b o ve t he tar get ra n ge. T h us, i n patie nts w h o ha ve e x perie nce d 
re nal d ysf u ncti o n, re q uir e c o nc urre nt dr u gs t hat mi g ht affect M T X cleara nce, or w h o are 
ot her wise u nsta ble, we will e m pl o y i ntra-c o urse tar geti n g of H D M T X. 
 
It s h o ul d be n ote d t h at a p pr o xi matel y 1 0 % of pr o visi o nal l o w-ris k A L L will be c ha n ge d t o 
sta n dar d-/ hi g h-ris k A L L beca use of p ositi ve mi ni mal resi d ual le u ke mia at t he e n d of 
i n d ucti o n.  I n t hes e cas es, H D M T X d osa ge after t he first d ose will be c h a n ge d t o t he 
hi g her a vera ge d os e of 5 g m/ m 2 ( 6 5 u M). 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 1. 4  
C o nti n uati o n treat me nt 
 
Af ter c o ns oli dati o n t hera p y, patie nts will recei ve ris k- directe d c o nti n uati o n treat me nt.  
L o w-ris k patie nts will recei ve dail y merca pt o p uri ne a n d wee kl y met h otre x ate wit h 
p ulses of de x a met has o ne a n d vi ncristi ne e ver y 3 t o 5 wee ks (f or t he first t w o years).  I n 
ra n d o mize d trials, de x a met has o ne treat me nt was s u peri or t o pre d nis o ne i n r e d uci n g 
C N S rela pse a n d i m pr o vi n g e v e nt-free s ur vi v al 3 8  partl y d u e t o its s u peri or C N S 
pe netrati o n. Merca pt o p uri ne will be c o nti n ue d d uri n g t he wee k of de x a met has o ne a n d 
vi ncristi ne treat me nt i n t his st u d y t o i nte nsif y s yst e mic t hera p y, as t he d ose i nte nsit y of 
mer ca pt o p uri n e was t he m ost i m p orta nt p har mac ol o gic varia ble i n deter mi ni n g 
treat me nt o utc o me i n T O T XII st u d y3 9.  Met h otre x ate will n ot be gi v e n d uri n g t he wee k 
of de x a met has o ne pl us vi ncristi ne t o re d uce t he ris k of t y p hlitis. 
 
C o nti n uati o n treat me nt f or sta n dar d- a n d hi g h-ris k cases i nc or p orates effecti ve 
treat me nt c o m p o ne nts of t he m ost s uccessf ul cli nical trials t o date. I nte nsif yi n g 
as para gi n ase t hera p y d uri n g t he earl y p has e of treat me nt i m pr o ve d o utc o me f or all ris k 
gr o u ps i n t he D F CI st u di es 2, f or p o or earl y res p o n ders ( 9 0 % of w h o m ha d B- li nea ge 
A L L) i n t he C C G a u g me nte d t hera p y 1, a n d f or T-cell cases i n t he Pe di atric O nc ol o g y 
Gr o u p P O G- 8 7 0 4 st u d y 4 0.  I nte nsi v e L-as p ara gi n ase treat me nt f aile d t o i m pr o ve 
o utc o me s i n a st u d y of l o w-ris k B-li nea ge A L L. He nce, i nte nsi ve as para gi nase t hera p y 
will c o nti n ue t o be gi ve n t o patie nts wit h T-cell A L L as well as t h ose wit h hi g h-ris k B-
li nea ge A L L i n T O T X VI as i n T O T X V. 
 
I ntr a ve n o us P E G- as para gi nase is i ncreasi n gl y use d i n fr o ntli ne A L L re gi m e n. I n 
T O T X VI, p atie nts wit h sta n dar d- or hi g h-ris k A L L will recei ve P E G-as para gi n ase 
ever y 2 w ee ks f or a t otal of 1 5 d oses d uri n g t he first 3 0 wee ks of c o nti n uati o n t hera p y. 
L o w-ris k patie nts will o nl y recei ve 4 d os es ( 2 i n eac h re-i n d ucti o n). 
 
Alt h o u g h t he o pti mal d ose of t he differe nt pr e parati o ns of as para gi n ase is n ot fir ml y 
esta blis he d, e q ui vale nt E F S has bee n re p ort e d wit h P E G-as para gi nase 2, 5 0 0 u nits/ m 2 
a n d nati ve L- as para gi nas e at 6, 0 0 0 u nits/ m 2 x 6 d oses4 1.  He nce t he d ose of 2, 5 0 0 
u nit s/ m2 f or P E G- as para gi nase h as bee n wi del y a d o pte d.  H o we ver, P E G-as para gi n ase 
at 2, 5 0 0 u nits/ m2 faile d t o de plete C S F as para gi ne i n s o me st u dies, s u g gesti n g t his d ose 
is ina de q uate f or C N S c o ntr ol. M ore o ver, L- as para gi n ase was gi v e n at 1 0, 0 0 0 u nits/ 
m 2/ d ose o n T OT X V. Beca use as para gi nas e has bee n s h o w n t o be s uc h a n i m p orta nt 
c o m p o ne nt t o m o der n A L L trials, a n d si nce T O T X V use d hi g her t ha n c o n ve nti o nal L-
as para gi n ase d oses, o n T O T X VI, patie nts will be ra n d o mize d t o recei ve t h e 
c o n ve nti o nal P E G- as para gi n ase d ose ( 2, 5 0 0 u nits/ m 2), or t he hi g her P E G-as para gi n ase 
d ose ( 3, 5 0 0 or 3, 0 0 0 u nits/ m 2). T he differe nce i n p har mac o ki netics a n d 
p har mac o d y n a mic meas ures, a n d o utc o me, will be st u die d i n t he 2 ar ms a n d se parat el y 
f or 3, 5 0 0 a n d 3, 0 0 0 u nits/ m2 if b ot h d oses are use d i n t he hi g her P E G-as para gi nase ar m. 
 
As i n T O T X V, use of e pi p o d o p h yll ot o xi ns will be li mite d t o hi g h-ris k A L L i n T O T X VI 
t o decrease t he ris k of t h era p y-relate d A M L4 1.  We will use c ycl o p h os p ha mi de a n d 
ant hrac ycli n es t o i nte nsif y treat me nt i n sta n dar d-/ hi g h-ris k cases. H o we ver, t otal 
c u m ulati ve d ose of c ycl o p h os p ha mi de is li mite d t o 4. 6 g m/ m 2 f or t he vast maj orit y of 
t he patie nts a n d t o 5. 4 g m/ m2 i n a b o ut 7 % patie nts w h o ha ve 5 % or m ore blasts o n da y 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 5 of i n d ucti o n t o re d uce t he pr o ble m of sterilit y (es peciall y i n b o ys). A nt hrac ycli ne 
cu m ulati ve d osa ge is li mite d t o 2 3 0 m g/ m 2 i n sta n dar d/ hi g h-ris k patie nts, a n d t o 8 0 
m g / m2 i n l o w-ris k cases.  T hese d osa ges of a nt hr ac ycli nes are ass oci ate d wit h a ver y 
l o w ris k of car di o m y o pat h y4 2. 
 
Rei n d ucti o n treat me nt is a n i nte gral c o m p o ne nt of m ost c o nte m p orar y trials, wit h 
be nefits e xte n di n g t o l o w-ris k cases.  A C C G st u d y s h o w e d t hat a n a u g me nte d B F M 
re gi me n (e q ui v ale nt t o t he use of d o u ble rei n d ucti o n) ca n e v e n a b olis h t he a d verse 
pr o g n ostic i m pa ct of p o or earl y res p o nse 1.  He nce, i n T O T X VI, all patie nts (re gar dless 
of r is k stat us) will recei v e t w o c o urses of rei n d u cti o n, al beit at differe nt i nte nsit y as 
deter mi ne d b y ris k gr o u p assi g n me nt.  I n l o w-ris k patie nts, d o x or u bici n will be o mitte d 
fr o m re-i n d u cti o n II, re d uci n g t he t otal c u m ulati ve a nt hrac ycli ne d ose t o 8 0 m g/ m 2 
(c o m pare d t o 1 1 0 m g/ m2 o n T O T X V) i n t his gr o u p. I n sta n d ar d- ris k a n d hi g h-ris k 
g r o u ps, hi g h- d os e c ytara bi ne ( 2 g m/ m2) is i nc or p orate d i n re- i n d ucti o n II beca use 
T O T XII s u g geste d t hat T-cell cas es be nefit fr o m t his treat me nt 3 7 a n d a n a d ult B F M 
st u dy s h o we d t hat hi g h- d ose c yt ara bi ne ca n mar ke dl y i m pr o ve o utc o me, e v e n i n 
patie nts wit h t he t ( 4; 1 1) A L L 4 3. 
 
Ge n der has l o n g b ee n rec o g niz e d as a pr o g n ostic fact or i n c hil d h o o d A L L.  B o ys ha ve 
c o nsiste ntl y fare d w orse t ha n girls, gi ve n e q ui vale nt t hera p y. Male patie nts treate d o n 
C C G, B F M, a n d T O T X V pr ot oc ols recei ve d a n e xte n de d d urati o n of treat me nt (i.e. 3 
years). H o we v er, i n T O T XIII B (i n w hic h t h e d urati o n of c he m ot hera p y f or b ot h males 
a n d fe males was 2. 5 years) a n d i n T O T X V, wit h o verall 5- year e v e nt- free s ur vi val rates 
o ver 8 0 %, male p atie nts fare d as well as fe male p atie nts.  He nce, i n T O T X VI, t he 
d ura ti o n of t hera p y will be t he sa me f or b ot h ge n d ers ( 2 ½ years).  As i n T O T X V, 
co nti n uati o n treat me nt be y o n d 2 years i n T O T X VI c o nsists of merca pt o p uri ne a n d 
met h otre x ate o nl y ( n o de x a met has o ne a n d vi ncristi ne p ulses).  M ore o v er, 
de x a met has o ne d ose will be decreas e d t o 6 m g/ m 2 bet wee n wee k 6 9 a n d wee k 1 0 1 t o 
decrease t he m or bi dit y fr o m de xa met has o ne t hera p y. 
 
2. 1. 5  
S u b-cli nical C N S treat me nt 
 
S i nce C N S irra diati o n ca n i n d uce seri o us l o n g-ter m se q uelae, i ncl u di n g gr o wt h 
retar dati o n, i ntellect ual i m pair me nt a n d brai n t u m ors, a n d i n vie w of t he o utsta n di n g 
C N S c o ntr ol i n T O T XIII A & B,  C N S irra diati o n was eli mi nate d alt o get her i n 
T O T X V, e x ce pt i n patie nts w h o de vel o pe d C N S rela pse. 
 
T he o verall 5- year c u m ul ati ve ris k of C N S rela pse was 3. 7 % + 1. 3 % ( S E) i n T O T X V, 
w hic h is c o m para bl e t o r es ults i n st u dies still usi n g pre ve nti ve C N S irra di ati o n. We 
attri b ute t his s uccess t o earl y i nte nsifi cati o n of i ntrat hecal treat me nt, es p eci all y i n 
patie nts at hi g h ris k of rela pse, a n d effecti ve s yst e mic treat me nt i ncl u di n g t he use of 
de x a met has o ne.  M ost C N S e ve nts o n T O T X V occ urre d i n p atie nts wit h T-cell 
li nea ge ( wit h c u m ulati ve ris k of 1 1. 1 % + 4. 8 %), or wit h a n y a m o u nt of blasts i n t he 
C S F ( 1 1 % + 4. 3 %). A rece nt  a nal ysis of T otal T hera p y st u dies XIII A, XIII B, XI V, 
a n d X V f urt h er i n dicate d t hat patie nts wit h t( 1; 1 9)/ E 2 A- P B X 1 ha ve a l o wer 
c u m ulati ve i nci de nce of a n y h e mat ol o gical r ela ps e b ut a si g nifi ca ntl y hi g h er 
i nci de nce of C N S rela p se ( p = 0. 0 0 5; 1 2. 4 % + 5. 9 % vs. 2. 7 % + 0. 7 % at 5 years)4 4. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
N ota bl y, all patie nts wit h is olate d C N S rela pse were ali ve i n se c o n d re missi o n after 
recei vi n g t heir first c o urs e of irra di ati o n f or treat me nt of C N S rela pse, res ulti n g i n n o 
si g nifica nt differe nce i n s ur vi val bet wee n p atie nts wit h B-li nea ge or T-li nea ge A L L, 
or bet wee n t h os e wit h or wit h o ut blasts i n C S F at dia g n osis.  He n ce, is olate d C N S 
rela pse i n patie nts w h o di d n ot recei ve pre v e nti ve C N S irra diati o n are c ura ble wit h 
retrie val t hera p y.  I n T O T X VI, i ntrat hecal treat me nt will be i nte nsifie d d uri n g 
i n d ucti o n treat me nt wit h 2 a d diti o nal i ntrat hecal treat me nt o n d a ys 4 a n d 1 1 f or 
patie nts wit h T-cell A L L, t( 1; 1 9)/ E 2 A- P B X 1, or a n y a m o u nt of le u k e mic blasts 
i de ntifia ble i n t he cere br os pi nal fl ui d at dia g n osis (i ncl u di n g t h ose wit h cere br os pi nal 
fl ui d c o nta mi nate d wit h le u ke mic- blast cells d ue t o a tra u matic l u m bar p u n ct ure, 
beca use t h e y are at hi g her ris k of C N S rela pse a n d ha ve a p o orer e ve nt-free s ur vi val 
if treat me nt is n ot i nte nsifie d).  T hes e patie nts t he n recei v e a d diti o nal i ntrat hecal 
d ose s e ver y 4 wee ks d uri n g t he first 5 6 wee ks of c o nti n uati o n t hera p y, as d o patie nts 
wit h n o i de ntifia ble blasts i n t he cere br os pi nal fl ui d w h o were j u d ge d t o ha ve a n 
i ncreas e d ris k of C N S rel a pse base d o n ot h er feat ures (i.e., t h ose wit h W B C ≥1 0 0 x 
1 0 9/ L, a n d P hila del p hia- c hr o m os o me p ositi ve cas es). 
 
As i n T O T X V, pre v e nti ve C N S irra diati o n is eli mi nate d alt o get her i n t his st u d y, 
e x ce pt i n patie nts w h o d uri n g c o nti n uati o n tr eat me nt ha ve m or p h ol o gi c e vi de nce of 
l y m p h o blasts i n t he C S F, c o nfir me d b y i m m u n ol o gical testi n g (i. e., T d T) o n t w o 
separat e occasi o ns.  We e x pect t hat t hese e ve nts s h o ul d n ot occ ur i n m ore t ha n 5 % of 
t he patie nts.  Patie nts are ma na ge d acc or di n g t o Secti o n 9. 4. 
 
2. 1. 6  R ati o nale f or m o dificati o n of merca pt o p uri ne a d mi nistrati o n (re visi o n 5. 5) 
 
Pri or t o re visi o n 5. 5, t his pr ot oc ol sti p ulate d t hat merca pt o p uri n e s h o ul d be ta ke n o n a n 
e m pt y st o mac h (i.e., > 2 h o urs after m eal) at b e dti me; patie nts s h o ul d n ot dri n k mil k or 
ta ke dair y pr o d u cts t o get her wit h merca pt o p uri ne. 
 
H o we ver, base d o n literat ure re vie w s u m marize d bel o w, t his c ha n ge d wit h a me n d me nt 6. 0 
a n d n o w sti p ulates t hat merca pt o p uri ne s h o ul d be gi ve n dail y at a c o nsiste nt ti me t hat 
ma xi mizes a d here nce wit h t he prescri b e d treat me nt. If a d ose is i na d verte ntl y misse d, t he n 
it s h o ul d be gi ve n as s o o n as t he o missi o n is n ote d, as l o n g as it is at least 6 h o urs pri or t o 
t he ne xt sc he d ule d d ose of M P. 
 
Pri or st u dies assessi n g t h e p har mac ol o gi cal a n d t h era pe utic i m pact of gi vi n g oral 
merca pt o p uri n e ( M P) wit h f o o d or wit h dair y pr o d ucts, or gi vi n g 6 M P at differe nt ti mes of 
da y h a ve pr o d uce d v aria ble res ults.  All of t he earl y st u dies 4 5 -4 7 e nr olle d s mall n u m bers of 
pa tie nts a n d re v eale d tre n ds i n differe n ces i n pea k plas ma c o nce ntrati o ns of pare nt dr u g or 
plas ma area- u n der-t he-c o nce ntrati o n-ti me c ur ve ( A U C), b ut t hese res ults were n ot 
statisticall y si g nifica nt.  Ot her st u dies 4 8; 4 9 re p orte d statisticall y si g nifica nt differe n ces i n 
time of ma xi m u m dr u g c o nce ntrati o n i n plas ma (t ma x)  a n d A U C i n t he fasti n g state of 
pare nt dr u g 4 8 or c ha n ges i n A L L dise ase free s ur vi val4 9 ass ociate d wit h ti me of da y of oral 
6 M P a d mi nistrati o n ( wit h better res ults re p orte d f or ni g htti me dr u g a d mi nistrati o n i n t hat 
t he ris k of rela ps e was 4. 6 ti mes greater wit h t he m or ni n g a d mi nistrati o n s c he d ule).   
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
H o we ver, t hese ol der st u dies di d n ot assess t hese varia bles i n t he c o nt e xt of treat me nt 
pr ot oc ols t hat utiliz e er yt hr oc yt e t hi o g u a ni ne n ucl e oti des ( T G N) l e vels t o g ui de t hera p y 
a dj ust me nts, n or di d t he y i ncl u de t hi o p uri ne d osi n g as p art of m ulti variate a nal ys es f or 
o utc o me pre dict ors.   
 
A m ore rece nt st u d y of 5 3 2 patie nts b y Sc h mie gel o w, et al. use d a C o x m ulti variate m o del 
t o s h ow t hat t he circa di a n sc he d ule ( m or ni n g vs. e ve ni n g vs. mi x e d) of M T X/ 6 M P was n ot 
of pr o g n ostic si g nifica nce f or t he ris k of rela ps e, a n d t he 1 0- year c u m ulati v e rela ps e ris k 
was bel o w 2 0 % i n all gr o u ps 5 0.  
 
A se parate rece nt st u d y assesse d t he effects of “ pill-ta ki n g” h a bits o n treat me nt a d here n ce, 
er yt hr oc yte T G N le vels & rel a pse ris k i n 4 4 1 c hil dre n e nr olle d o n t h e C O G A A L L 0 3 N 1 
st u d y5 1.  T his st u d y re p orte d n o ass ociati o n bet wee n rela ps e ris k a n d w het her 6 M P was 
ta ke n wit h f o o d ( p = 0. 5), wit h dair y ( p = 0. 2), w het her ta blets were s w all o we d w h ole vs. 
cr us hi n g/ c he wi n g ( p = 0. 7); I V), or ti me of d a y: e v e ni n g/ ni g ht vs. m or ni n g/ mi d- da y 
( p = 0. 9), var yi n g ti mes vs. n o n- var yi n g ti mes ( p = 0. 9). T he 6 M P ta ki n g h a bits were als o n ot 
ass ociate d wit h DI- a n d a ge-a dj uste d T G N le vels.  T he a ut h ors c o n cl u de d t hat t he 
co m m o nl y practice d restricti o ns c o ncer ni n g a d mi nistrati o n wit h f o o d or at be dti me di d n ot 
si g nifica ntl y i nfl ue n ce o utc o me i n t heir pr ot oc ol a n d patie nt c o h ort. 
 
Base d o n t h ese lar ger a n d ne wer st u dies, t hat i ncl u de m ore caref ul atte nti o n t o 6 M P d osi n g 
t ha n was tr ue i n t he earli er st u dies, a n d o n t he fact t hat 6 M P d ose is a dj uste d t o desire d 
bl o o d c o u nts, we pr o p ose t o lift t he restricti o ns c o ncer ni n g a d mi nisteri n g M P at be dti me 
a n d o n a n e m pt y st o mac h t o all o w patie nts t o ta ke 6 M P at a ti me of da y w hi c h is m ost 
li kel y t o yi el d f ull a d here nce t o t he pres cri be d d ail y d osi n g of 6 M P.  As f or a n y d ail y dr u g, 
we rec o m me n d t hat pare nts a d mi nister a n d/ or patie nts ta ke 6 M P at a c o nsiste nt ti me e ver y 
da y. We als o str o n gl y rec o m me n d t hat er yt hr oc yte T G N le vels c o nti n ue t o be m o nit or e d 
t o g ui de 6 M P t hera p y ( detect n o n-a d here n ce a n d/ or i na p pr o priate d osi n g). Li ke wis e, 
T P M T p he n ot y pe/ ge n ot y pe s h o ul d c o nti n ue t o be assesse d f or eac h patie nt t o g ui de t he 
selecti o n of o pti mal 6 M P d osa ges f or eac h p atie nt.  Fi nall y, A L L c o nti n uati o n t hera p y 
s h o uld c o nti n ue t o be g ui de d b y m eas ure me nt of W B C t hr o u g h o ut t hera p y, wit h d osa ge 
a dj uste d ma de as sti p ulat e d i n t he pri mar y A L L tr eat me nt pr ot oc ol. 
 
2. 2  
P har mac ol o gic St u dies 
 
2. 2. 1  Ge r mli ne ge netic p ol y m or p his ms 
 
Usi n g ca n di date ge n e a p pr oac hes, we a n d ot h ers ha ve i de ntifie d m ulti ple p ol y m or p his ms 
ass ociate d wit h rel a pse ris k, ac ute t o xicit y, a n d lat e effects (s uc h as sec o n d ca ncers) 1 2; 5 2- 5 6.  
Re plicati o n of ass ociati o ns fr o m o n g oi n g st u dies are re q uire d t o use t his i nf or mati o n t o 
i n di vi d ualiz e d osi n g f or t he maj orit y of t hese ass o ciati o ns, wit h t he e x ce pti o n of 
t hio p uri ne met h yltra nsferase ( T P M T), w hic h is alr ea d y bei n g use d t o i n di vi d ualize t hera p y 
( Secti o n 7. 1 0). 
 
Ge n o me wi de a nal yses are als o bei n g i nc or p orate d i nt o st u dies of treat me nt-relate d 
o utc o mes f or A L L 5 7; 5 8.  T he s u bstrate f or t hese ge n o me wi de st u dies ca n be D N A or R N A, 
a n d ma y i n v ol ve t he A L L blast material or ger mli ne material. Alt h o u g h t he c h oice of 
tiss ue t o ser ve as t he s u bstrate f or ge n o me- wi de assess me nts of ge ne e x pressi o n is n ot 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
clear, peri p heral bl o o d le u k oc ytes are a reas o na ble a n d accessi ble s o urce of “ ger mli ne” 
R N A, a n d we  ha ve use d t his tiss ue f or preli mi nar y st u dies o n T O T X V. 
 
B eca use of t h e hi g h false disc o ver y rat e i n here nt i n ge n o m e- wi de ass ociati o n st u dies, t he 
critical c o nce pt i n ge neti c st u dies is re plicati o n i n m ulti ple cli nical trials.  T h us, t o s o me 
exte nt, ge netic st u dies i n T O T X VI will be re peati n g a n al ys es o n earlier St. J u de a n d ot he r 
A L L st u dies.  T h os e p he n ot y pe/ ge n ot y p e relati o ns hi ps t hat are re plicate d will ha ve great er 
g e n eraliza bilit y i n t he f ut ure; s o me ass ociati o ns t h at d o n ot re plicate are li k el y d u e t o 
treat me nt differe nces a m o n g pr ot o c ols, a n d s o me will ha ve bee n d u e t o false p ositi ve 
ass ociati o ns.  T h ose ass o ciati o ns of great est i m p orta nce are t he s u bject of la b orat or y 
f oll o w- u p st u dies i n t he la bs of P har mace utical, O nc ol o g y, a n d Pat h ol o g y De part me nt 
fac ult y, as w ell as ot her gr o u ps. 
 
T w o ge netic p ol y m or p his ms t hat ha ve be e n li n ke d t o o utc o me p he n ot y pes b y  St. J u de 
i n vesti gat ors will be teste d o n T O T X VI, t he T Y M S en ha ncer re peat p ol y m or p his m a n d a n 
I L 1 5 S N P 5 8.  T he f or mer c o mes fr o m a ca n di date ge n e a p pr oac h a n d has bee n li n ke d t o 
rela pse ris k5 3 a n d t o oste o necr osis ris k5 9; t he latter is base d o n o ur ge n o me- wi de a nal ysis 
of  ger mli ne p ol y m or p his ms t hat are si g nifica ntl y relate d t o M R D stat us6 0. 
 
Gi ve n t he pace wit h w hic h ge n ot y pi n g tec h n ol o gi es are e v ol vi n g, it is n ot realistic t o 
descri be w h at ge n o mic i nterr o gati o ns will act uall y be us e d t o e val uat e ge n o mic 
deter mi na nts of efficac y a n d a d verse e v e nts, b ut it is clear t hat ge n o m e- wi d e 
i nterr o gati o ns will c o nti n ue t o e v ol ve t o bec o m e less e x pe nsi ve a n d m ore feasi ble d uri n g 
t he years t hat T O T X VI will accr ue p atie nts. Gi ve n t he relati vel y l o w c ost of pr os pecti vel y 
o btai ni n g ge n o mic material f or f ut ure st u dies, w e will c o nti n ue t o c ollect peri p heral bl o o d 
f or ger mli ne D N A a n d R N A is olati o n, as we ha v e f or T O T X V, a n d e m pl o y state- of-t he-
art tec h ni q ues t o ass ess w het her ge n o mic v ariati o n pre dicts ris k fact ors f or rela pse, 
( hemat ol o gi c or C N S), p o or res p o nse ( M R D p ositi vit y), ac ut e t o xicities (e. g. 
oste o ne cr osis, ne ur ot o xicit y, i nfecti o n), i nter me diate p har mac ol o gic p he n ot y p es (e. g. 
plas ma met h otre x ate cleara nce, s er u m le vels of bi o mar kers s uc h as ser u m c h olester ol or 
c ortis ol), a n d l o n g-ter m c o m plicati o ns of t hera p y (e. g. s ec o n d ca ncers, oste o pe nia). 
Refere n ce s er u m at dia g n osis will als o be c ollecte d f or t he p ote ntial use t o meas ure 
s ol u ble fact ors i n f ut ur e researc h, as w ell as ser u m f or “ bi o mar kers” (as i n 1 0. 3 a n d 1 6. 3) 
d uri n g t hera p y. 
 
E x a m ples of ge n ot y pe/ p h e n ot y p e ass ociati o n st u dies t hat will be perf or me d e xte n d o ur 
earlier w or k i n A L L trials t o defi ne ger mli ne ge n o mic variati o n 5 3; 5 9; 6 1- 6 4 t hat pre dicts t o xic 
a n d t hera p e utic res p o ns e; ge n o m e- wi de ge ne e x pressi o n t hat reflects ger mli ne varia bilit y 
a n d c orres p o n ds wit h res p o nse p he n ot y pes 1 2; 5 2; 5 4; 5 7 a n d ac q uire d ge n o mic c ha n ges t hat 
ma y affect A L L ris k gr o u p a n d treat me nt r es p o ns e 6 5; 6 6.  Sa m ple p o wer esti mates are 
i ncl u ded i n t he Statistical Secti o n 1 7. 5. 
 
T P M T e x hi bits ge netic p ol y m or p his m, wit h < 1 % of t he p o p ulati o n h o m oz y g o us deficie nt 
a n d 1 0 % heter oz y g o us 6 6.  We ha ve bee n usi n g i nf or mati o n o n patie nts' T P M T stat us t o 
assist i n d osa ge i n di vi d u alizati o n f or c o nti n uati o n t hera p y si nce 1 9 9 1 i n p atie nts e nr olle d 
at St. J u de.  We will c o nti n ue t o assess patie nts f or T P M T p he n ot y pe a n d ge n ot y pe, a n d 
use t hese data (al o n g wit h data o n cli nical t olera n ce of c h e m ot hera p y a n d meas ure me nts of 
acti ve t hi o p uri ne meta b olites i n re d bl o o d cells) as part of o ur al g orit h m f or d osa ge 
a dj ust me nt d uri n g c o nti n uati o n t hera p y o n T O T X VI.  Patie nts w h o are T P M T 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
H E T/ deficie nt will recei v e merca pt o p uri ne as p er T O T X V d uri n g i n d ucti o n i nstea d of 
t hi o g ua ni ne 
 
2. 2. 2  As para gi nase 
 
T o a d dress t he ra n d o mize d as para gi nase q u esti o ns, plas m a as para gi nase will be meas ure d 
d uri n g i n d ucti o n a n d rei n d ucti o ns.  T here are s u bsta ntial data fr o m ot her i n vesti gati o ns 6 7; 6 8 
s u p p orti n g t hat a tr o u g h l e vel at 1 4 da ys is i n t he eli mi nati o n p hase of t he dr u g’s 
c o nce ntr ati o n-ti mes-ti me c ur ves e v e n w he n t h e dr u g is a d mi nistere d I M.  Wit h t he first 
d ose d uri n g i n d u cti o n, a t otal of 3- 5 p ost- d ose sa m ples will be o btai ne d, ti me d t o c oi nci de 
wit h cli ni c visits a n d bl o o d dra ws, t o better assess P K after I V d osi n g.  D ue t o t he ver y 
l o n g half-life, t here is fle xi bilit y as t o w h e n t he sa m ples are o btai ne d, a n d Ba yesi a n 
m o deli n g per mits li mite d sa m pli n g.  T he g o als of t hese st u dies is t o defi ne t he ra n ge of 
tr o u gh plas ma as para gi nase c o nce ntrati o ns ac hie va ble wit h I V d osi n g of P E G-
as para gi n ase, t o c o m pare c o nce ntr ati o ns i n t he 2, 5 0 0 u nits/ m 2 vs.  3, 5 0 0 u nits/ m 2 (a n d 
3, 0 0 0 u nits/ m 2 if used) gr o u ps, a n d t o e x pl ore w het her as para gi nase c o nce ntrati o ns relate 
t o as para gi ne d e pleti o n a n d a nti-as para gi nase a nti b o dies. 
 
Aller gi c reacti o ns occ ur c o m m o nl y wit h a d mi nistrati o n of as para gi nase (a n e nz y me n ot 
prese nt i n h u ma ns) a n d ca n li mit its use.  M ore i m p orta ntl y, de v el o p me nt of a nti-
as para gi n ase a nti b o dies ( wit h or wit h o ut cli nical h y p erse nsiti vit y) ma y i n acti vate 
as para gi n ase a n d t h us att e n uate its a bilit y t o de plete as para gi ne s yste micall y.  Beca use 
as para gi n ase pla ys s uc h a pr o mi ne nt r ole i n T O T X VI, we will o btai n sa m ples f or a nti-
as para gi n ase a nti b o dies a n d plas ma as para gi nase ( base d o n a bi ol o gical ass a y of acti vit y, 
w hic h will t here b y reflect a n y i nacti vati n g effects of c o nc o mita nt a nti b o dies), a n d C S F 
as para gi n e, a p har mac o d y n a mic m eas ure of as p ara gi n ase effect a n d o ne feasi bl y meas ure d 
i n t he cli nic. 
 
As pa ra gi ne d e pleti o n is wi del y us e d as a n i n de x of as para gi nase effect. C S F c o nstit utes a 
c o n ve nie nt tiss ue f or sa m pli n g, beca use C S F as p ara gi n e le vels r eflect s yste mic le vels a n d 
are n ot s u bject t o t he diffic ulties i n i m me diate sa m ple pr ocessi n g ca us e d b y as p ara gi n ase 
i n bl o o d.  I n T O T X VI, i ntra ve n o us P E G- as p ara gi nase is re placi n g n ati ve E. c oli L-
as para gi n ase ( Els par), a n d will be a d mi nistere d i n a ra n d o mize d fas hi o n at t w o d ose le vels 
p ost re missi o n i n d ucti o n.  We will meas ure a nti-as para gi nas e a nti b o dies, as well as C S F 
as para gi n e de pleti o n i n all patie nts at i de ntical ti me peri o ds d uri n g t hera p y, t o e x pl ore 
w het her m or e fa v ora ble res ults are ass o ciate d wit h t he hi g her d ose of P E G- as para gi n ase, 
a n d w het her t h ese varia bles are relate d t o treat me nt o utc o me, t o xicities, a n d t o eac h ot her. 
 
I n T O T X V, ser u m mar kers s uc h as li pi ds, c h olester ol, a n d c ortis ol were clearl y i nfl ue nce d 
b y b ot h as p ara gi nas e a n d de x a met has o ne, a n d relate d t o a d verse e ve nts; m ore o ver, 
as para gi n ase a p p eare d t o ha ve a pr o mi ne nt effect o n de x a met has o ne p har m ac o d y na mics 6 9.  
T o e sta blis h t his relati o n, ser u m sa m ples ti me d rel ati ve t o as para gi nase a n d ster oi ds will 
be o btai ne d as w as d o ne o n T O T X V (as detaile d i n Ta ble 1 1. 2). 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 2. 3  
Deter mi nati o n of A L L bl ast se nsiti vit y t o a nti-le u ke mic a ge nts, i n vitro  
 
We ha ve pre vi o usl y st u die d t he e x vi v o se nsiti vit y a n d resista nce t o a nti-le u ke mic a ge nts 
of pri mar y le u ke mia cells is olate d fr o m ne wl y dia g n ose d c hil dre n wit h A L L 1 2; 1 3.  Ex viv o  
dr u g  s e nsiti vit y h as pre di cte d l o n g-ter m r ela pse ris k, is ass ociate d wit h dr u g-s pecific ge ne 
e x pressi o n patter ns, a n d is bei n g c o u ple d wit h precli nical st u dies i n cell li nes a n d m uri ne 
m o dels t o i de ntif y deter mi na nts of dr u g s e nsiti vit y i n la b orat or y m o dels. O ur pre vi o us 
st u dy i de ntifie d 4 2, 5 9, 5 4 a n d 2 2 ge ne pr o bes (c orres p o n di n g t o 1 9 t o 4 0 k n o w n ge nes per 
dr u g) t hat were differe nti all y e x presse d i n B-li nea ge A L L cells t hat were eit her se nsiti ve 
or resista nt t o pre d nis ol o ne, vi ncristi ne, L-as p ara gi nase or da u n or u bici n, res pecti vel y 1 2.  I n 
ad diti o n, we ha ve i de ntifi e d 4 5 ge nes differe ntiall y e x presse d i n A L L e x hi biti n g cr oss 
resista nce t o pr e d nis ol o ne, vi ncristi ne, as para gi nase, a n d da u n or u bi ci n 1 3.  O ur st u dies ha ve 
i de ntifie d ge nes n ot pre vi o usl y ass oci ate d wit h dr u g resista nce i n c hil d h o o d le u ke mia; 
discri mi nati n g ge n es bel o n g t o n u mer o us f u ncti o nal gr o u ps, a n d s pecific f u ncti o nal 
cate g ories were si g nifi ca ntl y o ver- re prese nte d f or s o me a nti-le u ke mic a ge nts 1 2; 1 3.  T hese 
fi n di n gs d oc u me nt t hat resista nce t o mec h a nisticall y disti nct a nti-le u ke mic a ge nts is 
ass ociate d wit h differe nti al e x pressi o n of differe nt f u ncti o nal gr o u ps of ge n es, i n s u p p ort 
of c o m bi nati o n c he m ot hera p y as t he p ara di g m f or ca ncer treat me nt.  M ore o ver, t hese 
fi n di n gs p oi nt t o pre vi o usl y u nrec o g nize d p ote ntial tar gets f or d e vel o pi n g ne w a ge nts t o 
au g m e nt t he efficac y of c urre nt c he m ot hera p y f or ac ute l y m p h o blastic le u ke mia.  T his is 
ill ustrate d b y o ur fi n di n g of M C L 1 o ver-e x pressi o n i n ster oi d resista nt A L L, a n d t h e 
s u bse q ue nt w or k of t he Ar mstr o n g La b at H ar var d, w h o s h o we d t hat ra p a m yci n ca n d o w n-
re g ulate M C L 1 pr otei n, a n d e n ha nce A L L se nsiti vit y t o ster oi ds7 0.  O ur st u dies ha ve als o 
s h o w n t hat t here are dr u g-s pecific c ha n ges i n ge ne e x pressi o n i n A L L, after i n vi v o 
treat me nt, a n d t hat dr u g c o m bi nati o ns are disti nct fr o m t he s u m of si n gle a ge nt 
treat me nt7 1.   I n T O T X VI we will c o nti n ue t o st u d y e x vi v o dr u g se nsiti vit y of pri mar y 
A L L bl asts t o a d diti o nal a nti-le u ke mic a ge nts ( 6 M P, 6 T G), i n a d diti o n t o e xte n di n g o ur 
pre vi o us st u dies, a n d f urt her i n vesti gate t he n at ure of ge ne e x pressi o n patter ns ass ociate d 
wit h re sista nce t o si n gle a nti-le u ke mic a ge nts or t o m ulti- dr u g cr oss resista nce. O ur 
h y p ot hesis is t hat t here is a defi na ble s et of ge n es t hat are differe ntiall y e x presse d i n 
pri mar y A L L cells e x hi biti n g de n ov o resista nce t o c he m ot hera p y a n d t hat i de ntificati o n of 
t hese ge nes will pr o vi de i m p orta nt ne w i nsi g hts i nt o t he basis of A L L resista nce a n d 
re veal p ote ntial n e w tar gets f or o verc o mi n g resista nce t o t hese wi del y use d me dicati o ns. 
T he w or k w e pr o p ose i n T O T X VI differs fr o m pri or w or k i n t hat ( 1) we are pri oritizi n g 
st u dies of merca pt o p uri n e a n d t hi o g u a ni ne ( dr u gs f or w hic h fe w p atie nts w ere e v al ua ble 
pre vi o usl y) a n d ( 2) we will si m ulta ne o usl y deter mi ne t he se nsiti vit y of t hes e ne w cases t o 
t he a nti-le u ke mic a ge nts we ha ve pre vi o usl y st u die d ( pre d nis o n e, vi ncristi ne, da u n o m yci n, 
as para gi n ase)1 2   i n or der t o el uci date ge n o mic det er mi na nts of m ulti- dr u g cr oss resista nce 
f or all 6 me dicati o ns.  We ha ve pre vi o usl y s h o w n t hat ge n e e x pressi o n patter ns ass ociat e d 
wit h m ulti- dr u g cr oss resista nce are disti nct fr o m ge n es c o nferri n g resista nce t o si n gle 
a ge nts 1 3.  We will als o use ot her ge n o me- wi de a p pr oac hes, i n cl u di n g S N P a n d ha pl ot y pe 
anal ys es, t o i de ntif y ge nes a n d ge netic p ol y m or p his ms li n ke d t o resista nce t o eac h of t h ese 
me dicati o ns ( n ot pre vi o usl y d o ne), a n d t o t he m ulti- dr u g cr oss resista nce p h e n ot y p e.  O ur 
pri or  w or k w as li mite d pre d o mi na ntl y t o B-li nea ge A L L.  I n T O T X VI, we ai m t o e xte n d 
t his w or k t o T-li nea ge A L L.  T his s u bset has a w orse pr o g n osis i n ma n y tr eat me nt 
pr ot oc ols, a n d t heref ore it is i m p orta nt t hat we u n dersta n d t he ge n o mic b asis of dr u g 
resista nce i n t his c o m m o n s u bt y pe of c hil d h o o d A L L. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 2. 3  P las ma h o m oc ystei ne l e v els 
 
I n T O T XI V a n d T O T X V st u dies, C S F a n d plas ma h o m oc ystei ne l e vels were meas ure d i n 
c o nj u ncti o n wit h H D M T X a d mi nistrati o n d uri n g C o ns oli dati o n t hera p y. T he rati o nale f or 
assessi n g M T X-i n d uce d c ha n ges i n h o m oc ystei ne is base d o n e vi de nce li n ki n g M T X 
e x p os ure t o ne ur ot o xicities (e. g., seiz ures) 7 2; 7 3, w hic h ha ve bee n h y p ot hesize d t o be 
ma nif este d, at least i n part, b y M T X-i n d uce d ele vati o n i n plas ma h o m oc ystei ne le vels.  A n 
anal ysis of T O T XI V data re veal e d a tr e n d i n ass ociati o n bet wee n i ncreas e d plas ma 
h o m oc ystei ne l e vels a n d i nci de nce of seiz ures 6 3.  W hile n o c orrelati o ns were o bser ve d 
bet wee n plas ma h o m o c ystei ne ( or seiz ures) wit h pre vi o usl y i de ntifie d M T H F R ge n ot y pes 
as was p ost ulate d 7 4; 7 5, it is li kel y t hat ot her ge netic p ol y m or p his ms u n derlie t he o bser ve d 
H D M T X- i n d uc e d t o xicities a n d i nter patie nt varia bilit y i n plas ma h o m oc ystei ne 
co nce ntr ati o ns.  We will c o nti n ue t o pr os pecti vel y assess plas ma h o m oc yst ei ne i n 
H D M T X c o urs es 1 a n d 2 of c o ns oli dati o n i n T otal X VI. Dat a will be use d t o pi n p oi nt 
g e n etic bi o mar kers ass ociate d wit h differe ntial plas ma h o m oc ystei n e le vels b ot h bef ore, 
a n d f oll o wi n g tr eat me nt wit h H D M T X, as well as t h ose c orrel ate d wit h a n y o bser ve d 
t o xicities. 
 
2. 3  
Bi ol o gic St u dies 
 
2. 3. 1 
Mi ni mal resi d ual disease 
 
W e a n d ot hers ha ve s h o w n t hat detecti o n of s u b micr osc o pic (" mi ni mal") disease str o n gl y 
c orrel ates wit h le u ke mia rela pse 7 6.  Usi n g b ot h fl o w c yt o m etric detecti o n of a berra nt 
i mm u n o p he n ot y pes a n d p ol y merase c h ai n reacti o n ( P C R) a m plificati o n of 
i m m u n o gl o b uli n a n d T-cell rece pt or ge nes, w e were a ble t o m o nit or mi ni mal resi d ual 
le u ke mia i n all patie nts i n T O T X V wit h hi g hl y c o nc or da nt r es ults.  We als o deter mi ne d 
t he degree of c orrel ati o n bet wee n le vels of resi d u al le u ke mia i n bl o o d vers us b o ne marr o w 
b y st u d yi n g paire d s a m pl es fr o m patie nts e nr olle d i n t he st u d y. M R D res ults i n peri p heral 
bl o o d were c o nc or da nt i n T-cell diseas e, b ut n ot i n B- cell li nea ge2 0.  I n T O T X VI we will 
m o nit or M R D usi n g pri maril y fl o w c yt o metr y; i n patie nts w h ose le u ke mi c cells lac k a 
s uita ble i m m u n o p he n ot y pe (esti mate d t o be 5 % or less) we will use t he P C R met h o d 
a p plie d i n T O T X V.  M R D ca n als o be f oll o we d b y t he ne xt ge nerati o n dee p se q ue nci n g of 
t he I g H l oc us i n B- A L L a n d T C R l oci i n T- A L L.  T he se nsiti vit y a n d s pecificit y are b etter 
t ha n fl o w- bas e d or P C R met h o ds7 7. 
 
Patie nts w h o ac hie ve n e gati ve M R D at t he e n d of i n d ucti o n i n T O T X V were u nli kel y t o 
ha ve rea p peara n ce of bl asts o n f urt her f oll o w u p.  He nce, p ost re missi o n b o ne marr o w 
sa m ples will o nl y be o btai ne d f or se q ue ntial M R D m o nit ori n g i n patie nts wit h detecta ble 
M R D at t he e n d of i n d ucti o n.  H o we ver, we will c o nti n ue t o m o nit or M R D i n all patie nts 
wit h T -cell A L L irres pecti ve of t heir M R D stat us at t he e n d of re missi o n i n d ucti o n 
be ca use T-cell cases h a v e hi g h er ris k of earl y rela pse c o m pare d t o B-li nea ge cases. 
B eca use w e s h o we d t h at M R D i n patie nts wit h T- A L L ca n b e effecti vel y m o nit ore d i n 
peri p heral bl o o d, we will use t his less-i n vasi ve pr oce d ure i nstea d of b o ne marr o w 
as pirates f or t his p ur p os e. F or B- A L L, we will als o f oll o w M R D of t he b o ne marr o w a n d 
peri p heral bl o o d b y d ee p se q ue nci n g met h o d t o deter mi ne if t his m ore se nsiti ve a n d 
s pecific test will s h o w c o nc or da nce u nli ke t he fl o w a n d P C R base d M R D t ests.  If 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c o nc or da nt, t he n we ca n m o nit or B- A L L patie nt usi n g a less i n vasi ve t esti n g of t he 
peri p heral bl o o d si milar t o T- A L L patie nts. 
 
I n v esti gat ors of t he C hil dre n’s O n c ol o g y Gr o u p ( C O G) de m o nstrate d t he pr o g n ostic val ue 
of deter mi ni n g M R D o n da y 8 of i n d ucti o n. I n T O T X VI, we will e x pl ore w het her da y 8 
M R D i n peri p heral bl o o d is a practical a p pr oac h t hat mi g ht p ote ntiall y all o w earl y 
t hera pe utic i nter ve nti o n i n f ut ure st u dies. 
 
I n eff orts t o i de ntif y n e w mar kers of l e u ke mia t o use f or M R D m o nit ori n g, we c o m pare d 
t he gene e x pressi o n pr ofile of m ore t ha n 3 0 0 dia g n ostic sa m ples of B-li nea ge A L L t o t hat 
of s orte d C D 1 9 + C D 1 0 + cells fr o m 4 n or mal b o ne marr o w sa m ples.  Se v eral ge nes were 
f o u n d t o be differe ntiall y e x presse d i n le u ke mic cells a n d a nti b o dies s uit a ble f or fl o w 
cyt o metri c stai ni n g are a vaila ble f or a s u bset of t h ese.  I n T O T X VI, we will c o m pare t he 
usef ul ness of t hese n e w mar kers t o m o nit or M R D b y fl o w c yt o metr y. 
 
A rare blast i de ntifie d b y m or p h ol o gic e x a mi nati o n of t he C S F at dia g n osis c urre ntl y 
u p gra de t he C N S r ela pse ris k cate g or y res ulti n g i n e xtra i ntrat hecal treat me nt.  Of 3 4 9 
pa tie nts e nr olle d o n T O T X VI si nce 2 0 0 7, o nl y o n e has ha d a C N S r ela pse t o date. M R D 
anal ysis of t he C S F b y fl o w or P C R base d tests is n ot feasi ble beca use t he C S F lac ks 
s ufficie nt cells.  We will use a dee p s e q ue n ci n g t ec h ni q ue t o e val uat e M R D i n C S F i n 
or der t o st u d y w het her le vels of M R D i n t he C S F at dia g n osis a n d d y n a mics of earl y M R D 
re d ucti o n i n C S F c o ul d b e use d t o f urt her refi ne o ur c urre nt classificati o n f or ris k of C N S 
rela pse.  T his mi g ht p ote ntiall y all o w t he re d ucti o n of i ntrat hecal t hera p y i n f ut ure st u dies 
i n c hil dre n wit h rare i de ntifia ble blast b y m or p h ol o g y b ut l o w le vels of M R D. 
 
2. 3. 2  N K  cell rece pt or st u d y 
 
T he  n or mal p h ysi ol o gical r oles of N K  cells are t o c o ntr ol i nfecti o n a n d pre ve nt ca ncer. I n 
fact, N K  cells are t he o nl y i m m u ne cells t hat ha ve bee n s h o w n b y pr os pecti ve c o h ort st u d y 
i n health y pers o ns t o ha v e i m m u n os ur veilla nce ca pa bilit y a gai nst h u ma n ca ncer 7 8.  I n a 
pr os pe cti ve st u d y of m ore t ha n 3 0 0 0 healt h y v ol u nteers w h o were f oll o we d f or 1 1 years, 
t he ris k of ca ncer was ass ociate d wit h decreas e d N K cell c yt ot o xicit y a gai nst K 5 6 2 
le u ke mia cells, decrease d e x pressi o n of t he N K  rece pt or N K R P 1, a n d decrease d 
pr o d ucti o n of c yt o ki nes s uc h as T N F α a n d I F Nγ i n N K cells. 
 
T hree rece nt st u dies of a d ult le u ke mia ha ve de m o nstrate d a dir ect li n k bet wee n le u ke mia 
an d N K  cell. I n o ne st u d y of patie nts wit h ac ute m yel oi d le u ke mia, t he maj orit y ( 1 6 of 1 8) 
of bl o o d sa m ples s h o we d defecti ve e x pressi o n a n d f u ncti o n of N K  cell –tri g geri n g 
rece pt ors ( N C Rs) ( d ull) 7 9.  T he e x pressi o n of N K  cell s urface rece pt ors was l o w, a n d t he 
c yt ol ytic acti vit y a gai nst a ut ol o g o us le u ke mia cells, a ut ol o g o us B l y m p h o blasts, a n d  N K  
cell–se nsiti ve cell li nes was wea k. T he a b n or mal N C R ( d ull) p he n ot y pe was c o nfir me d i n 
an ot her st u d y of 7 1 patie nts wit h ac ute m yel oi d le u ke mia a n d was f o u n d t o be prese nt i n 
va ri o us m or p h ol o gic a n d ge n ot y pic s u bt y pes of le u ke mia8 0.  I n t he t hir d st u d y of 2 5 A M L 
an d 1 4 A L L cases, t he e x pressi o n of H L A class I was fre q ue ntl y d o w nre g ulate d a n d t hat 
of  t he N K  cell rece pt or li ga n ds P V R a n d Necti n- 2 were u pre g ulate d 8 1.  T o get her,  t hese 
res ults s u g gest t hat N K  rece pt or –li ga n d i nteracti o n ma y be cr ucial f or t he de vel o p me nt of 
le u ke mia. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he n or malizati o n of N K cell rece pt or e x pressi o n ma y b e of pr o g n ostic val ue as N K cells 
ma y b e i m p orta nt f or t he c o ntr ol of le u ke mia rela pse a n d i nfecti o n.  T hese r oles of N K 
cells ha ve bee n s h o w n b y killer cell i n hi bit or y rece pt or ( KI R)- mis matc he d all o ge nei c ste m 
cell tra ns pla ntati o n 8 2.  L o n git u di nal st u d y of a d ult A M L p atie nts s h o we d t h at t he N C R 
( d ull) p he n ot y p e ac q uire d d uri n g le u ke mia de vel o p me nt was re v ersi ble i n patie nts 
ac hie vi n g c o m plete re missi o n after i n d ucti o n c he m ot hera p y 8 0.  Re versi bilit y of t he N C R 
( d ull) p hen ot y p e aft er c o m plete re missi o n s u g gest e d t hat le u ke mia cells mi g ht be i n v ol ve d 
i n N C R d o w n-re g ulati o n. Alter nati vel y, t he rec o ver y of n or mal N C Rs ma y all o w t he 
rec o ver y of n or m al N K cell f u ncti o n t hat c o ntri b utes t o t he ac q uisiti o n of re missi o n stat us. 
I nteresti n gl y, a c orrelati o n was f o u n d bet w ee n t he N C R ( d ull) p he n ot y pe a n d p o or 
s ur vi val i n A M L p atie nts after c he m ot hera p y8 0, s u g gesti n g t hat N K- defici e nt acti vati o n 
ca use d b y N C R d o w n-re g ulati o n c o ul d pla y a r ole i n treat me nt o utc o me.  T heref ore, we 
will  st u d y N K cell rece pt or e x pressi o n at dia g n osis a n d bef ore rei n d u cti o n t o el uci date t he 
r ole of N K cell i n t he de v el o p me nt a n d treat me nt r es p o nse of c hil d h o o d A L L. 
 
2. 3. 3  Gl o ba l ge ne e x pressi o n 
 
All dia g n ostic sa m ples will be e x a mi ne d f or gl o bal ge n e e x pressi o n usi n g micr oarra y 
c hi ps.  T his will c o nti n ue t o e nric h o ur u ni q ue data base o n t he ge ne e x pressi o n of A L L 
cells w hic h has bec o me a n i n val ua ble res o urce f or A L L i n v esti gat ors w orl d wi de. I n 
a d diti o n, t his will pr o vi de us wit h a n o p p ort u nit y t o vali date pr os pecti vel y t he ma n y 
retr os pecti ve o bs er vati o ns ma de i n past c orrelati ve st u dies i ncl u di n g gl o bal ge n e 
e x pressi o n.  I n a d diti o n t o e x a m ples me nti o ne d i n Secti o n 2. 2, c orrel ati ve st u dies 
perf or me d wit h sa m ples of patie nts e nr olle d i n T O T X V i de ntifie d se v eral ge n es w h ose 
e x pressi o n i n le u ke mic cells at dia g n osis was str o n gl y ass oci ate d wit h M R D d uri n g ( da y 
1 9) or at t he e n d of re missi o n i n d ucti o n t hera p y ( da y 4 6)1 0; 1 1.  After e x cl u di n g ge n es 
ass ociate d wit h ge n etic s u b gr o u ps, we f o u n d t hat s o me of t hese ge n es were als o str o n g 
pre dict ors of o v erall treat me nt o utc o me i n a n i n de pe n de nt c o h ort of 9 9 p atie nts e nr olle d i n 
T O T XIII 1 0; 1 1.  A f ull listi n g of t he ge nes ca n be f o u n d i n t he c orres p o n di n g p u blicati o ns. 
O ne  of t he ge nes w h ose e x pressi o n was m ost hi g hl y pre di cti ve f or o utc o m e was 
C A S P 8 A P 2 , w hic h e nc o d e a pr otei n t hat pr o m otes a p o pt osis a n d gl uc oc ortic oi d si g nali n g 
an d was f o u n d t o be e x presse d at l o wer le vels i n p atie nts wit h M R D at t he e n d of 
i n d ucti o n a n d a hi g h er ris k of rela pse1 0.  A n ot her set of ge nes re p orte d t o b e ass ociate d 
wit h i n vitr o dr u g resista nce i n c hil d h o o d A L L 1 2; 1 3, was als o ass ociate d wit h M R D o n da y 
1 9 1 1.  Ge nes f o u n d t o be o vere x presse d i n cases wit h i n vitr o dr u g resista nce a n d wit h 
M R D o n da y 1 9 i ncl u d e d H N P R F, H M G B 2 , H 2 A F Z , K P N A 2 , S N R P G, KI A A 0 9 2 2 , U 2 A F 2 
a n d C C D C 1 0 9 B . Ge nes wit h l o wer e x pressi o n i n patie nts wit h i n vitr o dr u g-resista nce a n d 
wit h M R D o n da y 1 9 i ncl u de d S L C 2 A 3 , M A F F , C D 6 9 , E G R 1, C K S 1 B a n d O T U B 1 . 
F i nall y, we i de ntifie d ge nes t hat were str o n gl y ass ociate d wit h M R D o n da y 1 9 or da y 4 6, 
a n d were als o i n de pe n d e nt pre dict ors of o utc o me i n a n i n de pe n de nt c o h ort, a n d e nc o d e d 
pr otei ns wit h k n o w n re g ulat or y f u ncti o ns i n cell c ycl e pr o gressi o n: C C N B 2 , C D C 2 , 
C K S 1 B , K L F 7, B R R N 1 , T O P 2 A, M A D 2 L 1 , B U B 3 , N U S A P 1 , P O L A 2 , E X O 1 , R N A S A H 2, 
M KI 6 7, a n d Z WI N T 1 1.  I n T O T X VI, we will st u d y t he ass ociati o n of t hese ge n es’ 
ex pressi o n wit h M R D o n da ys 1 5 a n d 4 2, a n d wit h i nci de nce of rela ps e. If t here are 
a nti b o dies a vaila ble f or t he pr otei ns e nc o d e d b y t he ge nes f o u n d t o b e ass ociate d wit h 
M R D a n d rela pse i n t he pre vi o us st u dies, t he e x pressi o n of t he pr otei ns will be m o nit ore d 
b y fl o w c yt o metr y a n d t h eir e x pressi o n will be rel ate d t o M R D o n da ys 1 5 a n d 4 2, a n d 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
cli nical o utc o me.  
 
2. 4  
Ne ur oi ma gi n g St u dies 
 
2. 4. 1 
I ma gi n g st u dies 
 
O n T O T XI V, M R i ma gi n g of t he brai n w as pr os p ecti vel y st u die d i n all patie nts at wee k 6 
of re missi o n i n d ucti o n, wee k 7, wee k 3 1 a n d wee k 1 2 0 of c o nti n uati o n treat me nt. We 
e val uate d t he l o n git u di nal pre vale nce of le u k o e nce p hal o pat h y i n 4 5 s u bjects b y treat me nt 
ris k ar m (l o w- a nd st a n dar d/ hi g h-ris k) 8 3.  Hi g her d oses a n d m ore c o urses of I V- M T X 
corres p o n d e d t o a hi g her ris k f or le u k oe n ce p hal o p at h y.  H o we ver, ma n y of t he c ha n ges 
res ol ve d aft er t he c o m pleti o n of t hera p y a n d t he effect of t hes e c ha n ges o n ne ur oc o g niti ve 
f u ncti o ni n g a n d q u alit y of life i n s ur vi v ors was n ot deter mi ne d.  A sec o n d st u d y of t his 
same patie nt c o h ort w as c o n d ucte d t o assess t he e xte nt of L E ( pr o p orti o n of w hite matter 
i mpacte d) t hr o u g h tiss ue se g me nt ati o n a n d t he r elati ve i nte nsit y of L E t hr o u g h relati ve 
ele vati o ns i n T 1 a n d T 2 rela x ati o n rates 8 4.   T he  pr o p orti o n of w hite matter affecte d i n 
b ot h treat me nt ris k gr o u ps i ncrease d si g nifica ntl y wit h a d diti o nal c o urses of I V- M T X, 
w hereas t he i nte nsit y of L E als o i ncrease d stea dil y; h o we v er, b ot h t he i nte nsit y a n d e xte nt 
of L E d ecli ne d si g nifica ntl y b y e n d of t hera p y. I n creases i n t he T 1 a n d T 2 rela xati o n rates 
a b o ve n or mal- a p peari n g w hite matter were si g nifi ca ntl y c orrelate d wit h eac h ot her a n d 
were d e pe n de nt o n t he pr o p orti o n of w hite matter affecte d. 
 
I n T O T X V, M RI of t h e brai n was pr os p ecti vel y st u die d i n all patie nts at wee k 6 of 
re missi o n i n d ucti o n, at first rei n d ucti o n, at wee k 4 8 a n d wee k 1 2 0 of c o nti n uati o n 
treat me nt. Preli mi nar y a n al ysis of t he first 2 2 9 patie nts t o c o m plete t hera p y s h o we d t hat 
w hite matter c ha n ges were f o u n d i n 2 9 % of b ot h l o w- a n d sta n dar d/ hi g h-ris k patie nts at 
first rei n d ucti o n. B y w ee k 1 2 0 of c o nti n uati o n, t he pre val e nce i n t he l o w-ris k patie nts ha d 
decrease d t o 2 4 % w hile 2 9 % of sta n dar d/ hi g h-ris k patie nts c o nti n ue d t o de m o nstrate w hite 
matter a b n or malit y. T he a vera ge pr o p orti o n of w hite matter affecte d b y t h ese 
a b n or malities was greater f or sta n dar d/ hi g h-ris k p atie nts ( 9. 2 %) t ha n f or l o w-ris k ( 6. 6 %) 
at first rei n d ucti o n b ut decreas e d b y m ore t ha n half b y wee k 1 2 0 of c o nti n u ati o n f or b ot h 
gr o u ps ( 4. 4 % sta n dar d/ hi g h a n d 2. 8 % l o w). 
 
Ne w ne ur oi ma gi n g te c h ni q ues a n d i ma ge pr ocessi n g met h o ds n o w e na ble researc hers t o 
i n vesti gate t he c o m ple x mat urati o n of t he h u ma n brai n8 5.  A l o n git u di nal i ma gi n g st u d y of 
4 5 c hil dre n bet wee n 5 a n d 1 1 years of a ge i ma ge d t wice, t w o years a part, was c o n d ucte d 
a n d pr ocess e d wit h t he Free S urfer s oft w are ( htt p://s urfer. n mr. m g h. har var d.e d u/ ) t o assess 
w h ole brai n c ortical t hic k ness 8 6.  T he brai n gre w at a rate of a p pr o xi matel y 0. 4 t o 1. 5 m m 
pe r year i n ma n y areas, pr o mi ne ntl y i n t he fr o nt al a n d occi pital re gi o ns.  C ortical t hi n ni n g 
wa s n ote d of a p pr o xi matel y 0. 1 5 t o 0. 3 m m per year i n ri g ht d orsal fr o ntal a n d bilateral 
pa rietal re gi o ns.  T hese n e w tec h n ol o gies e n a ble researc hers t o assess at y pi cal c ortical 
bra i n mat urati o n acr oss t he e ntire brai n t o i de ntif y s pecific ne ur oa nat o mical re gi o ns w hi c h 
ma y b e at i ncrease d ris k of i nj ur y a n d relat e t hese c ha n ges t o s pecific ne ur oc o g niti ve 
d o mai ns w hic h ma y b e n e gati vel y i m pacte d b y t h era p y. 
 
T he use of Diff usi o n Te ns or I m a gi n g ( D TI) i n as y m pt o matic patie nts d uri n g or after 
treat me nt f or A L L is a m ore rece nt de vel o p me nt.  K h o n g et al. pr os pecti vel y teste d t he 
ass ociati o n of w hite matt er fracti o nal a nis otr o p y ( F A) a n d i ntelli ge n ce q u otie nt (I Q) i n 1 8 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A L L s ur vi v ors a n d a ge- matc he d healt h y c o ntr ols 8 7.  A m o n g t he A L L s ur vi v ors, ni ne 
recei v e d H D M T X a n d ni ne u n der we nt cra nial irra diati o n wit h a tre n di n g differe nce 
bet we e n t he t w o gr o u ps. T he F A i n t he w hite matter of A L L s ur vi v ors was ofte n l o wer 
t ha n t hat i n t he a ge- mat c he d c o ntr ols, a n d t he differe ntial bet wee n t he F A i n patie nts 
relati ve t o t hat i n c o ntr ols was directl y pr o p orti o nal t o t he f ull-scale, perf or ma nce, a n d 
ver bal I Q s c ores of t he s ur vi v ors. T hese preli mi nar y fi n di n gs s u g geste d t h at w hite matter 
F A is a cli nicall y usef ul bi o mar ker f or t he assess me nt of treat me nt- relate d a berra nt brai n 
mat urati o n. 
 
As a n a ncillar y m eas ur e of m yeli n de gra d ati o n, q ua ntitati ve m ulti ple e x p o ne ntial T 2 
meas ure me nts ha v e t he a d va nta ges of pr o vi di n g b ot h m yeli n water fracti o n ( M W F) ma ps 
w hic h are n ot s e nsiti ve t o fi ber cr ossi n gs or de nsit y, a n d l o n g- T 2 water fracti o n ( L W F) 
ma ps w hic h are belie ve d t o s u g gest m ore s e vere d a ma ge. M W F ma ps ha v e bee n s h o w n t o 
c orrel ate str o n gl y wit h b ot h hist ol o gical stai ni n g f or m yeli n a n d wit h D TI meas ures of F A 
a n d ra dial diff usi vit y 8 8; 8 9.  Si g nals o n L W F ma ps s u g gest i nfla m mati o n, e xte nsi ve cell ular 
de str ucti o n wit h i ncreas e d e xtracell ular water, a n d se vere a x o nal da ma ge i n t he w hite 
matter 9 0. 
 
2. 4. 2  Ge netic p ol y m or p his ms 
 
Alt h o u g h se v eral c h e m ot hera pe utic a ge nts i n A L L t hera p y ma y c o ntri b ute t o ne ur ot o xicit y 
a n d ne gati ve n e ur oc o g niti ve o utc o mes, met h otre x ate has bee n t he pri mar y f oc us of ma n y 
st u dies9 1 -9 3.  T he d ose, c u m ulati ve e x p os ure, a n d i nf usi o n rate of met h otr e x ate ha ve b ee n 
ass ociate d wit h t he de gree of ne ur oc o g niti ve deficit 9 1; 9 4.  T hese sa me fact ors ha ve bee n 
ass ociate d wit h pre v ale n ce a n d i nte nsit y of w hite matter c ha n ges partic ularl y i n t he fr o nt al 
l o bes w hic h are ofte n ass ociate d wit h atte nti o n pr ocesses9 5; 9 6.  Met h otre x ate a n d its 
meta b olites i n hi bit f olate pat h wa y e nz y m es s uc h as 5, 1 0- met h yle netetra h y dr ore d uct ase 
( M TH F R) 9 7.  T he M T H F R e nz y m e has t w o p ol y m or p his ms, c haracterize d b y C 6 7 7 T a n d 
A 1 2 9 8 C, w hic h a lter t he f u ncti o n of t he e nz y m e, l ea di n g t o i ncrease d h o m oc ystei n e a n d 
re d uce d f olate. H o m o c ystei ne is c o n verte d t o met hi o ni ne b y met hi o ni ne s y nt hase ( M S), 
an d i n di vi d uals wit h M S deficie nc y h a ve ele vate d plas ma h o m oc yst ei ne le v els 9 8.  
A d diti o nal ke y e nz y mes t o c o nsi der i ncl u de t h y mi d ylate s y nt has e ( T S) a n d c ystat hi o ni ne 
beta s y nt h ase ( C B S). T S utilize circ ulati n g f olate t o c o n vert de o x y uri di ne m o n o p h os p hate 
t o de o x yt h y mi di ne m o n o p h os p hate, w hic h is esse ntial f or D N A s y nt hesis. C B S deficie nc y 
res ults i n classical h o m oc ystei n uria 9 9.  M S, T S, a n d C B S eac h h a ve p ol y m or p hic varia nts 
ca pa ble of i m pacti n g le v els of f olate a n d/ or h o m oc ystei n e. Alterati o ns i n t he f u ncti o n of 
f olate pat h wa y e nz y mes ma y i m pact c he m ot hera p y-relate d t o xic effects. 
 
O ne rece nt st u d y teste d t he h y p ot h esis t hat t hese p ol y m or p his ms ma y partiall y e x plai n t he 
i n di vi d ual variati o n i n c hil dre n de vel o pi n g atte nti o n deficits after treat me nt f or A L L1 0 0.  
F ort y-ei g ht s ur vi v ors of A L L were e val u ate d f or atte nti o n deficits a n d peri p heral bl o o d 
D N A was c ollecte d a n d ge n ot y p e d f or M T H F R p ol y m or p his ms.  Patie nts wit h t he C 6 7 7 T 
an d A 1 2 9 8 C ge n ot y pes were m or e li kel y t o ha ve atte nti o n deficits ( P = 0. 0 7). W hile t his 
st u d y di d pr o vi de str o n g preli mi nar y e vi de nce t hat M T H F R p ol y m or p his ms ma y pla y a n 
i nfl ue ntial r ole i n deter mi ni n g w hic h patie nts will de vel o p atte nti o n deficits after t hera p y 
f or A L L, t he s a m ple size was s mall a n d i nf or mati o n o n c u m ulati ve met h otre x ate e x p os ure 
a n d ster oi d d ose w as n ot a vaila ble.  T hes e res ults still nee d t o be re plicate d i n a lar ger 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c o h ort, w hic h w o ul d als o per mit t he i ncl usi o n of pr os pecti ve ne ur oi ma gi n g. 
 
2. 4. 3  Ima gi n g c ha n ges ass ociat e d wit h ne ur oc o g niti ve perf or ma n ce 
 
E val uati o n of ne ur o ps yc h ol o gical f u n cti o n of l o n g-ter m s ur vi v ors fr o m T O T XIII A 
s h o we d t hat 4 1 % ( 1 8/ 4 4) of t he patie nts treat e d wit h o ut cra nial irra di ati o n ha d F ull- Scale 
I Q sc ores at least 1 sta n d ar d de viati o n bel o w n or mal b ut o nl y 1 0 % ( 4/ 4 4) ha d s ufficie nt 
aca d e mic a n d atte nti o n d eficits t o q ualif y f or a n i nter ve nti o nal feasi bilit y st u d y 
( M E M FI X). Ni netee n of t he 4 4 patie nts ha d M RI e x a mi nati o ns s uita ble f or se g me nt ati o n 
a nal ysis a n d t hree of t hes e l o n g-t er m s ur vi v ors ( 1 6 %) ha d le u k oe nce p h al o p at h y o n t he 
e x a mi nati o ns. A direct relati o ns hi p bet wee n n or m al a p peari n g w hite matter v ol u me a n d 
ne ur oc o g niti ve perf or ma nce ( F ull- Scale I Q [r = 0. 3 3, p = 0. 1 6 5] a n d C P T Hits Reacti o n 
Ti me [r = 0. 4 4, p = 0. 0 5 9]) was als o de m o nstrate d i n t his pil ot st u d y. 
 
T o e x pa n d o n t hese fi n di n gs, w e rece ntl y e x a mi ne d 1 1 2 A L L s ur vi v ors treate d wit h eit her 
c he m ot hera p y al o ne ( n = 8 4) or i n c o m bi nati o n wit h irra diati o n ( n = 2 8) 1 0 1.  A gr o u p of 3 3 
he alt h y si bli n g c o ntr ols 6 t o 1 6 years ol d was als o recr uite d a n d i ma ge d. Perf or ma nce o n 
m ost  ne ur oc o g niti ve meas ures i n A L L s ur vi v ors d e m o nstrate d si g nifica nt d eficits fr o m 
n or mati ve test sc ores, b ut o nl y perf or ma nce o n t he atte nti o n meas ures e x cee de d o ne 
sta n dar d de viati o n fr o m t he n or mati ve mea n.  Perf or ma nce o n meas ures of aca d e mic 
ac hie ve m e nt differe d bet wee n t he t w o patie nt gr o u ps, a n d deficits e x cee di n g o ne st a n dar d 
de viati o n fr o m t he n or mati ve mea n were see n o nl y i n patie nts w h o recei ve d irra diati o n.  
Patie nts treate d wit h c he m ot hera p y al o ne ha d si g nifica ntl y s maller v ol u mes of w hite 
matter t ha n a ge- a n d se x- matc he d healt h y si bli n g c o ntr ols ( P = 0. 0 3), a n d p atie nts w h o 
recei v e d c he m ot hera p y a n d irra diati o n ha d e v e n s maller w hite matter v ol u mes t ha n t h ose 
treate d wit h c h e m ot hera p y al o n e ( P = 0. 0 2).  M ore o ver, s maller w hite matter v ol u mes 
corres p o n d e d t o lar ger deficits i n atte nti o n, i ntelli ge nce, a n d aca de mic ac hie ve me nt. 
 
In T O T X V, w e pr os pecti vel y teste d t h e ass ociati o n of w hite matter a b n or malit y wit h 
ne ur oc o g niti ve perf or ma nce.  We a nal yze d t he ass ociati o n bet wee n t he q ua ntitati ve 
mea s ures of n or mal a p peari n g w hite matter v ol u m e, T 1 a n d T 2 of w hite matter, o n wee k 
1 2 0 c o nti n uati o n treat me nt a n d t he ne ur oc o g niti ve perf or ma n ce of t he first 2 2 9 patie nts at 
t his sa me ti me p oi nt.  O nl y 1 4 0 s u bjects ha d n e ur oc o g niti ve testi n g a n d c orres p o n di n g 
ne ur oi ma gi n g p erf or me d. L o w er v ol u mes of n or mal a p peari n g w hite matter were 
si g nifica ntl y ass o ciate d wit h l o wer perf or ma nce i n mat h a n d s pelli n g i n l o w-ris k patie nts.  
A s u bsta ntial ass ociati o n als o e xiste d bet wee n n or mal a p peari n g w hite m atter v ol u me a n d 
rea di n g i n t hese sa m e patie nts.  Ele vate d T 1 rela xati o n rates i n t he sta n dar d/ hi g h ris k 
pa tie nts were ass ociate d wit h l o wer f ull-scal e, ver bal a n d perf or ma nce I Q as well as l o wer 
perf or ma n ce i n r ea di n g a n d s pelli n g.  Ele vat e d T 2 rela xati o n rates i n t he sta n dar d/ hi g h ris k 
patie nts were als o ass oci ate d wit h l o wer f ull-s cale, ver bal a n d perf or ma nce I Q as well as 
l o wer perf or ma n ce i n l o n g ter m me m or y. 
 
Differe nces i n n e ur oc o g niti ve perf or ma n ce bet w ee n ris k ar ms f or t hes e patie nts ca n best 
be a p preciate d b y e x a mi ni n g t he pr o p orti o n of s u bjects at least o ne sta n dar d de viati o n 
bel o w t he n or mati ve mea n o n eac h meas ure.  L o w-ris k s u bjects perf or me d relati vel y well 
o n i ntellect ual meas ures of f ull-scale, perf or ma nce, a n d ver bal I Q ( 1 7 %, 2 0 %, a n d 1 1 % 
m ore t ha n o ne sta n d ar d de viati o n bel o w t he n or mati ve mea n) w hile greater pr o p orti o ns of 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
sta n dar d/ hi g h-ris k s u bjects were m ore t h a n o ne sta n dar d de viati o n bel o w t h e n or mati ve 
mea n ( 3 2 %, 3 0 %, a n d 2 6 %). T his sa me patter n ca n be see n i n aca de mic p erf or ma nce 
mea s ures of m at h, rea di n g, a n d s p elli n g ( 5 %, 2 %, a n d 5 % f or l o w-ris k; a n d 2 6 %, 2 3 %, 
a n d 2 6 % f or sta n d ar d/ hi g h-ris k). 
 
B ase d o n t h ese ass o ciati o ns bet wee n w hite matter v ol u me a n d rela xati o n c h a n ges i n t hese 
patie nts a n d t he ass ociati o n of t hese c h a n ges wit h deficits i n ne ur oc o g niti ve perf or ma n ce, 
we pr o p ose t o c o nti n ue pr os pecti ve q ua ntitati ve i ma gi n g of t he d e vel o p me nt of patie nts 
treate d o n T O T X VI. T o refi ne o ur u n d ersta n di n g of t he i m pact of t hera p y o n t he 
de vel o pi n g brai n a n d t he mec ha nis ms t hat ma y be res p o nsi ble, we h a ve pr o p ose d t o 
i n vesti gate t he i nte grit y of t he w hite matter m yeli n usi n g D TI a n d de v el o p me ntal c ha n ges 
i n c ortical t hic k ness usi n g hi g h-res ol uti o n m ultis pectral i ma gi n g. T his will be t he first 
o p p ort u nit y t o directl y c o m pare ne ur oi ma gi n g of patie nts d uri n g tr eat me nt f or A L L wit h 
t h ose of healt h y c hil dre n matc he d o n selecte d c h aracteristics. T he n e ur o ps yc h ol o gic al 
batter y has als o be e n refi ne d t o be ma xi mall y s e nsiti ve t o t h ose brai n re gi o ns i de ntifie d as 
m ost  v ul nera ble i n rece nt ne ur oi ma gi n g st u dies. 
 
We ha ve rece ntl y i m ple me nte d a pr ot ot y pical N- bac k w or ki n g me m or y t as k f or f M RI, a n d 
ha ve pil ot st u dies wit h t he tas k u n der wa y i n 4 8 l o n g-ter m s ur vi v ors of A L L ( > 1 0 years 
p ost-t hera p y) a n d 2 5 a ge-si milar healt h y c o ntr ols.  Preli mi nar y ra n d o m effects gr o u p 
anal ysis h as de m o nstrate d acti vati o n i n t he t y pical net w or k of brai n re gi o ns t hat ha ve bee n 
re p orte d i n f M RI st u dies of t he N- Bac k tas k1 0 2 i ncl u di n g a nteri or ci n g ulate/ me dial fr o ntal, 
d ors olateral pr efr o nt al, ve ntr olateral prefr o ntal, fr o ntal p olar a n d parietal areas. A cti vati o n 
i n ri g ht d ors olateral prefr o ntal a n d ri g ht p arietal i n creas e d wit h i ncreasi n g w or ki n g 
me m or y l oa d, a n d bilateral acti vati o n i n ve ntr olateral prefr o ntal areas w as d etecte d o nl y i n 
t he 2- bac k c o n diti o n. I n t he A L L s ur vi v or gr o u p, we ha ve als o ac q uir e d resti n g state 
f M RI d ata wit h ac q uisiti o n para meters as re p orte d b y S or g et al1 0 3.  I n de p e n de nt 
co m p o ne nt a nal ysis (I C A) of t he resti n g state d ata re veal e d ne ural net w or ks wit h 
te m p orall y c orrelate d resti n g B O L D si g nal fl uct uati o ns, i ncl u di n g t he fr o nt al- pariet al a n d 
ve ntral fr o ntal n et w or ks i de ntifie d wit h t he ge neral li near m o del a nal ysis of data fr o m t he 
N- bac k tas k. I C A a nal ysis of t he resti n g state a n d N- bac k d ata als o r e veal e d ot her 
ne t w or ks t hat ma y be i nf or mati ve a b o ut t he ne ural c orrelat es of c o g niti ve deficits i n A L L 
s ur vi v ors, i ncl u di n g t he pri mar y se ns or y c ortices a n d t he defa ult m o de net w or k 1 0 3.  T he 
f M RI p ara di g m bas e d o n t he N- bac k t est of w or ki n g me m or y was desi g ne d a n d t he 
pr oce d ures were o pti mize d s pecificall y t o a d dress k n o w n ne ur oc o g niti ve deficits i n t he 
hi g hl y v ul nera bl e y o u n g p o p ulati o n of c hil d h o o d ca ncer s ur vi v ors.  F u ncti o nal M RI is a n 
i m p orta nt c o m ple me nt t o t he str uct ural i ma gi n g meas ures we pr o p os e t hat will hel p t o 
c haracteriz e t he f u n cti o nal c o nse q ue n ces of t hera p y-i n d uce d c h a n ges i n t h e gra y matter 
a n d w hite matter t hat c o nstit ute t he ne ural net w or ks i n t he brai n. 
 
2. 5  
P hila del p hia C hr o m os o me ( P h)- P ositi ve A L L 
 
P atie nts wit h P h + A L L, a gr o u p w hic h c o nstit utes less t ha n 5 % of c hil d h o o d A L L, h a ve a 
dis mal pr o g n osis w he n tr eate d wit h c h e m ot hera p y al o ne 2 4.  T he t( 9; 2 2) tra nsl ocati o n 
j u xta p oses t he brea k p oi nt cl uster re gi o n ( B C R) ge ne wit h t he A bels o n le u k e mia vir us 
pr ot o- o nc o ge n e ( A B L).  T he res ulta nt f usi o n pr ot ei n is a c o nstit uti vel y acti ve t yr osi n e 
ki nase t hat acti vates m ol ec ular casca des le a di n g t o cell pr oliferati o n, e n ha nce d cell 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
s ur vival, a n d alterati o ns i n cell a d hesi o n. T he t yr osi ne ki nase acti vit y of B C R- A B L is 
req uire d f or tra nsf or mati o n i n vitr o a n d i n m uri ne m o dels. I mati ni b was t he first t yr osi ne 
ki nase i n hi bit or de vel o pe d f or treat me nt of P h + le u ke mia 1 0 4- 1 0 8.   
 
B et wee n J u ne 2 0 0 0 a n d J u ne 2 0 0 4, fi ve patie nts wit h P h + A L L were e nr oll e d o n T O T X V.  
O ne patie nt was refract or y t o treat me nt a n d 2 s ustai ne d a he m at ol o gic rela pse. W he n 
i mati ni b beca me c o m merciall y a vaila ble, T O T X V was c o nse q u e ntl y a me n de d t o 
i nc or p orate i mati ni b i n t he treat me nt r e gi me n of P h + A L L patie nts.  All 4 P h + A L L 
pa tie nts e nr olle d aft er t he a me n d me nt re mai n i n c o nti n u o us c o m plete re missi o n. I mati ni b 
was well t olerat e d w he n i nc or p orat e d i nt o T O T X V bac k b o ne, wit h n o si g nifica nt a d de d 
t o xicit y, ma ki n g t he ris k- be nefit of i nc or p orati n g a t yr osi n e ki nase i n hi bit or i nt o t he 
t hera p y of t his hi g h ris k gr o u p w ort h w hile. 
 
T he rece ntl y a p pr o ve d dasati ni b is a p ote nt, br oa d s pectr u m A T P-c o m petiti ve i n hi bit or of 
se veral t yr osi ne ki n ases i ncl u di n g B C R- A B L a n d S R C. Dasati ni b is ~ 5 0 0-f ol d m ore 
p ote nt t ha n i mati ni b i n i n hi biti n g B C R- A B L a n d bi n ds t o b ot h acti ve a n d i nacti ve 
c o nf or mati o ns of c- A B L, w hereas i mati ni b o nl y bi n ds t o t he i nacti ve state. Dasati ni b 
de m o nstrate d si g nifica nt acti vit y a gai nst se veral a d va nce d h u ma n c hr o nic m yel oi d 
le u ke mia ( C M L) xe n o grafts, i ncl u di n g a n i mati ni b ac q uire d-resista nce m o d el c o m pletel y 
i nse nsiti ve t o i mati ni b1 0 9; 1 1 0.  F urt her m ore, earl y cli nical st u dies of dasati ni b ha ve 
de m o nstrate d its hi g h acti vit y a n d li mite d t o xicit y i n treati n g p atie nts wit h P h + le u ke mias, 
i ncl u di n g patie nts wit h refract or y P h + A L L2 5 -2 7.  He mat ol o gi c t o xicities a n d ple ural 
eff usi o ns are t he m ost c o m m o n a d verse e v e nts ass ociate d wit h dasati ni b. A d verse e v e nts 
are ma n a gea bl e wit h s u p p orti ve care a n d d ose re d ucti o n. A d ult patie nts wit h P h + le u ke mia 
treate d wit h das ati ni b at 1 0 0 m g o nce dail y ha d l o wer i nci de nce of a d verse e ve nts 
c o m pare d t o t h ose tr eate d wit h 5 0 m g t wice d ail y, 1 4 0 m g o nce dail y, or 7 0 m g t wice 
dail y.  M ost i m p orta ntl y, effic ac y was si milar wit h all d ose sc he d ules 1 1 1.  M. D. A n ders o n 
Ca ncer Ce nter i n vesti gat ors ha ve i nc or p orate d d asati ni b i nt o fr o ntli ne P h + A L L re gi me ns, 
a n d t he C O G is i nc or p orati n g it i nt o t heir fr o ntli ne P h + A L L pr ot oc ol. T h e c urre nt 
sta n dar d a d ult d ose is 7 0 m g gi ve n t wice dail y2 5.  I n t he o n g oi n g C O G P has e I trial, a 
starti n g d ose of 5 0 m g/ m2 t wice dail y was well t olerate d i n c hil dre n wit h s oli d t u m ors. 
 
In T O T X VI, we will b uil d o n t he e x perie nce of T O T X V w hic h safel y i nc or p orate d 
i mati ni b i nt o a n i nte nsi ve c he m ot hera p y b ac k b o n e f or patie nts wit h P h+ A L L. Dasati ni b 
wi ll be s u bstit ute d f or i mati ni b i n t he c he m ot hera p y bac k b o ne, starti n g at da y 2 2 of 
i n d ucti o n u ntil t he e n d of t hera p y. We will use t he e q ui vale nt of t he sta n d ar d a d ult d osa ge 
of 7 0 m g b.i. d., w hic h is 4 0 m g/ m 2 b.i. d. (see secti o n 8. 3 f or d ose m o dificati o n). F or 
pa tie nts w h o u n der g o he mat o p oietic ste m cell tra ns pla ntati o n, dasati ni b will be hel d 
d uri n g t he tra ns pla nt peri o d, a n d t he n res u me d aft er rec o ver y of marr o w f u ncti o n u ntil 1 
year p ost tra ns pla nt d ate or c o m pleti o n of 6 m o nt hs dasati ni b t hera p y p ost-tra ns pla nt, 
w hic he ver pr o vi des l o n ger e x p os ure t o dasati ni b p ost-tra ns pla nt. T he reas o n f or starti n g 
dasati ni b o n da y 2 2 of i n d ucti o n is t hat dasati ni b is b ot h a n i n hi bit or a n d s u bstrate f or 
c yt o c hr o me P 4 5 0 3 A 4. T heref ore, it is best t o a v oi d t he use of t his a ge nt d uri n g pr ol o n ge d 
treat me nt wit h pre d nis o n e a n d vi ncristi ne i n t he first t hree wee ks of i n d ucti o n. Als o, t his 
will still all o w us t o assess earl y res p o ns e t o c he m ot hera p y, w hic h is a n i m p orta nt fact or i n 
deter mi ni n g w h et her tr a ns pla nt is i n dicate d or n ot f or certai n P h + A L L. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 6   
I nfa nt A L L 
 
I nfa nt A L L c o nstit utes a b o ut 4 % of c hil d h o o d A L L, a n d is ass ociate d wit h a hi g h W B C at 
prese ntati o n, a hi g h fre q u e nc y of a n i m mat ure prec urs or B-li nea ge c haracterize d b y t he 
lac k of C D 1 0 e x pressi o n a n d t he pres e nce of M L L ge n e ( 1 1 q 2 3) rearra n ge m e nts. W hereas 
t he o utc o me of i nfa nts wit h a M L L ger mli ne A L L (i ncl u de 1 5- 2 0 % of i nfa nt A L L) is 
c o m para ble t o t hat of ol der c hil dre n wit h A L L, i nf a nts wit h M L L rearra n ge d A L L h a ve a 
dis mal pr o g n osis, es peciall y t h ose wit h a ge < 6 m o nt hs or W B C > 3 0 0 at dia g n osis 1 6; 1 7. 
 
I nfa nts wit h A L L w ere i n cl u de d i n T O T XII a n d T O T XIII. I n 1 9 9 9, a lar ge i nter nati o nal 
c olla b orati ve st u d y gr o u p de vel o pe d a c o m m o n treat me nt pr ot oc ol (I nterfa nt- 9 9) f or i nfa nt 
A L L t o tr y t o i m pr o ve t h e o utc o me f or t h ese ver y y o u n g c hil dre n.  St J u de j oi ne d t hat 
g r o u p, a n d i nfa nts w ere e nr olle d o n I nterfa nt- 9 9 w hile T O T X V e x cl u de d c hil dre n y o u n ger 
t ha n 1 year of a ge. 
 
Beca use t he res ults of I nt erfa nt- 9 9 pr ot oc ol were n ot s u peri or t o t hat of T O T XIII B, i nfa nts 
will  be e nr olle d i n T O T X VI. T h ose wit h o ut ger mli ne M L L ( 1 5 t o 2 0 % of i nfa nt A L L) will 
recei v e t he sa me ris k- dir ecte d treat me nt pla n as ol der c hil dre n.  T h e re mai ni n g 8 0 t o 8 5 % 
of i nf a nts wit h M L L rearra n ge me nt nee d i n n o vati ve t hera p y t o i m pr o ve t h eir dis mal 
o utc o me.  All i nfa nts wit h rearra n ge d M L L will be treate d o n t he sta n d ar d-/ hi g h-ris k ar m 
of T O T X VI. Cl of ara bi n e is a rece ntl y a p pr o ve d n o vel n ucle osi de a n al o g w hic h has s h o w n 
si gnifica nt acti vit y i n c hil dre n wit h A L L w h ose disease was refract or y t o sta n dar d 
a ge nts 1 7; 1 1 2; 1 1 3.  W he n gi ve n i n c o m bi nati o n wit h c ycl o p h os p ha mi de a n d et o p osi de, 
cl ofara bi ne i n d uce d re missi o ns i n o ver 2/ 3 of rela pse d a n d refract or y c hil dre n wit h 
A L L 1 1 4.  T his c o m bi nati o n will t heref ore b e gi ve n t o i nfa nts wit h M L L rearra n ge me nt o n 
da y 2 2 of re missi o n i n d ucti o n (re placi n g t h e c ycl o p h os p ha mi de, c yt ara bi ne, t hi o g ua ni ne). 
It will als o be a d mi nistere d i n c o m bi nati o n wit h de x a met has o ne a n d P E G- as para gi n ase o n 
wee ks 7 t o 9 of c o nti n uati o n re placi n g rei n d ucti o n I. 
 
2. 7  
Bac k gr o u n d a n d R ati o nale f or I ntesti nal Micr o bi o me O bjecti ves 
 
In crease d s usc e pti bilit y t o a n u m ber of pat h o ge ns i n c hil dre n wit h A L L ca n res ult i n 
si g nifica nt m or bi dit y a n d treat me nt dela ys, t h us c o m pr o misi n g o utc o me 1 1 5; 1 1 6.  Ac ute 
g astr o e nteritis is o ne of t he m ost c o m m o n diseases affec ts, partic ularl y i n c hil dre n.  Si nce 
t he N or wal k vir us was i de ntifie d as a ca use ti n g c hil dre n w orl d wi de.  Vir uses are 
rec o g niz e d as a m aj or ca use of t he gastr o e nteritis, t he n u m ber of viral a ge nts ass ociate d 
wit h diarr heal disease i n h u ma ns has pr o gressi vel y i ncreas e d.  U ntil t he rel ease of a 
vacci ne, r ota vir us was t h e m ost c o m m o n ca use of se vere di arr h ea i n c hil dre n u n der 5 years 
of a ge.  H u ma n astr o vir uses, calici vir uses a n d e nt eric a d e n o vir us are als o i m p orta nt 
eti ol o gic a ge nts of ac ute gastr o e nteritis. Ot her vir uses s uc h as t or o vir uses, c or o na vir uses, 
pic o bir na vir uses, Aic hi vir us a n d h u ma n b oca vir us are als o i ncreasi n gl y bei n g i de ntifie d 
as ca usati ve a ge nts of diarr hea.  Little is k n o w n a b o ut t he pre vale nce of e nt eric vir uses i n 
i mm u n oc o m pr o mise d c hil dre n.  Se veral st u dies fr o m t he 1 9 8 0’s ha ve s h o w n t hat c hil dre n 
wit h HI V or T- cell defici e ncies ca n de vel o p c hr o nic i nfecti o ns wit h se veral e nteric vir uses 
leadi n g t o p ersiste nt diarr hea, w hic h ca n ca use c o nsi dera ble pr o ble ms of m a na ge me nt.  B y 
e val uati n g t he p o p ulati o n d y na mics of t hese e nteric vir uses pri or t o a n d after 
che m ot hera p y, w e  will o btai n a greater u n dersta n di n g of  t he pre vale nce of t hese vir uses i n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t his patie nt p o p ulati o n wit h t he e ve nt ual g oal of i m pr o ve d dia g n ostics a n d pre dicti o ns of 
cli nical c o m plicati o ns. 
 
W e will st u d y t he i m pa ct of A L L t hera p y o n t he i ntesti nal micr o bi o me, a n d t he 
relati o ns hi p bet wee n t h e i ntesti nal micr o bi o me a n d t he i ncreas e d s usce pti bilit y of c hil dre n 
wit h A L L t o i nfecti o ns, i ncl u di n g gaster oe nteritis. T he i ntesti nal micr o bi o me c o nsists of 
all t he i ntesti nal micr o- or ga nis ms a n d t heir ass ociate d ge netic ele m e nts. Se veral li nes of 
e vi de nce s u g gest t hat t he i nteracti o ns bet wee n t he h ost's e nteric micr o bi ota a n d t h e i n nate 
i m m u ne s yste m are i m p orta nt i n m o d ulati n g t he i ntesti nal res p o nse t o ca n cer t hera p y1 1 7.  
Alterati o ns i n t he h ost micr o bi ota ca n tra nslate i nt o alterati o ns i n t he s usce pti bilit y of t he 
h os t t o i nfecti o n1 1 8.  Cl ostri di u m difficile is a co m m o n ca use of a nti bi otic-ass ociate d 
diarr hea i n t his patie nt p o p ulati o n.  As pert ur bati o ns of t he n or mal g ut micr ofl ora are 
t h o u ght t o pre dis p ose patie nts t o i nfecti o ns ca use d b y C. difficile , t hese i n vesti gati o ns will 
als o a d dress w h at alterati o ns i n t he micr ofl ora c orrelate wit h t he pre d o mi na nce of C. 
difficile i n t he gastr oi ntesti nal tract.  T he g ut micr o bi ota pla ys a cr ucial r ole i n t he 
de vel o p me nt of a n effecti ve i m m u ne res p o nse. 
 
Alter ati o ns i n t he g ut micr o bi ota ca n ha v e pr of o u n d c o nse q ue nces n ot o nl y f or i ntesti nal 
diseases b ut als o f or m o u nti n g a n effecti ve i m m u ne res p o nse a gai nst i n va di n g pat h o ge ns 
at vari o us sites i n t he h u ma n b o d y 1 1 9.  Rece nt st u dies ha ve s h o w n t hat cert ai n bacteri al 
s pecies i n t he g ut ca n b e utilize d t o esti mate t he ris k of a nti bi otic-ass ociate d diarr hea wit h 
a n err or rat e of 2 %, e m p hasizi n g t he rele va nt a p plicati o n of t hese data f or i m pr o ve d 
pre dicti o n of cli nical o ut c o mes 1 2 0.  I n s u m mar y, e xisti n g literat ure s u g gests t hat t he h u ma n 
mi cr o bi o me pla ys a vari et y of i m p orta nt r oles i n i m m u n ol o g y a n d i nfecti o us diseases. 
Alterati o ns i n t he h ost micr o bi ota ca n h a ve pr of o u n d effects o n t he t y p e a n d ma g nit u de of 
t he i m m u ne res p o nse a gai nst i n va di n g pat h o ge ns a n d t h us o n t he i nfecti o us c o m plicati o ns. 
W e w o ul d li ke t o i n vesti gat e t he effect of t he c h e m ot hera pe utic re gi me ns f or pe diatric 
A L L o n t h e g ut micr o bi o me, a n d w het her alterati o ns of t heir micr o bi o me ha ve s u bse q ue nt 
effects o n i nfecti o n-relat e d cli nical o utc o mes. 
 
2. 8  
I n cl usi o n of W o me n a n d Mi n orities 
 
Ac c or di n g t o i nstit uti o n al a n d NI H p olic y, t he st u d y will accessi o n res earc h partici pa nts 
re gar dl ess of ge n d er a n d et h nic bac k gr o u n d.  I nstit uti o nal e x perie nce c o nfir ms br oa d 
re pres e ntati o n i n t his re gar d. 
 
3. 0  
E LI GI BI LI T Y C RI T E RI A A N D S T U D Y E N R O L L M E N T  
 
3. 1  
I n cl usi o n Criteria 
 
3. 1 . 1 Di a g n osis of prec urs or B-cell or prec urs or T-cell A L L 
b y  i m m u n o p he n ot y pi n g. 
 
3. 1. 2  A ge < 1 8  years (i ncl usi ve). 
 
3. 1. 3  Li mite d pri or t hera p y, i ncl u di n g s yste mic gl uc oc ortic oi ds f or o ne wee k 
or  less, o ne d ose of vi ncristi ne, e mer ge nc y ra diati o n t hera p y t o t he 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
me diasti n u m a n d o ne d ose of i ntrat hecal c he m ot hera p y. Ot her 
circ u msta nces m ust be cleare d b y  PI  or c o- PI. 
 
3. 1. 5 
Writte n, i nf or me d c o nse nt a n d asse nt f oll o wi n g I nstit uti o nal 
R e vie w B oar d, N CI, F D A, a n d O H R P G ui deli nes. 
 
3. 2  
E x cl usi o n Criteria 
 
3. 2. 1  P artici pa nts wit h pri or t hera p y, ot her t ha n t hera p y s pecifie d i n 3. 1. 3. 
 
3. 2. 2  P artici pa nts w h o are pre g na nt or lactati n g. 
 
3. 2. 3  In a bilit y or u n willi n g ness of researc h partici pa nt or le gal 
g uar dia n/re prese ntati ve t o gi ve writte n i nf or me d c o nse nt. 
 
3. 3  
Researc h Partici pa nt Recr uit me nt a n d Scree ni n g  
 
R esearc h partici pa nts will be recr uite d b y  st u d y i n vesti gat ors t hr o u g h re g ular 
cli nical practice. 
 
3. 4  
E nr oll me nt O n  St u d y 
 
A me m ber of t he st u d y tea m will c o nfir m p ote ntial partici pa nt eli gi bilit y as 
de fi ne d i n Secti o n 3. 1 - 3. 2, c o m plete a n d si g n t he ‘ Partici pa nt Eli gi bilit y 
C hec klist’.  T he c o m plete d c hec klist will be fa xe d t o t he Ce ntral Pr ot oc ol a n d 
Da ta M o nit ori n g Office ( C P D M O) at 
; f oll o we d b y  a p h o ne call t o e xt. 
 t o e ns ure t hat t he fa x is recei ve d. Eli gi bilit y will be re vie we d, a n d e ntere d 
i nto t he Patie nt Pr ot oc ol Ma na ger ( P P M) s yste m. A researc h partici pa nt-s pecific 
co nse nt f or m a n d asse nt d oc u me nt, w here a p plica ble, will be ge nerate d. T he 
pr o t oc ol (if a p plica ble), a n d c o nse nt/asse nt d oc u me nt will be deli vere d t o t he 
area desi g nate d o n t he c hec klist. T he e ntire si g ne d i nf or me d c o nse nt/asse nt f or m 
m ust  be fa x e d t o t he C P D M O t o c o m plete t he e nr oll me nt pr ocess. 
 
T he  C P D M O is staffe d 7: 3 0 a m- 5: 0 0 p m C S T, M o n da y t hr o u g h Fri da y. A staff 
me m ber is o n call Sat ur da y, S u n da y, a n d h oli da ys fr om  8: 0 0 a. m. t o 5: 0 0 p. m. 
 
4. 0  
RI S K C L A S SI FI C A TI O N  
 
P atie nts are classifie d i nt o o ne of t hree cate g ories (l o w-, sta n dar d-, or hi g h-ris k) base d 
o n  t he prese nti n g a ge, le u k oc yte c o u nt, prese nce or a bse nce of C N S- 3 stat us or 
testic ular le u ke mia, i m m u n o p he n ot y pe, c yt o ge netics a n d m olec ular ge netics, D N A  
i n de x, a n d earl y res p o ns e t o t hera p y. He nce, defi niti ve ris k assi g n me nt (f or pr o visi o nal 
l o w-ris k or sta n dar d-ris k cases base d o n prese nti n g feat ures) will be ma de after 
co m pleti o n of re missi o n i n d ucti o n t hera p y.  T he criteria a n d t he esti mate d pr o p orti o n  of 
patie nts i n eac h cate g or y ( base d o n data fr o m T O T X V st u d y) are pr o vi d e d bel o w. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
4. 1  
Criteria f or L o w- Ris k A L L (a p pr o xi matel y 4 8 % of patie nts) 
 
 B -cell prec urs or A L L wit h D N A i n de x ≥1. 1 6, T E L- A M L 1 f usi o n, O R  a ge 1 t o 
9. 9 years a n d prese nti n g W B C < 5 0 x 1 0 9 / L. 
 M ust  n ot ha ve: 
o  C N S 3 stat us ( ≥ 5 W B C/ μ L of cere br os pi nal fl ui d wit h 
m or p h ol o g icall y i de ntifia ble blasts or cra nial ner ve pals y). 
o  O ve rt testic ular le u ke mia (e vi de nce d b y  ultras o n o gra m). 
o  A d ve rse ge netic feat ure s: t( 9; 2 2) or B C R- A B L f usi o n; t( 1; 1 9) wit h 
E 2 A- P B X 1 f usi o n; rearra n ge d M L L (as meas ure d b y  FI S H a n d/ or 
P C R) ; or h y p o di pl oi d y ( < 4 4 c hr o m os o mes). 
o  P o or earl y res p o ns e ( ≥1 % l y m p h o blasts o n da y 1 5  of re missi o n i n d ucti o n, 
≥0. 0 1 % l y m p h o blasts b y  i m m u n ol o gic or m olec ular met h o ds o n 
re missi o n date). 
 
4. 2  
Criteria f or Sta n dar d- Ris k A L L (a p pr o xi matel y 4 4 % of patie nts) 
 
 
All cases of T-cell A L L a n d t h ose of B-cell prec urs or A L L t hat d o n ot 
meet t he criteria f or l o w-ris k or hi g h-ris k A L L. 
 
4. 3   
Criteria f or Hi g h- Ris k A L L (a p pr o xi matel y 8 % of patie nts) 
 
 t( 9; 2 2) or B C R- A B L f usi o n. 
 Infa nts wit h t( 4; 1 1) or M L L f usi o n. 
 I n d ucti o n fail ure or > 1 % le u ke mic l y m p h o blasts i n t he b o ne marr o w 
o n  re missi o n date. 
 > 0. 1 % le u ke mic l y m p h o blasts i n t he b o ne marr o w i n wee k 7 of 
c o nti n uati o n treat me nt (i.e. bef ore rei n d ucti o n  I, ~ 1 4 wee ks p ost re missi o n 
i n d ucti o n). 
 Re -e mer ge nce of le u ke mic l y m p h o blasts b y  M R D (at a n y le vel) i n 
patie nts pre vi o usl y M R D ne gati ve. 
 P ersiste ntl y detecta ble M R D at l o wer le vels 
 Ea rl y T-cell prec urs or ( E T P) A L L, defi ne d  b y  l o w e x pressi o n of T-cell 
mar kers t o get her wit h a berra nt e x pressi o n of m yel oi d mar kers (as descri be d 
i n secti o n 2. 1. 1).  T he f oll o wi n g feat ures c haracterize E T P T- A L L: 
 
1)  L e vels of C D 5 e x pressi o n at least 1 0 f ol d l o wer t ha n t hat of n or mal 
pe ri p heral bl o o d T-l y m p h oc ytes. I n t he st u d y t h at i de ntifie d t his s u bset of 
T - A L L, we f o u n d t hat C D 5 e x pressi o n was 1 0  - > 2 0 0-f ol d l o wer t ha n t hat 
of  n or mal l y m p h oc ytes a n d me dia n perce nt le u ke mic cells e x pressi n g 
C D 5 i n t he 1 7 at y pical cases was 4 5 %, i n c o ntrast t o > 9 8 % f or t he 1 2 2 
of  t he t y pical gr o u p. 
2)  A bse nce ( < 1 0 %) of C D 1a a n d C D 8 e x pressi o n. 
3)  E x pressi o n of c yt o plas mic C D 3 t o get her wit h t he e x pressi o n of 1 or 
m ore  mar kers ass ociate d wit h m yel oi d le u ke mia s uc h as H L A- Dr, 
C D 3 4, C D 1 3, C D 3 3 or C D 1 1 b, w hile m yel o per o xi dase is < 3 % b y  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c yt o c he mistr y a n d/ or fl o w c yt o metr y. 
 
5. 0  
T R E A T M E N T P L A N  
 
Tr eat me nt will c o nsist of t hree mai n p hases: Re missi o n I n d ucti o n, C o ns oli dati o n, 
an d C o nti n uati o n. 
 
5. 1   
I ntrat hecal C he m ot hera p y 
 
As a tra u matic l u m bar p u nct ure at dia g n osis ma y res ult i n a p o orer o utc o me a n d 
t he nee d f or e xtra i ntrat hecal t hera p y s u bse q ue ntl y, all dia g n ostic l u m bar 
p u nc t ures will be perf or me d b y e x perie nce d pers o n nel, prefera bl y u n der ge neral 
anest hesia or dee p se dati o n. Tri ple i ntrat hecal c he m ot hera p y ( M H A) will be  
ad mi nistere d i m me diatel y after cere br os pi nal fl ui d is c ollecte d f or dia g n osis, a n d 
t he d osa ge is a ge- de p e n d e nt as f oll o wi n g: 
 
A ge  ( m o nt hs) Met h otre x ate  ( m g) H y dr oc ortis o ne ( m g) C ytara bi ne( m g)  V ol u me ( ml) 
< 1 2  
6  
1 2  
1 8  
6  
1 2 -2 3  
8  
1 6  
2 4  
8  
2 4 -3 5  
1 0  
2 0  
3 0  
1 0  
≥3 6  
1 2  
2 4  
3 6  
1 2  
 
Fre q u e nc y a n d  t otal n u m ber of tri ple i ntrat hecal treat me nts f or Re missi o n 
In d ucti o n is base d o n t he patie nt's ris k of C N S rela pse, as f oll o ws: 
 All patie nts wil l recei ve tri ple i ntrat hecal treat me nt o n da ys 1  a n d 1 5. 
 Patie nts wit h a n y of t he f oll o wi n g feat ures will recei ve a d diti o nal tri ple 
i ntrat hecal treat me nt o n da ys 8 a n d 2 2: 
- 
P hila del p hia c hr o m os o me 
- 
M L L rearra n ge me nt 
- 
H y p o di pl oi d y ( < 4 4) 
- 
W B C > 1 0 0  x 1 0 9/ L at prese ntati o n 
 P atie nts wit h a n y of t he f oll o wi n g feat ures will recei ve a d diti o nal tri ple 
i ntrat hecal treat me nt o n da ys 4, 8, 1 1, a n d 2 2: 
- 
T -cell A L L  
- 
t ( 1; 1 9)/E 2 A- P B X 1  
- 
C N S- 3 stat us (i.e., ≥5 W B C/ µ L of C S F wit h blasts or cra nial 
ne r ve pals y) 
- 
C N S- 2 stat us ( < 5 W B C/ µ L of C S F wit h blasts) 
- 
Tra u matic L P  ( > 1 0 R B C/ µ L of C S F wit h blasts) 
Le uc o v ori n resc ue ( 5 m g/ m2/ d ose, ma x 5 m g) P O will be gi ve n at 2 4 a n d 3 0 h o urs 
after eac h tri ple i ntrat hecal treat me nt d uri n g i n d ucti o n. F oll o w plas ma 
met h otre x ate le vels (starti n g 2 4 h o urs after i ntrat hecal t hera p y a n d u ntil le vel 
be c o mes u n detecta ble) i n patie nts wit h re nal d ysf u ncti o n or e xtra fl ui d i n t hir d 
s pace, a n d resc ue wit h le uc o v ori n acc or di n g t o P har m. D rec o m me n dati o n. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 2   
Re missi o n I n d ucti o n C he m ot hera p y ( 6 t o 7 wee ks) 
 
In d u cti o n treat me nt will be gi n wit h pre d nis o ne, vi ncristi ne, da u n or u bici n, P E G- 
as para gi n ase a n d tri ple i ntrat hecal treat me nt, f oll o we d b y c ycl o p h os p h a mi de pl us c yt ara bi n e 
pl us t hi o g ua ni ne .  De x a met has o ne will be s u bstit ute d f or pre d nis o n e i n patie nts wit h E T P 
i m m u n o p he n ot y pe.  Merca pt o p uri ne will be s u bstit ute d f or t hi o g ua ni n e i n T P M T 
H E T/ deficie nt patie nts.  Da u n or u bici n ma y be d el a ye d i n patie nts wit h fe brile ne utr o pe nia, 
e vi de nce of m uc ositis or i ncreas e d h y per bilir u bi ne mia (i.e., t otal bilir u bi n ≥2. 0 m g/ dl a n d 
direct bilir u bi n > 1. 4 m g/ dl).  Patie nts wit h m uc ositis s h o ul d be e val uate d f or her pes si m ple x 
i nfecti o n a n d treate d wit h ac ycl o vir or fa mcicl o vir if w or k- u p is p ositi ve. 
 
5. 2. 1 
Dr u g d osa ges (s ee secti o n 5. 2. 1. 1 f or d osi n g of i nfa nts a n d Secti o ns 
7. 0 a n d 8. 0 f or d ose m o dificati o n) 
Partici pa nts  
A ge nts  
D osa ges a n d r o utes  
# D ose  Sc he d ules  
All p artici p a nts  
 
Pre d nis o ne § or  
Pre d nis ol o ne §  
 
De x a met has o ne ( f or  
E T P i m m u n o p he n ot y p e 
o nl y)   
4 0 m g/ m 2/ da y P O ( di vi d e d t.i. d.) 
 
 
1 0 m g/ m 2/ da y P O di vi de d t.i. d.) 
4 m g/ m 2/ da y P O ( di vi de d t.i. d) 
2 m g/ m 2/ da y P O( di vi de d t.i. d) 
8 4  
 
 
6 3  
 
9  
 
1 2  
Da ys 1 –  2 8  
 
 
Da ys 1 -2 1  
 
Da ys 2 2 -2 4  
 
Da ys 2 5 -2 8  
 
Vi ncristi ne  
1. 5 m g/ m 2  I V ( ma x 2 m g) 
4  
Da ys 1, 8, 1 5, 2 2  
 
Da u n or u bici n *  
2 5 m g/ m 2   I V 
2  
Da ys 1 a n d 8  
 
P E G -as para gi nase  
3, 0 0 0 u nits/ m 2 I V 
1  
Da y 3  
D a y 1 5 M R D >  1 %  
 
P E G -as para gi nase  
3, 0 0 0 u nits/ m 2 I V 
1  
Da y 1 5  
D a y 1 5 M R D < 5 % (e xcl u di n g M L L + i nf a nts)  
 
C ycl o p h os p ha mi de †  
1 0 0 0 m g/ m 2 I V  
1  
Da y 2 2  
 
C yt ara bi ne  
7 5 m g/ m 2/ d ose I V  
8  
Da ys 2 3 -2 6, 3 0 -3 3  
 
T hi o g ua ni ne  
Merca pt o p uri n e ( T P M T 
H E T/ deficie nt patie nts o nl y)  
6 0 m g/ m 2/ d ose  P O 
1 4  
Da ys 2 2 -3 5  
 
Dasati ni b ( ‡) (P h + 
p artici p a nts o nly ) 
4 0 m g/ m 2 b.i. d  
Dail y  
Starti n g Da y 2 2 of 
i n d ucti o n t o 
c o nti n ue u ntil e n d of 
treat me nt 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
D a y 1 5 M R D >  5 % (e xcl u di n g M L L + i nf a nts)  
 
C ycl o p h os p ha mi de †  
3 0 0 m g/ m 2 I V  
4  
q 1 2 hrs , Da ys 2 2 -2 3  
C yt ara bi ne  
7 5 m g/ m 2/ d ose I V  
8  
Da ys 2 3 -2 6, 3 0 -3 3  
T hi o g ua ni ne  
Merca pt o p uri n e ( T P M T 
H E T/ deficie nt patie nts 
o nl y)  
6 0 m g/ m 2/ d ose  P O 
1 4  
Da ys 2 2 -3 5  
Dasati ni b ‡ (P h + 
p artici p a nts o nly ) 
4 0 m g/ m 2 b.i. d  
Dail y  
Starti n g Da y 2 2  of 
i n d ucti o n a n d 
c o nti n ue u ntil e n d of 
treat me nt 
Partici pa nts  
A ge nts  
D osa ges a n d r o utes  
# D ose  Sc he d ules  
I nf a nts wit h M L L +  
 
Cl ofara bi ne  
4 0 m g/ m 2/ d ose I V 
5  
Da ys 2 2 -2 6  
Et o p osi de  
1 0 0 m g/ m 2/ d ose I V 
5  
Da ys 2 2 -2 6  
C ycl o p h os p ha mi de  
3 0 0 m g/ m 2/ d ose I V 
5  
Da ys  2 2 -2 6  
* First d ose of  d a u n or u bici n m ay be  del aye d u ntil d ay  2 i n p atie nts wit h or  at  hi g h risk of  t u m or lysis sy n dr o me. 
Sec o n d d ose of  d a u n or u bici n c o ul d be  del aye d u p  t o o ne week if cli nic ally i n dic ate d. 
Sec o n d d ose of  P E G - as p ar a gi n ase t o be  give n as  s oo n  as  M R D > = 1 % is c o nfir me d a n d  n o  l ater t h a n d ay 2 1.  
†See 5. 2. 3. 2 f or t he nee d of  b o ne m arr o w ex a m a n d  t he criteri a of  st arti n g cycl o p h os p h a mi de pl us 
t hi o g u a ni ne o n  d ay  2 2.  § Or al pre d nis o ne c a n be  s u bstit ute d wit h met hyl pre d nis ol o ne at  2 0  m g/ m2/ d ay 
I V (t.i. d.) f or p atie nts w h o c a n n ot t oler ate t he or al me dic ati o n. 
D ay 2 2  vi ncristi ne will be  o mitte d f or i nf a nts wit h M L L +  
( ‡)St art d as ati ni b o n  d ay  2 2  f or P h + c ases. See Secti o n 7. 1 2. 
 
5. 2. 1. 1 D ose a dj ust me nt f or i nf a nts  
 
Wit h t he e x ce pti o n of vi ncristi ne, all d osa ges gi ve n t o i nfa nts ( < 1 year) will be base d o n 
b o d y s urface area. F or i nfa nts < 1 m o nt h of a ge, or f or i nfa nts < 3 m o nt hs of a ge b or n 
si g nifica ntl y pre mat urel y, a 5 0 % re d u cti o n i n d osa ges of da u n o m yci n, as p ara gi n ase, 
et o p osi de, met h otre x ate, t hi o p uri nes, c ycl o p h os p ha mi de, cl ofara bi ne, a n d c yt ara bi ne 
s h o ul d be ma de.  T he vi n cristi ne d osa ge f or patie nts < 1 2 m o nt hs of a ge or < 1 0 k g wei g ht 
is 0. 0 5 m g/ k g/ d ose. 
 
5. 2. 2  R e missi o n i n d ucti o n d ose m o dificati o ns 
 
See Secti o n 7. 0 f or treat me nt m o dificati o ns f or vi n cristi ne, da u n or u bici n, a n d P E G-
as para gi n ase a n d s ecti o n 7. 1 0 f or s u bstit uti o n of merca pt o p uri ne a n d m o difi cati o n of 
t hi o p uri ne d osi n g base d o n T P M T stat us.  F oll o wi n g Da y 2 2 treat me nt, c yt ara bi ne a n d 
t hi o g ua ni ne ma y b e hel d if patie nt de vel o ps fe brile ne utr o pe nia or gra d e 3 or 4 m uc ositis.  
If C-reacti ve pr ot ei n is n or mal, fe ver s u bsi des, c ult ures are n ot si g nifica nt a n d m uc ositis 
res ol ves, c ytara bi ne a n d t hi o g ua ni ne m a y be res u me d.  D oses ma y be c o m pletel y o mitte d 
if t he patie nt is be y o n d d a y 3 0 of re missi o n i n d ucti o n (i.e., half or m or e d oses of 
t hi o g ua ni ne ( or merca pt u p uri ne) a n d c yt ara bi n e ha ve bee n gi ve n), all o wi n g earl y b o ne 
marr o w rec o ver y a n d earl y i nitiati o n of c o ns oli dati o n t hera p y. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 2 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 2. 3  B o ne marr o w e val uati o ns 
 
Da y 1 5:  A b o ne marr o w as pirate will be d o ne o n da y 1 5 of re missi o n i n d ucti o n t o assess 
a nti-le u ke mic res p o ns e. T he prese n ce of > 1 % of le u ke mic blasts i n t he b o ne marr o w b y 
m or p h ol o gic e x a m or b y M R D st u d y is a n i n dicati o n f or a n a d diti o nal d ose of P E G-
as para gi n ase t o be a d mi nistere d bet wee n da ys 1 5 a n d 2 1 (f or m o dificati o ns d ue t o P E G-
as para gi n ase aller gic reacti o ns, see Secti o n 7. 9). 
 
Da y 2 2:  B o n e marr o w as pirate o n da y 2 2 will be perf or me d i n p atie nts w h o ha d recei ve d 
a n e xtra d ose of P E G- as para gi nas e d ue t o t he pres e nce of 1 % or m ore le u ke mic blasts i n 
t he b o ne marr o w o n da y 1 5.  Patie nts wit h resi d ual le u ke mia i de ntifie d o n da y 2 2 recei ve 
c ycl o p h os p ha mi de, t hi o g ua ni ne, a n d c yt ara bi ne as sc he d ule d if t heir cli nical c o n diti o n 
per mits, re gar dl ess of t heir A N C.  F or ot her patie nts, t he treat me nt ma y be dela ye d f or 3 t o 
7 da ys t o all o w s o me de gree of he mat o p oietic rec o ver y if A P C ( A N C + m o n oc yt e) 
< 3 0 0/ m m 3. 
 
E n d of i n d ucti o n- M R D res p o nse:  A b o ne marr o w as pirate will be perf or m e d o n da y 3 8-
4 2 of re missi o n i n d ucti o n, de pe n di n g o n w he n A N C has rec o v ere d t o > 3 0 0/ m m 3, W B C t o 
> 1, 0 0 0/ m m 3, a n d platelet c o u nt t o > 5 0 x 1 09/ L.  If t he date falls o n a wee k-e n d or h oli da y, 
t he pr oce d ure ma y b e perf or me d o n cl osest w or ki n g da y. M R D le v el will be deter mi ne d i n 
t his b o ne marr o w sa m ple. P o or res p o nse will be defi ne d as M R D le v el > 0. 0 1 % ( o ne or 
m ore l y m p h o blasts a m o n g 1 0 4 b o ne marr o w m o n o n uclear cells) b y eit her i m m u n ol o gic or 
m olec ular assa y. If t he res ult of M R D is p ositi ve, pr o visi o nal l o w-ris k cases will t he n be 
re-cl assifie d as sta n dar d-ris k ( M R D > 0. 0 1 % b ut less t ha n 1 %) or hi g h-ris k ( M R D > 1 %), 
a n d will recei v e s u bse q u e nt 3 d oses of H D M T X at a hi g her d osa ge (i.e., 5 g m/ m 2).  ( T hese 
patie nts w o ul d ha ve recei ve d t he first H D M T X of c o ns oli dati o n t hera p y at 2. 5 g m/ m 2.) 
 
5. 3  
C o ns oli dati o n Treat me nt ( 8 wee ks) 
 
5. 3 . 1 Dr u g d osa ges 
 
A ge nt  
D osa ge a n d  R o ute  
# D oses  Sc he d ule  
Hi g h  D ose  
Met h otre x ate  
( H D M T X) 
2. 5 g m/ m 2 (l o w ris k), or  
tar gete d 6 5 μ M (st d/ hi g h-ris k) 
4  
da ys  1, 1 5, 2 9  a n d 4 3  
Merca pt o p uri ne  
5 0 m g/ m 2/ da y 
5 6  
Da ys  1 t o 5 6  
 
W he n A N C > 3 0 0/ m m
3, > W B C 1, 0 0 0/ m m3, an d platelet c o u nt > 5 0 x 1 0 9/ L, c o ns oli dati o n 
treat me nt will be starte d, c o nsisti n g of hi g h d ose met h otre x ate (e ver y ot h er wee k f or 4 
d oses), dail y merca pt o p uri ne a n d I T c he m ot hera p y o n t he s a me dates of hi g h d ose 
met h otre x ate (see secti o n 5. 3. 4). 
 
See secti o n 5. 3. 5 (I nteri m C o nti n uati o n Treat me nt) a n d secti o n 7. 0 f or d ose a dj ust me nts. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 3. 2  Me rca pt o p uri n e a d mi nistrati o n 
 
Merca pt o p uri n e s h o ul d be gi v e n dail y at a c o nsiste nt ti me t hat ma xi mizes a d here n ce wit h 
t he prescri b e d treat me nt.  If a d ose is i na d v erte ntl y misse d, t he n it s h o ul d be gi ve n as s o o n 
as t he o missi o n is n ote d, as l o n g as it is at least 6 h o urs pri or t o t he ne xt sc he d ule d d ose.  
I n p atie nts f or w h o m hi g h d ose met h otre x ate treat me nt is dela ye d, merca pt o p uri ne ma y be 
c o nti n ue d u ntil 1 4 da ys after t he last c o urse of hi g h d ose met h otre x ate.  Merca pt o p uri ne 
ma y b e hel d i n t he pres e nce of A N C < 3 0 0/ m m 3, W B C < 1, 0 0 0/ m m3, platelet c o u nt 
< 5 0, 0 0 0/ m m 3 or gra d e 3 or 4 m uc ositis.  D osa ge of merca pt o p uri ne i n s u bse q ue nt c o urs es 
ma y b e re d u ce d t o 2 5 m g/ m 2/ da y i n patie nts w h o h a ve pr ol o n ge d n e utr o pe ni a after hi g h 
d ose met h otre x ate a n d m erca pt o p uri ne treat me nt.  See secti o n 7. 1 0 f or m o dificati o ns of 
merca pt o p uri n e base d o n T P M T stat us. 
 
5. 3. 3  Hi g h- d os e met h otre x ate ( H D M T X) a d mi nistrati o n 
 
T he d osa ge of hi g h d os e met h otre x ate de pe n ds o n t he ris k classificati o n of i n di vi d ual 
patie nts. Patie nts wit h sta n dar d- or hi g h-ris k A L L will recei ve 5 g m/ m 2, ( or a d ose 
targete d t o ac hie ve a stea d y-stat e plas ma c o n ce ntr ati o n of 6 5 M) a n d t h ose wit h l o w-ris k 
A L L 2. 5 g m/ m 2, ( or, w he n re q ueste d, a d ose tar get e d t o ac hie ve a stea d y-state 
c o nce ntr ati o n of 3 3 M) a d mi nistere d o ver 2 4 hr i ntra ve n o usl y. T he s u bse q ue nt d ose of 
hi g h d ose met h otr e x ate, merca pt o p uri n e a n d i ntrat hecal treat me nt will be dela ye d if A N C 
< 3 0 0/ m m 3, W B C < 1 0 0 0/ m m3, platelet c o u nt < 5 0 x 1 09/ L, S G P T > 5 0 0 U/ L, t otal bilir u bi n 
> 2 m g/ dl a n d dir ect bilir u bi n > 1. 4 m g/ dl, or m uc ositis is prese nt. S o di u m bicar b o nate m a y 
be gi v e n orall y at 1 g m/ m 2 e ver y 6 h o urs or i ntra ve n o usl y wit h pr e- h y drati o n fl ui d starti n g 
t he da y bef ore hi g h d ose met h otre x ate.  F or patie nts wit h D o w n s y n dr o me, hi g h d ose 
met h otre x ate a d mi nistrati o n will be m o difie d ( See Secti o n 7. 1. 1).  Ba se d o n pri or 
e x perie nce i n T O T X V, we a ntici pate t hat 2. 5 g/ m 2 s h o ul d ac hie ve t he tar get c o nce ntr ati o n 
of 3 3 M + 2 0 % i n 7 0 % of t he L R c o urses (see Secti o n 2. 1. 3 f or details a n d rati o nale).  
Cleara nce is esti mate d fr o m t he plas ma c o nce ntrati o ns u p t hr o u g h 4 8 h o urs fr o m 
met h otre x ate i nf usi o n, usi n g n o nli near c ur ve fitti n g a n d a Ba yesia n esti mati o n strate g y as 
i m ple me nte d i n A D A P T. 1 0 % of t he t otal d ose is a d mi nistere d as a l oa di n g d ose o ver 1 
h o ur a n d t he re mai n der o ver 2 3 h o urs. 
 
D osa ge i n di vi d ualiz ati o n ma y b e cli nicall y i n dicat e d i n select L R patie nts. I n t hese cas es, 
t he precise m et h o d f or tar geti n g will be d o c u me nt e d i n t he researc h d ata base f or eac h d ose 
of hi g h d ose m et h otre x ate gi v e n, al o n g wit h t he reas o n(s) t he d ose was tar gete d. 
 
Base d o n pri or e x perie nce i n T O T X V, we a ntici pate t hat 5 g/ m 2 s h o ul d ac hie ve t he 
tar gete d c o n ce ntr ati o n of 6 5 M + 2 0 % i n o nl y 6 2 % of t he c o urses (see Secti o n 2. 1. 3 f or 
details a n d rati o nale).  Cleara n ce is esti mate d fr o m t he plas ma c o nce ntrati o ns u p t hr o u g h 
4 8 h o urs fr o m met h otre x ate i nf usi o n usi n g n o nli n ear c ur ves fitti n g a n d a Ba yesia n 
esti mati o n strate g y b ase d o n pre dicti ve c h aracteristics (s uc h as ser u m creati ni ne a n d 
S G P T) as i m ple me nte d i n A D A P T. Te n perce nt of t he t otal d ose is a d mi nistere d as a 
l oa di n g d ose o v er 1 h o ur a n d t he re mai n d er o ver 2 3 h o urs. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 3. 3. 1  Pre - hy dr ati o n 
 
At least t w o h o urs bef ore hi g h d ose met h otr e x ate, pre h y drati o n I V fl ui d ( D 5 W + 4 0 m E q 
Na H C O 3/ L + 2 0 m E q K Cl/ L) will be a d mi nistere d at t he rate of 2 0 0 ml/ m2/ hr. At start of 
pre h y drati o n, o ne I V d os e of Na H C O 3 (u nless ot her wise cli nicall y i n dicat e d, 1 2 m E q/ m 2 
f or l o w-ris k patie nts a n d 2 5 m E q/ m2 f or sta n dar d-/ hi g h-ris k p atie nts) dil ute d i n 5 0 ml 
D 5 W will be gi ve n o ver 1 5 mi n utes.  Pre h y drati o n fl ui d ma y als o b e gi ve n o ver ni g ht at a 
rate of at least 1 0 0 ml/ m2/ hr. Hi g h d ose m et h otre x ate treat me nt will f oll o w, pr o vi de d t hat 
uri nar y p H is > 6. 5; e x ce pti o ns m ust be cleare d wit h t he p har mac o ki n etics ser vice a n d t he 
atte n di n g p h ysicia n. 
 
5. 3. 3. 2  Hi g h - d ose met h otrex ate i nf usi o n 
 
Met h otre x ate l oa di n g d os e will be gi v e n o ver 1 h o ur, f oll o we d i m me diatel y b y 
mai nte na nce i nf usi o n o v er 2 3 h o urs.  D uri n g t he met h otre x ate i nf usi o n, patie nts s h o ul d 
recei v e h y drati o n fl ui d wit h D 5 W + 4 0 m E q/ L Na H C O3 + 2 0 m E q K Cl/ L at 1 0 0- 1 5 0 
ml/ m 2/ hr. Uri ne p H will be m o nit ore d wit h eac h v oi d d uri n g i nf usi o n. A n I V b ol us of 1 2 
m E q/ m 2 Na H C O 3 will be gi ve n if uri ne p H is 6. 0; a n d 2 5 m E q/ m 2 will be gi ve n if uri ne 
p H is < 6. 0.  Acet az ola mi de 5 0 0 m g/ m 2 orall y e ver y 6 t o 8 h o urs ma y b e us e d if s yst e mic 
al kal osis li mits t he a d mi nistrati o n of bicar b o nat e f or uri n ar y al kali nizati o n.  Patie nts wit h 
e vi de nce of re n al d ysf u ncti o n or dela ye d cleara nce d uri n g t h e met h otre x ate i nf usi o n ma y 
recei v e less t ha n a 2 4 h o ur met h otre x ate i nf usi o n.  Bl o o d sa m ples f or met h otre x ate 
p ha r mac o ki netics will be dra w n acc or di n g t o Secti o n 1 0. 1. 
 
5. 3. 3. 3  L e uc ov ori n resc u e  
 
Le u c o v ori n, 1 5 m g/ m 2 (I V or P O) f or sta n d ar d-/ hi g h-ris k or 1 0 m g/ m2 ( P O or I V) f or l o w-
ris k cases, will be start e d at 4 2 h o urs after t he start of met h otre x ate a n d re p eate d e ver y 6 
h o urs f or a t otal of t hr ee d oses, as descri be d b y Reiter, et al 3 0.  T he d osa ge of le uc o v ori n 
will  be i ncreas e d i n patie nts wit h hi g h plas ma met h otre x ate c o nce ntr ati o ns ( > 1. 0 M at 4 2 
h o urs) a n d c o nti n ue d u ntil t he met h otre x ate c o nce ntrati o n is less t ha n 0. 1 0 M.  
A d diti o nal meas ures, s uc h as h y drati o n, he m o perf usi o n, or car b o x y p e pti dase will be 
c o nsi dere d i n patie nts wit h 4 2- h o ur met h otre x ate le vels > 1 0 M.  Patie nts wit h a hist or y of 
dela ye d Gra de 3 or 4 gastr oi ntesti nal t o xicit y wit h pri or met h otre x ate or a hist or y of 
t y p hlitis wit h a n y c h e m ot hera p y s h o ul d ha v e le uc o v ori n c o nti n ue f or 5, rat h er t ha n 3 
d oses; t h ose wit h earl y t o xicit y s h o ul d ha ve le uc o v ori n be gi n at 3 6 h o urs wit h s u bse q ue nt 
met h otre x ate; if t o xicit y rec urs, t he b aseli ne le uc o v ori n d osa ge s h o ul d als o be i ncrease d. 
 
5. 3. 4  IT c he m ot hera p y 
 
All patie nts will recei ve tri ple i ntrat hecal t hera p y e ver y ot her wee k f or f o ur d oses o n Da ys 
1, 1 5, 2 9, a n d 4 3 ( d osa ges are bas e d u p o n a ge, acc or di n g t o Secti o n 5. 1).  T he i ntrat hecal 
treat me nt s h o ul d be gi ve n o n t he sa me da y of t h e hi g h d ose met h otr e x ate a d mi nistrati o n.  
C o ns ult t he PI or P har ma c o ki netics if t he I T a n d hi g h d ose met h otr e x ate bec o me se parate d 
b y m ore t h a n 1 2 h o urs. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 3. 5  Interi m c o nti n uati o n treat me nt 
 
I nteri m c o nti n uati o n treat me nt will be gi ve n t o t he occasi o nal patie nts w h o, u p o n attai ni n g 
c o m plete re missi o n, are dee me d u na bl e t o t olerat e hi g h d os e met h otre x ate.  S pecific 
criteria t o use i nteri m c o nti n uati o n t hera p y i n cl u de disse mi nate d f u n gal i nfecti o n re q uiri n g 
s yste mic a ntif u n gal t hera p y, rece nt d e vel o p me nt of cere bral t hr o m b osis, or gra de 3 or 4 
re nal or h e patic d ysf u n cti o n. T here ma y b e ot her u nf oresee n reas o ns t hat w arra nt 
te m p orar y wit h h ol di n g of hi g h d ose m et h otre x ate. 
 
I nteri m treat me nt will c o nsist of oral merca pt o p uri ne 7 5 m g/ m2 per da y ( 5 0 m g/ m 2 per da y 
i n t h ose wit h A N C < 5 0 0) a n d i ntra ve n o us met h otre x ate 4 0 m g/ m2 per wee k; i ntrat hecal 
t hera p y ma y be gi v e n e v er y ot her wee k d uri n g t his peri o d of ti me a n d c o nti n ue d d uri n g 
t he s u bse q ue nt hi g h d os e met h otre x ate treat me nt f or a t otal of 4 d oses. Hi g h d ose 
met h otre x ate will be starte d w he n t he patie nt’s p h ysical c o n diti o n all o ws.  I n t he e ve nt t hat 
t he i nteri m t hera p y is l o n ger t ha n 4 wee ks, a n e xtra i ntrat hecal t hera p y ma y be gi v e n wit h 
t he last c o urse of hi g h d ose met h otre x ate. Patie nts wit h a defecti ve T P M T stat us ma y 
recei v e l o wer d os es of m erca pt o p uri ne. 
 
5. 4  
Rei nte nsificati o n Treat m e nt (f or Hi g h- Ris k A L L) 
 
Patie nts wit h hi g h-ris k le u ke mia ma y recei ve rei nte nsificati o n t hera p y a n d t he n will be 
offere d t he o pti o n of tra ns pla nt. T his treat me nt will atte m pt t o ma xi mize le u ke mic cell kill 
bef ore all o ge neic h e mat o p oietic ste m cell tra ns pla ntati o n ( H S C T).  F or pati e nts wit h 
P hila del p hia c hr o m os o me p ositi ve A L L, E T P T- A L L, a n d t h ose wit h i n d ucti o n fail ure or 
> 1 % le u ke mic l y m p h o bl asts ( deter mi ne d b y M R D st u d y) i n b o ne m arr o w at t he e n d of 
re missi o n i n d ucti o n, treat me nt will be gi ve n after c o ns oli dati o n t hera p y.  H o we ver, 
c o ns oli dati o n t hera p y ma y be s h orte ne d, d e pe n di n g o n patie nt’s res p o nse t o t hera p y a n d 
o n t he ti mi n g of tra ns pla ntati o n. F or patie nts wit h > 0. 1 % le u ke mic l y m p h o blasts 
( deter mi ne d b y M R D st u d y) i n b o n e marr o w i n wee k 7 of c o nti n uati o n tr eat me nt, t his 
treat me nt will be gi ve n after t he rei n d ucti o n I.  U p o n marr o w rec o ver y (i.e., A N C 
3 0 0/ m m 3, W B C 1 0 0 0/ m m 3 a n d platelet c o u nt 5 0 x 1 0 9/ L) after eac h c o urse of 
rei nte nsificati o n, b o ne m arr o w e x a mi nati o n wit h M R D st u d y will be re p eate d. 
 
T his treat me nt c o urse m a y be re peate d o nl y o nce if t he patie nt still has persiste ntl y 
p ositi ve M R D (i.e. > 0. 0 1 % blasts). All o ge neic he mat o p oietic ste m cell tra ns pla nt ati o n 
ma y pr ocee d aft er 1 c o urse of t he treat me nt if M R D bec o mes ne gati ve wit h t he first c o urse 
of treat me nt; ot her wis e, tra ns pla nt will be perf or m e d after t w o c o urses of treat me nt.  
Patie nts dee me d u ns uita ble f or t he tra ns pl a nt or w h o decli ne t he pr o ce d ur e or w h ose d o n or 
has yet t o b e i de ntifie d, will re mai n o n st u d y a n d recei v e s u bse q ue nt c he m ot hera p y as 
sc he d ule d.   
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he treat me nt sc h e me a n d d osa ge of c h e m ot hera p y are s u m marize d bel o w. 
 
A ge nt  
D osa ge a n d  r o ute 
# D oses  
Sc he d ule  
De x a met has o ne  
2 0 m g/ m 2/ da y P O or I V 
( di vi de d t.i. d) 
1 8  
Da ys  1 -6  
C ytara bi ne  
2 gra ms/ m 2, 3 -h o ur  I V 
i nf usi o n e ver y 1 2 h o urs  
4  
Da ys  1 -2  
Et o p osi de  
1 0 0 m g/ m 2, 1 -h o ur  I V 
i nf usi o n e ver y 1 2 h o urs  
5  
Da ys  3 -5  
I T M H A 
See Secti o n  5. 1 f or a ge- 
s pecific d ose  
1  
D a y  5  
P E G -as para gi nase 
3, 0 0 0 u nit s/ m2 I V 
1  
D a y  6  
 
Patie nts wit h s u b o pti mal res p o nse t o rei nte nsificati o n ma y recei ve o ne t o t w o c ycles 
of  cl ofara bi ne/c ycl o p h os p ha mi de/et o p osi de/ de x a met has o ne: 
 
A ge nt  
D osa ge a n d  r o ute 
# D oses  
Sc he d ule  
Cl ofara bi ne  
4 0 m g/ m 2/ da y, 2 -h o ur  I V 
i nf usi o n 
5  
Da ys  1 -5  
Et o p osi de  
1 0 0 m g/ m 2/ da y, 2 -h o ur  I V 
i nf usi o n 
5  
Da ys  1 -5  
C ycl o p h os p ha mi de  
3 0 0 m g/ m 2/ da y, 3 0 -6 0  
mi n ute  I V i nf usi o n 
5  
Da ys  1 -5  
De x a met has o ne  
8 m g/ m 2/ da y ( di vi de d t.i. d) 1 5  
Da ys  1 -5  
 
See Secti o n 5. 2. 1. 1 f or d osi n g f or i nfa nts. 
 
T his cl ofara bi ne/c ycl o p h os p ha mi de/et o p osi de/ de xa met has o ne c ycle ca n s u bstit ute 
f or t he sec o n d rei nte nsificati o n i n patie nts wit h hi g h ris k pr ocee di n g t o tra ns pla nt. 
P atie nts w h o are eli gi ble t o N K H E M c o ul d i nstea d be tra nsferre d t o tra ns pla nt t o 
recei ve N K H E M f oll o we d b y  all o ge neic H S C T.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5   
C o nti n uati o n Treat me nt ( 1 2 0 wee ks) 
 
P ost-re missi o n c o nti n uati o n treat me nt be gi ns after t he c o m pleti o n of 
co ns oli dati o n, pr o vi de d t hat t he A N C  3 0 0/ m m 3, W B C 1 0 0 0/ m m 3 a n d 
pla telet c o u nt 5 0 x 1 0 9/ L as well as n o e vi de nce of gra de 3 or 4 
m uc osit is. C o nti n uati o n treat me nt ( 1 2 0 wee ks) differs acc or di n g t o t he 
ris k classificati o n, as f oll o ws (a b bre viati o ns as defi ne d bel o w). 
 
Wee k  
Sta n dar d -/ Hi g h-Ris k  ( ‡) 
L o w -Ris k  
1  
D E X + D O X + V C R + M P  +  P E G -A S P  
M P +  D E X  +  V C R  
2  
M P  
M P +  M T X  
3  
¥ M P  +  P E G -A S P  
¥ M P +  M T X  
4  
D E X  +  D O X  +  V C R +  M P  
M P +  D E X  +  V C R  
5  
M P +  P E G -A S P  
M P +  M T X  
6  
M P  
M P +  M T X  
7  
* † Rei n d ucti o n I § 
* Rei n d ucti o n  I 
8  
Rei n d ucti o n  I 
Rei n d ucti o n  I 
9  
Rei n d ucti o n  I 
Rei n d ucti o n  I 
1 0  
M P  
M P +  M T X  
1 1  
D O X  +  V C R + M P  +  P E G -A S P  
M P +  M T X  
1 2  
* M P  
* M P +  M T X  
1 3  
M P +  P E G -A S P  
M P +  M T X  
1 4  
D E X  +  D O X  +  V C R + 6 M P  
M P +  D E X  +  V C R  
1 5  
M P +  P E G -A S P  
M P +  M T X  
1 6  
M P  
M P +  M T X  
1 7  
* † Rei n d ucti o n II  
* Rei n d ucti o n  II 
1 8  
Rei n d ucti o n  II 
Rei n d ucti o n  II 
1 9  
Rei n d ucti o n  II 
Rei n d ucti o n  II 
2 0  
N o c he m ot hera p y  
M P +  M T X  
¥Tri ple i ntr at hec al tre at me nt will be give n c ases wit h W B C 1 0 0 x 1 0 9/ L, T-cell A L L, t( 1; 1 9)/ E 2 A-
P B X, prese nce of P hil a del p hi a c hr o m os o me, M L L re arr a n ge me nt, hy p o di pl oi dy < 4 4, or C N S- 3 
st at us, wit h C N S- 2 or tr a u m atic l u m b ar p u nct ure wit h bl asts at di a g n osis.. 
*I T M H A ( met h otrex at e + h y dr oc ortis o ne + cyt ar a bi ne; see secti o n 5. 1 f or d os a ge) 
† M R D st u dy i n b o ne m arr o w f or p atie nts wit h p ositive M R D at e n d of re missi o n i n d ucti o n, a n d f or 
p atie nts wit h aty pic al T-li ne a ge A L L. F or ot her T-li ne a ge p atie nts peri p her al bl o o d c a n be use d 
i nste a d. 
§ P atie nts wit h M R D > 0. 1 % at week 7 receive rei nte nsific ati o n tre at me nt after Rei n d ucti o n I (see 
Secti o n 5. 4) 
See Secti o n 5. 5. 2 f or det ails o n Rei n d ucti o n tre at me nt. 
Dex a met h as o ne, vi ncristi ne a n d P E G- as p ar a gi n ase c a n be give n re g ar dless of bl o o d c o u nts, 
pr ovi de d t h at t he p atie nt is n ot sick.  Met h otrex ate, merc a pt o p uri ne a n d d ox or u bici n will be hel d if 
A N C < 3 0 0/ m m 3, W B C < 1 0 0 0/ m m3, or pl atelet c o u nt < 5 0 x 1 09/ L (see secti o n 8. 0 f or ot her d ose 
m o dific ati o ns). 
( ‡)C o nti n ue d as ati ni b i n P h +  c ases 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5. 1. 1  Dr u g d os a ges, sc he d ules a n d r o utes f or c o nti n u ati o n t her a py weeks 1 t o 6 
a n d 1 0 t o 1 6  
 
D E X ( de x a met has o ne) 
1 2 m g/ m 2 (st d/ hi g h ris k) or 8 m g/ m2 
(l o w ris k) P O  dail y ( di vi de d t.i. d.) f or 
5 da ys, Da ys 1- 5 
 
D O X ( d ox or u bici n) 
3 0 m g/ m 2 IV, Da y 1 
 
V C R ( vi ncristi n e) 
2 m g/ m 2  I V p us h ( ma x. 2 m g), Da y 1 
( 0. 0 5 m g/ k g f or patie nts < 1  year of a ge 
or  < 1 0 k g i n wei g ht) 
 
M P  ( merca pt o p uri ne) 
5 0 m g/ m 2 P O dail y at c o nsiste nt ti me * 
f or 7 da ys (st d/ hi g h ris k), Da ys 1- 7 
7 5 m g/ m 2 P O dail y at c o nsiste nt ti me * 
f or 7 da ys (l o w ris k), Da ys 1- 7 
 
P E G- A S P ( P E G-as para gi nase) 
2, 5 0 0 vs. 3, 5 0 0 u nits/ m 2 I V 
ran d o mizati o n, 
Da y 1 
 
M T X ( met h otre x ate) 
4 0 m g/ m 2  
I V Da y 1  
 
Se e Secti o n 5. 2. 1. 1 f or d osi n g f or i nf a nts . 
 
De x a met has o ne, vi ncristi ne, a n d as para gi nase will be gi ve n re gar dless of bl o o d 
c o u nts, pr o vi de d t hat t he patie nt is cli nicall y well.  D o x or u bici n, merca pt o p uri ne 
an d met h otre x ate will be hel d if W B C < 1 0 0 0/ m m 3 or  A N C < 3 0 0/ m m 3.  See 
S ecti o n 8. 0 f or f urt her details.  * Merca pt o p uri ne s h o ul d be gi ve n dail y at a 
co nsiste nt ti me t hat ma xi mizes a d here nce wit h t he prescri be d treat me nt.  If a d ose 
is i na d verte ntl y misse d, t he n it s h o ul d be gi ve n as s o o n as t he o missi o n is n ote d, as 
l o n g as it is at least 6 h o urs pri or t o t he ne xt sc he d ule d d ose. 
 
5. 5. 2  
R ei n d ucti o n treat me nt 
 
T his p hase of treat me nt will be starte d at wee ks 7 a n d 1 7 after b o ne marr o w 
e x a mi nati o n c o nfir ms c o m plete re missi o n.  D o x or u bici n a n d H D- c yt ara bi n e will 
be hel d if A N C < 3 0 0/ m m 3 or W B C < 1 0 0 0/ m m 3.  It is prefera ble t o start H D-
c yt ara bi ne w he n W B C > 1 8 0 0/ m m 3 a n d A N C > 3 0 0/ m m 3 
 
Rei n d ucti o n treat me nt will be gi ve n t wice: wee ks 7 t o 9 a n d wee ks 1 7 t o 1 9 f or all 
patie nts. 
 
I ntr at hecal treat me nt will be f oll o we d b y le uc o v ori n resc ue ( 5 m g/ m2/ d ose P O, 
ma x 5 m g) at 2 4 a n d 3 0 h o urs o nl y i n patie nts wit h pri or C N S t o xicities or i n 
patie nts wit h W B C < 1 5 0 0/ m m 3, or A N C < 5 0 0/ m m3 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5. 2. 1  R ei n d ucti o n I f or sta n dar d/ hi g h-ris k A L L e x cl u di n g M L L + i nfa nts ( ‡) 
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc he d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O ( di vi de d t.i. d.) 
4 5  
Da ys 1 -8, 1 5 -2 1  
Vi ncristi ne  
1. 5 m g/ m 2/ wee k I V 
0. 0 5 m g/ k g f or i nf a nts  < 1 yr  or 
< 1 0 k g ( ma x 2 m g)  
3  
Da ys 1, 8, 1 5  
D o x or u bici n  
3 0 m g/ m 2 I V 
2  
Da ys 1, 8  
P E G -as para gi nase  
2, 5 0 0 or 3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
Met h otre x ate + 
h y dr oc ortis o ne + 
Ara -C  
A ge -de p e n de nt, I T 
(secti o n 5. 1) 
1  
Da y 1  
 
5. 5. 2. 2  Rei n d ucti o n II f or sta n dar d/ hi g h-ris k A L L i n cl u di n g M L L + i nfa nts (‡)  
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc he d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O (t.i. d.) 
4 5  
Da ys 1 -8, 1 5 -2 1  
Vi ncristi ne  
1. 5 m g/ m 2/ wee k I V  
0. 0 5 m g/ k g f or i nf a nts < 1 yr or  
< 1 0 k g ( ma x 2 m g)  
3  
Da ys 1, 8, 1 5  
P E G -as para gi nase  
2, 5 0 0 or  3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
Met h otre x ate + 
h y dr oc ortis o ne +  
Ara -C  
A ge -de p e n de nt, I T  
1  
Da ys 1  
Hi g h -d os e 
c yt ara bi ne  
2 g m/ m 2 I V q 1 2 hr 
4  
Da ys 1 5, 1 6  
( ‡)P h + c ases c o nti n ue d as ati ni b  
 
5. 5. 2. 3  Rei n d ucti o n I f or l o w-ris k A L L 
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc h e d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O  
( di vi de d t.i. d.) 
4 5  
Da ys 1 -8, 1 5 -2 1  
Vi ncristi ne  
1. 5 m g/ m 2/ wee k I V  
0. 0 5 m g/ k g f or < 1 yr or  
< 1 0 k g ( ma x 2 m g)  
3  
Da ys 1, 8, 1 5  
P E G -as para gi nase  
2, 5 0 0 or 3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
D o x or u bici n  
3 0 m g/ m 2/ I V 
1  
Da y 1  
M et h otre x ate + 
h y dr oc ortis o ne + 
Ara -C  
A ge -de p e n de nt, I T  
1  
Da y 1  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5. 2. 4  R ei n d ucti o n II f or L o w Ris k A L L 
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc he d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O 
( di vi de d t.i. d.) 
4 5  
Da ys 1 -8, 1 5 -2 1  
Vi ncristi ne  
1. 5 m g/ m 2/ wee k I V 
0. 0 5 m g/ k g f or < 1 y r 
or < 1 0 k g ( ma x 2 m g)  
3  
Da ys 1, 8, 1 5  
P E G -as para gi nase  
2, 5 0 0 or 3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
Met h otre x ate + 
h y dr oc ortis o ne 
+ Ara -C  
A ge -de p e n de nt, I T  
1  
Da y 1  
 
5. 5. 2. 5 Rei n d ucti o n I f or M L L + i nfa nts 
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc he d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O ( di vi de d t.i. d.) 
4 5  
Da ys 1 -8 a n d   
1 5 -2 1  
Cl ofara bi ne  
4 0 m g/ m 2/ da y, 2-h o ur I V  
5  
Da ys 1 -5  
Et o p osi de  
1 0 0 m g/ m 2/ da y, 2-h o ur I V  
5  
Da ys 1 -5  
C ycl o p h os p ha mi de  
3 0 0 m g/ m 2/ da y, 1-h o ur I V  
5  
Da ys 1 -5  
P E G -as para gi nase  
2, 5 0 0 or 3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
Met h otre x ate + 
h y dr oc ortis o ne 
+ Ara -C  
A ge -de p e n de nt, I T  
1  
Da ys 1  
F or i nfa nts < 1 m o nt h of a ge, or f or i nfa nts < 3 m o nt hs of a ge b or n si g nifica ntl y 
pre mat urel y, a 5 0 % re d u cti o n i n d osa ges of as para gi n ase, et o p osi de, 
c ycl o p h os p ha mi de, d o x or u bici n, a n d cl of ara bi ne s h o ul d be ma de. 
 
5. 5. 3  Intr at hecal c he m ot hera p y 
 Tr i ple i ntrat hecal treat me nt will be gi ve n t o l o w-ris k cases wit h C N S- 1 
stat us ( n o i de ntifia ble blasts i n C S F) o n wee ks 7, 1 2, 1 7, 2 5, 3 3, 4 1, a n d 4 9. 
 Tr i ple i ntrat hecal treat me nt will be gi ve n t o l o w-ris k cases wit h C N S- 2, 
tra u matic C S F wit h blasts stat us, or W B C 1 0 0 x 1 0 9/ L at prese nt ati o n o n 
wee ks 3, 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5 a n d 4 9. 
 Tr i ple i ntrat hecal treat me nt will be gi ve n t o sta n dar d/ hi g h-ris k cases o n 
wee ks 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5 a n d 4 9. 
 Tr i ple i ntrat hecal treat me nt will be gi ve n t o ot her sta n dar d/ hi g h-ris k cases 
wit h W B C 1 0 0 x 1 0 9/ L at prese ntati o n, , T-cell A L L, t ( 1; 1 9)/ E 2 A- P B X 1, 
prese nce of P hila del p hia c hr o m os o me, M L L  rearra n ge me nt, h y p o di pl oi d y 
< 4 4, C N S- 2 or C N S- 3 stat us, or tra u matic l u m bar p u nct ure wit h blasts o n 
wee ks 3, 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5, 4 9, 5 7, 6 5, 7 3, 8 1, 8 9 a n d 9 7 .
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T O T X VI I ntrat he cal t hera p y 
 
I n d u cti o n 
C o ns oli dati o n  
C o nti n uati o n Wee k 1 -2 0  C o nti n uati o n Wee ks 2 1 -9 7  
All P hases  
Ris k -gr o u p  
C N S Stat us  
Da ys  
T otal  
Da ys  
T otal  
Wee ks  
T otal  
Wee ks  
T otal  
T ot al  
L o w -ris k, 
W B C < 1 0 0 x 
1 0 9/ L 
C N S 1  
1, 1 5  
2  
1, 1 5, 2 9, 
4 3  
4  
7, 1 2, 1 7  
3  
2 5, 3 3, 4 1, 4 9  
4  
1 3  
L o w -ris k, 
W B C > 1 0 0 x 
1 0 9/ L 
C N S 1  
1, 8, 1 5, 
2 2  
4  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9  
7  
1 9  
L o w -ris k 
C N S 2 or 
Tra u matic 
Blasts  
1, 4, 8, 
1 1, 1 5, 
2 2  
6  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9  
7  
2 1  
St d -/ hi g h-ris k 
W B C x > 1 0 0 x 
1 0 9/ L,  
h y p o di pl oi d y,  
P h +, or M L L +  
C N S 1  
1, 8, 1 5, 
2 2  
4  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3,  3 7, 4 1, 
4 5, 4 9, 5 7, 6 5, 7 3, 
8 1, 8 9, 9 7  
1 3  
2 5  
St d -/ hi g h-ris k, 
ot her  
C N S 1  
1, 1 5  
2  
1, 1 5, 2 9, 
4 3  
4  
7, 1 2, 1 7  
3  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9  
7  
1 6  
St d -/ hi g h-ris k  
C N S 2 or 
Tra u matic 
Blasts  
1, 4, 8, 
1 1, 1 5, 
2 2  
6  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1 , 
4 5, 4 9, 5 7, 6 5, 7 3, 
8 1, 8 9, 9 7  
1 3  
2 7  
T -cell 
t( 1; 1 9)/E 2 A -
P B X 1  
C N S 1, C N S 
2, or C N S 3  
1, 4, 8, 
1 1, 1 5, 
2 2  
6  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9, 5 7, 6 5, 7 3, 
8 1, 8 9, 9 7  
1 3  
2 7  
St d -/ hi g h-ris k  
C N S 3  
1, 4, 8, 
1 1, 1 5, 
2 2  
6  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9, 5 7, 6 5, 7 3, 
8 1, 8 9, 9 7  
1 3  
2 7  
 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 3 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T h us, t he t otal n u m bers of i ntrat hecal treat me nts f or vari o us s u b gr o u ps of p atie nts are 1 3 
(l o w-ris k cas es wit h W B C < 1 0 0 x 1 09/ L at pres e ntati o n a n d C N S 1 stat us), 1 9 (l o w-ris k 
cases wit h W B C > 1 0 0 x 1 0 9/ L at prese nt ati o n), 2 1 (l o w-ris k cas es wit h C N S 2 stat us or 
tra u matic C S F wit h blast stat us), 1 6 (st d-/ hi g h-ris k cases wit h C N S 1 stat us), 2 5 (st d-/ hi g h-
ris k cases wit h W B C > 1 0 0 x 1 0 9/ L at prese nt ati o n, prese nce of P hila del p hia c hr o m os o me, 
M L L rearra n ge me nt, or h y p o di pl oi d y < 4 4), 2 7 (st d-/ hi g h-ris k cases wit h T-cell 
p he n ot y p e, t( 1; 1 9)/ E 2 A- P B X 1, or C N S- 2 or C N S- 3 stat us, or tra u matic l u m bar p u nct ure 
wit h bl ast). T he n u m ber of i ntrat hecal treat me nts f or hi g h ris k patie nts will de pe n d o n 
w het her a n d w he n t he p atie nts will recei ve ste m cell tra ns pla ntati o n.  Le uc o v ori n will n ot 
be gi v e n after i ntrat he cal treat me nt d uri n g c o nti n u ati o n treat me nt u nless t he patie nt has a n 
a d verse reacti o n wit h pre vi o us i ntrat hecal or met h otre x ate treat me nt, e. g., s eiz ure or 
e nce p h al o pat h y, has r e nal d ysf u ncti o n res ulti n g i n hi g h plas ma met h otr e x ate 
c o nce ntr ati o n, or is D o w n s y n dr o me a n d has u n acce pta ble t o xicit y des pite d osa ge 
decreases.  Le uc o v ori n m a y b e gi ve n w h e n patie nt is ne utr o pe nic, at treati n g p h ysicia n’s 
discreti o n.  D o w n s y n dr o me patie nts will recei ve l e uc o v ori n wit h e ver y L PI T.  W hile 
i ntrat hecal treat me nts ma y be gi v e n at SJ C R H affiliate i nstit uti o ns, all patie nts m ust ha ve 
i ntrat hecal treat me nt gi ve n at St. J u de at least e ver y 1 6 wee ks, beca us e cl os e m o nit ori n g of 
cere br os pi nal fl ui d is a n esse ntial c o m p o ne nt of t hera p y. 
 
5. 5. 4  Tr eat me nt ( wee ks 2 1 t o 2 9) 
 
Wee k  
Sta n dar d/ Hi g h  Ris k  
L o w  Ris k  
2 1  
M P +  P E G - 
A S P + ‡ Dasati ni b  
M P +  M T X  
2 2  
M P  + ‡ Dasati ni b  
M P +  M T X  
2 3  
M P +  P E G -A S P + ‡ Dasati ni b  
M P +  M T X  
2 4  
C ycl o  +  Ara -C + ‡ Dasati ni b  
M P +  M T X  
2 5  
* D E X  +  V C R +  P E G - 
A S P + ‡ Dasati ni b  
* M P +  D E X  +  V C R  
2 6  
M P + ‡ Dasati ni b  
M P +  M T X  
2 7  
M P +  P E G -A S P + ‡ Dasati ni b  
M P +  M T X  
2 8  
C ycl o  +  Ara -C + ‡ Dasati ni b  
M P +  M T X  
2 9  
* D E X  +  V C R +  P E G - 
A S P + ‡ Dasati ni b  
( *) M P +  D E X  +  V C R  
*I T M H A ( m et h otrex a te + hy dr o c ortis o ne + cyt ar a bi ne; see secti o n 5. 1 f or 
d os a ge ) ( *)I T M H A f or l o w-risk c ases wit h W B C > 1 0 0 x 1 09/ L , C N S- 2 or 
tr a u m atic l u m b ar p u nct ure wit h bl ast.  
‡ O nly f or P h + p atie nts 
Merc a pt o p uri ne s h o ul d be give n d aily at a c o nsiste nt ti me t h at 
m axi mize s 
a d here nce wit h t he pres cri be d tre at me nt.  If a d os e is i n a dverte ntly misse d, t he n it 
s h o ul d be give n as s o o n as t he o missi o n is n ote d, as l o n g as it is at le ast 6 h o urs 
pri or t o t he next sc he d ule d d ose. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5. 5  Treat me nt ( wee ks 3 0 t o e n d of t hera p y) 
 
Wee k  
Sta n dar d/ Hi g h  Ris k  
L o w  Ris k  
3 0  
M P +  M T X + ‡ Dasati ni b  
M P +  M T X  
3 1  
M P +  M T X + ‡ Dasati ni b  
M P +  M T X  
3 2  
C ycl o  +  Ara -C + ‡ Dasati ni b  
M P +  M T X  
3 3  
* D E X  +  V C R + ‡ Dasati ni b  
* M P +  D E X  +  V C R  
3 4  
M P +  M T X + ‡ Dasati ni b  
M P +  M T X  
3 5  
M P +  M T X + ‡ Dasati ni b  
M P +  M T X  
3 6  
C ycl o  +  Ara -C + ‡ D asati ni b 
M P +  M T X  
3 7  
* D E X  +  V C R + ‡ Dasati ni b  
( *) M P +  D E X  +  V C R  
*I T M H A ( met h otrex ate + hy dr oc ortis o ne + cyt ar a bi ne; see secti o n 5. 1 f or 
d os a ge)  ( *)I T M H A f or l o w-risk c ases wit h W B C > 1 0 0 x 1 09/ L, C N S- 2 or  
tr a u m atic l u m b ar p u n ct ure wit h bl ast.  
‡O nly f or P h + p atie nts.  
Merc a pt o p uri ne s h o ul d b e give n d aily at a c o nsist e nt ti me t h at m axi mizes 
a d here nce wit h t he pres cri be d tre at me nt.  If a d ose is i n a dverte ntly misse d, t he n it 
s h o ul d be give n as s o o n as t he o missi o n is n ote d, as l o n g as it is at le ast 6 h o urs 
pri or t o t he next sc he d ule d d ose. 
 
5. 5. 5. 1  Dr u g d osa ges, sc h e d ules a n d r o utes f or c o nti n uati o n t hera p y fr o m wee k 2 1 t o 
e n d of t hera p y 
 
M P ( merca pt o p uri ne) 
7 5 m g/ m 2 P O dail y f or 7 da ys, Da ys 1- 7  
 
M T X ( met h otre x ate) 
4 0 m g/ m 2 I V or I M, Da y 1 
 
C ycl o ( C ycl o p h os p ha mi de)  
3 0 0 m g/ m 2 IV, Da y 1  
 
Ara- C ( C ytara bi ne) 
3 0 0 m g/ m 2 I V, Da y 1 
 
D E X ( de x a met has o ne) 
1 2 m g/ m 2 (st d/ hi g h ris k) or 8 m g/ m2 (l o w 
ris k) P O dail y ( di vi de d t.i. d.) f or 5 da ys, 
Da y 1- 5 bet w ee n wee k 2 1 a n d wee k 6 8 
 
6 m g/ m 2 P O  dail y ( di vi de d t.i. d.) x 5 da ys, 
Da y 1- 5 bet w ee n wee k 6 9 a n d wee k 1 0 1 f or 
all ris k gr o u ps 
 
V C R ( vi ncristi ne) 
2 m g/ m 2 I V p us h ( m a x 2 m g), Da y 1 
( 0. 0 5 m g/ k g f or patie nts < 1 yr or < 1 0 k g) 
 
P E G- A S P 
2, 5 0 0 vs. 3, 5 0 0 u nits/ m 2 IV ra n d o mizati o n 
( u ntil wee k 3 0) 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
De x a met has o ne, vi ncristi ne, a n d as para gi nas e will be gi v e n re gar dless of bl o o d c o u nts, 
pr o vi de d t hat t he patie nt is cli nicall y well. C ycl o p h os p ha mi de, c yt ara bi ne, merca pt o p uri n e 
a n d met h otre x ate will be hel d if W B C < 1 0 0 0/ m m 3, platelet c o u nt t o < 5 0 x 1 09/ L, or A N C 
< 3 0 0/ m m 3 (see Secti o n 8. 0 f or f urt her details).  M erca pt o p uri ne s h o ul d be gi ve n dail y at a 
co nsiste nt ti me t hat ma xi mizes a d here nce wit h t he prescri be d treat me nt.  If a d ose is 
i na d verte ntl y misse d, t he n it s h o ul d be gi ve n as s o o n as t he o missi o n is n ote d, as l o n g as it 
is at least 6 h o urs pri or t o t he ne xt sc he d ule d d ose. 
 
 
Merca pt o p uri n e a n d met h otre x ate will be re d uce d f or if W B C a n d A N C d o n ot i ncrease b y 
at least 2 f ol ds a wee k after t he start dat e of de x a m et has o ne p ulse.  E x ce pti o ns ca n be 
ma de  i n patie nts wit h W B C a n d A N C t hat d oes n ot d o u ble, b ut is o ver 3 0 0 0 a n d 1 2 0 0, 
res pecti vel y, wit h n o hist or y of pri or c h e m ot hera p y i nterr u pti o n or m yel os u p pressi o n (see 
Secti o n 8. 0 f or f urt her details). 
 
D oses of c ycl o p h os p h a mi de a n d c ytara bi ne ma y n ee d t o be re d uce d if patie nt misses 2 5 % 
of c he m ot hera p y a n d if t he l o w c o u nts dee m t o be relate d t o t his c o m bi nati o n. 
 
T he sa me treat me nt ( wee ks 3 0- 3 7) will be re p eate d f or a t otal of 5 ti mes, u ntil wee k 6 9 
(see Secti o n 5. 5. 3 f or i ntrat hecal t hera p y).  After wee k 6 9, all patie nts will recei v e dail y 
merca pt o p uri n e a n d w ee kl y met h otre x ate i nterr u pte d wit h p ulses of de x a met has o ne, 
vi ncr isti ne, a n d merca pt o p uri ne e ver y 4 wee ks. 
 
T he d ose of de x a met h as o ne will be decre ase d t o 6 m g/ m 2 bet wee n wee k 6 9 a n d wee k 
1 0 1, after w hic h o nl y merc a pt o p uri ne a n d met h otre x ate will be gi ve n. Intr at hecal 
treat me nt will be gi ve n e ver y 8 wee ks o nl y t o p atie nts at ris k of C N S rela pse after wee k 4 9 
a n d will be disc o nti n ue d after wee k 9 7. C o nti n uati o n t hera p y will be disc o nti n ue d after 
1 2 0 wee ks. 
 
5. 6  
He mat o p oietic Ste m Cell Tra ns pla ntati o n 
 
P atie nts w h o meet t he criteria of hi g h-ris k A L L are ca n di dates f or all o ge neic 
he mat o p oietic ste m cell tra ns pla ntati o n.  H o we ver, if t he o pti o n is decli ne d b y  t he 
patie nts or g uar dia ns, or t he pr oce d ure is dee me d u ns uita ble b y  t h e atte n di n g p h ysicia n 
an d t he pri nci pal i n vesti gat or, t he patie nt will re mai n o n st u d y a n d c o nti n ue t o recei ve 
che m ot hera p y. 
 
6. 0 
D R U G  I N F O R M A TI O N 
 
See A p pe n di x II f or i nf or mati o n o n t he i n di vi d ual dr u gs t o be use d i n t his pr ot oc ol. 
 
6. 1  
Dr u g S h orta ges a n d U n a vaila bilit y 
 
I n t he case of dr u g s h orta ges a n d u na vaila bilit y of a n y a ge nt use d i n t his pr ot oc ol, 
treati n g i n vesti gat ors are ur ge d t o c o ns ult wit h t he PI  or  c o -PI  a n d use t heir best cli nical 
j u d gme nt i n o pti mizi n g t hera pe utic i nte nt a n d e ns uri n g patie nt safet y i n ma na gi n g t he 
pr ot oc ol-s pecifie d t hera p y. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Alt h o u g h  t hese decisi o ns ma y c o nstit ute “ Pr ot oc ol Vi olati o ns,” t he y are u na v oi da ble 
an d ma de i n c o nsi derati o n of t he best i nterest of a n i n di vi d ual patie nt.  T hese will N O T  
be  c o nsi dere d m o nit ori n g/a u dit fi n di n gs if a p pr o priatel y d oc u me nte d.  M ost 
i mp orta ntl y, all pr ot oc ol de viati o ns m ust be n ote d i n t he researc h data base a n d t he 
alterati o ns i n t hera p y d ue t o t he a ge nt s h orta ge will be ca pt ure d.  T his s h o ul d be 
acc o m plis he d b y  e nteri n g “ d ose m o difie d” a n d details n ote d i n t he c o m me nts fiel d. 
 
7. 0 
T R E A T M E N T M O DI FI C A TI O N S  
 
7. 1  
D o w n S y n dr o m e P artici p a nts 
 
P artici pa nts wit h D o w n s y n dr o me are eli gi ble f or e nr oll me nt, wit h t he f oll o wi n g 
m o dificati o ns. 
 
7. 1. 1  H D M T X:  D osa ges of hi g h- d os e M T X will be m o difie d d ue t o t heir well- 
d oc u me nte d altere d p har mac o ki netics a n d e n h a nce d tiss ue se nsiti vit y t o M T X’s effects.  
T heir h y drati o n a n d al kali nizati o n re gi me n s h o ul d be t he sa me as o utli ne d i n Secti o n 
5. 3. 3.  H o we ver, t he d ose of H D M T X is 5 0 0 m g/ m 2 ( 5 0 m g/ m2  
o ver 1 h o ur a n d 4 5 0 
m g/ m 2 gi ve n o ver 2 3 h o urs). 
 
T he baseli ne le u c o v ori n resc ue will be gi n earl y (at h o ur 3 0 at 3 0 m g/ m 2 I V q 6 h o urs x 2 
d oses, f oll o we d b y 1 0 m g/ m 2   I V q 6 h o urs x 6 d oses).  If M T X pl as ma le v els are ele vate d, 
i ncreas e d le uc o v ori n resc ue will be rec o m me n d e d b y t he P har mace utical D e part me nt.  
Vi g or o us h y drati o n s h o ul d be ass ure d u ntil t he 4 2 h o ur M T X le vel is k n o w n. 
 
7. 1. 2  C o nti n uati o n l o w- d ose M T X:  T he l o w- d ose wee kl y M T X ( 4 0 m g/ m 2) d osa ge 
s h o ul d be a d mi nistere d at f ull d osa ge if p ossi ble.  If t he patie nt has s e vere ne utr o pe nia or 
le uc o pe nia ( w hic h dela ys s u bse q ue nt t hera p y) or gra de 4 m uc ositis ( or m uc ositis w hic h 
dela ys s u bs e q ue nt t hera p y) f oll o wi n g t he d os e of 4 0 m g/ m 2, t he d osa ge s h o ul d be 
decrease d t o 3 0 m g/ m 2.  If t hat d osa ge is si milarl y n ot t olerate d, t he n t he d osa ge ma y be 
f urt her decrease d t o 2 0 m g/ m2 a n d fi nall y t o 1 0 m g/ m 2, if necessar y.  If 1 0 m g/ m2 is als o 
n ot t olerate d, t he n le uc o v ori n s h o ul d be a d de d at 5 m g/ m 2 e ver y 6 h o ur f or 4 d oses starti n g 
4 2 h o urs fr o m t he M T X d osa ge, wit h titrati o n t o acce pta bl e t o xicit y. 
 
7. 1. 3  I ntr at hecal t hera p y:  I ntrat hecal treat me nt s h o ul d be a d mi nistere d as o utli ne d i n 
Secti o n 5. 1. 
 
7. 1. 4  P E G-as para gi nase: Patie nts wit h D o w n’s s y n dr o me will n ot be ra n d o mize d, a n d 
will all recei ve 2, 5 0 0 u nits/ m 2 P E G-as para gi nas e p ost re missi o n i n d ucti o n. 
 
7. 1. 5  D o w n s y n dr o me patie nts s h o ul d be cl osel y m o nit ore d.  D ose re d ucti o n ( 3 0 % t o 
5 0 %) s h o ul d be a p plie d as cli nicall y i n dicat e d (es p eciall y t o de xa met has o ne a n d hi g h- d ose 
c yt ara bi ne f or t he fe w p atie nts w h o w o ul d be treat e d o n t he sta n dar d ar m, a n d w h o are 
n ote d t o ha ve hi g her t ha n e x pecte d t o xicit y i n earlier p hases)  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
7. 2   
Re nal D ysf u ncti o n 
 
S u bcli nical re nal i m pair me nt ( n or mal ser u m creati ni ne b ut decreas e d G F R) ma y b e 
prese nt i n patie nts recei vi n g c o n c urre nt ne p hr ot o xic dr u gs (e. g. I V ac ycl o vir) w hic h, if 
p ossi ble, s h o ul d be hel d d uri n g a n d f or 2 0 h o urs after H D M T X i nf usi o ns or u ntil a de q uate 
M T X c leara nce has bee n d oc u me nte d. C o nsi derati o n t o dela yi n g M T X s h o ul d be gi ve n if 
a patie nt's ser u m creati ni ne i n dicates re nal i m pair me nt. 
 
7. 3  
He patic D ysf u n cti o n 
 
A nt hrac ycli nes a n d vi ncristi ne d osa ges s h o ul d be m o difie d i n patie nts wit h ele vate d direct 
bil ir u bi n c o nce ntrati o ns or ot her e vi de nce of biliar y o bstr ucti o n. ( M ore c o nser vati ve 
criteria will be use d f or a nt hrac ycli ne treat me nt d uri n g i nitial re missi o n i n d ucti o n, See 
S ecti o n 5. 2.) 
 
Dire ct bilir u bi n 2- 4 m g/ dl: 
5 0 % d osa ge decrease  
Dire ct bilir u bi n 4- 6 m g/ dl: 
7 5 % d osa ge decrease  
Dire ct bilir u bi n > 6  m g/ dl: 
wit h h ol d d ose 
 
P E G-as para gi nase ma y n ee d t o be wit h hel d i n pati e nts wit h ele vate d direct bilir u bi n 
c o nce ntrati o ns, es peciall y if t here is e vi de n ce of  m uc ositis. 
 
H D M T X s h o ul d be wit h hel d if t here is e vi de nce of e xisti n g m uc ositis or if t otal 
bilir u bi n > 2  m g/ dl a n d direct bilir u bi n > 1. 4 m g/ dl. 
 
S u bcli nical h y pertra nsa mi nase mia ( S G P T > 5 0 0 I U/ L) is a n i n dicati o n t o dela y o nl y 
hi g h- d ose met h otre x ate b ut n ot f or ot her c he m ot hera p y. 
 
7. 4  
O besit y 
 
Ac t ual b o d y wei g ht will be use d t o calc ul ate b o d y s urface area i n all patie nts a n d use d f or 
d osa ge cal c ulati o ns ( wit h t he e x ce pti o n t hat vi ncristi ne d osa ge is ca p pe d at 2 m g). 
 
7. 5 
Te stic ular Le u k e mia at Dia g n osis 
 
O vert testic ular le u k e mia occ urs i n 2 % of b o ys at dia g n osis, ge n erall y i n i nfa nts or 
a d olesce nts wit h h y perl e u k oc yt osis.  Ultras o n o gra m s h o ul d be perf or me d t o differe ntiate 
testic ular le u ke mia fr o m h y dr ocele a n d t o meas ure t he testic ular v ol u me.  O vert testic ular 
le u ke mia at dia g n osis per se is n ot a n i n dicati o n f or testic ular irra diati o n, as ma n y p atie nts 
ca n be s uccessf ull y treate d wit h c he m ot hera p y, i ncl u di n g hi g h- d ose met h otr e x ate.  
Ultras o n o gra m s h o ul d a gai n be perf or me d u p o n c o m pleti o n of re missi o n i n d ucti o n.  If 
testic ular size is still a b n or mall y e nl ar ge d, t h e s o n o gra m s h o ul d be re p eate d after 
c o ns oli dati o n treat me nt wit h hi g h- d ose met h otr e x ate a n d merca pt o p uri n e. Persiste ntl y 
e nlar ge d test es after c o ns oli dati o n treat m e nt will be bi o psie d.  Testic ular irra diati o n ( 2 4 
G y) will be a d mi nistere d i n t he rare p atie nts wit h p ositi ve bi o psies, after c o ns ultati o n wit h 
a ra diati o n o nc ol o gist. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
7. 6   
Vi ncristi ne Ne ur ot o xicit y 
 
T he  ma xi m u m si n gle d ose of vi ncristi ne m ust n ot e xcee d 2 m g. Mil d vi ncristi ne 
t o xicities (ja w pai n, c o nsti pati o n, a n d decrease d d ee p te n d o n refle x es) are a ntici pate d.  
L oss of v oice d ue t o v oc al c or d paral ysis ma y be a c o m plicati o n of vi ncristi ne t o xicit y 
b ut it m ust be differe ntiate d fr o m p har y n gitis or C a n di d a i nfecti o n of t h e c or d.  If 
persiste nt, se vere a b d o mi nal cra m ps, gait i m pair m e nt, se vere pai n (re q uiri n g narc otic 
treat me nt), or SI A D H de vel o p, t he d ose ma y be re d uce d t o 1 m g/ m2.  O nl y m ot or 
paral ysis or t y p hlitis warra nts wit h h ol di n g vi ncristi ne. 
 
7. 7  
Ve n o us T hr o m b oe m b olis m 
 
P atie nts w h o de vel o p cere bral or ot her ve n o us t hr o m b osis will recei ve l o w m olec ular 
wei g ht h e pari n t hr o u g h o ut treat me nt wit h As para gi nase ( d uri n g Rei n d ucti o n I a n d 
Rei n d ucti o n II i n l o w-ris k patie nts, d uri n g t he first 3 0 wee ks of c o nti n uati o n treat me nt i n 
sta n dar d-/ hi g h-ris k cases, a n d d uri n g rei nte nsificati o n I i n hi g h-ris k patie nts). Ac ute 
ma na ge me nt of t hr o m b osis will f oll o w t he St. J u de g ui deli nes o n t he use of t hr o m b ol ysis 
a n d a ntic oa g ulati o n; q uesti o ns s h o ul d be referre d t o t he PI or c o- PI. 
 
7. 8  
A vasc ular Necr osis of B o ne 
 
M R I e x a ms will be i nter prete d b y t he ra di ol o gist. If t here is e vi de nce of e pi p h yseal or 
meta p h ys eal hi p lesi o ns, k nee e pi p h yseal or meta p h yseal lesi o ns, or lesi o ns of tal us 
c o nsiste nt wit h a vasc ular necr osis of t he b o ne, t he patie nt will be referre d t o t he 
ort h o pe dic s ur ge o n, w h o will e val uate s y m pt o ms, a n d will assess t he se verit y a n d 
esti mate d ris k of pr o gressi o n. P h ysic al t hera p y, acti vit y m o dificati o ns, a n d s ur gical 
pr oce d ures will be rec o m me n de d as nee de d. Patie nts wit h hi p e pi p h ys eal lesi o ns or tal us 
lesi o ns affecti n g > 3 0 % of wei g ht- beari n g area will ha ve a n X-ra y of t he affecte d area, a n d 
will be assesse d at hi g her ris k f or pr o gressi o n. S y m pt o matic patie nts wit h s uc h fi n di n gs 
will li kel y h a ve t heir d e x a met has o ne st o p pe d, es peciall y if t he y are past r ei n d ucti o n II i n 
t hera p y. 
 
As y m pt o matic patie nts wit h s uc h fi n di n gs will li kel y ha v e t heir de x a met has o ne d ose 
hal ve d, es peciall y if t he y are past r ei n d ucti o n II i n t hera p y.  A n y p atie nts wit h X-ra y 
fi n di n gs of A V N are ca n di dates f or de x a met has o n e m o dificati o n, re gar dless of s y m pt o ms. 
All m o dificati o ns ( or lac k t here of) of d osa ge will be rec or de d i n t he researc h data bas e. 
Patie nts wit h pr o gressi o n of a n y lesi o ns or wit h w orse ni n g s y m pt o ms will be re-e val uat e d 
b y i ma gi n g a n d, if a p pr o priate, b y a d diti o nal ort h o pe dic f oll o w- u p.  If t he de x a met has o ne 
is disc o nti n ue d, t he, first c h oice will be t o re pl ace eac h wee k’s d osi n g wit h o ne d ose of 
met h otre x ate ( 4 0 m g/ m 2), if t olerate d.  See Secti o n 1 3. 4 f or a d diti o nal g ui deli nes. 
 
7. 9  
P E G- As para gi n ase 
 
P atie nts wit h aller gic reacti o ns or i nt olera nce t o P E G-as para gi nase s u bs e q ue ntl y will be 
gi ve n Er wi ni a L-as p ara gi nase i ntra m usc ularl y or i ntra ve n o usl y o ver 3 0- 6 0 mi n utes 
d urati o n. If aller g y occ urs wit h t he first P E G d ose a n d t h e patie nt re q uires a da y 1 5 d os e 
d uri n g  re missi o n i n d ucti o n, Er wi ni a L-as para gi nase will be gi ve n at 2 0, 0 0 0 u nits/ m 2/ d ose 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t hrice wee kl y f or 2 w ee ks (t otal of 6 d oses).  Aft er c o ns oli dati o n, i n patie nts ra n d o mize d 
t o 2, 5 0 0 u nits/ m2, eac h d ose of P E G will be re place d b y Er wi nia at 3 0, 0 0 0 u nits/ m2/ d ose 
t wice wee kl y ( 3 t o 4 da ys a part) f or 4 d oses. I n p atie nts ra n d o mize d t o 3, 5 0 0 u nits/ m2 or 
3, 0 0 0 u nits/ m 2, eac h d os e of P E G will be re place d b y Er wi nia at 4 2, 0 0 0 u nits/ m2/ d ose or 
3 6, 0 0 0 u nits/ m 2/ d ose, res pecti vel y, t wice wee kl y ( 3 t o 4 da ys a part) f or 4 d oses.  D uri n g 
R ei nte nsificati o n, Er wi nia will be gi v e n 3 6, 0 0 0 u nits/ m 2/ d ose, t wice wee kl y ( 3 t o 4 d a ys 
apart) f or 2 d oses.  N ati ve E. c oli as para gi nase ca n als o be gi ve n w he n cli nicall y i n dicat e d, 
b ut t his s h o ul d be disc usse d a n d a p pr o ve d b y t he PI or c o- PI. 
 
As para gi nas e treat me nt s h o ul d be dela ye d u ntil at least 2 h o urs after i ntrat h ecal treat me nt. 
 
If si g nifi ca nt i ncrease i n t o xicit y is n ote d i n t he ar m ra n d o mize d t o 3, 5 0 0 u nits/ m2 P E G-
as para gi n ase c o m pare d t o t he c o n ve nti o nal d ose ar m, P E G-as para gi nase d ose will be 
re d uce d t o 3, 0 0 0 u nits/ m2.  If si g nifica nt i ncreas e i n t o xicit y is n ote d wit h t he re d uce d 
d ose , ra n d o mizati o n will cease, a n d all patie nts will be treate d at t he c o n ve nti o nal d ose of 
2, 5 0 0 u nits/ m 2 (see secti o n 1 7. 0 f or details a n d st atistical a nal ysis). 
 
Patie nts w h o are i nt olera nt t o all as para gi nase f or m ulati o ns ca n ha ve as p ara gi n ase 
s u bstit ute d wit h met h otre x ate 4 0 m g/ m 2 I V o n wee ks 2 1, 2 2, 2 3, 2 6, a n d 2 7. 
 
7. 1 0  
T P M T Stat us a n d T hi o p uri ne D osa ge 
 
T P M T defects ha v e bee n li n ke d t o ac ute m yel os u p pressi o n a n d t o t he l o n g-ter m ris k of 
t hera p y-relate d A M L (t- A M L), e ve n i n t he c o nte xt of A L L t hera p y c o nsisti n g pri maril y of 
a nti meta b olites. St u dies re p orti n g a n ass ociati o n of T P M T defects wit h ris k of t- A M L 
i nc or p orate d m erca pt o p uri ne at a d osa ge of 7 5 m g/ m2/ da y, w hereas ma n y A L L tr eat me nt 
gr o u ps us e a starti n g d os a ge of 6 0 m g/ m 2/ da y a n d t he n titrate u p.  Alt h o u g h t he 
mec ha nis m is n ot k n o w n, patie nts wit h T P M T defects ha ve hi g her c o n ce ntr ati o ns of 
t hi o g ua ni ne n u cle oti des, a n d s u bstit uti o n of t hi o g ua ni ne f or g u a ni ne i n D N A ca n affect 
t o p ois o merase II- i n d uce d clea va ge of D N A i n t he prese n ce a n d a bse n ce of a 
t o p ois o merase II i n hi bit or. T o get her, t he cli nical a n d precli nical e vi d e nce s u g gest t hat t he 
1 0 %  of patie nts w h o carr y a v aria nt T P M T allele ma y b e at hi g her ris k f or sec o n dar y 
t u m ors.   Beca use s uc h p atie nts ofte n re q uir e d osa ge d ecreas es of t hi o p uri nes, a n d beca use 
(i n a setti n g i n w hic h d os a ge was a dj uste d i n a b o ut 1/ 3 of patie nts wit h T P M T defects) 
o verall le u ke mia-free s ur vi val was o utsta n di n g a m o n g patie nts wit h T P M T defects, w e are 
rec o m me n di n g t hat patie nts wit h p he n ot y pe or ge n ot y pe c o nsiste nt wit h at least o ne 
varia nt T P M T allele recei ve n o m ore t ha n 6 0 m g/ m 2/ da y of merca pt o p uri n e or t hi o g u a ni ne 
u nless it is clearl y d o c u m e nte d t hat c o m plia nce h as bee n g o o d a n d meta b olite le vels 
re mai n l o w ( < 1 0 0 p m ol/8 x 1 0 8 re d cells) (see secti o ns 8. 1 a n d 8. 2).  F urt h er c ha n ges i n 
merca pt o p uri n e d ose s h o ul d be titrate d base d o n W B C a n d A N C. E ver y eff ort s h o ul d be 
ma de t o kee p ot her a ntica ncer a ge nt d oses at pr ot oc ol le vels f or t hes e patie nts. A bl o o d 
sa m ple ( 5 ml) will be dra w n al o n g wit h r o uti ne la b w or k at Da y 3 of re missi o n i n d ucti o n 
t o all o w f or ti mel y T P M T ge n ot y pi n g. 
 
Assessi n g T P M T stat us: T P M T ge n ot y pe will be deter mi ne d b y allele-s pecific ge n ot y pi n g, 
directe d a gai nst t he 3 m ost c o m m o n i nacti vati n g p ol y m or p his ms at p ositi o ns 2 3 8, 4 6 0, 
a n d 7 1 9 of t he c D N A.  T hese 3 p ol y m or p his ms acc o u nt f or > 9 0 % of all varia nt alleles.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Ge n ot y pi n g will be e val u ate d t o assi g n p atie nts as ha vi n g h o m oz y g o us wil d-t y pe, 
heter oz y g o us, or h o m oz y g o us varia nt T P M T stat us.  As s pecifie d i n secti o n 8. 2, all 
pa tie nts als o ha ve 6 T G N t hi o p uri ne meta b olite meas ures at t he start of rei n d ucti o n I a n d 
T P M T acti vit y i n R B Cs assesse d at least b y wee k 1 7.  T he t hres h ol d f or o n-t hera p y, n o n-
transf use d T P M T acti vit y t hat is c o nsi dere d t he u p per b o u n ds f or h eter oz y g o us stat us ( 1 4 
u nits/ ml) is hi g her t ha n t hat f or off-t hera p y, n o n-tra nsf use d p atie nts ( 1 0 u nits/ ml). T he 
rati o of met h yl t hi o p uri n e meta b olites t o T G Ns ca n als o be use d t o assist i n p he n ot y pi n g 
t he patie nt if ge n ot y pe a n d acti vit y p he n ot y p e data are c o nflicti n g. If T P M T ge n ot y p e or 
acti vit y or met a b olite meas ures are c o nsiste nt wit h heter oz y g o us stat us, t h e patie nt will be 
c o nsi dere d h eter oz y g ot e; usi n g t hese criteria, a p pr o xi matel y 1 0 % of patie nts are e x pecte d 
t o be heter oz y g ot e or h o m oz y g o us v aria nts, i n a gree me nt wit h p o p ulati o n st u dies f or 
T P M T stat us. 
 
T h us, a p pr o xi matel y 1 0 % of patie nts are e x pecte d t o re q uire s u bstit uti o n of merca pt o p uri ne 
f or t hi o g u a ni ne o n t he basis of T P M T stat us.  See Secti o n 8. 2 f or a d diti o nal i nf or mati o n. 
 
7. 1 1 
Pa ncreatitis 
 
Ac ute he m orr ha gic p a ncreatitis is a c o ntrai n dicati o n t o c o nti n ue as para gi nase treat me nt. I n 
t he case of mil d t o m o derate pa ncreatitis, as para gi nase s h o ul d be hel d u ntil s y m pt o ms a n d 
si gns s u bsi de, a n d a m ylase a n d li pase le vels ret ur n t o n or mal a n d t he n res u me d. A n y 
patie nts wit h a b d o mi nal pai n s us pecte d of p a ncreatitis s h o ul d ha ve ser u m a m ylas e a n d 
li pase meas ure d as well as a n a b d o mi nal s o n o gra m or C T sca n d o ne.  I n t h e case of se vere 
pa ncreatitis (i.e. a b d o mi nal pai n of 7 2 h o urs or m ore, a m ylase l e vel t hree ti mes or m ore of 
t he u p per li mit of n or mal, a n d s o n o gra p hic or C T sca n e vi de nce of pa ncreatitis), 
as para gi n ase ma y be dis c o nti n ue d per ma ne ntl y w h e n t he p ossi bilit y of gl uc oc ortic oi d- or 
mer ca pt o p uri n e-i n d uce d pa ncreatitis is e x cl u de d. I n cases wit h mil d t o m o derate 
pa ncreatitis (a b d o mi nal pai n less t ha n 7 2 h o urs a n d a m ylas e a n d li pase l e vel less t ha n 
t hree ti mes t he u p per li mit of n or mal), as para gi nas e s h o ul d be hel d a n d res u me d o nce 
s y m pt o ms a n d si g ns s u bsi de d.  Call t he PI or c o- PI t o disc uss t he ma na ge m e nt if t he 
patie nt is as y m pt o matic ( wit h o ut a b d o mi nal pai n) a n d has o nl y ele vat e d a m yl ase or li pase 
le vels. C o nsi derati o n s h o ul d als o be gi ve n t o d e x a met has o ne- or merca pt o p uri ne- rel ate d 
pa ncreatitis. C o ntact t he PI or c o- PI t o disc uss t he ma na ge m e nt if t here is a p ossi bilit y 
t hat t he pancreatitis is d ue t o eit her of t hes e t w o dr u gs. 
 
7. 1 2 
P hila del p hia C hr o m os o me P ositi ve ( P h +) A L L 
 
P atie nts wit h P h + A L L will recei ve das ati ni b ( 4 0 m g/ m 2 b.i. d.), star ti n g o n da y 2 2 of 
i n d ucti o n c he m ot hera p y. Patie nts ma y recei v e 8 0 m g/ m2 dail y if better t olerate d. T his is 
e q ui vale nt t o t he sta n dar d a d ult d osa ge of 7 0 m g b.i. d., a n d is e q ual t o t he pr o p ose d 
dasati ni b d ose i n t he u pc o mi n g fr o ntli ne C O G re gi me n f or P h + A L L. If ple ural eff usi o n 
occ urs, or if d asati ni b i n d uce d m yel os u p pressi o n ( or ot her t o xicit y) i nterferes wit h t he 
a bilit y t o a d mi nister it c o nti n u o usl y wit h c he m ot hera p y, t he dasati ni b d ose will be 
decrease d b y 2 5 % t o 6 0 m g/ m 2 dail y w hic h is e q ui vale nt t o t he 1 0 0 m g dail y d ose t hat has 
bee n ass oci ate d wit h e q u al efficac y a n d better t olera nce i n a d ults 1 1 1; 1 2 1.  If 
m yel os u p pressi o n res ults i n t hera p y i nterr u pti o n at t he re d uce d dasati ni b d ose of 6 0 m g/ m 2 
da il y, das ati ni b will be re place d wit h i mati ni b ( 3 4 0 m g/ m2 dail y as gi ve n i n T O T X V). 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
8. 0  
D O S E M O DI FI C A TI O N S D U RI N G C O N TI N U A TI O N T H E R A P Y  
 
D osa ge of c o nti n uati o n treat me nt s h o ul d be titrate d t o kee p W B C bet wee n 1 8 0 0  a n d 
3 0 0 0/ m m 3, A N C bet wee n 5 0 0 a n d 1 2 0 0/ m m3 ( wit h t he e x ce pti o n of t he c o u nt o ne wee k 
after de x a met has o ne treat me nt), a n d platelet c o u nt 5 0 x 1 0 9/ L. 
 
F ull d ose of treat me nt will be a d mi nistere d w he n W B C 1 5 0 0/ m m 3, A N C is 3 0 0 / m m3 
a n d platelet c o u nt 5 0 x  1 0 9/ L; e x ce pt w he n d ose re d ucti o n is cli nicall y i n dicate d.  If 
patie nt is cli nicall y w ell a n d A N C < 3 0 0/ m m 3, f ull d ose of treat me nt ca n be a d mi nistere d if 
W B C > 1 5 0 0/ m m 3, platelet c o u nt > 5 0 x 1 0 9/ L, a n d A P C > 5 0 0/ m m 3. 
 
D o x or u bici n, c ycl o p h os p ha mi de, c ytara bi ne, met h otre x ate a n d merca pt o p uri ne ma y b e  
red uce d b y  3 0 t o 5 0 % if W B C is bet wee n 1 0 0 0 a n d 1 5 0 0/ m m 3 wit h A N C 3 0 0/ m m 3 a n d 
pla telet c o u nt 5 0 x 1 0 9/L.  Dis pr o p orti o nate d ose re d ucti o n of o ne a ge nt c o m pare d t o 
an ot her s h o ul d be a v oi de d u nless cli nicall y i n dicat e d. Fre q ue nt (e. g., wee kl y) c ha n ges of 
mer ca pt o p uri ne d oses s h o ul d be a v oi de d.  Patie nts w h o recei ve merca pt o p uri ne at a 
red uce d d ose f or l o n ger t ha n 2 wee ks s h o ul d ha ve a T G N le vel c hec ke d after at least 1 4 
da ys of  u ni nterr u pte d merca pt o p uri ne if t he pla n is t o c o nti n ue at re d uce d d oses. 
 
Merca pt o p uri ne a n d met h otre x ate will be re d uce d if W B C a n d A N C  d o n ot i ncrease b y  at 
least 2 f ol ds a wee k after t he start date of de x a met has o ne p ulse. E x ce pti o n ca n be ma de i n 
pa tie nts w h ose W B C a n d A N C  d o n ot d o u ble b ut are o ver 3 0 0 0 a n d 1 2 0 0 res pecti vel y 
wit h n o hist or y of pri or c he m ot hera p y i nterr u pti o n or m yel os u p pressi o n.  I n Sta n dar d Ris k 
patie nts c o nsi der re d uci n g c ycl o p h os p ha mi de a n d c ytara bi ne d ose if s us pecte d t o 
co ntri b ute t o m yel os u p pressi o n. De x a met has o ne, vi ncristi ne, a n d as para gi nase will be 
g i ve n re gar dless of bl o o d c o u nts, pr o vi de d t hat t he patie nt is cli nicall y well. O n t he wee ks 
of vi nc risti ne a n d de xa met has o ne p ulses, merca pt o p uri ne ma y be re d uce d b y  3 0 % t o 5 0 % 
i n patie nts wit h 
W B C < 1 5 0 0/ m m3 t he wee k after pri or de x a met has o ne p ulse. I n Sta n dar d 
Ris k patie nts c o nsi der re d uci n g c ycl o p h os p ha mi de a n d c ytara bi ne d ose if s us pecte d t o 
co ntri b ute t o m yel os u p pressi o n.  A dj ust me nts of d osa ges s h o ul d be ma de i n t he f oll o wi n g 
circ u msta nces, wit h re-e v al uati o n of t olera nce a n d t o xicities e ver y 8 t o 1 6 wee ks ( See 
secti o n 8. 3 f or das ati ni b m o dificati o n). 
 
8. 1  
D ose M o dificati o ns f or I na de q uate M yel os u p pressi o n 
 
Patie nts w h o miss less t ha n 2 5 % of t hera p y b ut ha ve persiste ntl y ( > 5 0 % of ti me; n ot 
c o u nti n g t he wee k after de x a met has o ne/ vi ncristi ne) hi g h W B C ( > 3 x 1 0 9/ L) a n d hi g h 
A N C ( > 1 0 0 0/ m m 3) s h o ul d be c o u nsele d o n c o m plia nce, p artic ularl y if 6 T G N le vels are 
< 1 0 0 p m ol/ 8 x 1 0 8 R B Cs.  If t he W B C re mai ns hi g h, merca pt o p uri n e a n d met h otre x ate 
d osa ges s h o ul d be i ncrease d b y 3 0 % (e. g., t o 1 0 0 m g/ m 2 a n d 5 0 m g/ m 2, res pecti vel y), 
usi n g a ste p wis e a p pr oac h if nee de d.  If patie nts h a ve a T P M T defect, merca pt o p uri ne 
d osa ge s h o ul d n ot be i ncrease d u nless t he T G N le vels are < 1 0 0 p m ol/ 8 x 1 0 8 R B Cs. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
8. 2   
D ose Decreases Base d o n Merca pt o p uri ne P har m ac ol o g y 
 
L o w ris k a n d sta n dar d/ hi g h ris k 
 
All patie nts o n b ot h ar ms will ha ve 6 T G N meas ure d at t he start of rei n d ucti o n I (i. e., wee k 
7). T P M T will be meas ur e d at t he start of rei n d ucti o n II ( wee k 1 7) or earlier if T P M T 
defects are s us pe cte d.  T P M T ge n ot y pe ma y b e use d t o i de ntif y T P M T varia nt alleles. 
6 T G N a n d T P M T will be meas ure d s u bse q ue ntl y i n patie nts wit h hi g h 6 T G N le vel, 
s us pecte d n o nc o m plia nce, pr o ble ms wit h t o xicities or hi g h bl o o d c o u nts. 
 
Patie nts missi n g 2 5 % of t hera p y w h o ha ve 6 T G N le vels > 1 0 0 0 p m ol/ 8 x 1 0 8 R B Cs will 
ha ve merca pt o p uri ne d os a ge re d u ce d t o ac hie ve a stea d y-state 6 T G N le vel bet wee n 2 0 0 t o 
1 0 0 0; t h ose wit h 6 T G N le vel < 1 0 0 0 will ha ve b ot h merca pt o p uri n e a n d met h otre x ate 
d osa ges re d u ce d b y 3 0 %. 
 
D osa ges will be re-e v al uate d e ver y 8 t o 1 6 wee ks.  Ot her ca us es of l o w bl o o d c o u nts 
s h o ul d als o be c o nsi dere d (see Secti o n 1 3. 5). 
 
Patie nts missi n g less t ha n 2 5 % of t hera p y a n d wit h W B C < 3 x 1 0 9/ L a n d A N C 
< 1 0 0 0 d o n ot nee d a n y c ha n ge i n d osa ge, re gar dless of 6 T G N le vel. See s ecti o n 7. 1 0 f or 
merca pt o p uri n e d osa ge a dj ust me nts.  
 
8. 3  
Dasati ni b D osa ge A dj ust me nts ( P h + A L L Patie nts O nl y) 
 
C o nsi der h ol di n g dasati ni b f or gra de III-I V n o n- h e mat ol o gical t o xicit y u ntil res ol uti o n t o 
gra de 1 or l ess. H ol d das ati ni b f or ple ural eff usi o n.  Ma y c o nsi der res u mi n g at r e d uce d ( 6 0 
m g / m2 dail y).  D os e ca n be escal ate d bac k t o 4 0 m g/ m 2 b.i. d. i f well t olerate d. Patie nts 
ma y recei ve 8 0 m g/ m 2 dail y if better t olerate d. C o nsi der re placi n g wit h i mati ni b 3 4 0 
m g/ m 2 dail y (as gi ve n o n T X V) if t o xicit y p ersists at re d uce d d osa ge.  All m o dificati o ns 
s h o uld be disc usse d wit h PI or c o- PI. 
 
C o nsi der re d uci n g das ati ni b d ose t o 6 0 m g/ m 2 dail y if m yel os u p pressi o n i nterferes wit h 
t he a bilit y t o a d mi nister t hera p y wit h o ut i nterr u pti o n. D ose ca n b e escalate d bac k t o 4 0 
m g/ m 2 BI D if t olerate d. Patie nts ma y recei v e 8 0 m g/ m 2 dail y if better t olerate d.  C o nsi der 
re placi n g wit h i mati ni b 3 4 0 m g/ m2 (as gi v e n o n T X V) if i nterr u pti o ns persist at re d uce d 
d osa ge. All m o dificati o ns s h o ul d be disc usse d wit h t he Pri nci pal I n vesti gat or. 
 
C o nsi der h ol di n g dasati ni b d uri n g peri o ds of m yel os u p pressi o n, u ntil A N C 3 0 0/ m m 3 a n d 
platelet c o u nt 5 0 x 1 0 9/ L. 
 
A v oi d c o nc urre nt use of dr u gs t hat are ge nerall y acce pte d t o h a ve a ris k of ca usi n g 
T orsa des de P oi ntes (i ncl u di n g: er yt hr o m yci n, ps e u d oe p he dri ne), a n d dr u gs k n o w n t o be 
i nterfere wit h C Y P 3 A 4. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 4 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
9. 0  
C O N TI N G E N C Y P L A N S F O R R E F R A C T O R Y DI S E A S E O R R E L A P S E  
 
9. 1   
I n d u cti o n Fail ures 
 
P atie nts w h o d o n ot attai n c o m plete re missi o n ( ≥5 % le u ke mic blasts i n b o ne marr o w) aft er 
re missi o n i n d ucti o n, c o ns oli dati o n treat me nt a n d rei nte nsificati o n treat me nt will be 
re m o ve d fr o m t he pr ot oc ol. T h ose w h o d o n ot ac hie ve a re missi o n after i n d ucti o n t h era p y, 
b ut s u bse q ue ntl y attai n c o m plete re missi o n after c o ns oli dati o n or rei nte nsificati o n 
treat me nt, are ca n di d ates f or all o ge nei c he mat o p oi etic ste m cell tra ns pla ntati o n. 
 
9. 2  
He mat ol o gi c Rela pse 
 
P atie nts wit h 2 5 % l y m p h o blasts i n marr o w as pir ate will b ec o me eli gi ble f or rela pse 
pr ot oc ols. 
 
9. 3  
E x tra me d ullar y Rela ps e 
 
Patie nts wit h a n y f or m of e xtra me d ullar y rela ps e (testes, o varia n, et c.) e x ce pt t hat of C N S 
will bec o me eli gi ble f or rela pse pr ot oc ols.  Patie nts wit h o vert C N S rela pse (i.e. 5 
W B C/ µ L of C S F wit h blasts) will re mai n o n st u d y a n d recei ve treat me nt o utli ne d i n 
Secti o n 9. 4.  Patie nts w h o ha ve < 5 W B C/ µ L of C S F wit h i de ntifia ble blasts are n ot 
co nsi dere d t o ha v e o vert C N S rela pse a n d will be treate d as o utli ne d i n Secti o n 9. 4. 
 
9. 4  
E mer ge nce of C S F L y m p h o blasts d uri n g Re missi o n Re q uiri n g C N S R a diati o n 
 
P re ve nti ve cra nial irra diati o n will n ot be gi ve n pr o p h ylacticall y t o p atie nts wit h C N S 
le u ke mia at dia g n osis or t o t h ose wit h hi g h-ris k le u ke mia. O nl y p atie nts wit h 
i m m u n ol o gicall y pr o ve n le u ke mic l y m p h o blasts i n C S F (re gar dless of cell c o u nt) d uri n g 
he mat ol o gic re missi o n o n t w o occasi o ns i n t he st u d y will recei ve t hera p e utic C N S 
irra diati o n i n c o ns ultati o n wit h ra di ot hera pists a n d after recei vi n g a sec o n d re missi o n 
i n d ucti o n (as i n Secti o n 5. 2) f oll o we d b y 1- 2 c ycles of rei nte nsificati o n (as i n Secti o n 5. 4) 
t o c o ns oli date b o ne marr o w re missi o n after i n d ucti o n. W het her 1 or 2 c ycles are t o be 
gi ve n will de p e n d o n ris k gr o u p, ti me t o e mer ge n ce of blasts i n C S F, i m m u n o p he n ot y p e of 
blasts, a n d i n di vi d ual patie nt t olera nce. I n ge neral, sta n dar d/ hi g h ris k partici pa nts or t h ose 
wit h earl y occ urre n ce ( < 1 8 m o nt hs) will recei ve 2 c ycles.  T his s h o ul d be disc usse d wit h 
t he pri nci pal i n vesti gat or. Tri ple i ntrat hecal t hera p y will be c o nti n ue d e ver y 3 t o 4 wee ks. 
 
C N S irra diati o n f or patie nts wit h C N S rela pse is i n dicate d as f oll o ws: cr a nial irra diati o n 
( 2 4 G y i n 1 6 fracti o ns) f or patie nts wit h < 5 W B C/ μ L of C S F occ urri n g wit hi n t he first 1 8 
m o nt hs of re missi o n; cra nial irra diati o n ( 1 8 G y i n 1 2 fracti o ns) f or t h ose wit h a n y n u m ber 
of le u ke mic l y m p h o bl asts i n C S F after 1 8 m o nt hs of i nitial re missi o n; a n d cra ni os pi nal 
irra diati o n ( 2 4 G y cra nial irra diati o n i n 1 6 fracti o ns pl us 1 5 G y s pi nal irra diati o n i n 1 0 
fracti o ns) f or patie nts wit h > 5 W B C/ μ L of C S F occ urri n g wit hi n t he first 1 8 m o nt hs of 
re missi o n. T h ose patie nts recei vi n g cra nial irra di ati o n o nl y s h o ul d recei ve 4 t o 5 tri ple 
i ntrat hecal t hera p y wit h le uc o v ori n resc ue d uri n g irra diati o n.  Merca pt o p uri ne a n d 
met h otre x ate will be wit h hel d f or at least o ne wee k pri or t o a n d d uri n g irra diati o n; 
s yste mic c h e m ot hera p y d uri n g irra diati o n will i n cl u de de x a met has o ne a n d vi ncristi ne wit h 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
or wit h o ut P E G-as para gi nase. C o nti n uati o n treat me nt will be gi ve n f or at least o ne year 
fr o m ti me of rela ps e (at l east 2 ½ years i ncl u di n g i nitial treat me nt). 
 
1 0. 0 
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C S T U DI E S  
 
1 0. 1 
Hi g h- D ose Met h otre x ate ( H D M T X) 
 
2- 3 ml of bl o o d will be o btai ne d i n E D T A t u bes ( p ur ple t o p) pre- d ose a n d bet wee n 0. 5 a n d 
6 hr, 2 3 hr, a n d 4 2 hr fr o m t he start of t he i nf usi o n. A d diti o nal sa m ples will be o btai ne d i n 
patie nts i n w h o m t here is cli nical s us pici o n of p o or cleara nce, or i n t h ose w h o ha ve hi g h 
plas ma M T X c o nce ntrati o n (e. g., > 0. 5 µ M at 4 2 h o urs), t o a dj ust le uc o v ori n resc ue. ( N ote: 
bl o o d s h o ul d be i n p ur ple t o p t u be t o facilitate d n ucleic aci d rec o v er y fr o m t he b uff y c o at). 
 
1 0. 2 
T hi o p uri nes 
 
B l o o d ( 3 ml) will be o btai ne d at wee k 7 a n d at w ee k 1 7 f or re d bl o o d cell t hi o p uri ne 
c o nce ntr ati o ns a n d T P M T acti vit y, res pecti vel y. A d diti o nal sa m ples ma y be o btai ne d as 
i n dicate d i n Secti o n 8. 2. 
 
1 0. 3 
As para gi nas e, De x a met h as o ne a n d Bi o mar kers 
 
S er u m f or a nti b o dies ( 2 ml bl o o d i n re d-t o p t u be) will be o btai ne d o n Da ys 1, 8, a n d 1 5 
of re missi o n i n d ucti o n t hera p y, da y 1 of c o ns oli dati o n, a n d at Da y 1 of wee ks 7, 8, 9, 1 7, 
a n d 1 9 acc or di n g t o o ur pre vi o usl y esta blis he d met h o ds.  A nti b o dies a gai nst nati ve 
E. C ol i ( Els par), P E G yl ate d E. C oli ( O ncas par), a n d Er wi nia as para gi nase are meas ure d 
b y a n E LI S A i n o ur la b orat or y. T h ose wit h sa gittal si n us t hr o m b osis or a n y dee p vei n 
t hr o m b osis will als o ha ve meas ure me nt of a nti-as para gi nas e a nti b o dies at t he ti me of 
t hr o m b osis. 
 
Plas ma f or as para gi nase ( 3 ml bl o o d) will be o btai ne d o n Da ys 1, 8, a n d 1 5 of re missi o n 
i n d ucti o n t hera p y ( pl us ~ 2- 3 a d diti o nal ti me p oi nts d uri n g t he first 1 4 da ys), da y 1 of 
c o ns oli dati o n, a n d at Da y 1 of wee ks 7, 8, 9, 1 7, a n d 1 9 acc or di n g t o o ur pre vi o usl y 
esta blis he d met h o ds. As para gi nas e will be meas ure d usi n g a s pectr o p h ot o metric assa y 
base d o n c o n v ersi o n of as para gi ne t o as p artic aci d 1 2 2. 
 
I n p atie nts wit h a s us pect e d cli nical aller gi c reacti o n t o a d ose of as p ara gi n ase, bl o o d 
sa m ples f or res earc h p ur p oses ( u p t o 5 sa m ples o ver u p t o 2 wee ks, n or m ore t ha n 2 
sa m ples i n a n y 2 4- h o ur ti me peri o d; eac h t o be n o m ore t ha n 3 ml of bl o o d i n p ur ple-t o p 
E D T A or re d-t o p t u be m a y b e c ollecte d if t he pati e nt has f u ncti o ni n g I V access. 
 
Plas ma f or meas ur e me nt of de x a met has o ne c o n ce ntrati o ns ( 3 ml i n gree n t o p t u be) will be 
o btai ne d o n Da y 8 of Rei n d ucti o ns I a n d II ( Da y 8 of wee ks 7 a n d 1 7). 
 
C S F fr o m t hera p e utic l u m bar p u nct ures will be c ollecte d at SJ C R H a n d place d i nt o 
s ulf osalic ylic aci d- c o ntai ni n g t u bes pri or t o i n d ucti o n t hera p y ( wit h I T M H A) a n d o n Da ys 
8 (if a p plica ble) a n d 1 5 of re missi o n i n d ucti o n t hera p y, a n d o n Da y 1 of c o ns oli dati o n a n d 
da y 1 of wee k 7 of Rei n d ucti o n I.  C S F as para gi ne le vels will be meas ure d acc or di n g t o 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
o ur pre vi o usl y esta blis he d met h o ds. A n a d diti o nal bl o o d sa m ple ( 3 ml gree n t o p t u be) will 
be o btai ne d o n t he da y of dia g n osis of sa gittal si n us t hr o m b osis or a n y d ee p vei n 
t hr o m b osis f or meas ure m e nt of as para gi nase c o nce ntrati o n. 
 
Ser u m ( 3 ml bl o o d i n re d-t o p t u be) will be o btai ne d at da y 1 5 of i n d ucti o n, da y 1 5 of 
c o ns oli dati o n, a n d at wee ks 7, 8, a n d 1 7 of c o nti n u ati o n f or ster oi d/as para gi nase 
bi o mar kers (e. g. ser u m li pi ds, c ortis ol).  
 
1 0. 4 
Plas ma H o m oc ystei n e 
 
A 2 m L sa m ple of bl o o d will be place d i n E D T A ( p ur ple-t o p) t u bes c ollecte d pre- 
i nf usi o n a n d, 6, 2 3 an d 4 2 h o urs p ost t he first a n d sec o n d c o urses of H D M T X d uri n g 
c o ns oli dati o n.  Sa m ples will be se nt t o t he Cli nical P har mac o ki netics La b a n d ke pt at 
4° C u ntil ce ntrif u gati o n.  After ce ntrif u gati o n, sa m ples will be fr oze n a n d assa ye d 
s u bse q ue ntl y f or h o m oc ystei ne. 
 
1 1. 0 
E V A L U A TI O N S, T E S T S, A N D O B S E R V A TI O N S  
 
1 1. 1  
Pretreat me nt E val u ati o n 
 
All partici pa nts s h o ul d be i n vite d t o partici pate i n t he Tiss ue Ba n ki n g Pr ot oc ol 
( TB A N K) at t he ti me of st u d y e ntr y. 
 
 C o m plete hist or y a n d p h ysical e x a m wit h caref ul n otati o n a n d assess me nt of 
cli nical si g ns r ele va nt t o le u ke mia. 
 C o m plete bl o o d c o u nt wit h differe ntial 
 C he mistr y pr ofile: gl uc os e, electr ol ytes, B U N, creati ni ne, L D H, uric aci d, 
bilir u bi n, S G O T, S G P T, calci u m, p h os p h or o us, ma g n esi u m, t otal pr otei n 
an d al b u mi n. 
 L i pi d scree n: T otal c h olester ol, tri gl yceri des, free fatt y aci ds a n d hi g h- 
de nsit y li p o pr otei n c h olester ol 
 Plas ma 1, 2 5- di h y dr o x y vita mi n D, oste ocalci n 
 T h yr oi d f u ncti o n tests (free T 4, T 4, T S H) 
 C hest x-ra y 
 B o ne marr o w e val uati o n: m or p h ol o g y, c yt oc he mistr y, 
i m m u n o p he n ot y pi n g, c yt o ge n etics, D N A i n d e x, m olec ular dia g n osis, 
M R D st u dies 
 L u m bar p u nct ure wit h C S F e x a mi nati o n (cell c o u nt wit h differe ntial of 
c yt os pi n pre parati o n) 
 N K cell rece pt or st u dies, e x ce pt i n patie nts recei vi n g ster oi ds. 
 Ot her st u dies as cli nicall y i n dicat e d, e. g. sic kle cell pre p, he m o gl o bi n 
electr o p h oresis a n d G 6 P D scree n f or blac k c hil dre n; varicella titer; H e patitis B 
a nti ge n; HI V, E B V, T O X O, C M V titers. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 1. 2  
Data t o be O btai n e d Seri all y W hile O nst u d y  
Test/e v al u ati o n  
At di a g n osis  
I n d ucti o n/ C o ns oli d ati o n 
C o nti n u ati o n  
Rei n d ucti o n I & II  
P h ysical E x a m  
At dia g n osis  
q 3 -7 da ys  
q 4 wee k  
q 3 -7 da y  
C B C wit h differe ntial  At dia g n osis  
wee kl y  
wee kl y  
wee kl y  
C oa g ulati o n scree n  
At dia g n osis  
--- 
--- 
--- 
Uric aci d, 
electr ol ytes, calci u m 
p h os p h or o us, 
ma g n esi u m  
At dia g n osis  
Bef ore eac h H D M T X  
 
As i n dicate d  
Da y 1 ( Wee ks 7 & 
1 7)  
Ser u m gl uc os e, 
uri nal ysis  
At dia g n osis  
As i n dicate d  
As i n dicate d  
As i n dicate d  
Bilir u bi n, S G O T, 
S G P T, t otal pr ot ei n, 
al b u mi n,  
L D H, B U N, 
creati ni ne  
At dia g n osis  
Bef ore eac h H D M T X  
As i n dicate d  
Da y 1 of Wee ks 7, 8, 
9, 1 7, a n d 1 9  
M R D *  
( See ta bles bel o w) 
At dia g n osis  
 
Da y 8, Da y 1 5  
( da y 2 2) * , a n d  
E n d of i n d ucti o n  
( Wee k 4 9)*  
Wee k 1 2 0  
( Da y 1 
Wee ks 7 & 1 7) *     
 
T ota l c h olester ol, 
tri gl yceri des, free 
fatt y aci ds, a n d hi g h-
de nsit y li p o pr otei n 
c h olester ol  
At Dia g n osis  
 - - -  
 
After 
c o m pleti o n of 
t hera p y ( Wee k 
1 2 0 or later)  
Da y 1 of eac h Re -
I n d u cti o n ( Da y 1 of 
Wee ks 7 a n d 1 7)  
C S F st u dies  
At dia g n osis 
( wit h first 
i ntrathecal 
treat me nt) 
Wit h eac h i ntrat hecal 
treat me nt 
Wit h eac h 
i ntrat hecal 
treat me nt; t he n  
q 1 6 w k  
 
Wit h eac h  
I ntr at hecal treat me nt 
C hest x -ra y 
At dia g n osis  
E n d of i n d ucti o n i n cases 
wit h me diasti nal mass at 
dia g n osis, t he n as 
i n dicate d.  
Bef ore eac h H D M T X i n 
patie nts o n dasati ni b a n d 
as i n dicate d  
As i n dicate d  
As i n dicate d  
M RI of hi ps a n d 
k nees  
(>  9 year -ol d o nl y)  
- - - 
- - - 
Off t hera p y  
After eac h 
rei n d ucti o n p hase 
( Wee ks 1 2-1 4 a n d 
2 2 -2 4)  
P T/ O T E val uati o n ( >  
9 year -ol d o nl y)  
- - - 
- - - 
Off t hera p y  
After eac h Re -
i n d ucti o n 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Test/e v al u ati o n  
At di a g n osis  
I n d ucti o n/ C o ns oli d ati o n 
C o nti n u ati o n  
Rei n d ucti o n I & II  
Ger mli ne D N A/ R N A  
- - - 
Da y 3 a n d d uri n g 
c o ns oli dati o n ( wit h bl o o d 
f or H D M T X) 
 
- - - 
- - - 
 
 
 
Ps yc h ol o g y * * * *  
 
Wee k 7 C o nti n uati o n 
( Wee k 1 Rei n d ucti o n I) 
Wee k 1 2 0  
T w o years p ost t hera p y  
M RI Brai n * *  
 
Wee k 7 C o nti n uati o n 
( Wee k 1 Rei n d ucti o n I) 
Wee k 1 2 0  
T w o years p ost 
t hera p y * * * 
F u ncti o nal 
M RI * * * * *  
 
 
Wee k 1 2 0  
 
R B C T P M T a n d 
T G N  
- - - 
Da y 3 ( T P M T)  
- - - 
Da y 1 of wee k 7 ( T G N) 
a n d wee k 1 7( T P M T)  
C Y P 2 D 6 g e n ot y pi n g  
 
Da y 1 5  
 
 
 
Plas ma 
H o m oc yst ei ne  
 
Pre a n d 6, 2 3, 4 2 h o urs 
p ost H D M T X # 1 a n d # 2.  
Secti o n 1 0. 4  
 
 
M T X 
P har mac o ki netics  
- - - 
Eac h H D M T X  
- - - 
 
as para gi n ase 
a nti b o dies  
Da y 1  
Da ys 1, 8, 1 5, a n d Da y 1 of 
c o ns oli dati o n  
- - - 
Da y 1 ( wee ks 7, 8, 9,  
1 7,  1 9 )  
C S F as para gi n e  
Wit h first 
i ntrat hecal 
Da ys 8, 1 5 i n d ucti o n a n d  
wee k 1 c o ns oli dati o n  
- - - 
Wee k 7 ( Da y 1)  
Ser u m bi o mar kers  
- - - 
Da y 1 5 of i n d ucti o n a n d 
c o ns oli dati o n  
- - - 
wee ks 7, 8, 1 7  
As para gi nas e acti vit y  
Da y 1  
Da ys 1, 8, a n d 1 5 pl us 2 -3 
time p oi nts o ver t he first 1 4 
da ys  of i n d ucti o n; Da y 1 
c o ns oli dati o n  
- - - 
Da y 1 ( wee ks 7, 8, 9, 
1 7, 1 9  
De x a met has o ne 
acti vit y 
Da y 8  
Da y 8 d uri n g wee ks 7 &  1 7  
- -
  
 
Q C T f or b o ne de nsit y  Wee k 1  
- - - 
Wee ks 1 2 0  
- - - 
Uri nal ysis  
As nee de d  
As nee de d  
As nee de d  
As nee de d  
T h yr oi d f u ncti o n  
At dia g n osis  
- - - 
As cli nicall y 
i n dicate d 
- - - 
A m m o nia l e vel 
- - - 
I n d u cti o n: Da y 1, 5, 8, 1 5, 
a n d 2 2 
C o ns oli dati o n: Da y 1  
S R/ H R 
partici pa nts 
o nl y:  
Da y 1 ( Wee ks 
1, 1 3, 2 3, & 2 9)  
Da y 1: ( Wee ks 7, 8, 9, 
1 7, 1 8, & 1 9)  
N K Cell Rece pt or  
At dia g n osis  
- - -  
- - -  
Wee k 7 ( Da y 1)  
St o ol s a m ples f or 
Micr o bi o me researc h  
 
1) pre -c he m o 
2) wit hi n 2 wee ks 
c o m pleti o n I n d u cti o n.  See 
secti o n 1 6. 7 
 
Da y 1 ( wee ks 7 &  1 7)  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
* See t a bles bel o w f or s a m ples re q uire d f or M R D st u dies  
* * M R  s h o ul d be o bt ai ne d bef ore st arti n g dex a met h as o ne. 
* * * P ati e nts wit h a b n or m al i m a gi n g ev al u ati o ns at week 1 2 0 will h ave a n extr a ex a m 
at  2 ye ars off t her a py t o re assess br ai n str uct ure.  
* * * * Ne ur o psyc h ol o gic al testi n g s h o ul d be perf or me d pri or t o i niti ati o n of  dex a met h as o ne 
o n d ay 1 of Rei n d ucti o n I. Testi n g m a y  be c o m plete d u p t o 4 weeks pri or t o d ay 1 of  
Re i n d ucti o n I t o a cc o m m o d ate a p atie nt’s tr a vel a n d tre at m e nt sc he d ule. If u n a ble t o 
sc he d ule pri or t o dex a met h as o ne, c o nt act Dr. C o n kli n f or sc he d uli n g. 
* * * * * F u ncti o n al M RI will be perf or me d o nly o n p atie nts w h o q u alify f or t his ex a m. F or a 
list of  eli gi bility re q uire me nts, s e e Secti o n 1 2. 0.  
* * * * * * N K Cell Rece pt or st u dies will n ot be d o ne i n p atie nts recei vi n g ster oi ds 
 
S a m ples re q uire d f or M R D st u dies d uri n g re missi o n i n d ucti o n 
Ti me p oi nt  
B -li nea ge A L L 
T -li nea ge A L L 
  Da y 8  
P B  
P B  
  Da y 1 5  
B M  
B M a n d P B  
 ( Da y 2 2 if M R D+  o n Da y 1 5)  
B M  
B M a n d P B  
  Da y 4 3  
B M  
B M a n d P B  
P B = peri p her al bl o o d; B M = b o ne m arr o w 
 
S a m ples re q uire d f or M R D st u dies p ost-re missi o n i n d ucti o n 
Ti me  p oi nt  
B -li nea ge A L L 
T -li nea ge A L L 
Da y 4 3 M R D +  
Da y 4 3 M R D - 
Da y 4 3 M R D + ( or 
“at y pical” T -A L L)  
Da y 4 3 M R D - 
Da y 1 ( Wee ks 7, 1 7, 4 9)  
B M  
N o ne  u nless 
cli nicall y 
i n dicate d, or 
M L L +  
B M a n d P B  
P B  
Wee k 1 2 0 ( off t hera p y)  
B M  
B M  
B M a n d P B  
B M a n d P B  
P B = peri p her al bl o o d; B M = b o ne m arr o w  
 
1 1. 3 
Off- T h era p y E v al uati o ns 
 
It is rec o m me n de d t hat p atie nts will be f oll o we d e ver y 4 m o nt hs f or 1 year, e ver y 6 
m o nt hs f or 1 year a n d t he n yearl y u ntil t he patie nt is i n re missi o n f or 1 0 years a n d is at 
least 1 8 years ol d.  T h ere after, t he p atie nt will bec o me al u m ni a n d will be f oll o we d 
acc or di n g t o t he i nstit uti o n’s p olic y.  D uri n g t he St. J u de visit, C B C wit h differe ntial a n d 
ot her la b orat or y st u dies as cli nicall y i n dicat e d will be o btai ne d.  It is rec o m me n de d t hat 
Q C T f or b o ne de nsit y be perf or me d at 5 years off-st u d y. 
 
Patie nts will be c o nsi dere d off t hera p y 3 0 da ys after last treat me nt ta k e n.  A d verse e ve nts 
will n ot be re p orte d w hil e patie nt is off-t hera p y u nless t he y are d ee me d rel ate d t o t hera p y 
b y t he site PI.  After attai ni n g c o nti n u o us, c o m plet e re missi o n f or 6 years or m ore, SJ C R H 
patie nts will be i n vite d t o partici pate i n t he l o n g-ter m f oll o w- u p u m brella pr ot oc ol a n d 
ma y  b e referre d t o t he After C o m pleti o n of T hera p y Cli nic ( A C T).  W he n a SJ C R H 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
patie nt has bee n i n r e missi o n f or 1 0 years a n d is at least 1 8 years of a ge, t h e patie nt will 
bec o me SJ C R H al u m ni a n d will be f oll o we d acc or di n g t o t he SJ C R H i nstit uti o nal p olic y. 
 
1 2. 0 
E V A L U A TI O N C RI T E RI A  
 
1 2. 1 
Res p o nse Criteria 
 
1 2. 1. 1  C o m plete re missi o n: M 1 marr o w stat us wit h rest or ati o n of n or mal 
he mat o p oiesis a n d n or mal perf or ma nce stat us. 
 
1 2. 1. 2  In d u cti o n fail ure:  5 % l e u ke mic blasts i n marr o w after 4 2 da ys of 
re missi o n i n d ucti o n treat me nt. 
 
1 2. 1. 3  B o ne marr o w rela pse: 2 5 % le u ke mic blasts i n marr o w 
 
1 2. 1. 4  C N S rela pse: 
pre parati o n. 
 
1 2. 1. 5  Testic ular rela pse: Is olat e d testic ular rela pse m ust be c o nfir me d 
pat h ol o gic all y; i n t he e v e nt of b o ne marr o w rela ps e, c o m bi ne d testic ular 
rela pse ca n be b ase d o n t estic ular e nlar ge me nt ( d o c u me nte d b y s o n o gra m) 
wit h o ut bi o ps y. 
 
1 2. 2  
T o xicit y E val u ati o n Criteria 
 
T his st u d y will utilize t he C T C A E Versi o n 3. 0 f or t o xicit y a n d perf or ma n ce re p orti n g.  A 
c o p y of t he C T C A E versi o n 3. 0 ca n be d o w nl o a de d fr o m t he C T E P h o me pa ge 
(htt p://cte p.i nf o. ni h. g o v) .  A d diti o nall y, t he t o xicities are t o be re p ort e d o n t he a p pr o pri ate 
data c ollecti o n f or ms. 
 
1 2. 3 
F u ncti o nal M RI E val uati o n Criteria 
 
P artici pa nts/ g uar dia ns will be gi ve n t he o pti o n t o a gree t o t his a d diti o nal res earc h t est 
eit her d uri n g t he i nf or m e d c o nse nt pr ocess f or C o ns oli dati o n a n d C o nti n uati o n of 
Treat me nt or b ef ore t he s ca n is perf or me d at e n d of treat me nt f or all t hree ris k ar ms.  O nl y 
t h ose patie nts w h o ha ve a gree d t o t his a d diti o nal test a n d meet t he f oll o wi n g eli gi bilit y 
criteria will be sc h e d ule d f or t his e x a m. 
 
 P atie nt is at least 8 years ol d at Wee k 1 2 0. 
 Patie nt’s pri mar y la n g ua ge is E n glis h. 
 Patie nt d oes n ot ha ve braces or ort h o d o ntic a p plia nces t hat ca us e i ma ge 
dist orti o n or si g nal l oss o utsi de of t he m o ut h a n d si n us area. 
 Patie nt d oes n ot ha ve a n y maj or p h ysic al, ne ur ol o gical, or ps yc hiatric c o n diti o n 
t hat w o ul d precl u de parti ci pati o n i n t he f u ncti o nal M RI. 
 Patie nt d oes n ot ha ve a d oc u me nte d lear ni n g dis a bilit y or atte nti o n dis or der 
t hat pre dates ca ncer dia g n osis. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 3. 0  
S U P P O R TI V E C A R E  
 
1 3 . 1 
Fe ver at Dia g n osis 
 
All patie nts wit h fe ver at dia g n osis will be a d mitte d f or br oa d s p ectr u m pare nteral 
a nti bi otic treat me nt u ntil a n i nfecti o us eti ol o g y ca n be e x cl u de d. 
 
1 3. 2  
Meta b olic Dera n ge me nts 
 
It is i m p orta nt t o pre v e nt or treat h y per urice mia a n d h y per p h os p hate mia wit h sec o n dar y 
h y p ocalce mia res ulti n g fr o m s p o nta ne o us or c he m ot hera p y-i n d uce d le u ke mic cell l ysis, 
es peciall y i n T-cell A L L. 
 
 P atie nts wit h lar ge l e u ke mic cell b ur de n s h o ul d recei ve h y drati o n a n d oral 
p h os p hate bi n der. 
 
 P atie nts wit h l ar ge l e u ke mic cell b ur de n wit h or wit h o ut h y per urice mia (e. g., W B C 
1 0 0 x 1 0 9/ L, uri c aci d 7. 5 m g/ dl or 6. 5 m g/ dl i n patie nts < 1 3 years ol d) ma y b e 
treate d wit h ras b uricas e if t he y h a ve n o hist or y of G 6 P D deficie nc y or o n g oi n g 
pre g na nc y.  F or patie nts n ot at hi g h ris k of h y per urice mia, h y drati o n, all o p uri n ol, 
a n d j u dici o us use of al kali nizati o n ( kee pi n g uri ne p H bet wee n 6. 5 a n d 7. 4) ma y b e 
s ufficie nt. 
 
1 3. 3 
H y p erle u k oc yt osis 
 
F or patie nts wit h e xtre me h y p erle u k o c yt osis (i. e., W B C > 3 0 0 x 1 0 9/ L), le u ka p heresis or 
e x c ha n ge tra nsf usi o n (i n s mall c hil dre n) ma y be c o nsi dere d. T he Direct or of t he Bl o o d 
Ba n k s h o ul d be c o ns ulte d f or t his pr oce d ure. 
 
1 3. 4 
A vasc ular Necr osis of B o ne 
 
Oste o necr osis of t h e b o n e, a k n o w n c o m plicati o n of treat me nt wit h c ortic oster oi ds, c a n be 
e x pecte d t o occ ur i n a p pr o xi matel y 1 0- 1 5 % of patie nts, es peciall y i n t h ose ol der t ha n ni ne 
years of a ge.  T his de v astati n g c o m plicati o n ma y res ult i n c olla pse of t he artic ulati n g 
s urface wit h s u bse q ue nt pai n a n d de vel o p me nt of art hritis. Earl y detecti o n of s mall lesi o ns 
will per mit i nter ve nti o n w hic h ma y pre v e nt pai n a n d irre v ersi ble da ma ge of t he j oi nts.  I n 
t his st u d y, all patie nts 9 years of a ge a n d ol d er will ha ve M RI sca ns of t he p el vis/ hi ps a n d 
k nees aft er eac h rei n d ucti o n p hase, at off t hera p y date, a n d as n ee de d t h ereafter. 
 
Patie nts dia g n ose d wit h oste o necr osis (see secti o n 7. 8) will be referre d t o ort h o pe dics. 
A n y p atie nt w h o de vel o ps s y m pt o ms of j oi nt pai n pri or t o or bet wee n sc he d ule d M RI 
sca ns s h o ul d ha ve a n M RI p erf or me d t o r ule o ut oste o necr osis or pr o gressi o n of t his 
c o m plicati o n. 
 
F or patie nts w h o re q uire s ur gical i nter ve nti o n, treat me nt will var y b ase d o n de gree of 
pr o gressi o n, i.e., o bser vati o n, c ore dec o m pressi o n, b o ne grafti n g a n d res urfaci n g 
he miart hr o plast y. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 3. 5  
Pa nc yt o p e nias 
 
Pa tie nts wit h pr ol o n ge d ( > 3 wee ks) u ne x plai ne d a ne mia ( he m o gl o bi n < 7 g/ dl) or 
ne utr o pe nia ( A N C < 3 0 0/ m m 3) d uri n g re missi o n s h o ul d be e val uate d f or B 1 9 par v o vir us 
i nfecti o n or he m ol ysis or t o xicit y fr o m n o n-c he m ot hera pe utic a ge nts (e. g., T M P/ S M Z). 
 
1 3. 6 
N utriti o nal S u p ple me ntati o n 
 
N utriti o nal or vita mi n t hera pies s h o ul d n ot res ult i n patie nts recei vi n g m or e t ha n t he R D A 
f or f olic aci d wit h dietar y a n d s u p ple me nt i nta ke, t o pre ve nt i nterfere nce wit h t he 
effecti ve ness of met h otr e x ate. 
 
1 3. 7 
Dr u g I nteracti o ns 
 
Be ca use c o nc urre nt use of e nz y me i n d uci n g a ntic o n v ulsa nts (e. g. p he n yt oi n, 
p he n o bar bital, a n d car ba maze pi ne) wit h a nti-le u ke mic t hera p y h as rece ntl y bee n 
ass ociate d wit h i nferi or E F S, e ver y eff ort s h o ul d be ma de t o a v oi d t hese a ge nts, as well as 
rifa m pi n, w hic h als o i n d uces ma n y dr u g met a b olizi n g e nz y mes. 
 
Ga ba pe nti n d oes n ot i n d uce he p atic dr u g meta b olizi n g e nz y mes a n d ma y b e a s uita ble 
alter nati ve a ntic o n v ulsa nt.  
 
Az ole a ntif u n gals (fl uc o n az ole, itrac o naz ole, v oric o naz ole, a n d ket oc o naz ol e) a n d t he 
macr oli de gr o u p of a nti bi otics (e. g. er yt hr o m yci n, rifa m pi n, a n d zit hr o ma x) ma y h a ve 
p ote nt i n hi bit or y effects o n dr u g- meta b olizi n g e n z y m es, a n d t he d oses of s o me a nti-
le u ke mic dr u gs (e. g. vi n cristi ne, a nt hrac ycli n es, ster oi ds, et o p osi de) ma y n ee d t o be 
red uce d i n s o me p atie nts o n c hr o nic az ole a ntif u n gals or a nti bi otics.  C o ns ult 
P har mac o ki netics if l o n g-ter m use of t hes e i nteracti n g dr u gs is u na v oi da ble. 
 
Pe nicilli ns i nterfere wit h t u b ular e x creti o n of met h otre x ate, a n d it is rec o m me n de d t hat a n 
alter nati ve n o n- p e nicilli n a nti bi otic be use d. 
 
1 3. 8 
D o w n S y n dr o m e 
 
P atie nts wit h D o w n’s s y n dr o me s h o ul d be cl osel y m o nit ore d f or t o xicit y, a n d offere d 
a g gressi ve s u p p orti ve care. Met h otre x ate d osa ge will be re d uce d as descri be d i n secti o n 
7. 1. 1.  Hist oricall y, m ost of t hese patie nts will be treate d i n t he l o w-ris k cat e g or y, a n d 
s h o ul d ha ve t heir c h e m ot hera p y d oses a p pr o pri atel y re d u ce d t o a v oi d u n d u e t o xicit y. Oral 
le uc o v ori n ( 5 m g/ m2 q 1 2 hr x 2) s h o ul d be gi ve n 2 4 hrs after eac h I T M H A. All D o w n’s 
patie nt will recei ve t h e c o n ve nti o nal ( 2 5 0 0 u nits/ m 2) d ose of P E G-as para gi nase p ost 
re missi o n i n d ucti o n a n d will n ot be i ncl u de d i n t he ra n d o mizati o n t o t he hi g her d ose of 
P E G-as para gi nase. A 3 0 % d ose re d u cti o n of de x a met has o ne a n d/ or hi g h d ose c yt ara bi ne 
s h o ul d be c o nsi dere d f or D o w n’s s y n dr o me patie nts treate d o n t he sta n dar d/ hi g h-ris k ar m 
w h o e x perie nce hi g her t h a n e x pecte d t o xicit y d uri n g earlier p hases of t hera p y. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 3. 9  
R S V P r o p h yl a xis 
 
All i nfa nts s h o ul d recei v e R S V pr o p h yla xis as per c urre nt i nstit uti o nal p olic y. 
 
1 3. 1 0 Pr o p h yla ctic A nti bi otics D uri n g Peri o ds of Pr ol o n ge d Ne utr o pe nia 
 
P atie nts wit h e x pecte d peri o ds of se vere ne utr o p e nia ( A N C < 3 0 0) of 5 da ys or l o n ger (e. g., 
d uri n g  i n d ucti o n, r ei n d ucti o n, a n d i nte nsificati o n) s h o ul d recei ve pr o p h yl actic a nti bi otics 
( va nc o m yci n + ci pr ofl o x aci n or cefe pi me) a n d a ntif u n gals ( micaf u n gi n if patie nt is 
recei vi n g w ee kl y vi ncristi ne, or v oric o naz ole if patie nt has c o m plete d all vi ncristi ne d oses 
i n t he treat me nt p hase). 
 
1 4. 0 
O F F- T R E A T M E N T A N D O F F- S T U D Y C RI T E RI A  
 
1 4. 1  
Off Treat me nt Criteria 
 
A pa tie nt is ta ke n off T O T X VI t hera p y if a n y of t he f oll o wi n g o cc urs: 
 
 F ail ure t o a c hie ve re missi o n after re missi o n i n d ucti o n, c o ns oli dati o n, a n d 
rei nte nsificati o n treat me nt 
 B o ne marr o w or e xtra me d ullar y (e x ce pt C N S) rel a pse  
 S ec o n d mali g n a nc y (e. g., t hera p y-i n d uce d A M L or brai n t u m or) 
 De vel o p me nt of u nacce pta ble t o xicit y d uri n g treat me nt ( wit h c o nc urre nce 
of t he PI or c o- PI) 
 P atie nts wit h se vere c o n ge nital i m m u n o deficie nc y (e. g. ata xia 
tela n gi ectasia) or HI V i nfecti o n will be ta ke n off T O T X VI t hera p y a n d 
will recei ve alter nate t h era p y (t o pre v e nt e xcessi ve t o xicities) wit h 
c urati ve i nte nt. 
 C o m pleti o n of all pr ot oc ol- prescri b e d treat me nt 
 P artici pa nt/fa mil y decisi o n t o wit h dra w fr o m pr ot oc ol treat me nt at a n y 
ti me f or a n y reas o n 
 I n v esti gat or deci d es c o nti n ue d pr ot oc ol treat me nt is n o l o n ger i n patie nt’s 
best i nterest 
 
1 4. 2 
Off St u d y Criteria 
 
A pa tie nt is ta ke n off T O T X VI st u d y if a n y of t h e f oll o wi n g occ urs: 
 
 Deat h 
 L ost t o f oll o w- u p 
 Wit h dra wal of c o nse nt f or c o nti n ue d f oll o w- u p 
 F o u n d t o be i neli gi ble (e. g., i nc orrect dia g n osis) 
 
F oll o w u p will st o p at t he ti me t he patie nt is off st u d y. T he f oll o w u p ti me of a n 
off-st u d y patie nt is ce ns ore d at t his p oi nt, a n d n o o utc o me data be y o n d t h e off- 
st u d y ti me will be use d i n a nal ys es. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 5 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 5. 0 
D A T A S A F E T Y M O NI T O RI N G B O A R D  
 
T he  pr ot oc ol pr o gress will be re vie we d a n d m o nit ore d b y t he St. J u de C hil dre n’s Researc h 
H os pital Data Safet y M o nit ori n g B o ar d ( D S M B).  Data s u m maries will be pr o vi de d t o t he 
D S M B b y t h e De p art me nt of Bi ostatistics after re vie w b y t h e Pri nci pal I n v esti gat or.  T he 
data will i ncl u de patie nt accr ual, de m o gra p hic s u m maries, gra de 3/ 4 t o xicities, maj or 
a d verse e ve nts (i.e. d eat hs, rela pses, sec o n d mali g na ncies) a n d res ults of i nteri m a n d fi nal 
a nal ys es as s pe cifie d i n t he pr ot oc ol.  T he d ata are retri e ve d fr o m t he dat a b ase a n d are 
re vie we d at e ver y T O T X VI meeti n g, w hic h is ge n erall y hel d t wice a m o nt h, a n d are 
reflecte d i n t he mi n utes, w hic h are pr o vi de d t o t he bi ostatisticia n. W he n t he a p pr o priate 
n u m ber of patie nts ha v e faile d or accr ue d, tri g geri n g i nteri m or fi n al a nal ysis, t he 
bi ostatisticia n will be i nf or me d b y t h e PI.  S h o ul d a safet y st o p pi n g r ule b e e x cee de d, t he 
pr ot oc ol will be te m p oraril y cl ose d u ntil t he D S M B ca n re vie w t he sit uati o n. Re p orti n g 
will c o m pl y wit h i nstit uti o nal g ui deli nes f or m o nit ori n g. 
 
1 6. 0 
BI O L O GI C S T U DI E S  
 
1 6. 1 
Mi ni mal Resi d ual Disease 
 
T his s t u d y will a p pl y i m m u n ol o gic a n d m olec ular met h o ds as d o ne i n T O T X V. T he 
le u ke mia mar kers c o m m o nl y use d t o st u d y mi ni mal resi d ual diseas e b y 4- c ol or fl o w 
c yt o metr y are liste d i n t he t a ble bel o w. D uri n g t h e c o urse of T O T X VI, we will gra d u all y 
i ncreas e t he para meters t o be st u die d si m ulta ne o usl y, ta ki n g a d va nt a ge of n o vel 
i nstr u me nts t hat all o w t he detecti o n of 6 or m ore fl u or oc hr o mes. T his s h o ul d all o w a 
better discri mi nati o n of le u ke mi a cells w hile re d u ci n g t he n u m b er of cells re q uire d f or t he 
a nal ysis. 
 
I m m u n o p he n ot y pic mar kers m ost c o m m o nl y use d t o st u d y M R D i n c hil dre n wit h A L L 
A L L  li nea ge 
P he n ot y pe  
Fre q ue nc y  ( %)† 
B -li nea ge 
C D 1 9/ C D 3 4/ C D 1 0/ T d T *  
3 0 -5 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 3 8 *  
3 0 -5 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 4 5 *  
3 0 -5 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 1 3  
1 0 -2 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 1 5  
5 -1 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 3 3  
5 -1 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ 7. 1  
3 -5  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 6 6c  
1 0 -2 0  
 
C D 1 9/ C D 3 4/ T d T/c yt o plas mic  µ *  
1 0 -2 0  
T -li nea ge 
T d T/ C D 3/ C D 5  
9 0 -9 5  
 
C D 3 4/ C D 3/ C D 5  
3 0 -5 0  
* T he use of t hese i m m u n o p he n oty pes f or M R D st u dies relies m ai nly o n differe nces i n i nte nsities of ex pressi o n  
bet wee n le uke mic ly m p h o bl asts a n d n or m al ly m p h oi d pr o ge nit or cells. T he re m ai ni n g c o m bi n ati o ns rely  m ai nly 
o n t he a berr a nt ex pressi o n of o ne of t he m arker s.  †Pr o p orti o n of c hil d h o o d A L L c ases i n w hic h o ne le uke mic 
cell i n 1 0 4 n or m al b o ne m arr o w cells c a n be  detecte d wit h t he liste d i m m u n o p he n oty pic c o m bi n ati o n. M ost c ases 
ex press m ore t h a n o ne c o m bi n ati o n s uit a ble f or M R D st u dies.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A n y p artici pa nt re gistere d i n T O T X VI w h ose l e u ke mic cells are a me na ble t o o ur assa ys 
will be eli gi ble f or testi n g.  Peri p h eral bl o o d sa m ples ( 5- 1 0 ml) will be ta k e n o n da y 8 i n 
all patie nts. B o ne marr o w sa m ples will be e x a mi ne d i n all patie nts o n da y 1 5 ( +/- 2 2) of 
remissi o n i n d ucti o n t hera p y a n d at c o m pleti o n of i n d ucti o n t hera p y; patie nts wit h T-
linea ge A L L will als o ha ve t heir peri p h eral bl o o d e x a mi ne d at t hese ti me p oi nts. All 
patie nts wit h B-li nea ge A L L wit h resi d ual blasts at e n d of i n d ucti o n will ha ve se q ue ntial 
M R D assa ys d uri n g re missi o n (e. g. d a y 1 of rei n d ucti o n I a n d II), a n d wee k 4 8 of 
c o nti n uati o n treat me nt. All patie nts wit h T-li nea ge A L L a n d resi d ual blasts at t he e n d of 
i n d ucti o n a n d t h ose wit h “at y pical” T- A L L will ha ve se q ue ntial M R D assa ys i n b o ne 
marr o w a n d p eri p heral bl o o d d uri n g re missi o n (e. g. da y 1 of rei n d u cti o n I a n d II), a n d 
wee k 4 8 of c o nti n uati o n treat me nt. Patie nts wit h T-li nea ge A L L a n d n o resi d ual blasts at 
t he en d of i n d ucti o n will ha ve M R D deter mi ne d o nl y i n peri p heral bl o o d at t he sa me ti me 
p oi nts. M R D will be als o deter mi ne d i n all patie nts w he ne ver cli nicall y i n dicate d. 
 
We will use dee p se q ue n ci n g te c h ni q ue t o e v al uate M R D i n C S F wit h t he ai m of 
deter mi ni n g w h et her l e vels of M R D i n t he C S F at dia g n osis a n d d y n a mics of earl y M R D 
re d ucti o n i n C S F c o ul d b e use d t o f urt her refi ne t h e ris k of C N S rela pse. T his mi g ht 
p ote ntiall y lea d t o i m pr o ve d classificati o n f or pati e nts at ris k of C N S rela pse a n d all o w t he 
re d ucti o n of i ntrat he cal t hera p y i n f ut ure st u dies i n c hil dre n wit h rare i de ntifia ble blast b y 
m or p h ol o g y b ut l o w le vels of M R D.  We will als o f oll o w M R D of t he b o ne marr o w a n d 
peri p heral bl o o d b y d ee p se q ue nci n g tec h ni q u e t o deter mi ne if t his m ore se nsiti ve a n d 
s pecific test will s h o w c o nc or da nce u nli ke t he fl o w a n d P C R base d M R D tests.  If 
c o nc or da nt, t he n we ca n m o nit or B- A L L patie nt usi n g a less i n vasi ve t esti n g of t he 
peri p heral bl o o d si milar t o T- A L L patie nts. 
 
1 6. 2  
Ger mli ne D N A/ R N A 
 
Peri p heral bl o o d ( 5 ml) at da y 3 (f or i nitial T P M T ge n ot y pi n g a n d as a bac k- u p f or a n y 
partici pa nts wit h earl y wit h dra wal or d eat h) a n d c o nc urre nt wit h t he bl o o d c ollecte d f or 
M T X plas ma le vels d uri n g c o ns oli dati o n.   Le u k o c yt es will be is olate d, a n d cells will be 
cr y o pres er ve d or D N A a n d R N A will be is olate d usi n g sta n dar d tec h ni q ues. 
 
A n ali q u ot of D N A fr o m e ver y patie nt w h o h as si g ne d T B A N K ( or its s uccee di n g b a n ki n g 
pr ot oc ol) will be a vaila bl e fr o m t he p har mac o ge netics D N A sa m ple t o t he Cell Ba n k 
la b orat or y. 
 
1 6. 3 
De x a met has o ne/ As para gi nase Ser u m P har mac o d y na mic Bi o mar kers 
 
B l o o d sa m ples ( 3 ml eac h) will be dra w n i n a re d t o p t u be at da y 1 5 of i n d ucti o n a n d da y 
1 5 of c o ns oli dati o n a n d at wee ks 7, 8, a n d 1 7 of c o nti n uati o n, a n d a gree n t o p t u be ( 3 ml 
eac h) will be dra w n o n D a y 8 of wee ks 7 a n d 1 7 of c o nti n uati o n. 
 
I n a d diti o n, hei g hts are n o w rec or de d caref ull y m o nt hl y o n a sta di o meter ( usi n g t he 
a vera ge of 3 re plicate m eas ures) a n d t hese d ata are e ntere d i n t he A S 4 0 0 a n d 
MI L LI/ P o w erc h art s yste ms.  B ot h c ortis ol a n d hei g ht c ha n ge ha v e bee n rel ate d t o 
gl uc o c ortic oi d plas ma A U C pre vi o usl y. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 6. 4  
Deter mi nati o n of A L L Blast Se nsiti vit y t o A nti- Le u ke mic A ge nts, i n vitro  
 
We will use a p orti o n of t he dia g n ostic b o ne marr o w fr o m eac h patie nt ha vi n g a n a de q u ate 
n u m ber of cells i n t he sa me e x vi v o dr u g se nsiti vit y assa y we ha v e pre vi o usl y use d t o 
meas ure resista nce t o a nti- leu ke mic a ge nts, as we ha ve pre vi o usl y des cri be d i n detail 1 3.  
W it hi n h o urs of sa m pli n g, m o n o n uclear cells are is olate d fr o m b o ne marr o w as pirates b y 
Fic oll- H y pa q u e gra di e nt; if necessar y, sa m ples are f urt her e nri c he d t o m ore t ha n 9 0 
perce nt le u k e mic blasts b y re m o vi n g n o n- mali g n a nt cells usi n g ma g netic acti vate d cell 
s orti n g.  Le u k e mic cells are t he n re-s us pe n de d i n c ult ure me di u m c o nsisti n g of R P MI 
1 6 4 0 s u p ple me nte d wit h 2 0 perce nt fetal calf ser u m, 2 m M L- gl uta mi ne, 2 0 0 g/ ml 
ge nt a mici n, 1 0 0 I U/ ml pe nicilli n, 1 0 0 g / ml stre pt o m yci n, 0. 1 2 5 g/ ml f u n giz o ne, a n d 5 
g/ ml i ns uli n, 5 g/ ml tra nsferri n a n d 5 n g/ ml s o di u m sele nite.  T hese t u m or cells are 
c ult ure d i n a 9 6- w ell micr o c ult ure plate i n t he prese nce of a ra n g e of dr u g c o nce ntr ati o ns. 
 
After 4 da ys of c ult ure, M T T ( 3- 4, 5- di met h ylt hiaz ol- 2, 5- di p he n yl tetraz oli u m br o mi de) is 
ad de d f or s e veral h o urs, as pre vi o usl y descri be d i n detail 1 3.  T his met h o d is use d t o 
de ter mi ne dr u g se nsiti vit y t o merca pt o p uri ne, t hi o g ua ni n e, pre d nis ol o ne, de x a met has o ne, 
vi ncr isti ne, L-as para gi nase, c yt ara bi ne, a n d d a u n or u bici n.   T hese st u dies re q uire < 2 x 1 05 
cells per well, f or 6 dr u g dil uti o ns i n d u plicate pl us 6 c o ntr ol wells, f or a t otal of 3 x 1 0 6 
cells per dr u g (If fe wer t ha n 2. 4 x 1 0 7 cells are a v aila ble, t he n we will w or k wit h t he 
Pat h ol o g y De p art me nt t o pri oritize w hic h dr u gs ca n be st u die d base d o n t he n u m ber of 
cells a vaila ble.  T his is t he sa me pr o ce d ure we h a v e ha d i n place si nce 2 0 0 0.) T he dr u g 
co nce ntr ati o n let hal t o 5 0 perce nt of t he le u ke mia cells ( L C 5 0- val ue) is use d as t he 
meas ure of cell ular dr u g resista nce. 
 
F or eac h a nti-l e u ke mic a ge nt, w e will treat t he i n vitr o i n di vi d ual dr u g a n d m ulti- dr u g 
cr oss se nsiti vities as c o nti n u o us p he n ot y pes i n dat a a nal yses. I n a d diti o n, we will se parat e 
patie nts i nt o t o p 2 5 %, mi d dle 5 0 % a n d b ott o m 2 5 % gr o u ps base d o n t heir dr u g 
se nsiti vities, ra n gi n g fr o m t he m ost resista nt t o t he m ost se nsiti ve. We will als o e x a mi ne if 
patie nts ca n be s e parate d i nt o gr o u ps bas e d o n a m o del base d cl usteri n g met h o d 
( M C L U S T) b ase d o n t heir dr u g s e nsiti vities. We will e x pl ore w het her i n di vi d ual dr u g 
se nsiti vities or m ulti- dr u g cr oss se nsiti vities differ a m o n g A L L s u bt y pes (e. g. B-li nea ge 
vs. T-cell). 
 
1 6. 5 
N K C ell R ece pt or St u d y 
 
Peri p heral bl o o d ( 3 ml) will be o btai ne d at dia g n osis f or i m m u n o p he n ot y pi n g a n d ( 8. 5 ml) 
bef ore rei n d ucti o n f or i m m u n o p he n ot y pi n g a n d ge n ot y pi n g f or N K cell rece pt ors as 
descri be d pre vi o usl y 8 2; 1 2 3.  Bl o o d sa m ples will be c ollecte d i n A C D ( yell o w-t o p) t u bes.  
We will assess N K cell rece pt ors i ncl u di n g KI Rs, N C Rs, N K G 2 D, D N A M- 1, 2 B 4, a n d 
N T B A.  T h e sa m ple s h o ul d be o btai ne d bef ore t h e a d mi nistrati o n of ster oi ds. 
 
1 6. 6 
I ntesti nal Micr o bi o me Researc h 
 
T o partici pate i n t his researc h, partici pa nts ca n n ot ha ve recei ve d c he m ot hera p y, f or l o n ger 
t ha n 7 2 h o urs, a n d m ust n ot ha ve recei ve d a nti micr o bial a ge nts f or > 7 2 h o urs wit hi n o ne 
wee k pri or t o e nr oll me nt.  Partici pa nts m ust als o n ot ha ve a cli nical or micr o bi ol o gicall y-
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
pr o ve n diarr heal ill ness. 
 
T w o st o ol s peci me ns will be c ollecte d fr o m res earc h partici pa nts, o ne is d uri n g a ti me 
peri o d bef ore starti n g i n d ucti o n c he m ot hera p y ( or u ntil t he first 7 2 h o urs after starti n g 
i n d ucti o n c he m ot hera p y), a n d t he sec o n d s a m ple will be c ollecte d wit hi n 2 wee ks after 
co m pleti o n of A L L re missi o n-i n d ucti o n c he m ot hera p y ( bef ore t he H D M T X d ose # 2 of t he 
c o ns oli dati o n p hase) t o i n vesti gate t h e c ha n ges i n t he g ut micr o bi ota. Pair e d st o ol sa m ples 
will be batc he d t o be a nal yz e d si m ulta ne o usl y. Bacterial ge n o mic D N A will be har veste d 
fr o m t hese sa m ples a n d utilize d f or ri b os o mal D N A se q ue nci n g t o deter mi ne t he o verall 
bacterial micr ofl ora pri or t o a n d f oll o wi n g c h e m ot hera p y. T h ese t w o met h o d ol o gies will 
pr o vi de a preli mi nar y i n v esti gati o n i nt o a n y n ota bl e alterati o ns i n bacterial di versit y 
res ulti n g fr o m t hera p e utic i nter ve nti o ns.  I n ta n de m, we will als o is olate R N A fr o m t hese 
sa m ples f or se q u e nci n g i n or der t o i de ntif y n o vel R N A vir uses. O nce n ot a ble differe nces 
i n t he micr o bi o me bef ore a n d after c he m ot hera p y are det er mi ne d, we will t he n atte m pt t o 
descri be t he gastr oi ntesti nal c o m plicati o ns d uri n g i n d ucti o n a n d o ver t he ne xt si x m o nt hs. 
I n p artic ular, we are i ntereste d i n w het her t h e a b u n da nce or a bse n ce of parti c ular bacteri al 
or viral pat h o ge ns will s h o w ass ociati o n wit h s u bse q ue nt gastr oi ntesti nal ill nesses. O ver 
t he a p pr o xi matel y 6 m o nt h peri o d after t h e c ollecti o n of t he sec o n d st o ol sa m ple, t w o 
f oll o w- u p st o ol sa m ples will be pr os pecti vel y c oll ecte d at ti me p oi nts w here patie nts are 
see n i n Me m p his: wit hi n 4 8 h o urs of Da y 1 of R ei n d ucti o n I a n d Rei n d ucti o n II. T hese 
st o ol sa m ples will be c ollecte d at t he s p ecifie d ti m e p oi nts irres pecti ve of i nta ke of 
a nti micr o bial a ge nts. I n a d diti o n, a 1. 0- 2. 0 m L v ol u me of left o ver st o ol s pe ci me ns 
c ollecte d at SJ C R H f or cli nical p ur p oses will be pr os pecti vel y o bt ai ne d fr o m t he cli nical 
bacteri ol o g y a n d vir ol o g y la b orat ories wit hi n 4 8 h o urs of c ollecti o n. T hes e st o ol sa m ples 
will be use d f or f urt her testi n g of bacterial a n d viral D N A usi n g P C R assa ys t hat will be 
de vel o pe d t o dete ct a n y viral or bact erial pat h o ge n t hat was pr o mi ne nt b y t he ge ne 
se q ue nci n g a n al ysis of t h e c ha n gi n g micr o bi o me.  T he sa me a p pr oac h will be use d t o 
i n vesti gate f u n gal pat h o ge ns.  Me dical r ec or ds will be re vie we d t o c ollect d ata a b o ut 
i nfecti o us diseases, pr o bi otics, a ntaci ds a n d a nti micr o bial use d uri n g t he st u d y peri o d. 
O nl y des cri pti ve statistics s uc h as me dia n, ra n ge a n d perce nt a ges will be us e d as 
a p pr o priate. T he pr o p ose d st u d y is i nte n de d t o be a pil ot i n vesti gati o n t o test feasi bilit y of 
t his a p pr oac h a n d o pti mi ze e x peri me ntal pr oce d ures. T he data a n d i nf or mati o n o btai ne d i n 
t hese i n vesti gati o ns will be utilize d as preli mi nar y data f or a lar ger scal e st u d y a n d f ut ure 
gra nt a p plicati o ns. 
 
1 6. 6. 1  Visi t A:  St o ol sa m ple will be c ollecte d d uri n g a ti me peri o d bef ore starti n g 
i n d ucti o n c he m ot hera p y ( or u ntil first 7 2 h o urs aft er starti n g i n d ucti o n c he m ot hera p y). T his 
s peci me n will be use d t o r u n t he la b orat or y i n v esti gati o n i n Dr. T u o m a ne n’s a n d Dr. 
Sc h ultz- C herr y’s rese arc h la b orat ories as d escri b e d i n secti o n 1 6. 7. 4. Visit A ca n occ ur o n 
t he sa me da y as s cree ni n g/e nr oll me nt. 
 
1 6. 6. 2  Visit B:  St o ol sa m ple will be c ollecte d wit hi n 2 w ee ks aft er c o m pleti o n of A L L 
re missi o n- i n d ucti o n c he m ot hera p y ( bef ore t h e H D M T X d ose # 2 of t he c o ns oli dati o n 
p ha se).  T his s peci me n will be use d t o r u n t he la b orat or y i n vesti gati o n i n Dr. T u o ma ne n’s 
a n d Dr. Sc h ultz- C herr y’s researc h la b orat ories as descri be d i n secti o n 1 6. 7. 4. 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 6. 6. 3  F oll o w- u p st o ol s peci me ns:  O ver t he a p pr o xi matel y 6 m o nt h peri o d after t he 
c ollecti o n of t he sec o n d st o ol sa m ple ( Visit B), t w o f oll o w- u p st o ol sa m ples will be 
pr os pecti vel y c ollecte d at ti me p oi nts w here patie nts are see n i n M e m p his: wit hi n 4 8 h o urs 
of Da y 1 of Rei n d u cti o n I a n d Rei n d ucti o n II. T h ese st o ol sa m ples will be c ollecte d at t he 
s pecifie d ti me p oi nts irres pecti ve of i nta ke of a nti micr o bial a ge nts. I n a d diti o n t o t hese 
sa m ples, 1. 0- 2. 0 m L of left- o ver st o ol s peci me ns c ollecte d at SJ C R H f or bacterial st o ol 
c ult ure a n d C. difficile t o xi n detecti o n will be pr os pecti vel y o btai ne d fr o m t he cli nical 
bacteri ol o g y a n d vir ol o g y la b orat ories, res pecti vel y, wit hi n 4 8 h o urs of c ollecti o n. T hese 
st o ol sa m ples will be use d f or f urt her testi n g of bacterial a n d vir al D N A usi n g P C R assa ys 
t hat will be de vel o pe d t o detect a n y vir al or bact eri al pat h o ge n t hat was pr o mi ne nt b y t he 
ge n e se q ue n ci n g a nal ysis of t he c ha n gi n g micr o bi o me.  T he sa me a p pr oac h will be use d t o 
i n vesti gate f u n gal pat h o ge ns. 
 
1 6. 6. 4  La b orat or y met h o ds a n d materials 
 
Fecal sa m ples will be c ollecte d a n d i m me diatel y place d i nt o R N A Pr otect, a sta bilizati o n 
rea ge nt. T u b es will be pre pare d i n a d va nce a n d st ore d u ntil sa m ple c ollecti o n. Sa m ples 
will t he n be pr ocesse d wit hi n 6 h o urs of c ollecti o n. Fecal sa m ples will be st ore d at - 8 0˚ C 
u ntil pr ocessi n g at a later ti me i n batc he d r u ns. D N A a n d R N A will be e xtracte d fr o m t he 
sa m ple b y b ea d- b eati n g f oll o we d b y p h e n ol c hl or of or m e xtracti o n or c ol u m n p urificati o n 
met h o ds.  A n y left- o ver st o ol s peci me ns after t h e c o m pleti o n of t he D N A a n d R N A 
e xtracti o n will be discar de d. 
 
T he g ut micr o bi ota will be se q ue nce d usi n g t w o i n de pe n de nt met h o d ol o gies. O ne 
met h o d ol o g y will utilize u ni versal pri mers a n d s u bcl o ni n g t o a m plif y t he ri b os o mal 
se q ue nces fr o m t he is olat e d bacterial D N A. T h ese s u bcl o nes will t he n be utilize d t o 
ge n erat e a n Ill u mi na ge n o mic li brar y. T he ot her a p pr oac h will utilize D N A a n d R N A t hat 
has bee n e nric he d fr o m a n y e u k ar y otic c o nt a mi nati o n wit h o ut a n y s u bcl o ni n g. O ur 
met h o d ol o g y s h o ul d yi el d a p pr o xi matel y 1 0 0 µ gs of D N A a n d 2 0 µ gs of R N A, s ufficie nt 
f or a p pr o xi matel y te n i n d e pe n de nt se q u e nci n g r u ns. T his will all o w f or t he deter mi nati o n 
of bacterial di versit y i n t he g ut as well as t he i de ntificati o n of n o vel, g ut ass ociate d vir uses 
t hat c orrel ate wit h d o w nstrea m cli nical o utc o mes. 
 
F or t he se q u e nci n g, 3 p M of eac h s m all li brar y will be l oa de d o nt o a fl o w cell o n t he 
Ill u mi na Cl uster Stati o n. A 3 p M P hi X D N A sa m ple was use d as a cl uster a n d se q ue nci n g 
c o ntr ol.  T he rea ds o n t he si n gle rea d fl o wcell will t he n be s u bjecte d t o 1 5 2 c ycles of 
se q ue nci n g o n t he Ill u mi na Ge n o me A n al yzer platf or m. T he base calls were a nal yz e d 
usi n g Ill u mi na's Pi peli ne versi o n 1. 4. 0. T his met h o d ol o g y all o ws f or t he ge n erati o n of 
a p pr o xi matel y 1 0 milli o n rea ds of a n a vera ge le n gt h of 1 0 0 base pairs, pr o vi di n g e x celle nt 
ge n etic c o v era ge.   
 
T he rea ds will t he n be a n al yze d b y a n u m b er of rea dil y a v aila ble s oft w are pr o gra ms 
s pecificall y desi g ne d f or meta ge n o mic a nal ysis a n d p h yl o ge n etic rec o nstr ucti o n. T his will 
all o w f or t he det er mi nati o n of c ha n ges i n o v erall bacterial di versit y a n d p o p ulati o n 
d y na mics. T his met h o d ol o g y will als o all o w f or t h e detecti o n of a n y k n o w n or pre vi o usl y 
u nc haracteriz e d vir uses i n t he sa m ple. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 7. 0 
N E U R OI M A GI N G S T U DI E S  
 
T he  ne ur oi ma gi n g ai ms are or ga nize d u n der t he h y p ot hesis t hat t hera p y f or A L L ca n h a ve 
a detri me ntal i m pact o n t he de vel o pi n g brai n res ulti n g i n ne ur oc o g niti ve deficits, w hic h 
will res ult i n decreas e d q ualit y of life i n s ur vi v ors. T hera p y i n d uce d i ma gi n g c h a n ges i n 
t he de vel o pi n g brai n (s u c h as m yeli n a n d c ortical t hic k ness de vel o p me nt) c o ul d partiall y 
be relate d t o ge netic p ol y m or p his ms ass ociate d wit h f olate meta b olis m. 
 
St u d y  
I n d ucti o n 
C o ns oli dati o n  
Wee k  7,  c o nti n uati o n  
( Wee k 1 Re -i n d ucti o n I) 
Wee k  1 2 0,  
c o nti n uati o n 
T w o  year  p ost  
t hera p y 
P sy ch ol o g y   
 
X  
X  
X  
M RI -brai n  
 
 
X *  
X  
X * *  
* M R s h o ul d be o bt ai ne d bef ore st arti n g dex a met h as o ne. 
* * P atie nts wit h a b n or m al i m a gi n g ev al u ati o ns at week 1 2 0 will h ave a n extr a ex a m at 2 
ye ars off t her a py t o re assess br ai n str uct ure.  
 
1 7. 1 
M R I ma gi n g 
 
M R I of t he brai n will be o btai ne d at 2 ti me p oi nts: W ee k 1 of Rei n d ucti o n I ( Wee k 7 
C o nti n uati o n bef ore starti n g de x a met has o ne) a n d wee k 1 2 0 of c o nti n uati o n t hera p y. T hes e 
st u dies were d esi g n e d t o yi el d l o n git u di nal meas ures of w hite matter i nte grit y 
( m yeli nati o n) a n d c ortical t hic k ness d uri n g tr eat m e nt. 
 
T he first M RI e x a mi nati o n at Rei n d ucti o n I will pr o vi de a q ua ntitati ve meas ure of m yeli n 
a n d c ortical t hic k n ess de vel o p me nt relati ve t o a ge n der a n d a ge mat c he d h ealt h y c o ntr ol 
gr o u p, w hic h ma y be disr u pte d b y t hera p y. T h e sec o n d M RI e x a mi nati o n is at wee k 1 2 0 of 
c o nti n uati o n (e n d of t hera p y). B y assessi n g all patie nts at t his ti me p oi nt, we ca n 
deter mi ne if t he n or m al brai n de vel o p me nt has b ee n affecte d b y t hera p y. 
 
T hese a b bre viate d cli nical M RI sca ns will c o nsist of T 1 sa gittal f or l ocalizati o n f oll o we d 
b y hi g h-res ol uti o n T 1, T 2/ P D, a n d F L AI R i ma ges c o veri n g t he e ntire cere br u m ac q uire d 
at 3 Tesla. T hes e are f oll o we d b y D TI a n d m yeli n water i ma gi n g. T he f ull e x a mi nati o n 
ca n be p erf or m e d i n a p pr o xi matel y 4 5 mi n utes f or c hil dre n n ot re q uiri n g se dati o n a n d 7 5 
mi n utes f or c hil dre n re q uiri n g se d ati o n. 
 
M ost  c hil dre n si x years of a ge a n d ol d er ca n t olerate t he pr oce d ure wit h o ut se dati o n. All 
sca ns will be e val u ate d b y a n e ur ora di ol o gist f or cli nicall y rel e va nt fi n di n gs t hat will be 
ca pt ure d i n a d ata re p orti n g f or m. 
 
T he T 1, T 2/ P D, a n d F L AI R i ma ges will be a nal yz e d wit h s oft ware de vel o p e d a n d 
vali date d at o ur ce nter s p ecificall y f or q ua ntificati o n of w hite matter c h a n ges a n d brai n 
tiss ue v ol u mes. T hese hi g h-res ol uti o n i ma ges will als o be use d t o assess c ortical t hic k ness 
base d o n t he se g me nt e d tiss ue ma ps usi n g t he Free S urfer s oft ware. D TI ac q uires a set of 
diff usi o n i ma ges i n si x or m ore directi o ns a n d us es t he m t o f ull y defi n e a diff usi o n te ns or 
f or eac h p oi nt i n t he i ma ge1 2 4; 1 2 5.  O nce t he te ns ors ha ve bee n calc ul ate d, Ei ge n v al ues ca n 
be  deri ve d a n d use d t o c alc ulate a p pare nt diff usi o n c oeffi cie nt ( A D C), per pe n dic ular a n d 
parallel diff usi o n c o effi cie nts ( D , D||), an d fracti o nal a nis otr o p y ( F A) ma ps f or t he w h ole 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
brai n. T hese me as ures are relate d t o t he i nte grit y of t he m yeli n s h eat h w hi c h restricts t he 
diff usi o n of water per pe n dic ular t o t he a x o ns wit hi n t he w hite matter fi ber tracts. M yeli n 
water i ma gi n g will be a n al yze d usi n g s oft ware de vel o pe d a n d vali dat e d at o ur ce nter 
s pecificall y f or q ua ntificati o n of m ulti-e x p o ne ntial T 2 rela xati o n data t o assess t he 
i nte grit y of t he m yeli n s h eat h. Q ua ntitati ve m ulti ple e x p o ne ntial fitti n gs of t he T 2 
rela x ati o n c o m p o ne nts i n w hite matter ca n b e use d t o ge n erate M W F m a ps (fr o m t he T 2 
c o m p o ne nts less t ha n 4 0- 5 0 ms) a n d L W F ma ps ( T 2 c o m p o ne nts 2 0 0- 8 0 0 ms). 
 
I ma gi n g fr o m a ver y lar ge a ge-si milar healt h y c o ntr ol p o p ulati o n has bee n c ollecte d u n der 
t he “ NI H M RI St u d y of N or mal Brai n De v el o p me nt”  
(htt p:// w w w. bic. m ni. m c gill.ca/ ni h p d/i nf o/ ). T he first p hase of t his pr oject e nr olle d 
c hil dre n a ges 4 years, 6 m o nt hs t hr o u g h 1 8 years (t otal N = 4 3 3). T his sa m ple was 
recr uite d acr oss t he si x Pe diatric St u d y Ce nt ers usi n g c o m m u nit y b ase d sa m pli n g t o reflect 
t he de m o gra p hics of t h e U nite d States i n ter ms of i nc o me, race, a n d et h nicit y. T he s u bjects 
are st u die d wit h b ot h i ma gi n g a n d cli nical/ be ha vi oral meas ures at t w o year i nter vals f or 
t hree ti me p oi nts. I m a gi n g c ollecte d i ncl u de d c o n ve nti o nal T 1-/ T 2-/ P D- wei g hte d M R 
i ma gi n g as w ell as diff usi o n te ns or i ma gi n g. T hes e i ma gi n g d ata sets will be a nal yz e d wit h 
t he sa me pr oce d ures us e d f or t he patie nt e xa mi nati o ns. 
 
1 7. 2 
Ge netic P ol y m or p his ms 
 
All patie nts wil l be ge n ot y p e d as descri be d i n secti o n 2. 2. 1. We will f oc us o ur a nal ysis o n 
a t he oreticall y j ustifie d cl ass of p ol y m or p his ms relate d t o t he f olate met a b olis m pat h wa y. 
All rele va nt f olate pat h w a y p ol y m or p his ms will be i ncl u de d, gi ve n t heir relati o ns hi p t o 
M T X treat me nt a n d ele v ate d h o m oc ystei ne. Ge nes of i nterest i ncl u de M T H F R, D H F R, 
T S, R F C, M S, M T R R, a n d C B S. 
 
1 7. 3 
Ps yc h ol o gical T esti n g 
 
A ge  a p pr o priate ps yc h ol o gic al testi n g will be perf or me d i n all partici pa nts at Wee k 1 of 
Rei n d ucti o n I ( Wee k 7 of C o nti n uati o n), at wee k 1 2 0 of C o nti n uati o n, a n d t w o years p ost 
t hera p y. Ps yc h ol o gical m eas ures were caref ull y selecte d base d o n ps yc h ol o g y a n d M RI 
fi n di n gs fr o m t he T O T X V pr ot oc ol, as well as t he a vaila ble researc h literat ure1 2 6 - 1 3 2. B ot h 
li nes of e m pirical s u p p ort c o n ver ge i n i de ntif yi n g atte nti o n/e x ec uti ve f u ncti o ns, me m or y 
( partic ularl y n o n v er bal) a n d pr ocessi n g s pee d as v ul nera ble c o g niti ve f u ncti o ns i n t his 
p o p ulati o n. B y f oc usi n g t he assess me nt batter y o n s pecific c o g niti ve f u n cti o ns, rat her t ha n 
m ore tra diti o nal gl o bal meas ures (i.e., I Q a n d aca d e mic ac hie ve me nt), t he pr o p ose d 
batter y will ha ve i ncreas e d se nsiti vit y t o t h ose deficits m ost li kel y t o be de m o nstrate d b y 
A L L s ur vi v ors. F urt her, a f oc use d assess me nt will facilitate t he i de ntificati o n of s pecific 
c o g niti ve areas f or earl y i nt er ve nti o n a n d assist i n t he i de ntificati o n of u n derl yi n g 
ne ur ol o gi cal mec h a nis ms. I n a d diti o n t o be ha vi oral s pecificit y, m eas ures w ere sel ecte d 
t hat ha ve ne ur oa nat o mic s pecificit y i n kee pi n g wit h T O T X V ne ur oi ma gi n g fi n di n gs. 
T heref ore, me as ures w ere select e d t h at are p ut ati vel y s u b ser ve d b y fr o ntal brai n re gi o ns 
(e. g., atte nti o n, fl ue n c y a n d w or ki n g m e m or y) a n d peri ve ntric ular areas (e. g., ver bal a n d 
n o n ver bal me m or y). M eas ures were als o c h os e n t hat ha ve bee n de m o nstrat e d i n ot her 
cli nical p o p ulati o ns t o be se nsiti ve t o w hite matter c ha n ges (i. e., pr ocessi n g s pee d a n d 
vis ual-s patial a bilities). 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
All selecte d meas ures ha ve a ge-s p ecific n or ms fr o m lar ge, re prese nt ati ve sta n dar dizati o n 
sa m ples. Meas ur es als o h a ve a p pr o priatel y de m o nstrate d relia bilit y a n d vali dit y. Gi ve n t he 
l o n git u di nal st u d y desi g n, meas ures w ere c h ose n wit h a p pr o priate test-retest relia bilit y a n d 
ne gli gi ble practice effects f or t he pr o p ose d i nter val bet wee n testi n g ti me p oi nts. A n eff ort 
was ma de t o select meas ures t hat c o ul d assess t he wi dest a ge ra n ge p ossi ble gi v e n t he 
li kel y a ge distri b uti o n at prese ntati o n a n d l o n git u di nal desi g n. N o net heless, n o si n gle 
i ntelli ge nce m eas ur e e xists t hat c o vers t his e ntire a ge s p ectr u m, s uc h t hat a se parat e I Q 
meas ure is ne e de d f or c hil dre n less t ha n t hree years of a ge. C hil dre n less t h a n t hree years 
of a ge will be a d mi nistere d t he M ulle n Scales of Earl y Lear ni n g 1 3 3.  Pare nt q uesti o n naires 
will  be t he sa me f or patie nts t o all o w f or l o n git u di nal a nal yses i ncl u di n g t his y o u n g gr o u p. 
Please see A p p e n di x VI f or a c o m plete listi n g of test meas ures, assesse d a bilities, 
ad mi nistrati o n a ge ra n ge a n d esti mate d testi n g ti m e f or c hil dre n. 
 
A pri mar y assess me nt g o al was t o select a batter y t hat c o ul d be a d mi nistere d i n a 
circ u mscri be d p eri o d of ti me t o re d uce t he ti me b ur de n f or c hil dre n, t heir p are nts a n d t he 
researc h te a m. T he a d mi nistrati o n ti me f or t he test batter y is 1- 3 h o urs, de p e n de nt o n t he 
a ge of t he c hil d a n d t he s pee d wit h w hic h t he y ca n c o m plete tas ks. It is a ntici pate d t hat t he 
a vera ge a d mi nistrati o n ti me will be 2 h o urs. T he ma xi m u m a d mi nistrati o n ti me of 3 h o urs 
is o nl y e x pecte d f or ol d er c hil dre n (i.e., 7- 8 years of a ge) or c hil dre n t h at are n ota bl y sl o w 
(e. g., u n us uall y sl o w s pe e d of c o g niti ve a n d/ or p h ysical pr ocessi n g). T h eref ore, t he 
a d mi nistrati o n le n gt h of t he c urre nt batter y rea dil y lies wit hi n t he sta n dar d le n gt h of 
t y pical cli nical a n d researc h batteri es. It is a ntici pate d t hat pare nts will s pe n d o n a vera ge 
of 4 5 mi n utes c o m pleti n g q uesti o n nair es w hile t h eir c hil d is bei n g assesse d i n a se parate 
r o o m. 
 
1 7. 4 
F u ncti o nal M R I m a gi n g 
 
B l o o d O x y ge n ati o n Le vel De pe n de nt I ma gi n g ( B O L D) is t he 'sta n dar d tec h ni q ue' us e d t o 
ge n erat e i ma ges i n f u ncti o nal M RI st u dies, a n d relies o n re gi o nal differe n ces i n cere bral 
bl o o d fl o w t o deli neate re gi o n al acti vit y d uri n g t h e perf or ma nce of a s p ecific 
ne ur oc o g niti ve tas k. B O L D i ma gi n g is a c q uire d acr oss t he e ntire brai n c o nti n u o usl y 
d uri n g t he p erf or ma nce of t he tas k. T he N- Bac k tas k is a pr ot ot y pical w or ki n g me m or y 
meas ure t hat re q uires a n o n-se date d p artici pa nt t o res p o n d t o a prese nte d sti m ul us (eit her 
letters or o bjects i n o ur i m ple me ntati o n) o nl y w he n it is t he sa me as t he o ne prese nt e d o n a 
trial a pre d eter mi ne d n u m ber ( N) pri or t o t he c urre nt trial. F or eac h letter partici pa nts nee d 
t o hit a res p o nse b utt o n w he n t he letter is i de ntical t o t he letter pres e nte d o ne or t w o bac k 
i n se q ue nce f or t he 1- b ac k a n d 2- bac k trials, res pecti vel y. A c o ntr ol c o n diti o n ( 0- bac k 
trial) will be use d d uri n g w hic h t he sa me c o nti n u o us strea m of si n gle letters or o bj ect is 
prese nte d b ut t he p artici p a nt nee d o nl y deci de w het her eac h letter or o bj ect matc hes a 
si n gle tar get c o m m u nicat e d at t he start of t he t as k. Patie nts w h o meet eli gi bilit y f or t he 
f u ncti o nal M RI (see Secti o n 1 2. 3) will u n der g o t his test at Wee k 1 2 0 of C o nti n uati o n.  I n 
a d diti o n t o t he letter a n d o bject versi o ns of t he N Bac k t as k, t he f u ncti o nal M RI will als o 
i ncl u de a tas k t o i de ntif y t he pri mar y vis ual c ort e x a n d a tas k t o i de ntif y resti n g net w or ks. 
 
F u ncti o nal B O L D i ma ges will be a nal yze d wit h S P M ( S P M 5, U ni versit y C olle ge L o n d o n, 
U K) via 2-le v el a nal ysis. N or malizati o n of f M RI data fr o m c hil dre n a n d a d ults t o t he sa me 
stere otactic brai n s pace h as bee n vali dat e d f or c hil dre n ol der t ha n 7 years 1 3 4; 1 3 5.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
I n d e pe n de nt c o m p o ne nt a nal ysis (I C A) of f M RI d ata will be c o n d uct e d wit h t he GI F T 
T o ol b o x  f or S P M. N- Bac k data will be a nal yze d acc or di n g t o a fi x e d-effect G L M. T as k-
i n d uce d acti vit y will be re prese nt e d b y a b o x car f u ncti o n c o n v ol ve d wit h t he ca n o nical 
he m o d y n a mic res p o nse f u ncti o n. After para meter esti mati o n, t he c o ntrasts reflecti n g t he 
effect of i nterest (e. g., 2- bac k > 1- b ac k) will be set i n t he m o del, a n d t he c orres p o n di n g 
co ntrast i ma ge will be ge nerate d. T h e c o ntr ast i ma ge fr o m eac h s u bject will t he n be use d 
as a vari a ble i n sec o n d-le vel, ra n d o m-effect a nal ysis t o i de ntif y gr o u p patter ns of 
acti vati o n a n d areas i n w hic h brai n acti vit y is ass o ciate d wit h be ha vi or al perf or ma nce.  
V o x els will be c o nsi dere d acti ve f or p < 0. 0 5, c orrecte d f or m ulti ple c o m paris o ns. O ur 
pri mar y a nal ysis will f oc us o n acti vati o n i n t he d ors olateral pr efr o nt al c orte x d uri n g t he N-
bac k tas k. 
 
1 8. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S  
 
T O T X VI h as a si n gle pri mar y o bj ecti ve t o c o m pare t he distri b uti o ns of c o nti n u o us 
c o m plete re missi o n ( C C R) of patie nts ra n d o mize d o n t he first da y of c o nti n uati o n p hase t o 
recei v e hi g h er d ose P E G-as para gi nase or t o recei ve c o n ve nti o nal d osi n g ( 2, 5 0 0 u nits/ m 2). 
T he stratifie d a n al ysis of t he pri mar y o bjecti ve will i ncl u de all eli gi ble patie nts as 
ra n d o mize d a n d will be c o n d ucte d c o nsiste nt wit h t he i nte nt-t o-treat h y p ot h esis. Zel e n’s 
ra n d o mizati o n al g orit h m, as i m ple me nte d i n t he De part me nt of Bi ostatistics si nce 1 9 9 2, 
will be use d wit h a bl oc ki n g fact or of 4 i n eac h strat u m. Details of t he desi g n, sa m ple siz e 
a n d statistical met h o d ol o g y re q uire d f or t he pri mar y o bjecti ve is a d dresse d i n Secti o n 1 7. 2 
a n d will be t he defi ni n g s a m ple siz e f or T O T X VI.  
 
T he ref us al of partici pati o n i n a n y of t he res earc h ai ms will n ot re n der a patie nt i neli gi ble 
f or T O T X VI; patie nts w h o ref use t o c o nse nt t o s o me or all of t he researc h o bjecti ves will 
still be e val ua ble f or ot her st u d y ai ms i ncl u di n g esti mati o n of t he distri b uti o ns of e ve nt-
free s ur vi val a n d s ur vi val. Desi g n p ara m eters f or t he pri mar y o bjecti ve will n ot be 
a dj uste d f or m ulti ple tests. H o we ver, wit hi n a sec o n dar y o bjecti ve it ma y b e a p pr o pri ate t o 
a p pl y met h o ds t o c o ntr ol t he t y pe I err or rate i n ter ms of t he fa mil y- wise t y pe I err or 
pr o ba bilit y or t he false disc o ver y rate, a n d t hes e are s pelle d o ut bel o w. All a nal yses of t he 
ra n d o mize d q uesti o n will be c o nsiste nt wit h t he “i nte nt t o treat” h y p ot hesis; t hat is, all 
eli gi ble ra n d o mize d patie nts will be f oll o we d f or t he pri mar y o utc o me a n d i ncl u de d i n 
a nal ys es as r a n d o mize d. T o t he e xte nt p ossi ble, as i n dicate d i n t he f oll o wi n g secti o ns, all 
eli gi ble patie nts will be i ncl u de d i n all a nal yses.  
 
Met h o d ol o g y f or a nal yzi n g dat a relat e d t o sec o n d ar y o bjecti ves are prese nt e d, b ut i n 
ge n eral p o w er calc ulati o ns are n ot pr o vi de d si nce t he sa m ple siz e f or t he trial is g o ver ne d 
b y t he pri mar y o bjecti ve. M ore o ver, if d uri n g t he c o urse of t his trial m ore a p pr o priate 
statistical met h o ds are i de ntifie d or de v el o pe d, t he n t h ose met h o ds will be use d t o a nal yze 
t he data. 
 
Effect siz e: T he i nte nt- t o-treat h y p ot hesis bei n g teste d i n T O T X VI is t hat d oses of P E G-
as para gi n ase hi g her t h a n c o n ve nti o nal d oses bei n g use d b y ot h er A L L researc h gr o u ps 
will i m pr o ve o utc o me of c hil dre n wit h A L L. T he trial will be gi n b y ra n d o mizi n g patie nts 
t o recei v e eit her 3, 5 0 0 u nits/ m2 or 2, 5 0 0I u nits/ m2 of P E G-as para gi nase d uri n g 
co nti n uati o n t hera p y a n d if 3, 5 0 0 u nits/ m 2 pr o ves t o be t o o t o xic (see 1 7. 1. 2) t he trial will 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c o nti n ue wit h patie nts bei n g ra n d o mize d t o eit her 3, 0 0 0 u nits/ m 2 or 2, 5 0 0 u nits/ m 2.  It 
s h o ul d be n ote d t hat t he i nte nt of T O T X VI is t o test w het her hi g her-t ha n-c o n ve nti o nal 
d oses of P E G-as para gi nase i m pr o ve o utc o me a n d n ot t o deter mi ne t he differe nce i n 
effic ac y or t o xicit y bet w ee n 3, 5 0 0 u nits/ m 2 a n d 3, 0 0 0 u nits/ m2 d osa ges. As disc usse d 
bel o w, s h o ul d t he hi g h er d ose of 3, 5 0 0 u nits/ m 2 pr o ve t o be t o o t o xic, we still will be a ble 
t o ge n erat e ne w i m p orta nt i nf or mati o n a n d i nter preta ble res ults.  
 
T he c o nje ct ure d effect size f or hi g h er d oses of P E G-as para gi nase re prese nts ris k- be nefit 
c o nsi derati o ns of w h at o utc o me is reas o n a ble t o e x pect a n d w o ul d j ustif y acce pti n g 
p ossi bl y sli g htl y hi g h er rates of ma na gea ble as para gi n ase t o xicities. W het her t he 
h y p ot hesize d effect size will be ass ociate d wit h e x p os ure t o 3, 5 0 0 u nits/ m 2 or 3, 0 0 0 
u nit s/ m2 is n ot k n o w n a n d w het her t here will be u nacce pta ble t o xicities ass ociate d wit h 
t he hi gher d ose is als o n ot k n o w n. W hat we d o k n o w is t hat t he trial wit h tra diti o nal 
statistical desi g n para met ers pr o vi des p o wer f or detecti n g a differe n ce i n 5- year 
c o nti n u o us c o m plete re missi o n ( C C R) rates of 8. 5 3 % bet wee n t he c o n v e nti o nal vers us t he 
hi g her d ose a n d fi nal i nter pretati o ns re q uire t hat t h e o verall effect size of 8. 5 3 % is 
mai ntai ne d if t o xicit y re q uires t hat t he d ose of P E G-as para gi nase b e re d uce d f or m 3, 5 0 0 
u nits/ m 2 t o 3, 0 0 0 u nits/ m2. Secti o n 1 7. 2 i ncl u des o ne of ma n y p ossi ble realizati o ns of t he 
trial t hat w o ul d be c o nsiste nt wit h a n o verall 8. 5 3 % i m pr o ve me nt i n t he 5- year C C R rate.  
We d o n ot k n o w w hat deli vera ble d ose of P E G-as para gi nas e is act uall y necessar y t o 
pr o d uce t hes e res ults. We d o belie ve d os es hi g h er t ha n c o n ve nti o nal d oses ca n be s afel y 
gi ve n a n d t hat t hese hi g h er d oses will pr o d uce i m pr o ve d o utc o me, w hi c h re mai ns a n 
i m p orta nt g oal f or c hil d h o o d A L L treat me nt as c urre ntl y n ot all c hil dre n are c ure d. 
 
I nter pret ati o n: We belie ve t hat 3, 5 0 0 u nits/ m
2 of P E G-as para gi nase ca n be deli vere d 
safel y wit hi n t he c o nte xt of T O T X VI ris k- directe d re gi me ns, a n d e x pect t hat t he m ost 
li kel y realizati o n of t he trial is t hat a t o xicit y m o nit ori n g r ule d uri n g c o nti n uati o n t hera p y 
will n ot be tri g gere d a n d we will n ot ha ve t o d ose-re d uce P E G-as para gi nas e. H o we v er, we 
ha ve pla n ne d a c o urse of acti o n if u nacce pta bl e t o xicit y were t o materialize.  
 
T he q uesti o n t hat re mai ns is w hat i nfere n ce will b e dra w n at t he e n d of t h e trial if d ose-
re d ucti o n of P E G- as para gi nas e is re q uire d. If it is necessar y t o d ose-re d uce, a n d if t he 
pla n ne d fi nal a n al ysis of t he trial res ults i n a p- val ue greater t ha n 0. 0 4 5, t he pri mar y 
c o ncl usi o n will be t hat, as i nte n de d t o be deli vere d i n T O T X VI, t he statistical e vi de n ce is 
n ot s ufficie nt t o c o ncl u de t hat t he distri b uti o ns of C C R bet wee n patie nts w h o w o ul d 
recei ve hi g her d os es of P E G-as para gi nas e a n d t h ose patie nts w h o w o ul d recei ve 
c o n ve nti o nal d osi n g differ. F urt her m ore, we w o ul d ha ve e vi de nce t hat, at t he a pri ori  
t hres h ol d set f or t o xicit y, 3, 5 0 0 u nits/ m2 of P E G-as para gi nas e was dee me d t o o t o xic. As 
wit h m ost a m pl y p o were d ne gati ve trials, a d diti o n al a nal yses will li kel y b e atte m pte d t o 
el uci date t he fi n di n gs. T h ese a n al ys es w o ul d pre d o mi na ntl y rel y o n esti mati o n a n d n ot 
testi n g, al beit wit h li mite d p o wer. We s pec ul ate o n o nl y a fe w of t h e ma n y p ossi ble 
reas o ns w h y t he tri al ma y e n d wit h t his res ult. It mi g ht be t hat t he o verall treat me nt res ults 
f or b ot h c o n ve nti o nal a n d hi g her d ose P E G-as p ara gi n ase re gi me ns were s o g o o d t hat n o 
differe nce c o ul d be det ecte d; t hat ha d 3, 5 0 0 u nits/ m 2 bee n t olerate d t he h y p ot hesize d 
diff ere nce m a y ha ve b ee n detecte d; t hat t here was e vi de nce t h at patie nts ra n d o mize d t o 
t he hi g her d ose P E G- as p ara gi nas e treat me nt re gi me n di d e x perie nce a better o utc o me b ut 
n ot as great as n ecessar y f or t he n u m ber of patie nts ra n d o mize d a n d e ve nts o bser ve d t o 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 6 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
s h o w a statistical differe nce; t hat patie nts ra n d o mize d t o c o n ve nti o nal d osi n g ha d a m uc h 
better o utc o me t ha n e x pecte d. P u blicati o n of fi n di n gs fr o m t his a de q uatel y p o were d 
ne gati ve st u d y w o ul d i ncl u de retr os pecti ve a n al ys es e x pl ori n g “ w h y, ” as w o ul d be 
e x pecte d b y j o ur nal re vi e wers a n d rea d ers. We m ust a d d t hat if t he trial were st o p pe d d ue 
t o f utilit y, t hes e a nal ys es w o ul d be c o n d ucte d wit h m uc h less statistical p o wer a n d w o ul d 
be less li kel y t o yiel d usef ul i nf or mati o n o n w hic h f ut ure i n vesti gati o ns c o ul d be b uilt.  
 
If it is necessar y t o d ose-re d uce a n d t he pla n n e d fi nal a nal ysis of t he trial r es ults i n a 
statisticall y si g nifi ca nt p- val ue ( < 0. 0 4 5), t he pri mar y c o ncl usi o n will be t hat, as i nte n de d 
t o be deli vere d i n T O T X VI, t he statistical e vi de n ce is s ufficie nt t o c o ncl u d e t hat t he 
distri b uti o ns of C C R bet wee n patie nts w h o w o ul d recei ve hi g her d oses of P E G-
as para gi n ase a n d t h ose p atie nts w h o w o ul d recei v e c o n ve nti o nal d osi n g are differe nt. 
F urt her m ore, w e w o ul d h a ve e vi de nce t hat, at t he a pri ori  t hres h ol d set f or t o xicit y, 3, 5 0 0 
u nit s/ m2 of P E G-as para gi nase was d ee me d t o o t o xic. A d diti o nal a nal yses will be re q uire d 
t o f ully el uci d ate t he fi n di n gs a n d a gai n we s p ec ul ate o n se veral p ossi ble reas o ns f or t he 
res ults. It mi g ht be t hat t he o utc o me f or p atie nts r a n d o mize d t o 3, 5 0 0 u nits/ m 2 was s o 
s u peri or t hat differe n ces f or t his strat u m d o mi nate d t he o verall res ults; t hat o utc o me f or 
patie nts ra n d o mize d t o b ot h 3, 5 0 0 u nits/ m 2 a n d 3, 0 0 0 u nits/ m2 were si milar a n d s u peri or 
t o the o utc o me f or patie nts w h o were ra n d o mize d t o 2, 5 0 0 u nits/ m 2; or t hat m ost patie nts 
ra n d o mize d t o hi g h d ose P E G-as para gi nase were i n t he 3, 0 0 0 u nits/ m2 re gi me n a n d t he 
o utc o me  was s u peri or t o t he o utc o me f or p atie nt r a n d o mize d t o c o n ve nti o nal d oses of 
P E G-as para gi nase. All t hree p ossi bilities are easil y i nter prete d a n d t he first w o ul d 
sti m ulate researc h as t o h o w 3, 5 0 0 u nits/ m 2 ma y b e safel y gi ve n. 
 
We ha ve p ur p osef ull y n ot s pecifie d a n accr ual n u m ber at w hic h t he tri al w o ul d be 
restarte d usi n g o nl y t he l o wer 3, 0 0 0 u nits/ m2 P E G-as para gi nase, if t h e hi g h er d ose is t o o 
t o xic, n or ha ve we s u g geste d t hat o utc o me at t hat ti me c o ul d hel p ma ki n g a decisi o n 
re gar di n g restarti n g t he trial. T here are si m pl y t o o ma n y s p ec ulati ve sce nari os t hat c o ul d 
occ ur a n d i n all li keli h o o d t here w o ul d be t o o little o utc o me i nf or mati o n t o s he d li g ht o n 
t he sit uati o n. H o we ver, T O T X VI will be m o nit ore d b y t he St. J u de D S M B t hat is 
c o m p ose d of se ni or, e x perie nce d cli nical trial e x perts. We ha ve c h ose n t o d esi g n t he tri al 
as we ha v e, k n o wi n g a n d f ull y e x pecti n g t hat t he D S M B will pr o vi de g ui da nce i n t he 
u nli kel y e v e nt t hat 3, 5 0 0 u nits/ m 2 pr o ves t o be t o o t o xic.   
 
S a m ple size & st u d y d ur ati o n : T he accr ual g oal of t his st u d y is 4 2 0 e val u a ble patie nts f or 
t he c o nti n uati o n p hase ra n d o mizati o n bet wee n hi g her d ose P E G-as para gi nase a n d sta n dar d 
d ose P E G-as para gi nase. T his sa m ple siz e is dictate d b y p o wer c o nsi derati o ns f or t he 
pri mar y o bjecti ve, as disc usse d i n Secti o n 1 7. 2. C urre nt T O T X V e x perie nce s h o ws t hat 
a b o ut 5 % of t he patie nts faile d t o e nter t he c o nti n uati o n p hase of treat me nt. Alt h o u g h e v er y 
eff ort will be ma d e t o c o nse nt patie nts t o t he ra n d o mize d st u d y, we a ntici p ate a p pr o xi matel y 
1 0 % of patie nts will n ot c o nse nt t o partici pate i n t he ra n d o mizati o n; t h us a n attriti o n rate of 
1 4. 5 % is e x pecte d a n d a t otal accr ual of a p pr o xi matel y 5 3 1 eli gi ble p atie nts t o T O T X VI 
will  be necessar y. Hist orical data fr o m T O T XIII A, T O T XIII B, a n d T O T X V (see Secti o n 
1 7. 2) i n dicate t hat t his accr ual g oal ca n be reac he d i n a b o ut 8. 6 years.  
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T his sa m ple siz e pr o vi des a p pr o xi matel y 8 0 % p o wer t o detect t he h y p ot hesiz e d 
i m pr o ve me nt i n t he distri b uti o n of C C R ( α = 0. 0 5; t w o-si de d test) f or patie nts treate d o n 
t he hi g h d ose P E G-as para gi n ase re gi me n. D ue t o t w o pla n ne d i nteri m a nal ys es, t he fi nal 
a nal ysis, if all 4 2 0 patie nts are ra n d o mize d, will be c o n d ucte d at t he 0. 0 4 5 le vel. T his fi nal 
anal ysis will be c o n d ucte d t hree years after t he last patie nt is ra n d o mize d. T h us, t he t otal 
d urati o n of t he st u d y c o ul d be a p pr o xi matel y 1 1. 6 years.  
 
1 8. 1  
Safet y M o nit ori n g  
 
T he  t hres h ol ds f or s afet y m o nit ori n g were c h ose n after caref ul c o nsi derati o n of t he 
p ote ntial ris k/ be nefit rati o f or t he trial. All eli gi ble patie nts w h o recei ve a n y T O T X VI 
i n d ucti o n t hera p y will be i ncl u de d i n safet y m o nit ori n g des cri be d b el o w fr o m t he i nitiati o n 
of i n d ucti o n t hera p y t o t h e be gi n ni n g of c o nti n uati o n t hera p y. All eli gi ble p atie nts w h o are 
ra n d o mize d a n d recei ve a n y c o nti n uati o n t hera p y will be i ncl u de d i n safet y m o nit ori n g 
descri be d b el o w f or t he i nter val fr o m i nitiati o n of c o nti n uati o n t hera p y t o t he e n d of Wee k 
3 5 of c o nti n uati o n. M o nit ore d e ve nts t hat occ ur after wee k 3 5 of c o nti n uati o n t hera p y are 
n ot li kel y t o be rel ate d t o P E G-as para gi nase a n d t h us will n ot be c o nsi dere d i n t he f or mal 
safet y m o nit ori n g pla n. 
 
Critical f or t he ti m el y s afet y m o nit ori n g descri be d i n t his secti o n is u p- t o- date a n d 
acc urate dat a f or a nal ysis. Eac h of t he m o nit ori n g a nal ys es, e x ce pt f or d eat h d uri n g 
i n d ucti o n, will be c o n d ucte d as f oll o ws: 
 
1.  T he  tri g geri n g e v e nt will be c o nfir me d b y t h e atte n di n g p h ysici a n a n d t h e pr ot oc ol 
PI. U p o n c o nfir mati o n, all ass ociate d i nf or mati o n f or t he e v e nt ( dates, gra d e, etc) 
will be l oc ke d (fr oze n) i n t he T O T X VI d ata bas e. 
2.  T he  pr ot oc ol bi ostatisticia n will e xtract data fr o m t he T O T X VI d ata bas e a n d 
c o n d uct t he a n al ysis. 
a. If t he safet y st o p pi n g t hr es h ol d is n ot reac he d, t h e trial c o nti n ues u na bate d 
an d t his will c o ncl u de t he a nal ysis f or t his e ve nt. 
b.  If t he safet y st o p pi n g t hr es h ol d is e x cee de d, t he a nal ysis is re p eate d b y 
ass u mi n g t hat patie nts w h o d o n ot ha ve data i n t h e T O T X VI data bas e 
c urre nt t o t he d ate of t he tri g geri n g e ve nt are “s afe” o n t hat date.  
i. 
If t he a n al ysis of t hes e data still e xcee ds t he st o p pi n g t hres h ol d, 
t he n t he a p pr o pri ate acti o n descri be d b el o w is e x ec ute d. 
ii. 
If t he a n al ysis of t hes e data d oes n ot res ult i n t he st o p pi n g t hres h ol d 
be i n g e x cee de d, t he n t h e rele va nt dat a i n t he T O T X VI data base is 
i m me diatel y ( wit hi n se veral da ys) u p dat e d a n d t he a nal ysis 
re peat e d. T his will c o nstit ute t he fi nal a nal ysis tri g gere d b y t he 
e ve nt a n d a p pr o priate acti o n will be ta ke n pe n di n g o n w het her t he 
st o p pi n g t hres h ol d is or is n ot e x cee de d. 
3.  S afet y m o nit ori n g r ules pr o vi de a statistical fra me w or k i n w hic h t o c o nsi der 
w het her o bser ve d t o xicities are e x cessi ve. U p o n c o m pleti o n of a n i nteri m a nal ysis, 
t he fi n di n gs will be re p orte d t o t he St. J u de D S M B t hat will ma ke 
rec o m me n dati o ns t o t he pr ot oc ol PI a n d a d vise t h e St. J u de lea ders hi p o n 
c o nti n ui n g, st o p pi n g or a me n di n g t he trial.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
F or t he m o nit ore d t o xicities d uri n g T O T X V i n d ucti o n, t he rece nt e x perie n ce (as of 
6/ 5/ 2 0 0 7) s h o ws t hat o ut of 4 5 3 patie nts, t here are 2 ( 0. 4 4 %) deat hs, 5 ( 1. 1 %) seiz ures 
( gra de 2 or m ore), 1 1 ( 2. 4 %) m uc ositis, a n d 1 1 ( 2. 4 %) i nfecti o ns ( gra de 4). As of 
5/ 2 3/ 2 0 0 7, t he c u m ulati ve i nci de nce of disse mi nat e d f u n gal i nfecti o ns till t he e n d of re-
i n d ucti o n II is 4. 6 % ± 1. 0 9 %, a n d is 5. 9 % ± 1. 2 4 % o ver t he e ntire treat me nt d urati o n. As of 
6/ 2 5/ 2 0 0 7 t here are 6 fat al c he m ot hera p y t o xicities o n T O T X V ( 4 at SJ: 2 i n i n d ucti o n, 1 
i n c o ns oli dati o n, a n d 1 i n c o nti n uati o n; 2 at C o o k’s: 1 i n re-i n d ucti o n I a n d 1 i n re-
I n d u cti o n II). All n o n-fat al t o xicities ha ve bee n m a na gea ble.  
 
Pa ncreatitis a n d dee p vei n t hr o m b osis ( D V T) are t w o as para gi nase  relate d t o xicities t hat 
will  be cl osel y m o nit ore d i n T O T X VI d ue t o t he i n creas e d e x p os ure of patie nts t o t his 
a ge nt. O n T O T X V t hera p y, n o patie nt e x perie nce d re peat e d e pis o des of pa ncreatitis or 
D V T i n t he i nter val bet w ee n i nitiati o n of t hera p y a n d t he be gi n ni n g of c o nti n uati o n 
t hera p y. D uri n g c o nti n uati o n t hera p y o n e patie nt di d e x perie nce t w o e pis o d es of D V T b ut 
n o patie nt e x perie nce d m ulti ple e pis o des of pa ncreatitis. 
 
Pa ncreatitis is a t o xicit y t hat is ass ociate d wit h as p ara gi nas e  treat me nt a n d t h us will be 
caref ull y m o nit ore d d uri n g i n d ucti o n a n d c o nti n uati o n t hera p y. T he c u m ulati ve i nci de nce 
of pa ncreatitis fr o m t he i nitiati o n of i n d ucti o n t hera p y t o t he be gi n ni n g of c o nti n uati o n 
t hera p y i n T O T X V was 0. 9 7 % ( S E = 0. 4 8 %) a n d t here was n o e vi de nce t hat t hat t he 
i nci de nce w as rel ate d t o ris k classificati o n wit h 2 e ve nts i n l o w ris k patie nts a n d 2 
e pis o des i n sta n dar d/ hi g h ris k patie nts w h o recei ve d m ore as para gi nase. All f o ur e ve nts 
occ urre d d uri n g t he first f o ur wee ks of i n d ucti o n t hera p y. T h e 9 5 % u p per c o nfi de nce 
b o u n d j ust pri or t o t he i nitiati o n of c o nti n uati o n t hera p y is 1. 7 6 %.  
 
T he c u m ulati ve i nci de n ce of pa ncreatitis fr o m t he i nitiati o n of c o nti n uati o n t hera p y t o t he 
e n d of re-i n d ucti o n II w as 2. 2 3 % ( S E = 0. 7 4 %) wit h t he last e pis o de bei n g o bser ve d 
wit hi n t w o wee ks of t he l ast d ose of as para gi nas e, w hic h was gi ve n i n wee k 2 1 of 
c o nti n uati o n t hera p y. T h e 9 5 % u p per c o nfi de n ce b o u n d at t he e n d of t his p eri o d is 
3. 4 5 % . T w o ot her e pis o des were o bser ve d i n wee ks 1 0 5 a n d 1 1 1 b ut neit her is t h o u g ht t o 
be relate d t o as para gi nas e e x p os ure a n d t hese are n ot use d i n t he esti mati o n. S/ H R patie nts 
recei v e d m ore e x p os ure t o as para gi n ase d uri n g T O T X V c o nti n uati o n t hera p y t h a n di d l o w 
ris k patie nts. H o we ver, as t he f oll o wi n g fi g ure ill ustrates, t here is n o e vi d e n ce of a d os e-
t o xicit y relati o ns hi p ( p = 0. 7 2). T h us, i n T O T X VI, L R a n d S/ H R patie nts will p o ole d t o 
m o nit or f or e x cessi ve e pis o des of pa ncreatitis.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
CI N of gr a d e 3 p a n cr e atiti s i n T ot al X V P ati e nt s
0
0. 0 0 5
0. 0 1
0. 0 1 5
0. 0 2
0. 0 2 5
0. 0 3
0. 0 3 5
0. 0 4
0. 0 4 5
0. 0 5
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 4 0
1 6 0
1 8 0
2 0 0
W e e k s fr o m t h e b e gi n ni n g of c o nti n u ati o n t h er a p y t o off t h er a p y
CI
L R
S H R
CI N of D e e p v ei n t hr o m b o si s i n cl u di n g gr a d e 2 i n T ot al X V P ati et n s
0
0. 0 0 5
0. 0 1
0. 0 1 5
0. 0 2
0. 0 2 5
0. 0 3
0. 0 3 5
0. 0 4
0. 0 4 5
0. 0 5
0
5
1 0
1 5
2 0
2 5
3 0
W e e k s fr o m b e gi n ni n g of st u d y t o t h e b e gi n ni n g of c o nti n u ati o n t h er a p y
CI
L R
S H R
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D V T, o n t he ot her h a n d, is a t o xicit y t hat d oes see m t o be ass ociate d wit h t he d ose of 
as para gi n ase as e vi de nce d b y t he c u m ulati ve i nci de nces of D V T d uri n g i n d ucti o n a n d 
c o nti n uati o n t hera p y o bs er ve d i n T O T X V. T he e pis o des of D V T ma y be o bser ve d 3- 4 
we e ks after t he last d ose of as para gi nase. We n ote t hat t he i ncreas e d i nci de nce c o ul d als o 
be relate d t o e x p os ure t o as para gi n ase i n t he c o nte xt of t he m ore i nte nse t hera p y t hat S/ H R 
patie nts recei ve d d uri n g t his peri o d. 
 
T he f oll o wi n g fi g ure s h o ws t he c u m ulati ve i nci de nce of D V T f or t he peri o d fr o m t he 
i nitiati o n of i n d ucti o n t hera p y t o t he i nitiati o n of c o nti n uati o n t hera p y o n T O T X V f or l o w 
ris k a n d sta n dar d & hi g h-ris k patie nts. T he c u m ulati ve i nci de nce f or l o w ris k patie nts 
( N = 2 3 8) is 0. 8 4 % ( S E = 0. 5 9 %) a n d f or S/ H R patie nts ( N = 1 7 6) is 4. 5 5 % ( S E = 1. 5 7 %). 
T he 9 5 % u p per c o nfi de n ce b o u n ds at t he e n d of t his peri o d are 1. 8 1 % a n d 7. 1 3 %, 
res pecti vel y. Gra y’s test c o m pari n g t he t w o c u m ulati ve i nci de nce f u ncti o ns is si g nifica nt 
( p = 0. 0 1 5). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
CI N of D e e p v ei n t hr o m b o si s i n cl u di n g gr a d e 2 i n T ot al X V P ati e nt s
0
0. 0 1
0. 0 2
0. 0 3
0. 0 4
0. 0 5
0. 0 6
0. 0 7
0. 0 8
0. 0 9
0. 1
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 4 0
1 6 0
1 8 0
2 0 0
W e e k s fr o m b e gi n ni n g of c o nti n u ati o n t h er a p y t o off t h er a p y
CI
L R
S H R
T he f oll o wi n g fi g ure s h o ws t he c u m ulati ve i nci de nce of D V T d uri n g T O T X V 
c o nti n uati o n t hera p y f or l o w ris k a n d sta n dar d & hi g h-ris k p atie nts. T he last d ose of 
as para gi n ase is gi ve n wee k 2 1 of c o nti n uati o n t hera p y a n d e pis o d es of D V T were s ee n i n 
S/ H R patie nts u p t o t hree wee ks later. T he c u m ulati ve i nci de nce f or l o w ris k patie nts 
( N = 2 0 9) is 1. 4 4 % ( S E = 0. 8 3 %) a n d f or S/ H R patie nts ( N = 2 0 5) is 8. 8 7 % ( S E = 2. 0 6 %). 
T he 9 5 % u p per c o nfi de n ce b o u n ds at t he e n d of t his peri o d are 2. 8 1 % a n d 1 2. 5 8 %, 
res pecti vel y. Gra y’s test c o m pari n g t he t w o c u m ulati ve i nci de nce f u ncti o ns is si g nifica nt 
( p = 0. 0 0 0 6). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 8. 1. 1 D u ri n g i n d u cti o n a n d t o t he i nitiati o n of c o nti n uati o n t hera p y 
 
F or m o nit ori n g p ur p oses we will c o u nt t he first e pis o de of a m o nit ore d t o xicit y s h o ul d t he 
sa me t o xicit y occ urs m ulti ple ti mes o n a si n gle patie nt d uri n g i n d ucti o n. T O T X VI has 
m ore i nte nse i n d ucti o n a n d I T t h era p y t ha n T O T X V. T heref ore we will cl osel y m o nit or 
t o xic deat h, pa ncreatitis, D V T a n d seiz ures d uri n g t he i n d ucti o n p hase. 
 
De at h:  Base d o n t h e T O T X V data, t he 9 5 % u p per c o nfi de nce b o u n d o n t he deat h rate 
d uri n g i n d ucti o n is 0. 9 5, w hic h i m plies t hat 9 9 % of patie nts w o ul d be e x pecte d t o s ur vi ve 
i n d ucti o n. Be gi n ni n g wit h t he sec o n d deat h d uri n g i n d ucti o n, we will c o nstr uct t he 9 5 % 
u p per c o nfi d e nce b o u n d of t he tr ue u n k n o w n pr o ba bilit y of s ur vi vi n g i n d ucti o n t hera p y, 
usi n g t he Bl yt h- Still- Cas ella met h o d, w he n a d eat h occ urs. If at a n y a nal ysis t his u p per 
b o u n d dr o ps bel o w 0. 9 9 0, we will cl ose t he trial t o accr ual a n d c o nsi d er c h a n ges t o t he 
i n d ucti o n t hera p y. N ote t hat t he de n o mi nat or i n t hese a nal ys es will be t he n u m ber of 
patie nts t hat ha ve c o m plete d i n d ucti o n t hera p y at t he ti me of t he i n de x deat h.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he f oll o wi n g t a ble ill ustrates t he st o p pi n g c haract eristics. 
 
St o p pi n g R ule f or De at h D uri n g I n d ucti o n 
N  
# Dt h.  
% 
Dt h.  
9 5 % U B  Decisi o n  
1 0 0  
2  
2. 0  
0. 9 9 5  
G o  
1 0 0  
3  
3. 0  
0. 9 8 9  
St o p  
2 0 0  
4  
2. 0  
0. 9 9 1  
G o  
2 0 0  
5  
2. 5  
0. 9 8 7  
St o p  
3 0 0  
6  
2. 0  
0. 9 9 1  
G o  
3 0 0  
7  
2. 3 3  
0. 9 8 8  
St o p  
 
P a ncre atitis ( Gr a de 3 or hi g her):  T he 9 5 % u p per c o nfi de nce b o u n d o n t he c u m ulati ve 
i nci de nce of pa ncreatitis d uri n g t he peri o d fr o m i nitiati o n of i n d ucti o n t o i nitiati o n of 
c o nti n uati o n t hera p y is 1. 7 6 %. P E G-as para gi nase has a l o n ger half-life t hat t he 
f or m ulati o n of as para gi n ase use d i n T O T X V a n d d ue t o t he e x pecte d i ncrease d efficac y of 
Pe g- as para gi nase, w e will t olerate a tr ue c u m ulati ve i nci de nce of 3 % b ef ore 
rec o m me n di n g t hat accr ual t o t he trial be st o p pe d. Be gi n ni n g wit h t he fift h patie nt 
e x perie nci n g a n e pis o de of pa ncreatitis pri or t o i nitiati o n of c o nti n uati o n t hera p y we will 
esti mate t he c u m ulati ve i nci de nce f u ncti o n a n d if t he 9 5 % l o wer c o nfi de n ce b o u n d is 
greater t ha n 3. 0 0 %, w e will rec o m me n d t hat accr ual ceas e. Fe w deat hs or rela pses 
(c o m peti n g e ve nts) are e x pecte d fr o m i nitiati o n of i n d ucti o n t hera p y t o t he be gi n ni n g of 
c o nti n uati o n t hera p y s o t he f oll o wi n g ta bl e base d o n t he bi n o mi nal distri b uti o n pr o vi des 
a p pr o xi mate  st o p pi n g criteria. 
 
N O T E:  We will u p gr a de a ny p a ncre atitis res ulti n g i n disc o nti n u ati o n of P E G-
as p ar a gi n ase t o Gr a de 3 (eve n if Gr a d e 2 by C T C A E v 3 criteri a). 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of 
P a ncre atitis: I n d ucti o n t o C o nti n u ati o n T her a p y  
N  
# E pis o des  
% E pis o des  
9 5 % 
L B  
Decisi o n  
1 0 0  
6  
6. 0 0 %  
2. 6 5 %  
G o  
1 0 0  
7  
7. 0 0 %  
3. 6 8 %  
St o p  
2 0 0  
1 0  
5. 0 0 %  
2. 9 6 %  
G o  
2 0 0  
1 1  
5. 5 0 %  
3. 1 2 %  
St o p  
3 0 0  
1 4  
4. 6 7 %  
2. 8 4 %  
G o  
3 0 0  
1 5  
5. 0 0 %  
3. 2 5 %  
St o p  
 
 
Seiz ures ( Gr a de 3 or hi g her):   T he 9 5 % u p p er c o nfi de nce b o u n d f or seiz ures d uri n g t he 
pe ri o d bet wee n i nitiati o n of i n d ucti o n t hera p y a n d t he be gi n ni n g of c o nti n uati o n t hera p y 
f or T O T X V was 1. 9 1 %. T O T X VI h as m ore i nte nse I T t hera p y t hat is c o nsi dere d 
p ote ntiall y m ore effecti v e t ha n T O T X V I T t hera p y, s o w e will t olerate a tr ue seiz ure 
i nci de nce of 3 %. Be gi n ni n g wit h t he fift h p atie nt e x perie nci n g a s eiz ure pri or t o i nitiati o n 
of c o nti n uati o n t hera p y, we will esti mate t he c u m ulati ve i nci de nce f u ncti o n a n d if t he 9 5 % 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
l o wer c o nfi d e nce b o u n d is greater t h a n 3. 0 0 %, we will rec o m me n d t hat accr ual ceas e. We 
will use t he sa me st o p pi n g criteria as f or pa n creatitis d uri n g i n d ucti o n (see a b o ve ta ble). 
 
D V T ( Gr a de 3 or hi g her): S/ H R patie nts will recei ve a hi g h er c u m ulati ve d ose of P E G-
as para gi n ase d uri n g i n d u cti o n t ha n L R patie nts a n d t h us, will be m o nit ore d se parat el y. 
Base d o n T O T X V, t he 9 5 % u p per b o u n d f or D V T d ue t o i n d ucti o n t hera p y f or L R p atie nts 
is 1. 8 1 % a n d f or S/ H R is 7. 1 3 %.   
 
P E G-as para gi nase h as a l o n ger half-life t hat t he f or m ulati o n of as para gi nas e use d i n 
T O T X V a n d d u e t o t he e x pecte d i ncreas e d efficac y of P E G-as para gi nase, we will t olerate 
a tr ue c u m ulati ve i nci d e n ce of 3 % i n L R patie nts b ef ore rec o m me n di n g t hat accr u al t o t he 
trial be st o p pe d. Be gi n ni n g wit h t he sec o n d patie nt e x perie nci n g a n e pis o de of D V T pri or 
t o i nitiati o n of c o nti n uati o n t hera p y, we will esti mate t he c u m ulati ve i nci de nce f u ncti o n 
a n d if t he 9 5 % l o wer c o nfi de nce b o u n d is greater t ha n 3. 0 0 %, we will rec o m me n d t hat 
accr ual cease.   
 
Fe w d eat hs or rela pses ( c o m peti n g e v e nts) are e x pecte d fr o m i nitiati o n of i n d ucti o n 
t hera p y t o t he be gi n ni n g of c o nti n uati o n t hera p y s o t he f oll o wi n g ta ble b as e d o n t he 
bi n o mi nal distri b uti o n pr o vi des a p pr o xi mate st o p pi n g criteria. 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of D V T  
L R P atie nts: I n d ucti o n t o C o nti n u ati o n T her a p y  
N  
# E pis o des  % E pis o des  9 5 % L B  Decisi o n  
5 0  
3  
6. 0 0 %  
2. 2 2 %  
G o  
5 0  
4  
8. 0 0 %  
3. 5 4 %  
St o p  
1 0 0  
6  
6. 0 0 %  
2. 6 5 %  
G o  
1 0 0  
7  
7. 0 0 %  
3. 6 8 %  
St o p  
1 5 0  
8  
5. 3 3 %  
2. 8 3 %  
G o  
1 5 0  
9  
6. 0 0 %  
3. 2 6 %  
St o p  
 
F or S/ H R patie nts we will t olerate a tr ue c u m ulati ve i nci de nce of 1 0 % b ef ore 
rec o m me n di n g t hat accr ual t o t he trial be st o p pe d. Be gi n ni n g wit h t he se ve nt h patie nt 
e x perie nci n g a n e pis o de of D V T pri or t o i nitiati o n of c o nti n uati o n t hera p y, we will 
esti mate t he c u m ulati ve i nci de nce f u ncti o n a n d if t he 9 5 % l o wer c o nfi de n ce b o u n d is 
greater t ha n 1 0. 0 %, w e will rec o m me n d t hat accr ual ceas e.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Fe w d eat hs or rela pses ( c o m peti n g e v e nts) are e x pecte d fr o m i nitiati o n of i n d ucti o n 
t hera p y t o t he be gi n ni n g of c o nti n uati o n t hera p y s o t he f oll o wi n g ta ble b as e d o n t he 
bi n o mi nal distri b uti o n pr o vi des a p pr o xi mate st o p pi n g criteria. 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of D V T  
S/ H R P atie nts: I n d ucti o n t o C o nti n u ati o n T her a p y  
N  
# E pis o des  % E pis o des  9 5 % L B  Decisi o n  
5 0  
8  
1 6. 0 0 %  
8. 2 2 %  
G o  
5 0  
9  
1 8. 0 0 %  
1 0. 4 6 %  
St o p  
1 0 0  
1 5  
1 5. 0 0 %  
9. 7 4 %  
G o  
1 0 0  
1 6  
1 6. 0 0 %  
1 0. 5 %  
St o p  
1 5 0  
2 1  
1 4. 0 0 %  
9. 9 1 %  
G o  
1 5 0  
2 2  
1 4. 6 7 %  
1 0. 1 4 %  
St o p  
 
1 8. 1. 2 D uri n g c o nti n uati o n t hr o u g h t he e n d of Wee k 3 5 a m o n g all ra n d o mize d 
pa rtici pa nts 
 
T he ra n d o mizati o n t o t w o differe nt d osi n g sc h e d ules of P E G-as para gi nas e d uri n g 
c o nti n uati o n t hera p y re q uires t hat we cl osel y m o nit or f or gra d e 3 or m ore p a ncreatitis a n d 
dee p vei n t hr o m b osis. T h e m o nit ori n g peri o d is fr o m da y 1 of c o nti n uati o n t o t he W ee k 
3 5, w hic h is a p pr o xi matel y 4 wee ks aft er t he last P E G-as para gi nase gi ve n t o t he S/ H R 
patie nts. F or m o nit ori n g p ur p oses, we will c o u nt t he first e pis o de of a m o nit ore d t o xicit y 
s h o ul d t he sa me t o xicit y occ urs m ulti ple ti mes i n a n i n di vi d ual patie nt d uri n g t he 
m o nit ori n g peri o d. 
 
M o nit ori n g f or p a ncreatitis a n d D V T will be base d o n t he c o m bi ne d treat me nt re gi me ns. 
H o we ver, if m o nit ori n g s u g gests t hat accr ual s h o ul d be st o p pe d, t he c u m ulati ve i nci de nce 
f u ncti o ns f or t he t w o treat me nt re gi me ns will be c o m pare d t o caref ull y ass ess w het her t h e 
pr o ble m is o nl y wit h t he hi g her d ose P E G-as p ara gi nase re gi me n. 
 
P a ncre atitis ( Gr a de 3 or hi g her):  T he 9 5 % u p per c o nfi de nce b o u n d of t he c u m ulati ve 
i nci de nce of pa ncreatitis o n T O T X V is 3. 4 5 % d uri n g c o nti n uati o n t hera p y. ( See secti o n 1 7. 1 
a b o ve) We e x pect t hat t h e i nci de nce will be greater o n T O T X VI d u e t o t he use of P E G-
as para gi n ase a n d are willi n g t o acce pt a tr u e rat e as hi g h as 7 %. T his i ncrease ris k of a 
ma na gea bl e t o xicit y is cli nicall y acce pt a ble d ue t o t he e x pecte d be nefits of usi n g P E G-
as para gi n ase. Be gi n ni n g wit h t he ni nt h patie nt e x perie nci n g a n e pis o de of pa ncreatitis pri or 
t o wee k 3 5 of c o nti n uati o n t hera p y, we will esti mate t he c u m ulati ve i nci de n ce f u ncti o n a n d 
if t he 9 5 % l o wer c o nfi de nce b o u n d is greater t ha n 7. 0 0 %, we will rec o m me n d t hat accr ual 
cease. Fe w deat hs or rela pses (c o m peti n g e ve nts) are e x pecte d fr o m i nitiati o n of 
c o nti n uati o n t hera p y t o t he e n d of wee k 3 5 s o t he f oll o wi n g ta ble b ase d o n t he bi n o mi nal 
distri b uti o n pr o vi des a p pr o xi mate st o p pi n g criteri a. 
 
N O T E:  We will u p gr a de a ny p a ncre atitis res ulti n g i n disc o nti n u ati o n of P E G-
as p ar a gi n ase t o Gr a de 3 (eve n if Gr a d e 2 by C T C A E v 3 criteri a). 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of 
P a ncre atitis: C o nti n u ati o n T her a p y t hr o u g h Wee k 
3 5  
N  
# E pis o des  
% E pis o des  
9 5 % 
L B  
Decisi o n  
1 0 0  
1 1  
1 1. 0 0 %  
6. 5 6 %  
G o  
1 0 0  
1 2  
1 2. 0 0 %  
7. 0 7 %  
St o p  
2 0 0  
2 0  
1 0. 0 0 %  
6. 8 3 %  
G o  
2 0 0  
2 1  
1 0. 5 0 %  
7. 2 8 %  
St o p  
3 0 0  
2 8  
9. 3 3 %  
6. 7 2 %  
G o  
3 0 0  
2 9  
9. 6 7 %  
7. 0 0 2 %  
St o p  
D V T ( Gr a de 3 or hi g her):   T he dat a fr o m T O T X V clearl y s h o ws t h at t he 
S/ H R patie nts e x perie nce d a hi g h er c u m ulati ve i nci de nce of D V T t ha n di d 
t he L R patie nts.  
 
As s h o w n i n secti o n 1 7. 1 a b o ve, t he 9 5 % u p p er c o nfi de nce b o u n d f or t he c u m ulati ve 
i nci de nce of D V T i n t he L R patie nts d uri n g c o nti n uati o n t hera p y was 2. 8 1 %. Si nce l o w 
ris k patie nts ra n d o mize d t o t he hi g h d ose P E T- A S P re gi me n are pr ojecte d t o e x perie nce 
o nl y a 2- 4 % i m pr o ve me nt i n d urati o n of C C R, we will n ot acce pt a rate of D V T m uc h 
hi g her t h a n t hat o bser ve d f or L R p atie nts i n T O T X V.  Be gi n ni n g wit h t he sec o n d patie nt 
ex perie nci n g a n e pis o de of D V T pri or d uri n g c o nti n uati o n t hera p y we will esti mate t he 
c u m ulati ve i nci de nce f u ncti o n a n d if t he 9 5 % l o w er c o nfi d e nce b o u n d is greater t ha n 
3. 0 0 %, we will rec o m me n d t hat accr ual cease.  
 
Fe w d eat hs or rela pses ( c o m peti n g e v e nts) are e x pecte d fr o m i nitiati o n of c o nti n uati o n 
t hera p y t o wee k 3 5 s o t he f oll o wi n g ta bl e base d o n t he bi n o mi nal distri b uti o n s h o ws 
a p pr o xi mate  st o p pi n g criteria.  
 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of D V T  
L o w Ris k: C o nti n u ati o n T her a p y t hr o u g h Wee k 3 5  
N  # E pis o des  % E pis o des  9 5 % L B  
Decisi o n  
5 0  
3  
6. 0 0 %  
2. 2 2 %  
G o  
5 0  
4  
8. 0 0 %  
3. 5 4 %  
St o p  
1 0 0  
6  
6. 0 0 %  
2. 6 5 %  
G o  
1 0 0  
7  
7. 0 0 %  
3. 6 8 %  
St o p  
1 5 0  
8  
5. 3 3 %  
2. 8 3 %  
G o  
1 5 0  
9  
6. 0 0 %  
3. 2 6 %  
St o p  
  
As s h o w n i n secti o n 1 7. 1 a b o ve, t he 9 5 % u p p er c o nfi de nce b o u n d o n t he c u m ulati ve 
i nci de nce of D V T i n S/ H R patie nts d uri n g c o nti n u ati o n t hera p y i n T O T X V is 1 2. 5 2 %. We 
w o ul d acce pt a sli g htl y hi g her i n ci de nce, 1 5 %, f or t he S/ H R patie nts t hat recei ve d t he l o w 
d ose P E G-as para gi nase re gi me n of T O T X VI. T he S/ H R patie nts ra n d o mize d t o t he hi g h 
d ose P E G-as para gi nase re gi me n are e x pecte d t o d eri ve c o nsi dera ble be nefit i n ter ms of 
i m pr o ve d distri b uti o n of C C R a n d s o we are willi n g t o acce pt a hi g h er rate of D V T i n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t hese patie nts, 2 0 %. Be gi n ni n g wit h t he ele ve nt h p atie nt e x perie nci n g a n e pis o de of D V T 
pri or d uri n g c o nti n uati o n t hera p y we will esti mate t he c u m ulati ve i nci de nce f u ncti o n a n d 
if t he 9 5 % l o wer c o nfi de nce b o u n d is greater t ha n 1 7. 5 0 %, we will rec o m me n d t hat 
accr ual cease. Fe w d eat hs or rela pses (c o m peti n g e ve nts) are e x pecte d fr o m i nitiati o n of 
c o nti n uati o n t hera p y t o wee k 3 5 s o t he f oll o wi n g ta ble base d o n t he bi n o mi nal distri b uti o n 
s h o ws a p pr o xi mate st o p pi n g criteria. 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of D V T  
S/ H R Ris k: C o nti n u ati o n T her a p y t hr o u g h Wee k 
3 5  
N  
# E pis o des  % E pis o des  
9 5 % 
U B  
Decisi o n  
5 0  
1 3  
2 6. 0 0 %  
1 6. 2 %  
G o  
5 0  
1 4  
2 8. 0 0 %  
1 8. 6 %  
St o p  
1 0 0  
2 4  
2 4. 0 0 %  
1 7. 1 3 %  
G o  
1 0 0  
2 5  
2 5. 0 0 %  
1 8. 0 4 %  
St o p  
1 5 0  
3 4  
2 2. 6 7 %  
1 7. 1 6 %  
G o  
1 5 0  
3 5  
2 3. 3 3 %  
1 7. 7 6 %  
St o p  
 
1 8. 1. 3 D uri n g e ntire t hera p y: disse mi nate d f u n gal i nfecti o ns 
 
T he  sa me as i n T O T- X V trial, we will m o nit or t he i nci de nce of disse mi nat e d f u n gal 
i nfecti o ns. We will m o nit or a gai nst a bas eli ne rat e of 5 % a n d will s u g gest m o dif yi n g t he 
st u d y if t here is statistical e vi de nce t h at t he disse mi nate d f u n gal i nfecti o n rate e x cee ds 
1 0 %. T he o verall si g nifica nce le vel will be 0. 0 5 6 7 wit h a p o wer of 0. 9 9 6 7 t o detect t he 
u nacce pta ble hi g her l e vel. 
 
O nl y t he first e ve nt i n a gi ve n patie nt will be c o u nte d alt h o u g h we will cl osel y m o nit or f or 
re peat e d i nfecti o ns.  Sa m ple siz e ( de n o mi nat or) is t he n u m ber of p atie nts eit her w h o ha v e 
rec o vere d fr o m t he sec o n d re-i n d ucti o n or de v el o p e d visceral f u n gal i nfecti o n bef ore 
rec o ver y fr o m se c o n d rei n d ucti o n.  T he n u merat or is t he n u m ber of t he first e ve nts a m o n g 
all m o nit ore d patie nts (i.e. t h ose i n de n o mi nat or).  Accr u al will be s us pe n d e d if t he n u m ber 
of e ve nts ( n u merat or) is e q ual t o or e x cee ds t hat c orres p o n di n g t o eac h sa m ple siz e. 
 
I nteri m anal ysis  
Sa m ple s ize 
( patie nts)  
M o dif y if # p atie nts 
wit h disse mi nate d 
f u n gal infecti o ns   
1  
3 0  
6  
2  
6 0  
9  
3  
1 2 0  
1 4  
4  
1 8 0  
1 8  
5  
2 4 0  
2 1  
6  
3 0 0  
2 8  
7  
3 6 0  
3 1  
8  
4 2 0  
3 3  
9  
4 8 0  
3 5  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 7 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 8. 1. 4  Decrease of P E G-as p ara gi nase d os e i n t he Hi g her D ose P E G-as para gi nas e re gi me n.  
 
O nce a n y of t he st o p pi n g c o n diti o ns f or t he m o nit ori n g peri o d i n t he C o nti n uati o n p hase is 
met, we will caref ull y e x a mi ne a n d a n al yze all t he t o xicit y i nci de nces. Treat me nt o utc o me 
( C C R, E F S a n d s ur vi val) will n ot  be a nal yze d si m pl y d ue t o a st o p pi n g criteria ha vi n g 
bee n met. Certai nl y if t here has bee n a rece nt pla n ne d a nal ysis of o utc o me, t he D S M B 
ma y c o nsi der t hat i nf or m ati o n i n f or matti n g t heir rec o m me n dati o n. C u m ulati ve i nci de nce 
f u ncti o ns of t he c o ncer ni n g t o xicit y f or t he t w o treat me nt re gi me ns will be c o m pare d f or 
e vi de nt t hat t he m o nit ore d t o xicities are m ore pre v ale nt i n t he 3 5 0 0 u nits/ m 2 re gi me n. We 
will  als o c o nsi der w het her t he u p per c o nfi de nce b o u n ds f or eac h t he t w o re gi me ns e x cee d 
w hat were p ost ulate d t o be acce pta ble. If st o p pi n g criteria are e x cee de d f or b ot h re gi me ns, 
w hic h is n ot e x pecte d, c o nsi derati o n will be gi v e n t o st o p pi n g t he trial. If o nl y t he hi g her 
d ose re gi me n has e x cessi ve t o xicit y, t he n c o nsi derati o n will be gi ve n t o re d uci n g t he d os e 
of P E G-as para gi nase t o 3 0 0 0 u nits/ m 2 a n d t o c o nti n ue t he ra n d o mizati o n.  
 
Ass u mi n g t hat t he pr ot oc ol is a me n de d t o re d uce t he d ose of P E G-as para gi nase, t he 
ran d o mizati o n w o ul d c o nti n ue a n d t he fi nal a n al ysis a n d a n y s u bse q ue nt i nteri m a nal yses 
of t he pri mar y st u d y q uesti o n w o ul d be stratifie d b y patie nts r a n d o mize d pri or t o a n d p ost 
t he pr ot oc ol a me n d me nt. All patie nts w h o were ra n d o mize d at t he ti me t hat t he hi g h d ose 
of P E G-as para gi nase was 3 5 0 0 u nits/ m 2 will be i ncl u de d i n t he i n t he “ pri or a me n d me nt” 
strat u m; all patie nts ra n d o mize d after t he P E G-as para gi nas e d ose was re d u ce d t o 3 0 0 0 
u nits/ m 2 will be i ncl u de d i n t he “ p ost a me n d me nt” strat u m. N ote t hat t he fi ve ori gi n al 
strata are mai ntai ne d wit hi n t his u m brella stratificati o n wit h n o c ha n ge i n t he ra n d o mize d 
se q ue nce of ra n d o mize d bl oc ks; s o t he ra n d o mizati o n bet wee n hi g her d ose P E G-
as para gi n ase a n d c o n ve nti o nal d osi n g will re mai n bala nce d. Zele n’s ra n d o mizati o n 
sc he me wit h bl oc k sizes of 4 will be use d. T h us, t he a bs ol ute w orst case f or i m bala nce 
bet wee n hi g h d ose P E G- as para gi n ase a n d c o n ve nti o nal d ose P E G-as para gi nase wit hi n 
eit her a me n d me nt d efi ne d strata is 1 0 patie nts. Certai nl y t his i m bala nce is u nli kel y t o 
oc c ur as i n d e pe n de ntl y i n eac h strat u m, ra n d o mizati o n is c o ntr olle d b y ra n d o m se q ue nces 
of ra n d o m bl oc ks of size 4. T h us a n y i m bal a nce t h at ma y o cc ur s h o ul d b e s mall a n d t h us 
will ha ve little effect o n t he statistical p o wer of t h e trial. 
 
T he a b o ve pla n a d mits t he use of all dat a t o a d dress t he pri mar y st u d y q u esti o n a n d a v oi ds 
ha vi n g t o ma d e a d h oc d ecisi o ns as t o w het her t h e trial s h o ul d be a me n de d t o start all o ver 
a gai n. E ve n patie nts w h o e x perie nce t o xicities, w hic h are ma na gea ble, ma y still be nefi t 
fr o m t he treat me nt a n d t o xicities s h o ul d n ot be a reas o n f or e x cl u di n g t he m fr o m t he 
pri mar y a nal ysis. F urt her m ore, t he pr o p ose d f utilit y a n al ysis, disc uss e d bel o w, w o ul d 
li kel y st o p t he trial if, i n fact, 3 0 0 0 m g/ m2 is n ot as effecti ve as has b ee n h y p ot hesiz e d f or 
t he hi gh d ose P E G-as para gi n ase re gi me n. F urt h er m ore, realisticall y if t he 3 5 0 0 u/ m 2 d ose 
is t o o t o xic t he n t he m o nit ori n g b o u n daries will be e x pecte d t o be reac he d relati vel y earl y 
d uri n g t he tri al, at w hic h ti me fe w C C R/ E F S-relat e d e ve nts will ha ve o cc urre d; t h us t he 
t o xicit y-st o p pi n g ti me p oi nt is n ot li kel y t o occ ur at a ti me t hat statisticall y mea ni n gf ul 
c o m paris o ns of o utc o me ca n be c o n d ucte d a n d i nter pret e d. T heref ore, we d o n ot pla n t o 
perf or m a n y a nal ysis of o utc o me d ue t o earl y e x cessi ve t o xicit y. Clearl y if i nteri m 
anal ys es of o utc o me h a v e alrea d y bee n c o n d ucte d, t he n t h ose res ults w o ul d be a vaila ble 
f or t he D S M B w h e n t he y c o nsi der a n d a d vise re gar di n g a n y o bser ve d statistical st o p pi n g 
criteria f or t o xicities.   
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T o xicit y m o nit ori n g r ules w o ul d be rei nitialize d wit h t his maj or c ha n ge i n t hera p y a n d if 
3 0 0 0 u nit s/ m2 s u bse q ue ntl y pr o ves t o be t o o t o xic t he n t he trial w o ul d li kel y be cl ose d, as 
t he pri mar y res earc h q uesti o n w o ul d n o l o n ger be via ble. 
 
If t o xicit y is e x cessi ve i n b ot h treat me nt re gi me ns, seri o us c o nsi derati o n as t o w het her t he 
st u d y s h o ul d c o nti n ue usi n g P E G-as para gi nase. T his e ve nt w o ul d li kel y res ult i n per ma ne nt 
cl os ure of t he tri al or at t he ver y least a maj or c h a n ge i n t he tr eat me nt r e gi me ns. 
 
1 8. 2 
Pri mar y O bj ecti ve 
 
T he  pri mar y o bje cti ve of t his st u d y is t o c o m pare t he distri b uti o ns of c o nti n u o us c o m plete 
remissi o n of patie nts ra n d o mize d o n t he first da y of c o nti n uati o n p hase t o r ecei ve hi g h er 
d ose of P E G-as p ara gi nas e or t o recei ve c o n ve nti o nal d ose ( 2, 5 0 0 u nits/ m 2). 
 
Desi g n:  T his st u d y will be c o n d ucte d b y a n o pe n-l a bel, ra n d o mize d trial. Partici pati n g 
pa tie nts will be ra n d o mize d t o recei ve eit her hi g h d ose P E G-as para gi nase or c o n ve nti o nal 
d osi n g of 2, 5 0 0 u nits/ m 2 P E G- As para gi n ase per d ose d uri n g t h e c o nti n uati o n p hase. 
 
T he ra n d o mizati o n will be stratifie d b y se v eral f act ors base d o n t he f oll o wi n g 
c o nsi derati o n: L o w ris k a n d sta n dar d/ hi g h ris k patie nts recei ve differe nt treat me nts i n t he 
c o nti n uati o n p hase; t here ha ve bee n re p orts t hat c hil dre n wit h T-cell A L L be nefit m ore 
fr o m as para gi nase tr eat m e nt t ha n c hil dre n wit h B-li nea ge A L L; a n d Da y- 1 9 M R D 
p ositi vit y ( ≥0. 0 1 %) is a n i m p orta nt pr o g n ostic fact or o n T O T X V.  
 
T he f oll o wi n g t a ble s h o ws t he 5- year C C R rate si nce c o nti n uati o n i n eac h strat u m o n 
T O T X V (as of 4/ 5/ 2 0 0 7). Patie nts wit h n o Da y- 1 9 M R D res ults are e x cl u de d. 
 
Str at a  
n  
5 -ye ars C C R si nce 
c o nti n u ati o n Esti m ate  ±  
S E ( %)  
L R  
1 5 2  
9 6. 1 ± 3. 5  
S R & T -cell & M R D 1 9 +  
2 7  
7 3. 5 ± 2 1. 8  
S R & T -cell & M R D 1 9 - 
1 9  
8 8. 9 ± 1 3. 3  
S R & B -cell & M R D 1 9 +  
6 3  
7 7. 2 ± 1 1. 1  
S R & B -cell & M R D 1 9 - 
2 7  
7 6. 4 ± 1 5. 1  
H R  
1 4  
3 9. 3 ± 2 1. 6  
 
T h us, t he ra n d o mizati o n will be stratifie d first b y t he ris k stat us f or t he c o nti n uati o n p hase 
(L o w, Sta n dar d, Hi g h; se e Secti o n 4. 0), t he n wit hi n Sta n dar d ris k b y li nea ge ( T-li nea ge, 
B-li nea ge) a n d f urt her wit hi n t he T- li nea ge b y Da y- 1 5 M R D le v el ( < 0. 0 1 % vs. ≥0. 0 1 %), 
creati n g 5 strat a. 
 
T he ra n d o mizati o n will occ ur o n t he starti n g d a y of t he c o nti n uati o n p hase, at w hic h ti me 
all i nf or mati o n necess ar y f or perf or mi n g t he ra n d o mizati o n s h o ul d be a vaila ble. I n t he rare 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
case t hat i m m u n o p he n ot y p e a n d/ or Da y- 1 5 M R D is n ot a vaila ble, we will ma ke t he 
f oll o wi n g ass u m pti o ns: If i m m u n o p he n ot y pe is u n k n o w n at t he ti me t he ra n d o mizati o n is 
t o be e x ec ute d, t he n it will be ass u me d B-li nea ge. If Da y- 1 5 M R D is u n k n o w n at t he ti me 
of ra n d o mizati o n, t he n it will be ass u me d ne gati ve ( < 0. 0 1 %). Past e x perie n ce i n dicate t hat 
fe w patie nts will fall i nt o t hese u n k n o w n cate g ories. 
 
N ote o nl y eli gi ble p atie nts w h o c o nse nt a n d are ra n d o mize d are e val ua bl e f or t his o bjecti ve. 
T he st u d y e n d p oi nt is d urati o n of c o nti n u o us c o m plete re missi o n p ost ra n d o mizati o n. 
D urati o n of C C R will be meas ure d fr o m t he ra n d o mizati o n date t o t he date of i nitial fail ure 
f or patie nts w h o f ail. Fail ure i ncl u des t he f oll o wi n g e n d p oi nts: 
 
 rela pse i n a n y site 
 sec o n d mali g n a nc y 
 de at h d uri n g re missi o n 
 
D urati o n of C C R will be meas ure d t o t he d ate of l ast c o ntact f or p atie nts w h o are fail ure 
free at t he ti me of a n al ys es.  
 
Accr u al: T h e distri b uti o n of t he le n gt h of t he ti me i nter val bet wee n t w o c o nsec uti ve 
e nr oll me nts (t he i nter- arri val ti me) o n T O T X V (e x cl u di n g patie nts treate d at C o o k’s) is 
dis pl a ye d i n t he f oll o wi n g fi g ure, i n w hic h t he ti m e u nit is year. T his distri b uti o n will be 
use d i n t he M o nte Carl o esti mati o n of statistical p o wer. T he m ea n i nter-arri val ti me o n 
T O T X V is esti mate d 0. 0 1 8 1 year; t he sta n d ar d de viati o n of i nter-arri val ti me is esti mate d 
0. 0 1 9 5 year. T h us t he esti mate d e nr oll me nt fre q u e nc y is a p pr o xi matel y 5 6 patie nts per 
year. We e x pect t he e nr oll me nt fre q ue nc y i n T O T X VI will be si milar a n d t h us t he accr ual 
g oal will be ac hie v e d i n 8 t o 9 years. T he t otal accr ual ti me will be assesse d b y t he 
si m ulati o n st u d y i n t he p o wer c o nsi derati o n secti o n. 
0. 0
0. 0 5
0. 1 0
0. 1 5
0
1 0
2 0
3 0
4 0
I nt er- arri v al ti m e o n T O T A L- X V
 
Hist oric al d at a:  T he f oll o wi n g ta ble a n d fi g ure s h o w res pecti vel y t h e 5- year K M 
esti mates of d urati o n of C C R fr o m t he be gi n ni n g of c o nti n uati o n t hera p y i n T O T XIII A, 
B, a n d T O T X V (e x cl u di n g C o o k’s patie nts) st u di es. Beca use T O T X V di d n ot i ncl u de 
i nfa nts, o utc o me data of t he i nfa nts o n t he I N F A N T 9 9 pr ot oc ol w h o e nr olle d after 
T O T X V was o p e ne d w ere a d de d t o T O T X V o utc o me t o i m p ute t he sce nari o of i ncl u di n g 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
C C R Si n c e C o nti n u ati o n
0
0. 1
0. 2
0. 3
0. 4
0. 5
0. 6
0. 7
0. 8
0. 9
1
0
2
4
6
8
1 0
1 2
1 4
1 6
y e ar
Pr o b a bilit y
T 1 3 A
T 1 3 B
T 1 3 A B
T 1 5 +i nf n
i nfa nts o n T O T X V.  Pati e nts w h o faile d t o e nter t he c o nti n uati o n p hase were e x cl u de d. 
N ote i n t his ta ble t here are 1 6 i nfa nts a n d 1 1 T O T X V patie nts wit h o ut Da y- 1 9 M R D are 
i ncl u de d f or “ T 1 5 +I nf n.”  
 
S T U D Y  
T ot al  
Ac hie vi n g C R  
# P ati e nts  
E nter e d 
C o nti n u ati o n  
# I nf a nts  
E ntere d  
C o nti n u ati o n  
5 -Ye ar C C R 
R ate  
Fr o m I niti ati o n 
of C o nti n u ati o n  
Esti m ate ± S E 
( %) 
T 1 3 A  
1 6 2  
1 6 0  
4  
7 8. 1 ± 3. 3  
T 1 3 B  
2 4 2  
2 3 7  
1 0  
8 2. 6 ± 2. 5  
T 1 3 A & B 
c o m bi ne d  
4 0 4  
3 9 7  
1 4  
8 0. 8 ± 2. 0  
T 1 5 +I nf n (as of 
4/ 5/ 0 7)  
3 7 5  
3 2 9  
1 6  
8 5. 6 ± 4. 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he f oll o wi n g t a ble s h o ws t he 5- year d urati o n of C C R rates fr o m t he be gi n ni n g of 
c o nti n uati o n t hera p y of t hese pre vi o us st u dies b y ris k strata, w here i nfa nts descri be d a b o ve 
were a d de d t o t he T O T X V Sta n dar d/ Hi g h ris k strat u m.  
 
RI S K A R M S  
n  
5 -Ye ar C C R R ate  
Fr o m I niti ati o n of 
C o nti n u ati o n  
Esti m ate ± S E ( %)  
T 1 3 A S/ H  
1 5 0  
7 6. 7 ± 3. 4  
T 1 3 B S/ H  
1 2 3  
7 6. 4 ± 3. 8  
T 1 5 S/ H wit h i nfa nts (as of 
4/ 5/ 2 0 0 7)  
1 7 1  
7 6. 1 ± 7. 3  
T 1 3 A L  
1 0  
1 0 0 ± 0. 0  
T 1 3 B L  
1 1 4  
8 9. 3 ± 2. 9  
T 1 5 L (as of 4/ 5/ 2 0 0 7)  
1 5 8  
9 6 . 2 ± 3. 4 
 
T O T XIII A a n d B c o m bi ne d pr o vi de a n a de q uat e descri pti o n of t he C C R distri b uti o n i n 
rece nt st u dies a n d will be use d as preli mi nar y d ata f or p o wer c o nsi derati o n, as descri be d 
bel o w. Beca us e T O T X V has n ot st o p pe d accr ual a n d has relati vel y s h ort f oll o w- u p, it will 
be use d sec o n d aril y f or p o wer c o nsi derati o n. 
 
A n al ysis:  T he fi nal a nal ysis of t he pri mar y o bjecti ve will be t hree years aft er t he last 
pa tie nt is ra n d o mize d. T he pri mar y a n al ysis is a M a ntel- Hae nszel (stratifie d l o g-ra n k) test 
c o m paris o n of t he distri b uti o ns of C C R f or patie nts ra n d o mize d t o t he t w o treat me nt ar ms, 
usi n g t he strata d efi ne d f or ra n d o mizati o n. P o wer c o nsi derati o n f or t his a nal ysis is gi ve n 
bel o w. Ka pla n- Meier ( K M) esti mates of t he distri b uti o n of C C R f or eac h treat me nt ar m 
will be pr o vi de d.  
 
T w o i nteri m a nal yses, o n e at t he e n d of year 3 a n d o ne at year 6. 5 are pla n ne d. T he 
a nal ys es will perf or m t w o-si de d Ma ntel- Hae nszel (stratifie d l o g-ra n k) test c o m paris o n of 
t he distri b uti o ns of C C R f or patie nts ra n d o mize d t o t he t w o treat me nt ar ms, usi n g t he 
strata defi ne d f or ra n d o miz ati o n a n d t he statistical si g nifica n ce le vel α = 0. 0 0 5. A f utilit y 
a nal ysis as detaile d bel o w will be c o n d ucte d as part of t he 6. 5 year i nteri m a nal ysis if t he 
c o m paris o n at t he 0. 0 0 5 l e vel is n ot statisticall y si g nifica nt. D ue t o t he t w o pla n ne d 
i nteri m a nal ys es, t he fi nal a nal ysis will be c o n d u ct e d at α = 0. 0 4 5. 
 
S u bset a nal ys es c o m pari n g t he t w o ar ms wit hi n strata ma y be c o n d ucte d as well, usi n g t he 
l o g-ra n k test. T hese s u bs et a nal yses will ha ve li mite d statistical p o wer t o detect 
differe n ces a n d will be i nter prete d wit h e xtre me ca uti o n as descri pti ve. K M esti mates of 
t he distri b uti o n of C C R b y treat me nt ar m wit hi n eac h strat u m will be pr o vi de d. 
 
P o w er c o nsi der ati o n:  Here p o wer c o nsi derati o n is de vel o pe d bas e d o n t he u nstratifie d 
test. O verall, t he 5- year C C R rate fr o m i nitiati o n of c o nti n uati o n t hera p y i n T O T XIII A & 
B c o m bi ne d a n d T O T X V pl us i nfa nts are 8 0. 8 ± 2. 0 % a n d 8 5. 6 ± 4. 4 %, res pecti vel y; t he 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5 - year C C R rate fr o m i nitiati o n of c o nti n uati o n t hera p y i n t h e T O T X V l o w ris k strat u m is 
9 6. 2 ± 3. 4 %. We belie ve t hat t he effect size i n eac h ris k- base d strat u m as s h o w n bel o w is 
cli nicall y me a ni n gf ul, base d o n t he c o nsi derati o ns: ( 1) pre vi o us fr o nt-li ne A L L tri als ha ve 
s h o w n t hat a t hera p y a u g me nte d wit h as para gi nas e c o ul d i m pr o ve 5- year e ve nt-free 
s ur vi val b y 2 0 %; 1 a n d patie nts recei vi n g less as para gi nase t hera p y c o ul d h a ve 5- year E F S 
re d uce d b y 1 7 %;2  ( 2) males will n ot be recei vi n g t he a d diti o nal 2 6 wee ks of c o nti n uati o n 
t hera p y o n T O T X VI; ( 3) T O T X VI will i ncl u de a p pr o xi matel y 2 0 i nf a nts a n d ( 4) t he 
f oll o w u p ti me of T O T X V is still s h ort. 
 
P ost ul ate d effect size i n e ac h str at u m b ase d o n T O T X V 
Str at u m  
n ( %)  
5 -Y C C R 
si nce 
c o nti n u ati o n 
Esti m ate ± 
S E ( %)  
P ost ul a
te 5 -y 
C C R 
i n t he 
2 5 0 0 u/
m 2 ar m  
( %) 
P ost ul ate
5 -y C C R 
i n t he 
hi g h -
d ose ar m  
( %) 
Wei g hte d 
effect size  
H R  
1 4 ( 4. 6 4)  
3 9. 3 ± 2 1. 6  
3 2  
6 4  
1. 4 8 4  
S R & T -
cell & M R D 1 9 +  
2 7 ( 8. 9 4)  
7 3. 5 ± 2 1. 8  
6 6  
9 2  
2. 3 2 4  
S R & T -
cell & M R D 1 9 - 
1 9 ( 6. 2 9)  
8 8. 9 ± 1 3. 3  
8 2  
9 2  
0. 6 2 9  
S R & B -cell 
9 0 
( 2 9. 8 0) 
7 7. 3 ± 9. 2  
7 3  
9 2  
5. 6 6 2  
L R  
1 5 2 
( 5 0. 3 3) 
9 6. 1 ± 3. 5  
9 4  
9 8  
2. 0 1 2  
O verall  
3 0 2  
 
8 1. 5 7 9  
9 3. 7 2 2  
1 2. 0 2 1  
 
T he l o w ris k gr o u p n o net heless c o ntri b utes a n a p precia ble a m o u nt of effect ( 2 %, t he t hir d 
hi g hest) t o t he o v erall effect size. Alt h o u g h t he statistical p o wer is m ostl y br o u g ht b y t he 
effects i n t he S/ H ris k gr o u ps, we c h o ose t o r a n d o mize t he l o w ris k patie nts as well i n or der 
t o ha ve a n o p p ort u nit y t o f ull y u n dersta n d P E G-as para gi nas e P K (i n b ot h i nte nsi vel y a n d 
less i nte nsi vel y treate d p atie nts), t o e val uate t heir t olera nce t o hi g her d ose of as para gi nase, 
a n d t o o bser ve t heir l o n g ter m o utc o me i n t he c o nt e xt of t he T O T X VI t hera p y. As is s h o w n 
bel o w, we will ha ve a de q uate statistical p o wer t o d etect t he p ost ulate d effect size i n t he 
e ntire c o h ort. 
 
T h us f or T O T X VI, we p ost ulate o verall t he 5- year C C R rate p ost ra n d o mizati o n will be 
a p pr o xi matel y 8 2 % i n t h e 2 5 0 0 U/ m 2 ar m a n d 9 4 % i n t he hi g h d ose P E G-as para gi n ase 
ar m. T he st u d y will be p o were d t o det ect a 1 2 % differe n ce i n t he fi ve- year C C R rate. 
 
C o nsi deri n g t he pr o b a bilit y distri b uti o n of t he fail ure ti mes, t he f oll o wi n g fi g ure s h o ws a 
n o n para metri c esti mate of its hazar d rate f u n cti o n base d o n t he C C R distri b uti o n fr o m 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T O T XIII A & B c o m bi ne d. T his esti mate is c o nstr ucte d via s pli ne esti mates of t he q ua ntile 
a n d q ua ntile de nsit y f u ncti o ns of t he C C R distri b uti o n a n d is a s pecial case of t he 
esti mat ors i n vesti gate d b y C he n g. 1 3 6 T he e x p o ne ntial distri b uti o n ass u m pti o n of a c o nsta nt 
ha zar d rate is cl earl y vi ol ate d. As t he hazar d rate f u ncti o n is o nl y a p pr o xi matel y c o nsta nt 
d uri n g years o n e a n d t hree, it is n ot reall y feasi ble t o esti mate t his f u ncti o n wit h a se q ue nce 
of piece- wise e x p o ne ntials. W e ca n esti mate t he statistical p o wer f or a n y gi ve n sa m ple a n d 
effect sizes b y si m ulati o n usi n g n o n para metric esti mates o btai ne d fr o m t he hi g h q ualit y 
preli mi nar y data. He re w e esti m ate t he p o w er f or 3 0 0 e v al u a ble p atie nts at t he a b o ve-
s pecifie d effect size. Si m ulati o n als o all o ws f or o btai ni n g esti mates of ot her i m p orta nt trial 
pa ra meters (e. g., t h e pr o b a bilit y distri b uti o n of t he t otal accr ual ti me t o reac h t he tar get of 
3 0 0 e val ua ble p atie nts) t hat are n ot a vaila ble fr o m c o n ve nti o nal met h o ds.  
F ail ur e ti m e ( y e ar)
H a z ar d r at e
0 
1 
2 
3 
4 
5 
6 
7 
8 
9
1 0
0. 0 
0. 0 2 
0. 0 4 
0. 0 6 
0. 0 8 
0. 1 0 
0. 1 2
E sti m at e d H a z ar d R at e F u n cti o n fr o m T- 1 3 A & B
 
T he statistical p o wer of a t w o-si de d l o g-ra n k test at t he 5 % si g nifica nce l e v el f or t he 
sa m ple siz e of 3 0 0 a n d t he p ost ulate d effect size is esti mate d b y 1 0 0 0 si m ul ati o n r u ns. 
T he M o nte C arl o esti m ate of t he p o w er is 0. 8 5, wit h 9 5 % c o nfi de nce i nter v al ( CI) 
[ 0. 8 3, 0. 8 8]. T he esti mate d pr o ba bilit y t hat m or e t ha n 7 years of t otal accr ual ti me will be 
re q uire d is 0. 0 2 ( 9 5 % CI [ 0. 0 1, 0. 0 3]), a n d t he esti mate d pr o ba bilit y of less t ha n 6 years 
t otal accr ual ti me is 0. 2 4 ( 9 5 % CI [ 0. 2 1, 0. 2 6]).  
 
C o nsi deri n g t o i ncl u de t h e rece nt ( 4/ 5/ 2 0 0 7) T O T X V o utc o me data as preli mi nar y d ata f or 
M o nte Carl o p o wer esti mati o n as well, t he f oll o wi n g fi g ures s h o w K M esti mates of t he 
C C R s ur vi val c ur ve wit h p oi nt- wise 9 5 % CI ( d otte d li nes) a n d tic k mar ks i n dicati n g 
ce ns ori n g, f or T O T XIII A a n d T O T XIII B, T O T X V pl us i nfa nts, T O T X V Sta n dar d/ Hi g h 
ris k, a n d T O T X V L o w ris k.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
0 
2 
4 
6 
8
1 0 
1 2 
1 4
0. 0 
0. 2 
0. 4 
0. 6 
0. 8 
1. 0
T- 1 3 A & B
0 
2 
4 
6 
8
1 0 
1 2 
1 4
0. 0 
0. 2 
0. 4 
0. 6 
0. 8 
1. 0
T- 1 3 & 1 3 B, T- 1 5 +I nf n
0. 0 
1. 0 
2. 0 
3. 0 
4. 0 
5. 0 
6. 0
0. 0 
0. 2 
0. 4 
0. 6 
0. 8 
1. 0
T- 1 5 L o w Ri s k
0. 0 
1. 0 
2. 0 
3. 0 
4. 0 
5. 0 
6. 0
0. 0 
0. 2 
0. 4 
0. 6 
0. 8 
1. 0
T- 1 5 S/ H Ri s k
 
E x cessi ve ce ns ori n g wit hi n 6 years i n T O T X V is n oticea ble, e v e n i n t he l o w ris k c o h ort; 
e vi de nt of rel ati vel y s h ort f oll o w u p ti me. T he f oll o wi n g fi g ure s h o ws n o n p ara metri c 
hazar d rate f u ncti o n esti mates fr o m T O T XIII A, T O T XIII B, a n d T O T X V wit h i nfa nts 
c o m bi ne d ( All), T O T X V wit h i nfa nts, a n d T O T XIII A & B. T h e irre g ular s ha pe of t he 
hazar d rate f u ncti o n esti mate f or T O T X V is lar gel y d ue t o hea v y ce ns ori n g ca use d b y lac k 
of f oll o w u p. 
ti m e ( y e ar)
H a z ar d R at e
0 
1 
2 
3 
4 
5 
6 
7 
8 
9
1 0
0. 0 
0. 0 2 
0. 0 4 
0. 0 6 
0. 0 8 
0. 1 0 
0. 1 2
T 1 5 +I nf n
T 1 3 A B
All
H a z ar d R at e F u n cti o n E sti m at e s
 
M o nte Carl o esti mates of t he statistical p o wer of t he l o g ra n k test base d T O T XIII A, 
T O T XIII B, a n d T O T X V pl us i nfa nts is 8 4 %, wit h t he 9 5 % CI [ 0. 8 1, 0. 8 6]. 
 
C o nser vati vel y we ne xt c o nsi der p ost ulati n g t he effect sizes base d o n t he p oi nt esti mates 
fro m t he T O T X V d ata: 8 5. 1 9 9 % vs. 9 3. 7 2 2 % C C R at year 5 si nce c o nti n uati o n; see ta ble 
bel o w. B ase d o n T O T XIII A a n d XIII B preli mi n ar y d at a, t he esti m ate d p o wer at 5 % 
si g nific a nce le vel is 0. 7 9 1 ( 9 5 % CI [ 0. 7 6 6, 0. 8 1 6]) if t he s a m ple size is i ncre ase d t o 
4 2 0.  F o r t his sa m ple siz e t he pr o ba bilit y of m ore t ha n 9. 5 accr ual is 0. 0 5 4 ( 9 5 % CI [ 0. 0 4 0, 
0. 0 6 8]); t he pr o ba bilit y of less t ha n 8. 5 year accr ual is 0. 2 4 7 ( 9 5 % CI [ 0. 2 2 0, 0. 2 7 4]). 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
P ost ul ate d effect size i n e ac h str at u m b ase d o n p oi nt esti m ates fr o m T O T X V 
Str at u m  
n ( %)  
5 -Y C C R 
si nce 
c o nti n u ati o n 
Esti m ate ± 
S E ( %)  
P ost ul ate
5 -y C C R 
i n t he 
2 5 0 0 u/ m
2 ar m  
( %) 
P ost ul ate
5 -y C C R 
i n t he 
hi g h -
d ose ar m  
( %) 
Wei g hte d 
effect size  
H R  
1 4 ( 4. 6 4)  
3 9. 3 ± 2 1. 6  
3 9  
6 4  
1. 1 6 0  
S R & T -
cell & M R D 1 9 +  
2 7 ( 8. 9 4)  
7 3. 5 ± 2 1. 8  
7 3  
9 2  
1. 6 0 1  
S R & T -
cell & M R D 1 9- 
1 9 ( 6. 2 9)  
8 8. 9 ± 1 3. 3  
8 9  
9 2  
0. 1 8 9  
S R & B -cell 
9 0 ( 2 9. 8 0)  
7 7. 3 ± 9. 2  
7 7  
9 2  
4. 4 7 0  
L R  
1 5 2 
( 5 0. 3 3) 
9 6. 1 ± 3. 5  
9 6  
9 8  
1. 0 0 7  
O verall  
3 0 2  
 
8 5. 1 9 9  
9 3. 7 2 2  
8. 5 3 3  
 
F utilit y assess me nt at ye ar 6. 5: If t he i nteri m a n al ysis at year 6. 5 fails t o detect a 
statisticall y si g nifica nt differe nce at t he 0. 0 0 5 le vel (t w o-si de d test) bet wee n t he t w o P E G-
as para gi n ase re gi me ns, a f utilit y a nal ysis, as re q u este d b y t he C T- S R C, will be c o n d ucte d. 
We n ote t hat cli nical trials t hat are desi g ne d wit h statistical p o wer of 8 0 % t o detect a 
h y p ot hesize d effect h a ve a pr o ba bilit y of 0. 2 0 ( 2 0 %) of bei n g “f utile” e v e n if t he 
h y p ot hesize d effect size is tr ue. I n t his c o nte xt “f utilit y” d oes n ot mea n t hat t he researc h 
h y p ot hesis is n ot tr ue b ut rat her t hat at t he fi nal a nal ysis n o statisticall y si g nifica nt 
differe n ce is det ecte d.  
 
T h us, t he g o al of t his f utilit y a nal ysis is t o assess earl y e vi de nce t hat t he c o nject ure d 
8. 5 3 % effect size bet wee n hi g h d ose P E G-as para gi nase a n d c o n v e nti o nal d osi n g of P E G-
as para gi n ase is t o o o pti mistic a n d c o nti n ue d ra n d o mizati o n will wit h hi g h pr o ba bilit y 
res ult i n a f utile fi nal a n al ysis (i.e., fi nal p- val ue > 0. 0 4 5). T he si m ulati o n st u d y i n dicat es 
t hat at year 6. 5 we will h a ve o bser ve d a p pr o xi matel y 3 7 % of t he t otal n u m ber of e v e nts 
e x pecte d at t he pla n ne d fi nal a nal ysis. Gi ve n t he g oal a n d t he li mite d a m o u nt of 
i nf or mati o n e x pecte d t o be a vaila ble 6. 5 year after i nitiati o n of ra n d o mizati o n, we pr o p ose 
t he f oll o wi n g n o n-st a n dar d a p pr oac h. T his pr o p os e d f utilit y a n al ysis is n ot gr o u n de d i n 
peer-re vie we d p u blis he d statistical researc h, b ut w e belie ve t hat t he m et h o d is vali d a n d 
i n dee d at first gla n ce it d oes ha ve s o me n ecess ar y o perati n g c h aracteristics of a f utilit y 
a nal ysis. We f ull y e x pect t o c o m plete researc h o n t he pr o p ose d met h o d wit hi n a year a n d 
at t hat ti me or wit h t he first T O T X VI pr ot o c ol a m e n d me nt i ncl u de t he fi n al f utilit y 
a nal ysis desi g n a n d j ustificati o n f or C P S R M C c o nsi derati o n. If we are u na ble t o j ustif y t he 
statistical vali dit y of o ur met h o d, we will s witc h t o a sta n dar d a p pr oac h.  
 
We will c o n d uct t he f utilit y a nal ysis i n a wa y t hat t he fi nal pla n ne d a n al ysis will n ot be 
affecte d s h o ul d t he trial c o nti n ue t o t hat a nal ysis. F or t his p ur p ose we defi n e “f utilit y” as 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t he (c o n diti o nal) e v e nt t hat t he t w o-si de d test i n t he fi nal a nal ysis is n ot st atisticall y 
si g nifica nt at t he 0. 0 4 5 le vel gi ve n t h at t he n ull h y p ot hesis of n o differe nce is n ot rejecte d 
i n fa v or of t he o n e-si de d alter nati ve h y p ot hesis t hat t he hi g h d ose P E G-as para gi nase 
re gi me n has s u peri or distri b uti o n of C C R, at s o me yet t o be d efi ne d si g nifica nt le vel γ. We 
call t he c o n diti o nal pr o ba bilit y of (faili n g t o reject t he n ull h y p ot hesis b y t he t w o-si de d 
test at t he 0. 0 4 5 le vel i n t he fi nal a nal ysis gi ve n faili n g t o reject t he n ull h y p ot hesis i n 
fa v or of t he o ne-si de d alter nati ve at t he si g nifica n ce le vel γ i n t he f utilit y assess me nt) t he 
pr o b a bility of f utility  ( P o F u(γ)), w hic h we n ote is a f u ncti o n of γ.  
 
Af ter 6. 5 years of ra n d o mizati o n, we will declare t he trial statisticall y f utile, if we fail t o 
reject, at t he γ si g nifi ca n ce le vel, t he n ull h y p ot hesis of n o differe n ce a gai nst t he o ne-si de d 
alter nati ve h y p ot hesis t hat t he hi g h d ose P E G-as para gi nase re gi me n has t he s u peri or 
dist ri b uti o n of C C R.  
 
T he si g nifica nce le vel γ is a para m eter t o be deter mi ne d t o e ns ure t he f utilit y assess me nt h as 
t he foll o wi n g desir a ble o perati n g c haracteristics: ( 1) If t he act ual effect size is at least as 
p ost ulate d (i.e., 8. 5 %), t h e n wit h pr o ba bilit y great er t ha n 0. 8 0 t he trial will c o nti n ue; ( 2) If t h e 
act ual effect size is ver y s mall ( or e ve n if t he hi g h d ose P E G-as para gi nase re gi me n act u all y is 
less effecti ve), wit h hi g h pr o ba bilit y t he trial will be declare d f utile a n d he nce ra n d o mizati o n 
is st o p pe d. T he val ue of γm  t hat ma xi mizes P o F u(γ) has t hese pr o perties. I nt uiti vel y, t h e 
de cisi o n r ule t hat st o ps t he trial f or faili n g t o r eject t he n ull h y p ot hesis at t h e γ m  si g nifica nce 
le vel ma xi mizes t he pr o ba bilit y of i de ntif yi n g w he n c o nti n ue d ra n d o mizati o n a n d f oll o w u p is 
n ot li kel y t o pr o d uce a st atisticall y si g nifica nt r es ult. 
 
T he pr o ba bilit y of f utilit y a n d t h e pr o ba bilit y of declari n g t he trial f utile at vari o us γ 
va l ues a n d effect sizes are esti mate d b y si m ulati o n usi n g t he sa me preli mi nar y data as i n 
t he a b o ve p o w er c o nsi derati o n. At t he 8. 5 % effect size, t he esti mate d pr o ba bilit y of f utilit y 
is ma xi mize d at γ = 0. 3 1 5 a n d P o F u( 0. 3 1 5) = 0. 5 3 9 ( 9 5 % CI [ 0. 5 1 7, 0. 5 6 1]). T his mea ns t hat 
if t he act ual effect size is 8. 5 % a n d if we fail t o rej ect t he n ull h y p ot h esis i n fa v or of t he 
o ne-si de d alter nati ve at t he 3 1. 5 % le vel, t he n wit h 5 3. 9 % pr o ba bilit y we will n ot reje ct t he 
n ull h y p ot hesis at t he 0. 0 4 5 le vel usi n g t he t w o-si de d test i n t he fi nal a nal ysis. T he 
pr o ba bilit y of declari n g f utilit y (st o p pi n g t he trial w he n it s h o ul d ha ve c o nti n ue d) w he n 
t he tr ue effect size is 8. 5 % f or γ = 0. 3 1 5 is esti mate d t o be 0. 1 0 2 ( 9 5 % CI [ 0. 0 8 9, 0. 1 1 5]). 
T he f oll o wi n g t a ble s h o ws t he o perati n g c h aracteristic of t he f utilit y assess me nt usi n g 
γ = 0. 3 1 5 at a fe w effect sizes ( ne gati ve effect size mea ns t hat t he 5- year C C R of t he hi g h 
d ose P E G-as para gi nase re gi me n is a ct uall y l o wer b y t he gi ve n a m o u nt). 
 
  
  
  
Pr o ba bilit y of f utilit y   
Pr o ba bilit y of declari n g 
Tr ue effect size  
P o F u( 0. 3 1 5) ( 9 5 % CI)  
f utilit y/st o p ( 9 5 % CI) 
8. 5 %   
  
0. 5 3 9 ([ 0. 5 1 7, 0. 5 6 1])   
0. 1 0 2 ([ 0. 0 8 9, 0. 1 1 5]) 
4. 0 %   
  
0. 9 6 4 ([ 0. 9 5 6, 0. 9 7 2])   
0. 3 7 8 ([ 0. 3 5 6, 0. 3 9 9]) 
2. 0 %   
  
0. 9 0 8 ([ 0. 8 9 5, 0. 9 2 1])   
0. 7 7 3 ([ 0. 7 5 5, 0. 7 9 1]) 
-4. 0 %   
  
0. 8 2 0 ([ 0. 8 0 3, 0. 8 3 7])   
0. 8 7 9 ([ 0. 8 6 5, 0. 8 9 3]) 
 
S o if t he tr ue effect size is 4. 0 % ( 2. 0 %) i n fa v or of t he hi g h d ose P E G-as para gi n ase 
re gi me n, t he n wit h pr o ba bilit y 0. 3 7 8 ( 0. 7 7 3), t he trial will st o p at 6. 5 years. Wit h 
pr o ba bilit y 0. 6 2 2 ( 0. 2 3 7) t he trial will c o nti n ue a n d t he pr o ba bilit y t hat t he fi nal t w o-si de d 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 8 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
test will be statisticall y si g nifica nt is 0. 0 3 6 ( 0. 0 9 2) gi ve n t he tri al c o nti n ues t o t he p oi nt of 
fi nal a nal ysis. N ote t hat t he 2. 0 % effect size has a hi g her pr o ba bilit y of res ulti n g i n a 
statisticall y si g nifica nt fi n di n g d ue t o t he fi n al test bei n g t w o-si de d; t hat is s o meti mes t he 
c o n ve nti o nal d ose ar m will ha ve a s u peri or distri b uti o n of C C R. 
  
T h us, w e will decl are t he tri al st atistic all y f utile t o c o nti n ue a n d st o p accr u al b ase d 
o n t he 6. 5 ye ar a n al ysis, if t he test of t he n ull a g ai nst t he o ne-si de d alter n ati ve t h at 
t he hi g h d ose P E G- as p a r a gi n ase re gi me n h as t he better distri b uti o n of C C R is n ot 
si g nific a nt at t he 3 1. 5 % le vel. 
 
T he a b o ve pla n f or t he f utilit y a n al ysis will eit her be j ustifie d b y s oli d statistical scie nce 
i ncl u di n g assess me nt of t he o perati n g c h aracteristi cs wit hi n a year of pr ot oc ol i nitiati o n or 
t he desi g n will be re pla ce d wit h a m ore sta n dar d a p pr oac h.  
 
I n s u m mar y, t o ha ve acce pta ble p o wer t o detect a reas o na bl e a n d cli nicall y mea ni n gf ul 
i mpr o ve me nt i n t he distri b uti o n of d urati o n of C C R f or t he hi g h- d ose P E G-as para gi n ase 
re gi me n, we will accr ue 5 3 1 patie nts wit h t he e x pectati o n t hat 4 2 0 will be ra n d o mize d. 
T his n u m ber of patie nts will pr o vi de a p pr o xi matel y 8 0 % statistical p o wer ( α = 0. 0 5; t w o-
si de d test) t o detect a n i m pr o ve me nt of 8. 5 3 % i n t he 5- year C C R f or t he hi g h- d ose 
re gi me n as c o m p are d t o t he sta n dar d- d ose re gi me n. Zel e n’s ra n d o mizati o n al g orit h m, as 
i mple me nte d i n t he De part me nt of Bi ostatistics si nce 1 9 9 2, will be use d wit h a bl oc ki n g 
fact or of 4 i n eac h strat u m.   T w o i nteri m a nal ys es f or efficac y are pla n ne d after 3 a n d 6. 5 
y ears after i nitiati o n of ra n d o mizati o n a n d a f utilit y a n al ysis will als o be c o n d ucte d at t he 
6. 5 year mar k. T he st u d y d urati o n is esti mate d t o re q uire a p pr o xi matel y 8. 6 years of 
accr ual a n d t he fi nal a nal ysis of t he pri mar y o bjecti ve will be 3 years after t he last patie nt 
is ra n d o mize d. T h us t he t otal st u d y d urati o n will b e 1 1- 1 2 years.  
 
1 8. 3 
T hera p e utic O bjecti ves 
 
T o esti m ate t he eve nt-fre e s urviv al a n d over all s urviv al of c hil dre n wit h A L L w h o are 
tre ate d wit h risk- directe d t her a py a n d t o c o m p are t he E F S res ults of T O T X VI wit h t h at 
of T O T X V. 
 
T hese a n al ys es will o nl y be c o n d ucte d at t he ti me t he pla n ne d i nteri m a nal yses c o m pari n g 
t he t w o c o nti n uati o n re gi me ns are c o m plete d. T hat is after 3 a n d 6. 5 years of accr ual. 
 
E F S will be meas ure d fr o m t he date of c o m plete res p o nse t o t he date of i nitial fail ure f or 
patie nts w h o fail. Fail ure i ncl u des t he tra diti o nal e n d p oi nts of fail ure t o ac hie ve a 
c o m plete re missi o n, rela pse i n a n y site, sec o n dar y mali g na n c y, a n d deat h d uri n g i n d ucti o n 
or re missi o n. E F S ti me will be meas ure d t o t he dat e of last c o ntact f or patie nts w h o are 
fail ure free at t he ti me of a nal ysis. T h e E F S ti me is defi ne d t o be zer o ( 0) f or patie nts w h o 
die d ur i n g i n d ucti o n t hera p y or fail t o ac hie ve a c o m plete re missi o n. 
 
T he f oll o wi n g t a ble a n d fi g ure s h o w res p ecti vel y t he 5- year a n d E F S distri b uti o n 
esti mates of T O T XIII A, T O T XIII B, a n d T O T X V pl us i nfa nts.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
E F S di stri b uti o n
0
0. 1
0. 2
0. 3
0. 4
0. 5
0. 6
0. 7
0. 8
0. 9
1
0
2
4
6
8
1 0
1 2
1 4
1 6
y e ar
Pr o b a bilit y
T 1 3 A
T 1 3 B
T 1 3 A B
T 1 5 +i nf n
S T U D Y  
n  
T ot al  
 
n  
I nf a nts  
5 -Ye ar E F S  
Esti m ate ± S E ( %)  
T 1 3 A  
1 6 5  
5  
7 7. 0 ± 3. 3  
T 1 3 B  
2 4 7  
1 0  
8 0. 9 ± 2. 5  
T 1 3 A & B c o m bi ne d  
4 1 2  
1 5  
7 9. 3 ± 2. 0  
T 1 5 +I nf n (as of 4/ 5/ 0 7)  
3 8 1  
1 6  
8 3. 7 ± 4. 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T he f oll o wi n g t a ble s h o ws t he 5- year E F S of t h ese pre vi o us st u dies b y ris k strata, w here 
i nfa nts descri be d a b o ve were a d de d t o t he T O T X V Sta n dar d/ Hi g h ris k strat u m.  
 
RI S K A R M S  
n  
5 -Ye ar E F S Esti m ate ± S E 
( %) 
T 1 3 A S/ H  
1 5 1  
7 6. 8 ± 3. 4  
T 1 3 B S/ H  
1 2 6  
7 6. 1 ± 3. 8  
T 1 5 S/ H wit h i nfa nts  
1 9 4  
7 5. 8 ± 6. 6  
T 1 3 A L  
1 1  
1 0 0 ± 0. 0  
T 1 3 B L  
1 1 6  
8 9. 5 ± 2. 9  
T 1 5 L  
1 8 1  
9 5. 7 ± 3. 4  
 
Ka pla n- Mei er esti mates of E F S a n d s ur vi val will be pr o vi de d a n d c o m pare d hist oricall y 
wit h t h ose of T O T X V, T O T XIII A a n d T O T XIII B. All eli gi ble patie nts e nt ere d o n 
T O T X VI will be i ncl u de d i n t hese a nal yses, as a p pr o priate. I nfa nts will be e x cl u de d fr o m 
t he T otal X VI f or c o m paris o ns wit h T O T X V as o nl y c hil dre n at least o ne year of a ge at 
dia g n osis were tr eate d o n T otal X V. C o m paris o ns will be ma de b ot h u nstratifie d a n d 
stratifie d b y T O T X VI defi ne d ris k gr o u ps.  S o me ass u m pti o ns will be necessar y as n ot all 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
fact ors defi ni n g ris k o n T O T X VI will be a v aila ble f or all patie nts treate d o n T O T XIII A 
a n d B. T h e c o m paris o ns wit h T O T X V defi n e t he sta n dar ds wit h w hic h t he fi nal res ults of 
t his st u d y s h o ul d be c o m pare d t o ass ure c o nti n ue d pr o gress t o war ds t he St. J u de g oal of 
i m pr o vi n g t he c ure rate of c hil d h o o d A L L. T he f oll o wi n g ta ble s h o ws t he rece nt E F S i n 
T O T X V ( D ata fr oze n o n 4/ 5/ 2 0 0 7). 
 
E F S i n T O T A L - X V  
Year  
Ris k  
Fail  
Ce ns  
Pr o b  
S E  
0  
3 6 5  
6  
0  
0. 9 8 4  
0. 0 0 7  
1  
3 5 9  
1 1  
5 2  
0. 9 5 0  
0. 0 1 2  
2  
2 9 6  
7  
6 7  
0. 9 2 5  
0. 0 1 7  
3  
2 2 2  
3  
6 1  
0. 9 1 0  
0. 0 2 2  
4  
1 5 8  
3  
5 3  
0. 8 8 7  
0. 0 2 9  
5  
1 0 2  
4  
3 6  
0. 8 4 6  
0. 0 4 2  
6  
6 2  
0  
5 0  
0. 8 4 6  
0. 0 9 2  
7  
1 2  
0  
1 2  
0. 8 4 6  
0. 3 3 2  
 
T hese c o m paris o ns are n ecessar y t o assess t he i m pr o ve me nt i n o utc o me t h at t he ris k- base d 
T O T X VI t hera p y f or A L L has o v er t he T O T X V t hera p y.  
 
Si nce male patie nts will recei ve s h orter d urati o ns of t hera p y o n T O T X VI t ha n o n T O T X V, 
we will s pecificall y c o m pare t he distri b uti o ns of E F S f or male p atie nts bet wee n t hese t w o 
trials. Als o we will c o m pare t he distri b uti o ns of C C R fr o m t he p oi nt t hat T O T X VI t hera p y 
f or male patie nts c eases. 
 
T o st u dy w het her i nte nsifyi n g i n d ucti o n, i ncl u di n g fr acti o n ate d cycl o p h os p h a mi de a n d 
t hi o g u a ni ne, i n p atie nts wit h d ay 1 5 M R D > 5 %, will res ult i n i m pr ove d le uke mi a 
cyt ore d ucti o n i n t his s u b gr o u p c o m p are d t o T X V. 
  
 
T hese a n al ys es will o nl y be c o n d ucte d at t he ti me t he pla n ne d i nteri m a nal yses c o m pari n g 
t he t w o c o nti n uati o n re gi me ns are c o m plete d. T hat is after 3 a n d 6 years of accr ual. 
  
 
As of 3/ 2 1/ 0 7, T O T X V d ata i n dicate t hat 4 5/ 4 3 9 = 1 0. 5 % of patie nts ha d Da y- 1 9 M R D of 
at least 5 %. A m o n g t his s u b gr o u p, 9/ 4 5 = 2 0 % ac hie ves ne gati ve M R D ( < 0. 0 1 %) at Da y 
4 6, a n d 8 0 % re m ai ns M R D p ositi ve at t he e n d of re missi o n i n d ucti o n ( 9 5 % CI [ 0. 6 8 3, 
0. 9 1 6 8]). T he a nal ysis will first c o m pare t he pr o p orti o n of T O T X V patie nts w h o ha d Da y-
1 9 M R D ≥5 % wit h t he pr o p orti o n of patie nts o n T O T X VI wit h Da y- 1 5 M R D ≥5 %. Ne xt 
we will c o m pare t h e pr o p orti o n of patie nts wit h Da y- 1 5 M R D ≥5 % o n T O T X VI w h o are 
Da y- 4 2 M R D p ositi ve wit h t he pr o p orti o n of Da y- 4 6 M R D p ositi ves i n t he c orres p o n di n g 
s u b gr o u p i n T O T X V b y Fis her’s e x act test. Wit h t he accr ual of a p pr o xi matel y 3 5 0 
patie nts, we c o nser vati vel y a ntici pate t h ere will be at least 3 4 patie nts w h o ha ve Da y- 1 5 
M R D ≥5 %. T he f oll o wi n g ta ble s h o ws t he p o wer of t w o-si de d e x act test at t he 0. 0 5 
si g nifica n ce le v el f or se v eral p ost ulate d pr o p orti o ns of Da y- 4 2 M R D p ositi ve patie nts a n d 
sa m ple siz es fr o m eac h trial. 
  
  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
CI N of i s ol at e d C N S r el a p s e s i n St. J u d e p ati e nt s fr o m T ot al X V
0
0. 1
0. 2
0. 3
0. 4
0. 5
0. 6
0. 7
0. 8
0. 9
1
0
1
2
3
4
5
6
7
Y e ar s fr o m C R d at e
CI
C N S- 2 or C N S- 3 or tr a u m ati c bl a st + or T- c ell wit h W B C > = 1 0 0
N. T 1 5 Pr o p. T 1 5  
N. T 1 6 Pr o p. T 1 6  
P o wer  
  
  
  
4 5  
0. 6 8 
  
3 4  
0. 5 0 
  
0. 3 4 
  
  
  
4 5  
0. 8 0 
  
3 4  
0. 5 0 
  
0. 7 7 
 
  
  
4 5  
0. 9 2 
  
3 4  
0. 5 0 
  
0. 9 9 
 
  
  
4 5  
0. 8 0 
  
3 4  
0. 5 5 
  
0. 6 2 
 
  
  
4 5  
0. 9 2 
  
3 4  
0. 5 5 
  
0. 9 7 
 
  
  
4 5  
0. 8 0 
  
3 4  
0. 6 0 
  
0. 4 4 
 
  
  
4 5  
0. 9 2 
  
3 4  
0. 6 0 
  
0. 9 2 
 
T o assess w het her i nte nsific ati o n of C N S directe d i ntr at hec al a n d syste mic c he m ot her a py 
will i m pr ove o utc o me i n p atie nts at hi g h risk of C N S rel a pse . 
 
T he se a n al ys es will o nl y be c o n d ucte d at t he ti me t he pla n ne d i nteri m a nal yses c o m pari n g 
t he t w o c o nti n uati o n re gi me ns are c o m plete d. T hat is after 3 a n d 6 years of accr ual. 
 
T he T O T X V e x perie nce has c o nfir me d t hat C N S- 2 a n d C N S- 3 stat us, tra u matic l u m ber 
p u nct ure wit h blast, a n d T-li nea ge wit h W B C m ore t ha n 1 0 0, 0 0 0 re mai n hi g hl y ass ociat e d 
wit h C N S rela pse. O n T otal X V, 9 8 of 3 5 9 ( 2 3. 3 %) patie nts fell i nt o t his cate g or y of bei n g 
hi g h ris k f or C N S r ela pse. Of partic ular i nterest here is is olate d C N S rela ps e. O n T O T X V, 
as of 4/ 5/ 2 0 0 7 all C N S rela pses i n t his s u b gr o u p are is olate d, t he c u m ulati ve i nci de nce of 
w hic h is gi ve n b el o w. T h e 5- year c u m ulati ve i nci d e nce of is olat e d C N S rela pse is 
1 0. 4 % ± 4 %. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F or T O T X VI, c u m ulati v e i nci de nces of is olate d C N S rela pse as w ell as c o m bi ne d C N S 
rela pse a m o n g all patie nts, a n d a m o n g t he hi g h-ris k C N S patie nts ( defi ne d as ha vi n g a n y 
of C N S- 2 or 3, tra u matic L P wit h blast, or T-li nea ge wit h W B C > 1 0 0, 0 0 0) will be 
esti mate d b y t he Kal bflis c h- Pre ntice esti mat or. 1 3 7 T he c u m ulati ve i nci de n ce f u ncti o ns of 
is olate d a n d c o m bi ne d C N S rela pse a m o n g t hes e hi g h-ris k C N S patie nts o n T O T X VI will 
be c o m pare d t o t he c orres p o n di n g gr o u p o n T O T X V usi n g Gra y’s test. 1 3 8  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 8. 4  
E x pl orat or y P har mac ol o gic O bj ecti ves 
 
T o i de ntify p h ar m ac o ge netic, p h ar m ac oki netic a n d p h ar m ac o dy n a mic pr e dict ors f or 
tre at me nt-rel ate d o utc o mes i n t he c o ntext of t he syste mic t her a py use d i n t h e pr ot oc ol. 
 
T his e x pl orat or y o bjecti v e is i n c o ncert wit h t he bi ol o gical o bjecti ve “ T o i d e ntif y n e w 
pr o g n ostic fact ors b y a p pl yi n g de vel o pi n g tec h n ol o gies t o st u d y patie nt material (e. g., 
st ore d plas ma, ser u m, cere br os pi nal fl ui d, a n d n or mal a n d le u ke mic cells.” Statistical 
c o nsi derati o ns f or t his ai m will be gi ve n i n Secti o n 1 7. 5. 
  
 
T o c o m p are t he p h ar m ac oki netics a n d p h ar m ac o d y n a mics of P E G- as p ar a gi n ase give n i n 
hi g her d ose of ( 3, 5 0 0 u nits/ m 2 or 3, 0 0 0 u nits/ m2) vers us t h ose of P E G- as p ar a gi n ase give n 
i n c o nve nti o n al d ose ( 2, 5 0 0 u nits/ m 2) i n t he c o nti n u ati o n p h ase.  
  
 
C o m paris o n of a P K/ P D meas ure me nt at a fi x e d ti me p oi nt bet w ee n t he t w o P E G-
as para gi n ase ar ms will be d o ne b y t he Wilc o x o n ra n k-s u m test. C o m paris o n of a 
l o n git u di nal P K/ P D meas ure me nt will be d o ne b y ge n eral li near m o dels ( G L M) f or 
re peat e d meas ur es t o acc o u nt f or i ntra- patie nt c orrelati o n; s uc h a m o del will i ncl u de t he 
treat me nt ar m, a p atie nt r a n d o m effect, a n d p ossi bl y ot her c o vari ates as mai n effects as 
well as i nteracti o n effects b y t hese fact ors w he n d ee me d as a p pr o priat e. F or c o m paris o n 
p ur p oses s y m metrizi n g a n d varia nce sta bilizi n g tra nsf or mati o ns ma y be a p plie d t o t he 
P K/ P D meas ure me nts if necessar y, t o ma ke t he data better a d here t o t he m o del ass u m pti o n 
of n or mal distri b uti o n f or t he res p o nse varia ble. 
 
1 8. 5 
E x pl orat or y Bi ol o gic al O bjecti ves 
 
T o deter mi ne t he pr o g n ostic v al ue of d ay 8 levels of mi ni m al resi d u al dise ase i n 
peri p her al bl o o d. 
 
C u m ulati ve i nci de nce hazar d re gressi o n m o deli n g 1 3 9 will be use d t o m o del t he ca use-
s pecific fail ures of h e mat ol o gical or c o m bi ne d he mat ol o gical r ela pses (i ncl u di n g fail ures 
t o ac hie ve re missi o n, f or w hic h ti me t o e ve nt is set t o zer o) as a f u ncti o n of Da y- 8 M R D 
le vel, al o n g wit h ot her k n o w n pr o g n ostic fact ors as c o vari ates. T he Da y- 8 peri p heral 
bl o o d M R D le vels will be treate d i n t w o wa ys: as a c o nti n u o us varia ble, a n d cate g orize d 
i nt o t w o or t hree cate g ori es; f or e x a m ple 0 % t o < 1 % vs. 1 % t o < 1 0 % vs. 1 0 % a n d m ore.  
 
T o ge n oty pe n at ur al killer ( N K) cell rece pt ors a n d me as ure t heir e x pressi o ns at di a g n osis 
a n d bef ore rei n d ucti o n, a n d t o ass oci ate t hese fe at ures wit h tre at me nt o utc o me. 
 
F or t his e x pl orati ve o bjecti ve, ass ociati o ns of ge n ot y pes ( or ge n e e x pressi o ns) wit h l o n g-
ter m treat me nt o utc o mes will be e x pl ore d b y fail ure ti me m o dels1 3 9; ass ociati o ns of t he 
ge n ot y p es wit h cate g orical cli nical o utc o mes (e. g., M R D stat us at t he e n d of i n d ucti o n) 
will be a nal yze d b y c o nti n ge n c y ta bles a n d C hi-s q uare tests; ass ociati o ns of ge n e 
e x pressi o ns wit h cate g orical cli nical o utc o mes will be a nal yz e d b y ra n k- bas e d pr oce d ures 
s uch as t he Wilc o x o n test. 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T o i de ntify ne w pr o g n ostic f act ors by a p plyi n g devel o pi n g tec h n ol o gies t o st u dy p atie nt 
m ateri al (e. g., st ore d pl as m a, ser u m, cer e br o-s pi n al fl ui d, a n d n or m al a n d le uke mic cells). 
 
T his is a n e x pl orat or y o bjecti ve. Bi o mar kers t o be c o nsi dere d ma y c o me fr o m se veral 
s o urces i ncl u di n g ( b ut n ot li mite d t o) ca n di date ge nes a n d de vel o pi n g tec h n ol o gies s uc h as 
m R N A e x pressi o n arra ys, e x o n e x pressi o n arra ys, S N P arra ys, arra y C G H, a n d 
pr ote o mics. T he basic a p pr oac h t o t his o bjecti ve will be ge n ot y p e- p he n ot y pe ass ociati o n 
st u dies a n d ge n o me- wi de ass ociati o n a nal ysis ( G W A). Us uall y, t he ge n ot y p e will reflect 
ger mli ne D N A v ariati o n, R N A tra nscri pt variati o n (“f u ncti o nal ge n o mic varia bilit y), or 
ac q uire d ge n o mic vari ati o n (fr o m c o m paris o ns of blast a n d ger mli ne D N A variati o n). Of 
c o urse, b ot h R N A variati o n a n d ac q uir e d ge n o mic variati o n ca n als o be c o nsi dere d 
p he n ot y p es t hat are partl y a pr o d uct of ger mli ne v ariati o n t he msel ves. We ha ve a m ple 
e x perie nce i n e x peri me nt ati o n a n d a nal yses f or ge n o me- wi de a n d ca n di dat e ge ne 
a p pr oac h es 2; 1 0; 1 2; 5 2- 5 7; 5 9; 6 1- 6 5; 1 4 0 
 
Statistical met h o d ol o gies f or G W A a n d ge n ot y pe- p he n ot y p e ass ociati o n a n al yses b ase d o n 
ca n di date ge nes r ece ntl y de vel o pe d i n t his i nstit uti o n a n d else w h ere will be a p plie d t o t he 
da ta a nal yses f or t his ai m.1 4 1- 1 4 3 Alt h o u g h o ur a nal ys es caref ull y e val u ate false disc o ver y 
rate1 4 4 a n d w he n necessar y, us e per m utati o n tec h ni q ues f or assi g ni n g “ p val ues” t o 
ass ociati o ns, t he pri mar y “ vali dati o n” of ge n ot y p e/ p he n ot y p e ass ociati o ns is de pe n de nt 
u p o n re plicati o n i n m ulti ple cli nical st u dies, bi ol o gical pla usi bilit y a n d/ or l a b orat or y 
m o del verificati o n. T heref ore, statistical tests are o nl y a p art of t he e val uati o n of 
ge n ot y p e/ p he n ot y pe ass o ciati o ns. We ne xt ill ustrate t he ma g nit u de of false p ositi ve a n d 
false ne gati ve err ors t hat we a ntici pate f or t hese st u dies b y t w o t y pes of st u di es: 
ha pl ot y pe- p he n ot y pe ass ociati o n a n d micr oarra y ge n e e x pressi o n pr ofili n g, after a 
c o nsi derati o n f or p o wer of testi n g ca n di date ge ne p ol y m or p his ms. 
 
P o w er of testi n g c a n di d ate ge ne p ol y m or p his ms. A n e x a m ple f or t he p o wer t o e val u ate 
a ca n di dat e ge n ot y pe a n d a dic h ot o m o us p he n ot y p e (e. g. M R D vs. n o M R D) is gi ve n here. 
A n I L 1 5 S N P (rs I D # A- 4 2 6 4 5 1 9) o bser ve d i n o n e of o ur ge n o m e- wi de a n al yses of 
g er mli ne p ol y m or p his ms relate d t o e n d- of-i n d ucti o n M R D stat us has a mi n or allele 
fre q ue n c y of ~ 1 0 %. O n t he SJ c o h ort i n t he T T ge n ot y pe 1 8. 9 8 % ( 0. 1 8 9 8) were M R D 
p ositi ve w hereas i n t he T C/ C C ge n ot y pe 3 7. 2 5 % ( 0. 3 7 2 5) were M R D p ositi ve. We will 
test w het her t his p ol y m or p his m is si milarl y ass oci ate d wit h M R D stat us (e n d of i n d ucti o n) 
i n T O T X VI. Wit h a sa m ple siz e of 4 0 0, at t he 0. 0 5 si g nifica n ce le vel t here will be 8 2. 7 8 % 
p o wer t o dete ct t he differe nce of 0. 1 8 2 7 ( 1 8. 9 8 % vs. 3 7. 2 5 %) o bs er ve d i n t he ge n o me-
wi de st u d y. 
 
H a pl ot y pes a n d a c o nti n u o us v ari a ble p he n ot y pe. T his is ill ustrate d f or a mi ni m u m 
sa m ple siz e of 3 0 0,  a t otal of 4- 1 0 maj or ha pl ot y p es, a n d t he ass u m pti o n t hat t he s mallest 
n u m ber  of i n di vi d uals i n t he m ost rare ge n ot y p e/ ha pl ot y pe b e 1 0 % or n = 3 0. F or 
statistical p o wer we c o ns er vati vel y c o nsi der t w o less fa v ora ble sa m ple siz e a n d effect 
c o nfi g urati o ns. If t here are te n gr o u ps wit h res p ecti ve sa m ple siz es 1 0, 1 0, 2 0, 2 0, 4 0, 4 0, 
6 0, 6 0, 2 0, 2 0, a n d t he mea ns (f or e x a m ple, f or a c o nti n u o us varia ble reflecti n g t o xicit y, 
s uc h as h o m oc ystei ne le v el) i n t he first fi ve ha pl ot y p e gr o u ps differ fr o m t h e o verall me a n 
b y 2, 2, 2, 2, a n d 1 ti mes wit hi n- gr o u p sta n d ar d de viati o n, res pecti vel y, t here will be 8 1 % 
p o wer t o dete ct t his differe nce at t he 5 % si g nifica nce ( o ne- wa y A N O V A).  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A ntici p ate d f alse disc o ver y r ate. T o ill ustrate t he ma g nit u de of false p ositi ve a n d fals e 
ne gati ve err ors w e ma y e nc o u nter i n a ge n o m e- wi de ass ociati o n a n al ysis ( G W A) s uc h as 
ge n e e x pressi o n pr ofili n g, we s h o w t he a v era ge p o wer ( A P) a n d a ntici pate d false disc o ver y 
rate (a F D R) 1 4 5 base d o n a data set use d i n a rece nt st u d y of ge n e e x pressi o n, M R D a n d 
rela pse of A L L.1 2 T his data set c o nsists of l o g-tra nsf or me d si g n al i nte nsities fr o m 9 9 
Aff y metri x U 1 3 3 A Ge ne C hi ps r u n o n t he dia g n ostic b o ne marr o w bl asts of 9 9 T O T XIII B 
patie nts a n d t heir ti me t o A L L rela ps e (fail ure) or l ast f oll o w u p. Ass ociati o n bet wee n t he 
e x pressi o n of eac h pr o beset a n d fail ure ti me is test e d b y c u m ulati ve i nci de nce hazar d rate 
re gressi o n,1 3 9 creati n g 2 2 2 7 6 P val ues, o ne f or eac h pr o beset. T he f oll o wi n g fi g ure s h o ws 
t he pr ofile i nf or mati o n criteri o n1 4 1 (I p) c o m p ute d f or t his set of P val ues.  
al p h a
I p
0. 0
0. 0 2
0. 0 4
0. 0 6
0. 0 8
0. 1 0
0
2 0 0 0 
4 0 0 0 
6 0 0 0 
8 0 0 0
1 0 0 0 0 
1 2 0 0 0
pi 0 = 0. 9 3 0 4 al p h. o pt = 0. 0 0 3 5 0 4 F D R = 0. 2 2 6 4  mi n I p = 1 2 8. 8 4 5 7 
 
T he pr o p orti o n of pr o b es ets ( ge ne e x pressi o ns) n ot ass ociate d wit h rela ps e is esti mate d 
pi 0 = 9 3 %, t he “ o pti mal” P- val ue c ut off (al p ha. o pt) b y I p t hat bala nces t he l e vels of fals e 
p ositi ve a n d false ne gati ve err ors is 0. 0 0 3 5, a n d at t his al p ha le vel t he F D R is esti mate d 
2 2. 6 4 %.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he f oll o wi n g t a ble s h o ws, base d o n t he a b o v e s et of  P val ues, t he a ntici pate d n u m ber of 
false p ositi ves (a N F P), tr ue p ositi ves (a N T P), a n d a F D R i n o ne ge ne e x pressi o n pr ofili n g 
a nal ysis f or se v eral c o m bi nati o ns of t he pr o p orti o n of n o n-ass ociati ve ge nes ( π), n u m ber of 
n o n-ass ociati ve ge n es ( m 0), n u m ber of ass ociati ve ge n es ( m 1), a n d al p ha le vels. T he t otal 
n u m ber  of pr o b esets is m 0 + m 1 = 2 2 2 7 6. 
 
 
 
α = 0. 0 0 1  
α = 0. 0 0 3  
α = 0. 0 0 5  
π = 9 0 %  
m 0 = 2 0 0 4 8  
m 1 = 2 2 2 8  
a N T P  
aN F P  
a F D R ( %)  
1 4 6  
2 0  
1 2. 0 8  
2 2 7  
6 0  
2 0. 9 2  
2 9 2  
1 0 0  
2 5. 5 7  
π = 9 3 %  
m 0 = 2 0 7 1 7  
m 1 = 1 5 5 9  
a N T P  
a N F P  
a F D R ( %)  
1 4 5  
2 1  
1 2. 4 8  
2 2 5  
6 2  
2 1. 6 2  
2 8 8  
1 0 4  
2 6. 4 3  
π = 9 9 %  
m 0 = 2 2 0 5 3  
m 1 = 2 2 3  
a N T P  
a N F P  
a F D R ( %)  
1 4 4  
2 2  
1 3. 2 8  
2 2 2  
6 6  
2 3. 0 2  
2 2 3  
1 1 0  
2 8. 1 3  
 
V ali d ati o n i nfere nce f or ge ne e x pressi o n. We pla n t o vali date o n T O T X VI a n u m ber of 
ca n di date ge nes i de ntifie d fr o m t he pre vi o us ge n e e x pressi o n pr ofili n g a nal ys es of 
T O T X V a n d T O T XIII data. T o vali date t hese ge ne e x pressi o ns f or t heir ass ociati o n wit h 
t he p he n ot y p es of i nterest (e. g. ge ne e x pressi o ns relate d t o M R D a n d rel a pse; see Secti o n 
2), t w o met h o ds will be a p plie d. First a ge n e- b y - ge ne e x a mi nati o n will be perf or me d: T h e 
sa me a nal yses i n t he pre vi o us p u blicati o ns will be a p plie d t o t he vali dati o n data ( data 
c ollecte d o n T O T X VI), a n d t h e ge nes of i nterest will be e x a mi ne d f or t heir ass ociati o n 
wit h t he p he n ot y p es acc or di n g t o t he test P val ues a n d w het her t h e sa me directi o ns of 
ass ociati o n are o bs er ve d i n t he vali dati o n data a n d t he pre vi o us a nal yses. It is i m p orta nt t o 
realize t hat d ue t o u nc o ntr olla ble ra n d o m variati o ns t he o bser ve d  statistical si g nifica n ce 
( P val ues) of t hes e ge nes i n t he pre vi o us st u dies is u nsta ble a n d is u nli kel y t o re plicate – 
t he test P val ue of eac h ge ne c o m p ute d o n t he vali dati o n data ca n b e eit her greater or 
s maller t ha n t hat i n t he pre vi o us a nal yses. F or t his reas o n, w e d o n ot i nsist t hat t he tests of 
t hese ge nes o n t he v ali dati o n data ha ve t o reac h e q ual or hi g h er si g nifica n ce le vels t ha n i n 
t he pre vi o us a nal yses. I nstea d, we will test t he n ull h y p ot hesis t hat t he P val ues of t hese 
g e n es fr o m t he v ali dati o n data are c o m pletel y ra n d o ml y ( u nif or ml y) distri b ute d bet wee n 0 
a n d 1 a gai nst t he alter nati ve t hat t he y t e n d t o cl uster t o war d 0. T his will be acc o m plis he d 
b y a p er m utati o n test. Sec o n d, a rece ntl y de v el o pe d met h o d 1 4 6 will be a p plie d t o vali date 
g e n e c o- e x pressi o n cl usters ge nerate d fr o m t hese ca n di date ge nes. A c o-e x pressi o n cl uster 
f or a ca n di date ge ne is a set of ge nes w h os e e x pressi o n is hi g hl y c orrelat e d wit h t he 
ca n di date ge ne. T his met h o d will als o hel p t o disc o ver i nteresti n g ge n es t hat p ote ntiall y 
carr y si milar bi ol o gical f u ncti o ns or are i n t he s a me pat h wa y wit h t he ca n di date ge nes b ut 
di d n ot meet t he p urel y statistical si g nifica n ce criteria use d i n t he pre vi o us a nal yses. 
 
1 8. 6 
E x pl orat or y ne ur oi ma gi n g o bjecti ves 
 
T he se e x pl orat or y o bjecti ves i n v ol ve case-c o ntr ol c o m paris o ns, a nal yses of t he 
ass ociati o ns bet wee n a n u m ber of ne ur oi ma gi n g meas ure me nts ge n erate d at t w o ti me 
p oi nts ( wee k 1 of re-i n d u cti o n I a n d wee k 1 2 0 of c o nti n uati o n) a n d ne ur oc o g niti ve tests 
d o ne at t he sa me ti me p oi nts, a n d  a nal ys es of t he ass ociati o ns bet wee n t h e 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
ne ur oi ma gi n g m eas ur e me nts a n d t he f olate p at h w a y ge netic p ol y m or p his ms. T hera p y 
differe n ces as i n dicate d b y ris k ( S/ H vs. L) a n d t he i nte nsit y of I T t hera p y (e. g., n u m b er 
of I Ts recei ve d b ef ore t he M RI) will be ta ke n as c o variates (a dj usti n g fact ors) i n t he 
m o dels. S u bset a nal yses wit hi n certai n patie nt gr o u ps (e. g., S/ H a n d L ris k) ma y b e 
pe rf or me d as well. T he a nal yses f or a si milar st u d y o n T O T X V res ulte d i n a b o ut 4, 0 0 0 
statistical tests. We a ntici pate t hat a lar ge n u m ber of statistical tests will be pr o d uce d f or 
t his ai m o n T O T X VI as well. A dj ust me nts f or m ulti ple tests will be perf or me d usi n g 
rece nt met h o ds f or esti mati o n a n d c o ntr ol of t he false disc o ver y rate.1 4 2, 1 4 3 
 
T o use q u a ntit ative M R me as ures ( Diff usi o n Te ns or I m a gi n g a n d hi g h res ol uti o n 
v ol u metric i m a gi n g) t o assess differe nces i n myeli n a n d c ortic al t hick ness dev el o p m e nt i n 
p atie nts tre ate d f or A L L rel ative t o he alt hy c o ntr ols m atc he d f or a ge a n d g e n der. 
 
T he c o m paris o n will be p erf or me d f or eac h M R ti me p oi nt ( Wee k 1 of re-i n d ucti o n I a n d 
wee k 1 2 0 of c o nti n uati o n) se paratel y. P ossi ble l o n git u di nal c ha n ge will be vis ualize d b y 
statistical gra p hi cs. Ne ur oi ma gi n g meas ure me nts of m yeli n a n d c ortical t hic k ness bet wee n 
patie nts a n d a ge a n d ge n der matc he d n or mal healt h y c o ntr ols will be c o m pare d b y t w o-
sa m ple t tests. S u bset a nal yses wit hi n certai n patie nt gr o u ps (e. g., S/ H a n d L ris k) m a y be 
perf or me d as well.  
 
T o assess t he i m p act of f ol ate p at h w ay ge netic p oly m or p his ms o n myeli n a n d c ortic al 
t hick ness devel o p me nt a n d ne ur oc o g nitive perf or m a nce.  
 
Ass ociati o ns bet wee n t he ge n etic p ol y m or p his ms a n d t he i ma gi n g m eas ure me nts a n d t he 
ne ur oc o g niti ve meas ure me nts will be a nal yze d b y a n u m b er of ge neral li near m o dels. T he 
i ma gi n g a n d n e ur oc o g niti ve varia bles will be ta k e n as de pe n de nt v aria bles; t he 
p ol y m or p his ms a n d cli nical fact ors (s uc h as ris k a n d I T i nte nsit y) will be ta k e n as 
c o variates. S u bset a n al ys es wit hi n certai n patie nt gr o u ps (e. g., S/ H a n d L ris k) ma y b e 
perf or me d as well.  
 
T o assess i m p act of fr o nt al- p ariet al l o be myeli n a n d c ortic al t hick ness devel o p me nt o n 
ne ur oc o g nitive perf or m a nce i n atte nti o n, w orki n g me m or y, fl ue n cy, vis u al-s p ati al 
re as o ni n g a n d pr ocessi n g s pee d. 
 
Descri pti ve statistics of t he i ma gi n g a n d t he ne ur o ps yc h ol o gical test res ults will be 
pr o vi de d. Cr oss-secti o nal a nal ys es will be d o ne usi n g ra n k- base d pr oce d ures a n d ge neral 
linear m o dels. Ge n eral li near m o dels a cc o u nti n g f or re peate d meas ures ( b y a patie nt 
ran d o m effect f or e x a m ple) will be a p plie d t o a nal yz e t he l o n git u di nal data (t w o ti me 
p oi nts). T hera p y differe n ces as i n dicat e d b y ris k ( S/ H vs. L) a n d t h e i nte nsit y of I T t h era p y 
(e. g., n u m ber of I Ts recei ve d bef ore t he M RI) will be ta ke n as c o vari ates (a dj usti n g 
fact ors) i n t he m o d els. S u bset a nal yses wit hi n certai n patie nt gr o u ps (e. g., S/ H a n d L ris k) 
ma y b e perf or me d as well.  
 
T o i n vesti gate t h e relati o ns hi p bet wee n t he c h a n ge i n i ma gi n g me as ure me nts a n d t he 
a m plit u de of B O L D si g n al c ha n ge a n d t he v ol u me of acti vate d c orte x will use a si m ple 
li near re gressi o n m o del.  We will test t o assess w het her t here is a si g nifica nt li near 
relati o ns hi p bet wee n t h e m yeli n disr u pti o n a n d B O L D acti vati o n i n s pecifi c c ortical 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
re gi o ns. Si milar a nal ysis will be carri e d o ut wit h c ha n ge of c ortical t hic k ness as c o variat es 
a n d eit her t he B O L D si g nal a m plit u de or t he acti v ate d v ol u me as de p e n de nt varia ble.  
 
1 8. 7 
E x pl orat or y I ntesti nal Mi cr o bi o me O bjecti ve 
 
T his i s a pr os pecti ve st o ol ba n ki n g st u d y.  St o ol sa m ples will be c ollecte d fr o m all eli gi ble 
patie nts a n d st ore d f or f urt her testi n g.  Descri pti ve statistics s uc h as me dia n, ra n ge a n d 
perce nt a ges will be use d as a p pr o priat e t o meas ure t he o verall alterati o n i n c o m p ositi o n 
a n d p o p ulati o n d y n a mics of g ut micr ofl ora a n d t o descri be t he fre q u e nc y a n d se verit y of 
gastr oi ntesti nal ill nesses d uri n g i n d ucti o n p has e of c he m ot hera p y a n d t he s u bse q ue nt 6 
m o nt hs. T o ta ke i nt o acc o u nt t he differe n ces i n t h e i n d ucti o n, c o ns oli d ati o n a n d 
c o nti n uati o n p hases of c h e m ot hera p y, a n al ysis of t he data will be stratifie d base d o n t he 
A L L ris k classificati o n ( L o w ris k, Sta n dar d ris k, a n d Hi g h-ris k). 
 
1 9. 0  
S A F E T Y A N D A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S 
 
1 9. 1 
Re p orti n g A d vers e E x perie nces ( A Es) a n d Deat hs 
 
O nl y “ u n a ntici pate d pr o ble ms i n v ol vi n g ris ks t o partici pa nts or ot hers” referre d t o 
hereafter as “ u na ntici pat e d pr o ble ms” are re q uir e d t o be re p orte d t o t he St. J u de I R B 
pr o m ptl y, b ut i n n o e ve nt later t ha n 1 0 w or ki n g d a ys after t he i n ves ti gat or first lear ns of 
t he u na ntici pate d pr o ble m. Re gar dless of w h et her t he e ve nt is i nter nal or e xter nal (f or 
e x a m ple, a n I N D safet y re p ort b y t h e s p o ns or p urs ua nt t o 2 1 C F R 3 1 2. 3 2), o nl y a d v erse 
e ve nts t hat c o nstit ute u na ntici pate d pr o ble ms are re p orta ble t o t he St. J u de I R B.  As 
f urt her des cri be d i n t he d efi niti o n of u na ntici pate d pr o ble m, t his i ncl u des a n y e v e nt t hat i n 
t he PI’s o pi ni o n w as: 
 
 U ne x pecte d (i n ter ms of nat ure, se v erit y, or fre q u e nc y) gi ve n ( 1) t he researc h 
pr oce d ures t hat are descri be d i n t he pr ot oc ol-rel ate d d oc u me nts, s uc h as t h e I R B-
ap pr o ve d researc h pr ot o c ol a n d i nf or me d c o nse nt d oc u me nt, as well as ot h er 
rele va nt i nf or m ati o n a vaila ble a b o ut t he res earc h; ( 2) t he o bser ve d rate of 
occ urre nce (c o m pare d t o a cre di ble b aseli ne f or c o m paris o n); a n d ( 3) t he 
c haracteristics of t he s u bj ect p o p ulati o n bei n g st u die d; a n d 
 R elate d or p ossi bl y relate d t o partici pati o n i n t he researc h; a n d 
 Seri o us; or if n ot seri o us s u g gests t hat t he researc h places s u bjects or ot h ers at a 
greater ris k of har m (i ncl u di n g p h ysical, ps yc h ol o gical, ec o n o mic, or s ocial har m) 
t ha n was pre vi o usl y k n o w n or rec o g nize d.  
 
U nrelate d, e x pecte d deat hs d o n ot re q uire re p orti n g t o t he I R B.  T h o u g h deat h is “seri o us”, 
t he e ve nt m ust meet t he ot her t w o re q uir e me nts of “rel ate d or p ossi bl y relate d” a n d 
“ u ne x pecte d/ u na ntici pate d” t o be c o nsi dere d re p orta ble. 
 
Deat hs meeti n g re p orti n g re q uire me nts are t o be re p orte d i m me diatel y t o t h e St. J u de I R B, 
b ut i n n o e ve nt later t ha n 4 8 h o urs after t h e i n vesti gat or first lear ns of t he d eat h.  
 
T h e f oll o wi n g d efi niti o ns a p pl y wit h r es pect t o re p orti n g a d v erse e x perie nces:  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 9 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Seri o us A d verse E ve nt:  A n y a d verse e ve nt te m p orall y ass ociate d wit h t he s u bject’s 
pa rtici pati o n i n researc h t hat meets a n y of t he f oll o wi n g criteria: 
 
 res ults i n deat h; 
 is life-t hreate ni n g ( pl aces t he s u bject at i m me diate ris k of deat h fr o m t he e v e nt as it 
occ urre d); 
 req uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n; 
 res ults i n a persiste nt or si g nifica nt disa bilit y/i nca pacit y; 
 res ults i n a c o n ge nital a n o mal y/ birt h defect; or 
 an y ot h er a d v erse e ve nt t hat, base d u p o n a p pr o pri ate me dical j u d g me nt, m a y 
je o par dize t he s u bject’s h ealt h a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t his defi niti o n (e x a m ples of s uc h e ve nts 
i ncl u de:  a n y s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u ncti o ns, 
aller gic br o n c h os pas m re q uiri n g i nte nsi ve treat me nt i n t he e mer ge nc y r o o m or at 
h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt 
h os pitalizati o n, or t he de vel o p me nt of dr u g de p e n de nc y or dr u g a b use), a 
c o n ge nital a n o mal y/ birt h defect, s ec o n dar y or c o n c urre nt ca ncer, me dicati o n 
o ver d ose, or is a n y m e dical e ve nt w hi c h re q uir es treat me nt t o pre ve nt a n y of t he 
me dical o utc o mes pre vi o usl y list e d.   
 
U ne x pec te d A d ve rse E v e nt:  
 
 A n y a d vers e e ve nt f or w hic h t he s pecificit y or se verit y is n ot c o nsiste nt wit h t he 
pr ot oc ol-relat e d d oc u me nts, i ncl u di n g t he a p plica ble i n vesti gat or br oc h ure, I R B 
a p pr o ve d c o ns e nt f or m, I n vesti gati o nal N e w Dr u g (I N D) or I n vesti gati o nal De vice 
E x e m pti o n (I D E) a p plicati o n, or ot her rele va nt s o urces of i nf or mati o n, s uc h as 
pr o d uct la beli n g a n d pac ka ge i nserts; or if it d oes a p pear i n s u c h d oc u me nts, a n 
e ve nt i n w hic h t he s pecificit y, se verit y or d urati o n is n ot c o nsiste nt wit h t he ris k 
i nf or mati o n i ncl u de d t herei n; or  
 T he  o bser ve d rate of occ urre nce is a cli nicall y si g nifica nt i ncrease i n t he e x pecte d 
rate ( b ase d o n a cre di ble baseli ne rat e f or c o m paris o n); or  
 T he occ urre n ce is n ot c o nsiste nt wit h t he e x pecte d nat ural pr o gressi o n of a n y 
u n derl yi n g dise ase, dis or der, or c o n diti o n of t he s u bject(s) e x perie n ci n g t h e 
a d verse e ve nt a n d t h e s u bject’s pre dis p osi n g ris k fact or pr ofile f or t h e a d v erse 
e ve nt.  
 
I nter n al E ve nts: E ve nts e x perie nce d b y a researc h partici pa nt e nr olle d at a site u n der t he 
j uris dicti o n of St. J u de I R B f or eit her m ultice nter or si n gle-ce nter res earc h pr ojects. 
 
E xter n al E ve nts:  E ve nts e x perie nce d b y partici pa nts e nr olle d at a site e xter nal t o t he 
j uris dicti o n of t he St. J u de I nstit uti o nal Re vie w B oar d (I R B) or i n a st u d y f or w hic h St. 
Ju de is n ot t he c o or di nati n g ce nter or t he I R B of rec or d. 
 
U n a ntici p ate d Pr o ble m I n v ol vi n g Ris ks t o S u bjects or Ot hers: A n u n a ntici pate d 
pr o ble m i n v ol vi n g ris ks t o s u bjects or ot hers is a n e ve nt w hic h was n ot e x pecte d t o occ ur 
a n d w hic h i ncreases t he de gree of ris k p ose d t o r esearc h p artici pa nts.   
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 0  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
S uc h e ve nts, i n ge neral, meet all of t he f oll o wi n g criteria:  
 
 u ne x pecte d;  
 relate d or p ossi bl y rel ate d t o partici pati o n i n t he researc h; a n d  
 s u g gests t hat t he researc h places s u bjects or ot h ers at a greater ris k of h ar m 
(i ncl u di n g p h ysic al, ps yc h ol o gical, ec o n o mic, or s ocial har m) t ha n was pre vi o usl y 
k n o w n or rec o g niz e d.  A n u na ntici pate d pr o ble m i n v ol vi n g ris k t o s u bjects or 
ot hers ma y e xist e ve n w he n act ual h ar m d oes n ot occ ur t o a n y p artici pa nt.  
 
C o nsiste nt wit h F D A a n d O H R P g ui da nce o n re p orti n g u na ntici pat e d pr o bl e ms a n d 
a d verse e ve nts t o I R Bs, t he St. J u de I R B d oes n ot re q uire t he s u b missi o n of e xter nal 
e ve nts, f or e x a m ple I N D safet y re p orts, n or is a s u m mar y of s uc h e v e nts/re p orts re q uire d; 
h o we ver, if a n e v e nt gi vi n g rise t o a n I N D s afet y or ot her e xter nal e ve nt re p ort c o nstit utes 
a n “ u na ntici pate d pr o ble m i n v ol vi n g ris ks t o s u bjects or ot hers ” it m ust be re p orte d i n 
acc or da nce wit h t his p olic y.  I n ge neral, t o be re p orta ble e xter nal e ve nts n ee d t o ha ve 
i m plicati o ns f or t he c o n d uct of t he st u d y (f or e x a m ple, re q uiri n g a si g nifica nt a n d us uall y 
safet y-relate d c ha n ge i n t he pr ot oc ol a n d/ or i nf or me d c o nse nt f or m). 
 
Alt h o u g h s o me a d v erse e ve nts will q ualif y as u n a ntici pate d pr o ble ms i n v ol vi n g ris ks t o 
s u bjects or ot hers, s o me will n ot; a n d t here ma y b e ot her u na ntici pat e d pr o ble ms t hat g o 
be y o n d t h e defi niti o ns of seri o us a n d/ or u ne x pecte d a d verse e ve nts.  E x a m ples of 
u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o s u bjects or ot hers i ncl u de: 
 
 Im pr o p erl y sta gi n g a p artici pa nt’s t u m or res ulti n g i n t he partici pa nt bei n g assi g ne d 
t o a n i nc orrect ar m of t h e researc h st u d y; 
 T he  t heft of a researc h c o m p uter c o ntai ni n g c o nfi d e ntial s u bject i nf or mati o n 
( breac h of c o nfi de ntialit y); a n d  
 T he c o nta mi nati o n of a st u d y dr u g.  U na ntici pate d pr o ble ms ge nerall y will warra nt 
c o nsi derati o n of s u bsta nti ve c ha n ges i n t he researc h pr ot oc ol or i nf or m e d c o nse nt 
pr ocess/ d oc u me nt or ot h er c orrecti ve acti o ns i n or der t o pr otect t he s afet y, welfare, 
or ri g hts of s u bj ects or ot hers.  
 
2 0. 0 
I N F O R M E D C O N S E N T P R O C E S S  
 
2 0. 1 
C o nse nt/asse nt at Re missi o n I n d ucti o n a n d P ost Re missi o n T hera pies 
 
T he pr ocess of i nf or me d c o nse nt f or T O T X VI will f oll o w i nstit uti o nal p olic y. T h e 
i nfor me d  c o nse nt pr ocess is a n o n g oi n g o ne t hat be gi ns at t he ti me of dia g n osis a n d e n ds 
after t he c o m pleti o n of t hera p y.  I nf or me d c o nse nt s h o ul d be o btai ne d b y  t h e atte n di n g 
p h ysicia n or his/ her desi g nee, i n t he prese nce of at least o ne n o n- p h ysicia n wit ness.  
I nitiall y, i nf or me d c o nse nt will be s o u g ht f or t he T B A N K pr ot oc ol (researc h st u d y), 
bl o o d tra nsf usi o n (if nee de d), t he first i ntrat hecal t hera p y (if t he dia g n osis of le u ke mia is 
certai n eit her b y  referral b o ne marr o w s mears or bl o o d s mears at SJ C R H), a n d treat me nt 
wit h rec o m bi na nt urate o xi dase, if nee de d.   After t he dia g n osis of A L L is esta blis he d, we  
will  i n vite t he patie nt t o partici pate i n t he T O T X VI pr ot oc ol, as well as o btai n sta n dar d 
me d ical c o nse nt f or HI V testi n g.  After t he patie nt attai ns c o m plete re missi o n, we  will 
see k i nf or me d c o nse nt f or t heir partici pati o n i n ris k- directe d i nte nsificati o n/c o nti n uati o n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 1  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t hera p y (l o w-, sta n dar d- or hi g h-ris k acc or di n g t o prese nti n g feat ures, treat me nt res p o nse 
an d t he le vel of mi ni mal resi d ual le u ke mia).  Rare patie nts wit h l o w- or sta n dar d- ris k 
le u ke mia ma y b e  reassi g ne d t o hi g h-ris k t hera p y d ue t o persiste ntl y hi g h mi ni mal 
resi d ual le u ke mia (see Secti o n 5. 3). T hese patie nts will be as ke d t o re- c o nse nt wit h t he 
hi g h-ris k t hera p y c o ns e nt. T he ti meli ne f or vari o us i nf or me d c o nse nts is i n dicate d i n t he 
fi gure bel o w. 
 
At prese ntati o n:  
T B A N K  (researc h st u d y) 
Bl o o d  tra nsf usi o n 
Tri ple i ntrat hecal  treat me nt 
 
 
Dia g n osis  of  A L L  esta blis he d:  
T O T X VI  i n d ucti o n t hera p y (researc h st u d y) 
 
 
U p o n ac hie vi n g c o m plete re missi o n: 
L o w- * , sta n dar d-* , or hi g h-ris k 
i nte nsificati o n/c o nti n uati o n t hera p y (researc h st u d y) 
* R are  p atie nts will s u bse q ue ntly be tre ate d wit h hi g h-risk t her a py d ue t o t he 
pe rsiste nce of mi ni m al resi d u al dise ase, per pr ot oc ol. 
 
T hr o u g h o ut t he e ntire treat me nt peri o d,  partici pa nts a n d t heir pare nts recei ve c o nsta nt 
e d ucati o n fr o m healt h pr ofessi o nals at SJ C R H a n d are e nc o ura ge d t o as k q uesti o ns 
regar di n g alter nati ves a n d t hera p y. All fa milies ha ve rea d y access t o c ha plai ns, 
ps yc h ol o gists, s ocial w or kers, a n d t he St. J u de o m b u ds pers o n f or s u p p ort, i n a d diti o n t o 
t hat pr o vi de d b y  t he pri m ar y p h ysicia n a n d ot her cli nicia ns i n v ol ve d i n t heir care.  We  
will als o o btai n ver bal asse nt fr o m c hil dre n 7 t o 1 4 years ol d a n d writte n asse nt f or all 
pa tie nts > 1 4 years of a ge. 
 
2 0. 2 
C o nse nt at A ge of Maj orit y 
 
T he  a ge of  maj orit y i n t he state of Te n nessee is 1 8 years ol d. Researc h partici pa nts o n 
acti ve t hera p y m ust be c o nse nte d at t he ne xt cli nic visit after t heir 1 8 t h birt h da y. 
Partici pa nts, w h o ha ve reac he d a ge of  maj orit y a n d ha ve c o m plete d all pr ot oc ol- directe d  
t hera p y, wi ll be re-c o nse nte d wit h a se parate c o nse nt s pecificall y f or t his p ur p ose 
( AO M c o nse nt). Partici pa nts, w h o reac h a ge of maj orit y after t he 5 year pr ot oc ol 
req uire d f oll o w- u p, will be f oll o we d f or s ur vi val a n d late effects as per t he SJ L T F U. A 
wa i ver f or A O M c o nse nt will be re q ueste d f or t hese partici pa nts at St. J u de. 
 
If a n affiliate site is l ocate d i n a state w here a differe nt a ge of maj orit y a p plies, t hat 
l ocati o n m ust c o nse nt t he partici pa nts acc or di n g t o t heir l ocal la ws. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 2  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2 0. 3 
C o nse nt W he n  E n glis h  is N ot t he Pri mar y La n g ua ge 
 
W he n E n glis h is n ot t he patie nt, pare nt, or le gall y a ut h orize d re prese ntati ve’s pri mar y 
la n gua ge, t he S ocial W or k de part me nt will deter mi ne t he nee d f or a n i nter preter. T his 
i nf ormati o n will be d oc u me nte d i n t he partici pa nt’s me di cal rec or d. Eit her a certifie d 
i nter preter or t he tele p h o ne i nter preter’s ser vice will be use d t o tra nslate t he c o nse nt 
i nfor mati o n. T he pr ocess f or o btai ni n g a n i nter preter a n d f or t he a p pr o priate use of a n 
i nter preter is o utli ne d o n t he I nter preter Ser vices, O H S P, a n d C P D M O we bsites. 
 
2 1. 0 
D A T A C O L L E C TI O N, M O NI T O RI N G A N D  C O N FI D E N TI A LI T Y 
 
2 1. 1 
Data C ollecti o n 
 
Ele ctr o nic case re p ort f or ms (e-C R Fs) will be c o m plete d b y  t he SJ C R H 
Le u ke mia/ L y m p h o ma C R As. Data will be e ntere d fr o m rec or d directl y i nt o a sec ure 
C RI S data base, de vel o pe d a n d mai ntai ne d b y  St. J u de Cli nical Researc h I nf or matics. 
 
Data ma na ge me nt will be s u per vise d b y  t he Direct or of Cli nical Trials 
Ma na ge me nt, 
a n d Ma na ger of Cli nical Researc h O perati o ns f or t he Le u ke mia/ L y m p h o ma Di visi o n, 
w or ki n g wit h Dr. J e ha a n d her desi g nees.  All pr ot oc ol-s pecific data a n d all gra de 3- 5 
ad verse e ve nts will be rec or de d b y  t he cli nical researc h ass ociates i nt o t he C RI S 
da ta base, i deall y wit hi n 2- 4 wee ks of c o m pleti o n of  st u d y p hase. All q uesti o ns will be 
dire cte d t o t he atte n di n g p h ysicia n a n d/ or PI  a n d re vie we d at re g ularl y-sc he d ule d 
w or ki n g meeti n gs. T he atte n di n g p h ysi cia ns ( or t heir desi g nees) are res p o nsi ble f or 
ke e pi n g u p-t o-date r oa d ma ps i n t he patie nt’s pri mar y SJ C R H me dical c hart. 
 
R e g ular ( bi- m o nt hl y) s u m maries of t o xicit y a n d pr ot oc ol e ve nts will be ge nerate d f or t he 
PI  a n d t he de part me nt of Bi ostatistics t o re vie w. 
 
It is u n d erst o o d t hat de viati o ns fr o m t he pr ot oc ol s h o ul d be a v oi de d, e x ce pt w he n 
ne cessar y t o eli mi nate a n i m me diate hazar d t o a researc h partici pa nt. I n s uc h case, t he 
de viati o n m ust be re p orte d t o t he I R B.   H o we v er, it is e x pecte d t hat patie nts will 
oc casi o nall y miss s o me d oses or recei ve t he wr o n g d ose of oral c he m ot hera p y.  
C o m plia nce wit h oral me dicati o n will be ca pt ure d i n t he C RI S data base a n d 
ap pr o priatel y d oc u me nt e d i n t he partici pa nts’ me dical rec or ds.  A p pr o priatel y 
d oc u me nte d d oses of misse d or wr o n g d oses of c h e m ot hera p y will n ot c o nstit ute a 
de vi ati o n u nless t he a m o u nt i n q uesti o n is o ver 1 0 %  of t he e x pecte d t otal d ose d ue i n t he 
res pecti ve pr ot oc ol c ycles (t hese are s pecifie d i n t he C RI S T O T X VI data base).   Misse d 
d ose s d o n ot i ncl u de d oses hel d or re d uce d f or me dical reas o ns (t o xicit y, ill ness) a n d will 
n ot be c o nsi dere d pr ot oc ol de viati o ns or vi olati o ns. 
 
2 1. 2 
St u d y M o nit ori n g 
 
S o urce d oc u me nt verificati o n of eli gi bilit y f or all SJ C R H cases will be perf or me d wit hi n 
t w o wee ks of c o m pleti o n of e nr oll me nt. T his will i ncl u de verificati o n of a p pr o priate 
d oc u me nta ti o n of c o nse nt. M o nit ori n g of ti meli ness of seri o us a d verse e ve nt re p orti n g 
will  be d o ne as e ve nts are re p ort e d i n T R A C K S. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 3  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
M o nit ori n g of t his pr ot oc ol is c o nsi dere d  t o be i n t he “ m o derate” ris k cate g or y. T he 
M o nit ori n g Pla n is o utli ne d i n a se parate d oc u me nt fr o m t his pr ot oc ol, b ut has bee n 
s u b mitte d f or re vie w a n d a p pr o val b y  t he Cli nical Trials Scie ntific Re vie w C o m mittee a n d 
t he I nstit uti o nal Re vie w B oar d. 
 
St. J u de affiliates a n d d o mestic c olla b orati n g st u d y sites will be m o nit ore d o n-site b y  a 
re prese ntati ve of St. J u de at i nter vals s pecifie d i n t he Data a n d Safet y 
M o nit ori n g Pla n.  
Inter nati o nal c olla b orat ors will be m o nit ore d acc or di n g t o t he st u d y-s pecific m o nit ori n g 
pla n.  
 
2 1. 3 
C o nfi de ntialit y 
 
S t u d y n u m bers will be use d i n place of a n i de ntifier s uc h as a me dical rec or d n u m ber. N o 
researc h partici pa nt na mes will be rec or de d o n t he data c ollecti o n f or ms. T he list 
co ntai ni n g t he st u d y n u m ber a n d t he me dical rec or d n u m ber will be mai ntai ne d i n a 
l oc ked file a n d will be destr o ye d after all data ha ve bee n a nal yze d.   T he me dical rec or ds 
of st u d y partici pa nts ma y be re vie we d b y  t he St. J u de I R B, F D A, a n d St. J u de cli nical 
researc h m o nit ors.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 4  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2 2. 0  R E F E R E N C E S  
Refere n ce List 
 
  
1.  Nac h ma n J B, Sat her H N, Se nsel M G et al. A u g me nte d p ost-i n d ucti o n t hera p y f or c hil dre n 
wit h hi g h-ris k ac ute l y m p h o blastic le u ke mia a n d a sl o w res p o nse t o i nitial t hera p y. 
N. E n gl.J Me d. 1 9 9 8; 3 3 8: 1 6 6 3- 1 6 7 1. 
 
2.  Sil ver ma n L B, Gel b er, R. D., a n d Dalt o n, V. K. I m pr o ve d o utc o me f or c hil dre n wit h ac ute 
l y m p h o blastic le u ke mia: Res ults of Da na Far ber C o ns orti u m Pr ot oc ol 9 1- 0 1. Bl o o d 9 7, 
1 2 1 1- 1 2 1 8. 2 0 0 1. 
 
3.  V ora, A., Mitc hell, C. D., Le n n ar d L, a n d et.al. T o xicit y a n d efficac y of 6-t hi o g na ni ne 
vers us 6- merca pt o p uri ne i n c hil d h o o d l y m p h o bl astic le u ke mia: a ra n d o mize d trial. La ncet 
3 6 8, 1 3 3 9- 1 3 4 8. 2 0 0 6. 
 
4.  
Mitc hell C D, Ric har ds S M, Ki nse y S E et al. Be n efit of de x a met has o ne c o m pare d wit h 
pre d nis o l o ne f or c hil d h o o d ac ute l y m p h o blastic le u kae mia: r es ults of t he U K Me dical 
Researc h C o u n cil A L L 9 7 ra n d o mize d trial. Br.J Hae mat ol. 2 0 0 5; 1 2 9: 7 3 4- 7 4 5. 
 
5.  B ostr o m B C, Se nsel M R, Sat her H N et al. De x a met has o ne vers us pre d nis o ne a n d dail y 
oral vers us w ee kl y i ntra v e n o us merca pt o p uri ne f or patie nts wit h sta n dar d-ris k ac ute 
l y m p h o blastic le u ke mia: a re p ort fr o m t he C hil dre n's Ca ncer Gr o u p. Bl o o d 
2 0 0 3; 1 0 1: 3 8 0 9- 3 8 1 7. 
  
6.  
Matl o u b Y, Li n de m ul der S, Ga y n o n P S, a n d et.al. I ntr at hecal tri ple t hera p y decreases 
ce ntral ner v o us s yste m rela pse b ut fails t o i m pr o ve e ve nt-free s ur vi v al w he n c o m paire d 
wit h itrat hecal met h otre x ate: res ults of t he C hil dre n's Ca ncer Gr o u p ( C C G) 1 9 5 2 st u d y f or 
sta n dar d-ris k ac ute l y m p h o blasti c le u ke mia, re p orte d b y t he C hil dre n's O nc ol o g y Gr o u p. 
Bl o o d 1 0 8, 1 1 6 5- 1 1 7 3. 2 0 0 6. 
  
7.  Pi n heir o J P, B o os J. T he best wa y t o use as p ara gi n ase i n c hil d h o o d ac ute l y m p hatic 
le u kae mia--still t o be defi ne d? Br.J Hae mat ol. 2 0 0 4; 1 2 5: 1 1 7- 1 2 7. 
 
8.  
Wetzler M, Sa nf or d B L, K urtz ber g J et al. Effecti ve as para gi ne de pl eti o n wit h pe g ylat e d 
as para gi n ase res ults i n i m pr o ve d o utc o mes i n a d ult ac ute l y m p h o blastic l e u ke mia: Ca ncer 
a n d Le u ke mia Gr o u p B St u d y 9 5 1 1. Bl o o d 2 0 0 7; 1 0 9: 4 1 6 4- 4 1 6 7. 
 
9.  Hiji ya N, Fra n kli n J, R ytti n g M. A p has e I st u d y of cl ofara bi ne i n c o m bi nati o n wit h 
c ycl o p h os p ha mi de a n d et o p osi de: a ne w re gi me n i n pe diatric patie nts wit h r efract or y or 
rela pse d ac ute le u k e ma [a bstract]. A S H A n n ual Meeti n g A bstracts 2 0 0 7; 2 5: 
 
1 0.  Fl ot h o C, C o usta n- S mit h E, Pei D et al. Ge nes c o ntri b uti n g t o mi ni mal resi d ual disease i n 
c hil d h o o d ac ute l y m p h o blastic le u ke mia: pr o g n ostic si g nifica nce of C A S P 8 A P 2. Bl o o d 
2 0 0 6; 1 0 8: 1 0 5 0- 1 0 5 7. 
 
1 1.  Fl ot h o C, C o usta n- S mit h E, Pei D et al. A set of ge nes t hat re g ul ate cell pr oliferati o n 
pre dicts treat me nt o utc o me i n c hil d h o o d ac ute l y m p h o blastic le u ke mia. Bl o o d 
2 0 0 7; 1 1 0: 1 2 7 1- 1 2 7 7. 
 
1 2.  H olle ma n, A., C he o k, M. H., de n B o er, M. L., a n d et.al. Ge ne-e x pressi o n patter ns i n dr u g-
resista nt ac ute l y m p h o blastic le u ke mia cells a n d res p o nse t o treat me nt. N. E n gl.J Me d. 
3 5 1, 5 3 3- 5 4 2. 2 0 0 4. 
 1 3.  L u gt hart S, C he o k M H, de n B oer M L et al. I d e ntificati o n of ge nes ass ociate d wit h 
c he m ot hera p y cr ossresista nce a n d treat me nt r es p o nse i n c hil d h o o d ac ute l y m p h o blastic 
le u ke mia. Ca ncer Cell 2 0 0 5; 7: 3 7 5- 3 8 6. 
 1 4.  P ui C H, E va ns W E. Treat me nt of ac ute l y m p h o blastic le u ke mia. N. E n gl.J. Me d. 
2 0 0 6; 3 5 4: 1 6 6- 1 7 8. 
 
1 5.  P ui C H, Relli n g M V, D o w ni n g J R. Ac ute l y m p h o blastic le u ke mia. N. E n gl.J. Me d. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 5  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2 0 0 4; 3 5 0: 1 5 3 5- 1 5 4 8. 
 
1 6.  Hil de n, J. M., Di n n d orf P A, Meer ba u m S O, a n d et.al. A nal ysis of pr o g n ostic fact ors of 
acute l y m p h o blastic le u k e mia i n i nfa nts: re p ort o n C C G 1 9 5 3 fr o m t he C hil dre n's 
O nc ol o g y Gr o u p. Bl o o d 1 0 8, 4 4 1- 4 5 1. 2 0 0 6. 
 1 7.  Pieters R, Sc hra p pe M, D e L P et al. A treat me nt pr ot oc ol f or i nfa nts y o u n ger t ha n 1 year 
wit h ac ute l y m p h o bl astic le u kae mia (I nterfa nt- 9 9): a n o bser vati o nal st u d y a n d a 
m ultice ntre ra n d o mise d trial. La ncet 2 0 0 7; 3 7 0: 2 4 0- 2 5 0. 
 1 8.  P ui C H, Ca m pa na D, E va ns W E. C hil d h o o d ac ute l y m p h o blastic le u kae mia --c urre nt stat us 
a n d f ut ure p ers pecti ves. La n cet O n c ol. 2 0 0 1; 2: 5 9 7- 6 0 7. 
 1 9.  P ui C H, E va ns W E. Ac ute l y m p h o blastic le u ke mia. N. E n gl.J. Me d. 1 9 9 8; 3 3 9: 6 0 5- 6 1 5. 
 2 0.  C o usta n- S mit h E, Sa nc h o J, Be h m F G et al. Pr o g n ostic i m p orta nce of meas uri n g earl y 
cleara nce of le u ke mic cells b y fl o w c yt o metr y i n c hil d h o o d ac ute l y m p h o bl astic le u ke mia. 
Bl o o d 2 0 0 2; 1 0 0: 5 2- 5 8. 
 2 1.  P ui C H. Ce ntral ner v o us s yste m diseas e i n ac ute l y m p h o blastic le u ke mia: pr o p h yla xis a n d 
treat me nt. He mat ol o g y. A m. S oc. He mat ol. E d uc. Pr o gra m. 2 0 0 6 1 4 2- 1 4 6. 
 
2 2.  P ui C H, Sa n dl u n d J T, Pei D et al. I m pr o ve d o utc o me f or c hil dre n wit h ac ut e 
l ym p h o blastic le u ke mia: res ults of T otal T hera p y St u d y XIII B at St J u de C hil dre n's 
Researc h H os pital. Bl o o d 2 0 0 4; 1 0 4: 2 6 9 0- 2 6 9 6. 
 
2 3.  P ui C H, Ga y n o n P S, B o yett J M et al. O utc o me of treat me nt i n c hil d h o o d ac ute 
l y m p h o blastic le u kae mia wit h rearra n ge me nts of t he 1 1 q 2 3 c hr o m os o mal re gi o n. La ncet 
2 0 0 2; 3 5 9: 1 9 0 9- 1 9 1 5. 
 
2 4.  Aric o M, Valse cc hi M G, Ca mitta B et al. O utc o me of treat me nt i n c hil dre n wit h 
P hila del p hia c hr o m os o me- p ositi ve ac ute l y m p h o blastic le u ke mia. N. E n gl.J Me d. 
2 0 0 0; 3 4 2: 9 9 8- 1 0 0 6. 
 
2 5.  Tal paz M, S ha h N P, Ka ntarjia n H et al. Dasati ni b i n i mati ni b-resista nt P hila del p hia 
c hr o m os o me- p ositi ve le u ke mias. N. E n gl.J. Me d. 2 0 0 6; 3 5 4: 2 5 3 1- 2 5 4 1. 
 2 6.  Ott ma n n O, D o m bret H, Marti nelli G et al. Dasati ni b i n d uces ra pi d he mat ol o gic a n d 
c yt o ge netic res p o nses i n a d ult patie nts wit h P hila del p hia c hr o m os o me p ositi ve ac ute 
l y m p h o blastic le u ke mia wit h resista nce or i nt olera nce t o i mati ni b: i nteri m res ults of a 
p hase 2 st u d y. Bl o o d 2 0 0 7; 1 1 0: 2 3 0 9- 2 3 1 5. 
 2 7.  Ka ntarjia n H, Pas q ui ni R, Ha mersc hl a k N et al. D asati ni b or hi g h- d os e i mati ni b f or 
c hr o nic- p h ase c hr o nic m yel oi d le u ke mia after fail ure of first-li ne i mati ni b: a ra n d o mize d 
p hase 2 trial. Bl o o d 2 0 0 7; 1 0 9: 5 1 4 3- 5 1 5 0. 
 2 8.  C o usta n- S mit h E, M ulli g ha n C G, O nci u M et al. E arl y T-cell prec urs or le u kae mia: a 
s u bt ype of ver y hi g h-ris k ac ute l y m p h o blastic le u kae mia. La n cet O nc ol 2 0 0 9; 1 0: 1 4 7- 1 5 6. 
 2 9.  Sc hra p pe M, Zi m mer ma n n M, M oric ke A et al. D e x a met has o ne i n I n d ucti o n Ca n 
Eli mi nate O ne T hir d of All Rela pses i n C hil d h o o d Ac ute L y m p h o blastic Le u k e mia 
( A L L): Res ults of A n I nt er nati o nal Ra n d o mize d Trial i n 3 6 5 5 Patie nts ( Trial AI E O P- B F M 
A L L 2 0 0 0). A S H A n n ual Meeti n g A bstracts 2 0 0 8; 1 1 2: 7. 
 
3 0.  Reiter A, Sc hra p p e M, L u d wi g W D et al. C he m ot hera p y i n 9 9 8 u nselecte d c hil d h o o d 
ac ute l y m p h o blastic le u k e mia patie nts. R es ults a n d c o ncl usi o ns of t he m ultice nter trial 
A L L- B F M 8 6. Bl o o d 1 9 9 4; 8 4: 3 1 2 2- 3 1 3 3. 
 3 1.  C o nter V, Aric o M, V alsecc hi M G et al. I nte nsi ve B F M c he m ot hera p y f or c hil d h o o d 
A L L: i nteri m a n al ysis of t he AI E O P- A L L 9 1 st u d y. Ass oci azi o ne It alia na E mat ol o gia 
O nc ol o gi a Pe diatrica. Hae mat ol o gica 1 9 9 8; 8 3: 7 9 1- 7 9 9. 
 3 2.  Gal pi n AJ, Sc h uetz J D, Mass o n E et al. Differe n ces i n f ol yl p ol y gl uta mate s y nt hetas e a n d 
di h y dr of ol ate re d u ctase e x pressi o n i n h u ma n B-li nea ge v ers us T-li nea ge le u ke mic 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 6  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
l y m p h o blasts: mec ha nis ms f or li n ea ge differe nces i n met h otre x ate p ol y gl uta m ylati o n a n d 
c yt ot o xicit y. M ol. P har m ac ol. 1 9 9 7; 5 2: 1 5 5- 1 6 3. 
 
3 3.  S y n ol d T W, Relli n g, M. V., B o yett, J. M., a n d et.al. Blast cell met h otre x ate- p ol y gl uta m ate 
acc u m ulati o n i n vi v o defers b y li nea ge, pl oi d y, a n d met h otre x ate d ose i n ac ute 
l y m p h o blastic le u ke mia. J Cli n I n vest 9 4, 1 9 9 6- 2 0 0 1. 1 9 9 4. 
 
3 4.  Nie me yer C M, G el ber R D, Tar bell NJ et al. L o w- d ose vers us hi g h- d ose m et h otre x ate 
d uri n g re missi o n i n d ucti o n i n c hil d h o o d ac ute l y m p h o blastic le u ke mia ( Pr ot oc ol 8 1- 0 1 
u p date). Bl o o d 1 9 9 1; 7 8: 2 5 1 4- 2 5 1 9.  
 3 5.  E va ns W E, Sc hell MJ, P ui C H. M T X cleara nce is m ore i m p orta nt f or i nter me diate-ris k 
A L L. J. Cli n. O nc ol. 1 9 9 0; 8: 1 1 1 5- 1 1 1 6. 
 3 6.  
Wall A M, Gajjar A, Li n k A et al. I n di vi d ualize d met h otre x ate d osi n g i n c hil dre n wit h 
rela pse d ac ute l y m p h o blastic le u ke mia. Le u ke mia 2 0 0 0; 1 4: 2 2 1- 2 2 5. 
 3 7.  E va ns W E, Relli n g M V, R o d ma n J H et al. C o n ve nti o nal c o m pare d wit h i n di vi d ualize d 
c he m ot hera p y f or c hil d h o o d ac ute l y m p h o blastic le u ke mia. N. E n gl.J. Me d. 1 9 9 8; 3 3 8: 4 9 9-
5 0 5. 
 3 8.  B ostr o m B, G a y n o n P S, Sat her H N. De x a met has o ne ( D E X) decreas es ce ntral ner v o us 
s yste m ( C N S) rela pse a n d i m pr o ves e ve nt-free s ur vi val ( E F S) i n l o wer ris k ac ute 
l y m p h o blastic le u ke mia ( A L L) [a bstract]. A m S oc of Cli nical O nc ol o g y 1 9 9 8; 1 7: 5 2 7 9. 
 
3 9.  Relli n g, M. V., Ha n c oc k, M. L., B o yett, J. M., a n d et.al. Pr o g n ostic i m p orta nce of 6-
merca pt o p uri n e d ose i nte nsit y i n ac ute l y m p h o blastic le u ke mia. Bl o o d 9 3, 2 8 1 7- 2 8 2 3. 
1 9 9 9. 
 4 0.  A m yl o n M D, S h uster J, P ulle n J et al. I nte nsi ve hi g h- d ose as para gi nase c o ns oli dati o n 
i m pr o ves s ur vi val f or pe diatric patie nts wit h T cell ac ute l y m p h o bl astic le u ke mia a n d 
a d va nce d sta ge l y m p h o blastic l y m p h o ma: a Pe diatric O nc ol o g y Gr o u p st u d y. Le u k e mia 
1 9 9 9; 1 3: 3 3 5- 3 4 2. 
 4 1.  P ui C H, Relli n g M V, Be h m F G et al. L-as para gi n ase ma y p ote ntiate t he l e u ke m o ge nic 
effect of t he e pi p o d o p h yll ot o xi ns. Le u ke mia 1 9 9 5; 9: 1 6 8 0- 1 6 8 4. 
 4 2.  N ys o m K, H ol m K, Li psitz S R et al. Relati o ns hi p bet wee n c u m ulati ve a nt hrac ycli ne d os e 
a n d late car di ot o xicit y i n c hil d h o o d ac ute l y m p h o blastic le u ke mia. J. Cli n. O nc ol. 
1 9 9 8; 1 6: 5 4 5- 5 5 0. 
 4 3.  L u d wi g W D, Rie der H, Bartra m C R et al. I m m u n o p he n ot y pic a n d ge n ot y pic feat ur es, 
cli nical c haracteristics, a n d treat me nt o utc o me of a d ult pr o- B ac ute l y m p h o blastic 
le u ke mia: res ults of t he Ger ma n m ultice nter trials G M A L L 0 3/ 8 7 a n d 0 4/ 8 9. Bl o o d 
1 9 9 8; 9 2: 1 8 9 8- 1 9 0 9. 
 4 4.  J e ha S, Pei D, Rai m o n di S C et al. I ncreas e d ris k f or C N S rela pse i n pr e- B cell le u ke mia 
wit h t he t( 1; 1 9)/ T C F 3- P B X 1. Le u k e mia 2 0 0 9; 2 3: 1 4 0 6- 1 4 0 9. 
 4 5.  B urt o n N K, A h er ne G W. T he effect of c otri m o x az ole o n t he a bs or pti o n of orall y 
a d mi nistere d 6- merca pt o p uri ne i n t he rat. Ca ncer C he m ot her. P har mac ol. 1 9 8 6; 1 6: 8 3- 8 4. 
 4 6.  Laf olie P, Bj or k O, Ha y d er S, A hstr o m L, Pet ers o n C. Varia bilit y of 6- merca pt o p uri ne 
p har mac o ki netics d uri n g oral mai nte na nce t hera p y of c hil dre n wit h ac ute le u ke mia. 
Me d. O nc ol. T u m or P har mac ot her. 1 9 8 9; 6: 2 5 9- 2 6 5. 
 
4 7.  L o n ner h ol m G, Kre u ger A, Li n dstr o m B, M yr dal U. Oral merca pt o p uri ne i n c hil d h o o d 
le u ke mia: i nfl ue nce of f o o d i nta ke o n bi oa vaila bilit y. Pe diatr. He mat ol. O nc ol. 1 9 8 9; 6: 1 0 5-
1 1 2. 
 4 8.  Riccar di R, Balis F M, Ferrara P et al. I nfl ue n ce of f o o d i nta ke o n bi oa vaila bilit y of oral 6-
merc a pt o p uri n e i n c hil dr e n wit h ac ute l y m p h o blastic le u ke mia. Pe diatr. He mat ol. O nc ol. 
1 9 8 6; 3: 3 1 9- 3 2 4.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 7  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
4 9.  Ri var d G E, H o y o u x C, I nfa nte C, a n d et. al. Mai nte na nce c he m ot hera p y f or c hil d h o o d 
ac ute l y m p h o blastic le u k ae mia: better i n t he e ve ni n g. La n cet 3 2 6, 1 2 6 4- 1 2 6 6. 1 9 8 5. 
 
5 0.  Sc h mie gel o w K, Gl o mstei n A, Kristi nss o n J et al. I m pact of m or ni n g vers us e ve ni n g 
sc he d ule f or oral met h otre x ate a n d 6- merca pt o p uri ne o n rela ps e ris k f or c hil dre n wit h 
ac ute l y m p h o blastic le u k e mia. N or dic S ociet y f or Pe diatric He mat ol o g y a n d O nc ol o g y 
( N O P H O). J. Pe diatr. He mat ol. O nc ol. 1 9 9 7; 1 9: 1 0 2- 1 0 9. 
 5 1.  Li n ds y Ha ge ma n W, Y. C. Hee y o u n g Ki m, K or n e ga y N et al. 3 6 9 I m pact of 6 
Meca pt o p uri ne ( 6 M P) Pill- Ta ki n g Ha bits o n A d here nce, T hi o g ua ni ne N ucle oti de ( T G N) 
Le v els a n d Rela ps e Ris k i n C hil dre n wit h Ac ute L y m p h o blastic Le u k e mia ( A L L):  R es ults 
fr o m a C hil dre n's O nc ol o g y Gr o u p ( C O G) St u d y ( A A L L 0 3 N 1) [a bstract]. A S H 
2 0 1 4; 2 0 1 4: 
 
5 2.  Ye o h EJ, R oss M E, S h urtleff S A et al. Classificati o n, s u bt y pe disc o v er y, a n d pre dicti o n of 
o utc o me i n pe diatric ac ut e l y m p h o blastic le u ke mia b y ge ne e x pressi o n pr ofili n g.  Ca ncer 
C ell 2 0 0 2; 1: 1 3 3- 1 4 3. 
 
5 3.  R oc ha J C, C he n g C, Li u W et al. P har mac o ge neti cs of o utc o me i n c hil dre n wit h ac ute 
l y m p h o blastic le u kemia . Bl o o d 2 0 0 5; 1 0 5: 4 7 5 2- 4 7 5 8. 
 5 4.  C he o k, M. H. a n d E va ns, W. E. Ac ute l y m p h o blastic le u ke mia: a m o del f or t he 
p har mac o ge n o mics of ca ncer t hera p y. Nat. Re v. Ca ncer 6, 1 1 7- 1 2 9. 2 0 0 6. 
 
5 5.  E va ns W E, Relli n g M V. M o vi n g t o war ds i n di vi d u alize d me dici ne wit h 
p har mac o ge n o mics.  Nat ure 2 0 0 4; 4 2 9: 4 6 4- 4 6 8. 
 5 6.  Relli n g M V, P ui C H, C he n g C, E v a ns W E. T hi o p uri ne met h yltra nsferase i n ac ute 
l y m p h o blastic le u ke mia. Bl o o d 2 0 0 6; 1 0 7: 8 4 3- 8 4 4. 
 5 7.  B o g ni A, C he n g C, Li u W et al. Ge n o me- wi de a p pr oac h t o i de ntif y ris k fact ors f or 
t hera p y-relate d m yel oi d l e u ke mia. Le u k e mia 2 0 0 6; 2 0: 2 3 9- 2 4 6. 
 5 8.  Ya n g JJ, C he n g C, Ya n g W et al. Ge n o me- wi de I nterr o gati o n of Ger mli ne Ge netic 
Variati o n Ass ociate d Wit h Treat me nt Res p o nse i n C hil d h o o d Ac ute L y m p h o blastic 
Le u k e mia. J A M A: T he J o ur nal of t he A merica n Me dical Ass ociati o n 2 0 0 9; 3 0 1: 3 9 3- 4 0 3. 
 5 9.  Relli n g M V, Ya n g W, D as S et al. P har mac o ge netic ris k fact ors f or oste o n ecr osis of t he 
hi p a m o n g c hil dre n wit h le u ke mia. J. Cli n. O nc ol. 2 0 0 4; 2 2: 3 9 3 0- 3 9 3 6. 
 6 0.  Ya n g J, C he n g C, Ya n g W et al. Ge n o me- wi de ger mli ne variati o n a n d tr eat me nt res p o nse 
i n ac ule l y m p h o bl astic le u ke mia ( A L L) [a bstract]. A m J H u m Ge net 2 0 0 7; Meeti n g 
A bstract: 
 
6 1.  Kis hi S, C he n g C, Fre n c h D et al. A ncestr y a n d p har mac o ge netics of a ntile u ke mic dr u g 
t o xicit y. Bl o o d 2 0 0 7; 1 0 9: 4 1 5 1- 4 1 5 7. 
 6 2.  Kis hi S, Ya n g W, B o urea u B et al. Effects of pre d nis o ne a n d ge netic p ol y m or p his ms o n 
et o p osi de dis p ositi o n i n c hil dre n wit h ac ute l y m p h o blastic le u ke mia. Bl o o d 2 0 0 4; 1 0 3: 6 7-
7 2. 
 6 3.  Kis hi S, Grie ner J, C he n g C et al. H o m oc yst ei ne, p har mac o ge netics, a n d n e ur ot o xicit y i n 
c hil dre n wit h le u ke mia. J Cli n O nc ol 2 0 0 3; 2 1: 3 0 8 4- 3 0 9 1. 
 6 4.  Bla nc o J G, E dic k MJ, Ha nc oc k M L et al. Ge netic p ol y m or p his ms i n C Y P 3 A 5, C Y P 3 A 4 
a n d N Q O 1 i n c hil dre n w h o de vel o pe d t hera p y-rel ate d m yel oi d mali g na n ci es. 
P har mac o ge n etics 2 0 0 2; 1 2: 6 0 5- 6 1 1. 
 6 5.  
M ulli g ha n C G, G o or ha S, Ra dt ke I et al. Ge n o me- wi de a nal ysis of ge n etic alterati o ns i n 
ac ute l y m p h o blastic le u k ae mia. Nat ur e 2 0 0 7; 4 4 6: 7 5 8- 7 6 4. 
 6 6.  
Wei ns hil b o u m R M, Sla de k S L. Merca pt o p uri ne p har mac o ge netics: m o n o ge nic i n herita nce 
of er yt hr oc yt e t hi o p uri ne met h yltra nsferase acti vit y. A m J. H u m. Ge net. 1 9 8 0; 3 2: 6 5 1- 6 6 2. 
 6 7.  A vra mis VI, Se ncer S, Pericl o u A P et al. A ra n d o mize d c o m paris o n of nati ve Esc heri c hia 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 8  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c oli as para gi n ase a n d p ol yet h yle ne gl yc ol c o nj u gate d as para gi nase f or treat m e nt of 
c hil dre n wit h ne wl y dia g n ose d sta n dar d-ris k ac ute l y m p h o blastic le u ke mia: a C hil dre n's 
Ca ncer Gr o u p st u d y. Bl o o d 2 0 0 2; 9 9: 1 9 8 6- 1 9 9 4. 
 
6 8.  Vieira Pi n heir o J P, We n ner K, Esc h eric h G et al. Ser u m as para gi nase acti vities a n d 
as para gi n e c o nce ntrati o ns i n t he cere br os pi nal fl ui d after a si n gle i nf usi o n of 2, 5 0 0 
IU/ m( 2) P E G as para gi nase i n c hil dre n wit h A L L treate d acc or di n g t o pr ot oc ol C O A L L-
0 6- 9 7. Pe diatr. Bl o o d Ca n cer 2 0 0 6; 4 6: 1 8- 2 5. 
 6 9.  Ya n g L, Pa netta J C, Cai X et al. As para gi nase ma y i nfl ue n ce de x a met has o ne 
p har mac o ki netics i n ac ut e l y m p h o blastic le u ke mia. J Cli n O nc ol 2 0 0 8; 2 6: 1 9 3 2- 1 9 3 9. 
 7 0.  
Wei G, T w o me y D, La m b J et al. Ge ne e x pressi o n- base d c h e mical ge n o mics i de ntifies 
ra pa m yci n as a m o d ulat or of M C L 1 a n d gl uc oc ortic oi d resista nce. Ca n cer Cell 
2 0 0 6; 1 0: 3 3 1- 3 4 2. 
 7 1.  C he o k M H, Ya n g W, P ui C H et al. Treat me nt-s pecific c ha n ges i n ge ne e x pressi o n 
discri mi nate i n vi v o dr u g res p o nse i n h u ma n le u ke mia cells. Nat. Ge n et. 2 0 0 3; 3 4: 8 5- 9 0. 
 7 2.  Q ui n n C T, Grie ner J C, B otti glieri T et al. Ele v ati o n of h o m oc yst ei ne a n d e x citat or y a mi n o 
aci d ne ur otr a ns mitters i n t he C S F of c hil dre n w h o recei v e met h otre x ate f or t he treat me nt 
of ca ncer. J Cli n O nc ol 1 9 9 7; 1 5: 2 8 0 0- 2 8 0 6. 
 7 3.  Drac ht ma n R A, C ole P D, G ol de n C B et al. De xtr o met h or p ha n is effecti ve i n t he treat me nt 
of s u bac ute met h otre x ate ne ur ot o xicit y. Pe diatr. He mat ol O nc ol 2 0 0 2; 1 9: 3 1 9- 3 2 7. 
 7 4.  Brattstr o m L, Wilc ke n D E, O hr vi k J, Br u di n L. C o m m o n met h yl e netetra h y dr of olate 
re d uctas e ge ne m utati o n lea ds t o h y p er h o m oc ystei ne mia b ut n ot t o vasc ular disease: t he 
res ult of a meta-a nal ysis. Circ ulati o n 1 9 9 8; 9 8: 2 5 2 0- 2 5 2 6. 
 7 5.  C ha n g o A, E m er y- Fill o n N, de C o urc y G P et al. A p ol y m or p his m ( 8 0 G- > A) i n t he 
re d uce d f olate carrier ge ne a n d its ass ociati o ns wit h f olate stat us a n d h o m oc ystei n e mia. 
M ol Ge net Meta b 2 0 0 0; 7 0: 3 1 0- 3 1 5. 
 7 6.  Ca m pa na D. Deter mi nati o n of mi ni mal resi d ual disease i n le u kae mia patie nts. 
Br.J. Hae mat ol. 2 0 0 3; 1 2 1: 8 2 3- 8 3 8. 
 7 7.  Fa ha m M, Z h e n g J, M o or hea d M et al. Dee p-se q u e nci n g a p pr oac h f or mi ni mal resi d ual 
disease dete cti o n i n ac ute l y m p h o blastic le u ke mia. Bl o o d 2 0 1 2; 1 2 0: 5 1 7 3- 5 1 8 0. 
 7 8.  I mai K, M ats u ya ma S, Mi ya k e S, S u ga K, Na kac hi K. Nat ural c yt ot o xic acti vit y of 
peri p heral- bl o o d l y m p h o c yt es a n d ca ncer i nci de nce: a n 1 1- year f oll o w- u p st u d y of a 
ge n eral p o p ulati o n. La ncet 2 0 0 0; 3 5 6: 1 7 9 5- 1 7 9 9. 
 
7 9.  C ostell o R T, Si v ori S, Marce n ar o E et al. Defecti v e e x pressi o n a n d f u ncti o n of nat ural 
killer cell-tri g geri n g rece pt ors i n patie nts wit h ac ute m yel oi d le u ke mia. Bl o o d 
2 0 0 2; 9 9: 3 6 6 1- 3 6 6 7. 
 
8 0.  Fa uriat C, J ust- La n di S, Mallet F et al. Deficie nt e x pressi o n of N C R i n N K cells fr o m 
ac ute m yel oi d le u ke mia: E v ol uti o n d uri n g le u ke mia treat me nt a n d i m pact of le u ke mia 
cells i n N C R d ull p he n ot y pe i n d ucti o n. Bl o o d 2 0 0 7; 1 0 9: 3 2 3- 3 3 0. 
 8 1.  Pe n de D, S pa g giari G M, Marce n ar o S et al. A n al ysis of t he rece pt or-li ga n d i nteracti o ns i n 
t he nat ural killer- me di ate d l ysis of fres hl y is olate d m yel oi d or l y m p h o blastic le u ke mias: 
e vi de nce f or t he i n v ol ve me nt of t he P oli o vir us rece pt or ( C D 1 5 5) a n d Necti n- 2 ( C D 1 1 2). 
Bl o o d 2 0 0 5; 1 0 5: 2 0 6 6- 2 0 7 3. 
 8 2.  Le u n g W, I ye n gar R, T ur ner V et al. Deter mi na nts of a ntile u ke mia effects of all o ge neic 
N K cells. J.I m m u n ol. 2 0 0 4; 1 7 2: 6 4 4- 6 5 0. 
 8 3.  Re d dic k W E, Glass J O, Helt o n KJ et al. Pre vale nce of le u k o e nce p h al o pat h y i n c hil dre n 
treate d f or ac ut e l y m p h o blastic le u ke mia wit h hi g h- d ose met h otre x ate. AJ N R A m 
J. Ne ur ora di ol. 2 0 0 5; 2 6: 1 2 6 3- 1 2 6 9. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 0 9  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
8 4.  Re d dic k W E, Glass J O, Helt o n KJ et al. A q ua ntitati ve M R i ma gi n g assess me nt of 
le u k oe nce p h al o pat h y i n c hil dre n treate d f or ac ute l y m p h o blastic le u ke mia wit h o ut 
irra diati o n. AJ N R A m J. Ne ur ora di ol. 2 0 0 5; 2 6: 2 3 7 1- 2 3 7 7. 
 8 5.  T o ga A W, T h o m ps o n P M, S o well E R. Ma p pi n g brai n mat urati o n. Tre n ds Ne ur osci. 
2 0 0 6; 2 9: 1 4 8- 1 5 9. 
 8 6.  S o well E R, T h o m ps o n P M, Le o n ar d C M et al. L o n git u di nal ma p pi n g of c ortical t hic k ness 
a n d brai n gr o wt h i n n or m al c hil dre n. J. Ne ur osci. 2 0 0 4; 2 4: 8 2 2 3- 8 2 3 1. 
 8 7.  K h o n g P L, Le u n g L H, F u n g A S et al. W hite matter a nis otr o p y i n p ost-treat me nt c hil d h o o d 
ca ncer s ur vi v ors: pr eli mi nar y e vi de nce of ass ociati o n wit h ne ur oc o g niti ve f u ncti o n. 
J. Cli n. O nc ol. 2 0 0 6; 2 4: 8 8 4- 8 9 0. 
 8 8.  La ul e C, K ozl o ws ki P, Le u n g E et al. M yeli n wat er i ma gi n g of m ulti ple scler osis at 7 T: 
c orrel ati o ns wit h hist o pat h ol o g y. Ne ur oi ma ge. 2 0 0 8; 4 0: 1 5 7 5- 1 5 8 0. 
 8 9.  
Ma dler B, Dra b ycz S A, K oli n d S H, W hittall K P, Mac ka y A L. Is diff usi o n a nis otr o p y a n 
acc urate m o nit or of m yeli nati o n? C orrelati o n of m ultic o m p o ne nt T 2 rela x ati o n a n d 
diff usi o n te ns or a nis otr o p y i n h u ma n brai n. Ma g n Res o n.I m a gi n g 2 0 0 8; 2 6: 8 7 4- 8 8 8. 
 9 0.  La ul e C, Va vas o ur I M, Ma dler B et al. M R e vi de nce of l o n g T 2 water i n p at h ol o gical 
w hite matter. J Ma g n Res o n.I ma gi n g 2 0 0 7; 2 6: 1 1 1 7- 1 1 2 1. 
 9 1.  
M o nt o ur- Pr o ul x I, K ue h n S M, Kee ne D L et al. C o g niti ve c h a n ges i n c hil dre n treate d f or 
ac ute l y m p h o blastic le u k e mia wit h c he m ot hera p y o nl y acc or di n g t o t he Pe diatric 
O nc ol o g y Gr o u p 9 6 0 5 pr ot oc ol. J. C hil d Ne ur ol. 2 0 0 5; 2 0: 1 2 9- 1 3 3. 
 9 2.  Es p y K A, M o ore I M, Ka uf ma n n P M et al. C he m ot hera pe utic C N S pr o p h yl a xis a n d 
ne ur o ps yc h ol o gic c h a n ge i n c hil dre n wit h ac ute l y m p h o blastic le u ke mia: a pr os pecti ve 
st u d y. J. Pe diatr. Ps yc h ol. 2 0 0 1; 2 6: 1- 9. 
 9 3.  Kae mi n g k K L, Care y M E, M o ore I M, H erzer M, H utter JJ. Mat h wea k nesses i n s ur vi v ors 
of ac ute l y m p h o blastic le u ke mia c o m pare d t o healt h y c hil dre n. C hil d Ne ur o ps yc h ol. 
2 0 0 4; 1 0: 1 4- 2 3. 
 9 4.  Care y M E, H oc k e n berr y MJ, M o ore I M et al. Brief re p ort: effect of i ntra ve n o us 
met h otre x ate d ose a n d i nf usi o n rate o n ne ur o ps yc h ol o gical f u n cti o n o ne year aft er 
dia g n osis of ac ute l y m p h o blastic le u ke mia. J. Pe diatr. Ps yc h ol. 2 0 0 7; 3 2: 1 8 9- 1 9 3. 
 9 5.  Br o w n R T, Ma d a n- S wai n A, Pais R et al. C he m ot hera p y f or ac ut e l y m p h o c ytic l e u ke mia: 
c o g niti ve a n d aca de mic s e q uelae. J. Pe diatr. 1 9 9 2; 1 2 1: 8 8 5- 8 8 9. 
 9 6.  Paa k k o E, Harila- Sa ari A, Va ni o n paa L et al. W hite matter c h a n ges o n M RI d uri n g 
treat me nt i n c hil dre n wit h ac ute l y m p h o blastic le u ke mia: c orrelati o n wit h 
ne ur o ps yc h ol o gical fi n di n gs. Me d. Pe diatr. O nc ol. 2 0 0 0; 3 5: 4 5 6- 4 6 1. 
 9 7.  G ol d ma n I D, Mat herl y L H. T he cell ular p har mac ol o g y of met h otre x ate. P har mac ol. T h er. 
1 9 8 5; 2 8: 7 7 - 1 0 2. 
 9 8.  Ulric h C M, R o bie n K, S par ks R. P har mac o ge neti cs a n d f olate m eta b olis m -- a pr o misi n g 
directi o n. P har mac o ge n o mics. 2 0 0 2; 3: 2 9 9- 3 1 3. 
 
9 9.  Kra us J P, Oli veri us o va J, S o k ol o va J et al. T he h u ma n c yst at hi o ni ne beta-s y nt hase ( C B S) 
ge n e: c o m plete se q u e nce, alter nati ve s plici n g, a n d p ol y m or p his ms. Ge n o mi cs 
1 9 9 8; 5 2: 3 1 2- 3 2 4.  
 1 0 0.  Kr ull K R, Br o u wers P, Jai n N et al. F ol ate pat h w a y ge netic p ol y m or p his ms are relate d t o 
atte nti o n dis or ders i n c hil d h o o d le u ke mia s ur vi v ors. J. Pe diatr. 2 0 0 8; 1 5 2: 1 0 1- 1 0 5. 
 1 0 1.  Re d dic k W E, S ha n Z Y, Glass J O et al. S maller w hite- matter v ol u mes are ass ociate d wit h 
lar ger deficits i n atte nti o n a n d lear ni n g a m o n g l o n g-ter m s ur vi v ors of ac ute l y m p h o blastic 
le u ke mia. Ca ncer 2 0 0 6; 1 0 6: 9 4 1- 9 4 9. 
 1 0 2.  O we n A M, Mc Milla n K M, Lair d A R, B ull m ore E. N- bac k w or ki n g me m or y p ara di g m: a 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 1 0  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
meta-a nal ysis of n or m ati ve f u ncti o nal ne ur oi ma gi n g st u dies. H u m Brai n M a p p. 
2 0 0 5; 2 5: 4 6- 5 9.  
 1 0 3.  S or g C, Rie dl V, M u hla u M et al. Selecti ve c h a n ges of resti n g-state n et w or ks i n 
i n di vi d uals at ris k f or Alz hei mer's diseas e. Pr oc. Natl. Aca d. Sci. U. S. A 2 0 0 7; 1 0 4: 1 8 7 6 0-
1 8 7 6 5. 
 1 0 4.  Dr u ker BJ, Sa w yers C L, Ka ntarjia n H et al. Acti vit y of a s p ecific i n hi bit or of t he B C R-
A B L t yr osi ne ki nas e i n t he blast crisis of c hr o ni c m yel oi d le u k e mia a n d ac ute 
l y m p h o blastic le u ke mia wit h t he P hila del p hia c hr o m os o me. N. E n gl.J. Me d. 
2 0 0 1; 3 4 4: 1 0 3 8- 1 0 4 2. 
 1 0 5.  Ott ma n n O G, Dr u ker BJ, Sa w yers C L et al. A p hase 2 st u d y of i mati ni b i n patie nts wit h 
rela pse d or refract or y P hila del p hia c hr o m os o me- p ositi ve ac ute l y m p h oi d le u ke mias. 
Bl o o d 2 0 0 2; 1 0 0: 1 9 6 5- 1 9 7 1. 
 1 0 6.  
Wass ma n n B, Pfeifer H, Sta dler M et al. Earl y m olec ular res p o nse t o p osttr a ns pla ntati o n 
i mati ni b deter mi nes o utc o me i n M R D + P hila del p hia- p ositi ve ac ute l y m p h o blastic 
le u ke mia ( P h + A L L).  Bl o o d 2 0 0 5; 1 0 6: 4 5 8- 4 6 3. 
 1 0 7.  Lee S, Ki m D W, Ki m YJ et al. Mi ni mal resi d ual disease- bas e d r ole of i mati ni b as a first-
li ne i nteri m t hera p y pri or t o all o ge n eic ste m cell tr a ns pla ntati o n i n P hila del p hia 
c hr o m os o me- p ositi ve ac ute l y m p h o blastic le u ke mia. Bl o o d 2 0 0 3; 1 0 2: 3 0 6 8- 3 0 7 0. 
 1 0 8.  T h o mas D A, Fa derl S, C ortes J et al. Treat me nt of P hila del p hia c hr o m os o me- p ositi ve 
ac ute l y m p h oc ytic le u ke mia wit h h y per- C V A D a n d i mati ni b mes yl ate. Bl o o d 
2 0 0 4; 1 0 3: 4 3 9 6- 4 4 0 7. 
 1 0 9.  Carter T A, W o dic ka L M, S ha h N P et al. I n hi biti o n of dr u g-resista nt m uta nts of A B L, KI T, 
a n d E G F rece pt or ki nases. Pr oc. Natl. Aca d. Sci. U. S. A 2 0 0 5; 1 0 2: 1 1 0 1 1- 1 1 0 1 6. 
 1 1 0.  S ha h N P, Tra n C, Lee F Y et al. O verri di n g i mati ni b resista nce wit h a n o vel A B L ki nas e 
i n hi bit or. Scie nce 2 0 0 4; 3 0 5: 3 9 9- 4 0 1. 
 1 1 1.  Ka ntarjia n H, Ott ma n n O, Pas q ui ni R. Dasati ni b ( S P R Y C E L) 5 0 m g or 7 0 m g BI D vs. 
1 0 0 m g or 1 4 0 Q D i n patie nts wit h c hr o nic m yel oi d le u ke mia i n c hr o nic p hase ( C M L- C P) 
resista nt or i nt olera nt t o i mati ni b:  res ults of t he C A 1 8 0- 0 3 4 st u d y [a bstract]. A S H A n n ual 
Meeti n g A bstracts 2 0 0 6; 7 4 6. 
 1 1 2.  J e ha S, Ga n d hi V, C ha n K W et al. Cl ofara bi ne, a n o vel n ucle osi de a n al o g, is acti ve i n 
pe diatric patie nts wit h a d va nce d le u ke mia. Bl o o d 2 0 0 4; 1 0 3: 7 8 4- 7 8 9. 
 1 1 3.  J e ha, S., Ga y n o n P S, Razz o u k, B., a n d et.al. P hase II st u d y of cl of ara bi ne i n pe diatric 
pati e nts wit h refract or y or rela pse d ac ute l y m p h o blastic le u ke mia. J Cli n O nc ol 2 4, 1 9 1 7-
1 9 2 3. 2 0 0 6. 
 1 1 4.  Hiji ya N, Ga y n o n P, Barr y E et al. A m ulti-ce nter p hase I st u d y of cl ofara bi ne, et o p osi de 
a n d c ycl o p h os p ha mi de i n c o m bi nati o n i n pe diatri c patie nts wit h refract or y or rela pse d 
ac ute le u k e mia. Le u ke mi a 2 0 0 9; 2 3: 2 2 5 9- 2 2 6 4. 
 1 1 5.  Baile y L C, Reill y A F, R hei n g ol d S R. I nfecti o ns i n pe diatric patie nts wit h he mat ol o gic 
mali g na n cies. Se mi n. He mat ol 2 0 0 9; 4 6: 3 1 3- 3 2 4. 
 1 1 6.  S u n g L, Ga mis A, Al o nz o T A et al. I nfecti o ns a n d ass ociati o n wit h differe nt i nte nsit y of 
c he m ot hera p y i n c hil dre n wit h ac ute m yel oi d le u ke mia. Ca ncer 2 0 0 9; 1 1 5: 1 1 0 0- 1 1 0 8. 
 1 1 7.  Pac ke y C D, Ci or ba M A. Micr o bial i nfl ue nces o n t he s mall i ntesti nal res p o nse t o ra diati o n 
i nj ur y. C urr. O pi n. G astr o e nter ol. 2 0 1 0; 2 6: 8 8- 9 4. 
 1 1 8.  Se kir o v I, Fi nla y B B. T h e r ole of t he i ntesti nal mi cr o bi ota i n e nteric i nfecti o n. J P h ysi ol 
2 0 0 9; 5 8 7: 4 1 5 9- 4 1 6 7. 
 1 1 9.  Clar ke T B, Da vis K M, L ys e n k o E S et al. Rec o g niti o n of pe pti d o gl yca n fr o m t he 
micr o bi ota b y N o d 1 e n ha nces s yste mic i n nate i m m u nit y. Nat Me d 2 0 1 0; 1 6: 2 2 8- 2 3 1. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 1 1  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 1 2 0.  de la C oc hetiere M F, M o ntassier E, Har d o ui n J B et al. H u ma n i ntesti nal micr o bi ota ge ne 
ris k fact ors f or a nti bi otic-ass ociate d diarr hea: pers pecti ves f or pre ve nti o n. Ris k fact ors f or 
a nti bi otic-ass ociate d diarr hea. Micr o b. Ec ol. 2 0 1 0; 5 9: 8 3 0- 8 3 7. 
 1 2 1.  H oc h ha us A, Ka ntarjia n H M, Baccara ni M et al. Dasati ni b i n d uces n ota bl e he mat ol o gic 
a n d c yt o ge netic res p o nses i n c hr o nic- p has e c hr o ni c m yel oi d le u ke mia aft er fail ure of 
i mati ni b t hera p y. Bl o o d 2 0 0 7; 1 0 9: 2 3 0 3- 2 3 0 9. 
 1 2 2.  Ha k LJ, Relli n g M V, C h e n g C et al. As para gi nase p har mac o d y n a mics differ b y 
f or m ulati o n a m o n g c hil dre n wit h ne wl y dia g n ose d ac ute l y m p h o blastic le u ke mia. 
Le u k e mia 2 0 0 4; 1 8: 1 0 7 2- 1 0 7 7. 
 1 2 3.  Le u n g W, I ye n gar R, Tri plett B et al. C o m paris o n of killer I g-li ke rece pt or ge n ot y pi n g a n d 
p he n ot y pi n g f or selecti o n of all o ge neic bl o o d ste m cell d o n ors. J.I m m u n ol. 
2 0 0 5; 1 7 4: 6 5 4 0- 6 5 4 5. 
 1 2 4.  Basser PJ, J o nes D K. Diff usi o n-te ns or M RI: t h e or y, e x peri me ntal desi g n a n d data a nal ysis 
- a tec h nic al re vie w. N M R Bi o me d. 2 0 0 2; 1 5: 4 5 6- 4 6 7. 
 1 2 5.  Le B D, M a n gi n J F, P o u p o n C et al. Diff usi o n te ns or i ma gi n g: c o nce pts a n d a p plicati o ns. 
J. Ma g n Res o n.I m a gi n g 2 0 0 1; 1 3: 5 3 4- 5 4 6. 
 1 2 6.  Ca m p bell L K, Sc a d ut o M, S har p W et al. A meta-a nal ysis of t he n e ur oc o g niti ve se q uel ae 
of treat me nt f or c hil d h o o d ac ute l y m p h oc ytic le u ke mia. Pe diatr. Bl o o d Ca n cer 2 0 0 7; 4 9: 6 5-
7 3. 
 1 2 7.  
M oles ki M. Ne ur o ps yc h ol o gical, n e ur oa n at o mical, a n d ne ur o p h ysi ol o gi cal c o nse q ue nces 
of C N S c he m ot hera p y f or ac ute l y m p h o blastic le u ke mia. Arc h. Cli n. Ne ur o ps yc h ol. 
2 0 0 0; 1 5: 6 0 3- 6 3 0. 
 1 2 8.  Be dell BJ, Nara ya n a P A. A ut o matic re m o val of e xtra me ni n geal tiss ues fr o m M R i ma ges 
of h u ma n brai n. J. Ma g n Res o n.I m a gi n g 1 9 9 6; 6: 9 3 9- 9 4 3. 
 1 2 9.  
M ul her n R K, Wasser ma n A L, Fair cl o u g h D, Oc hs J. Me m or y f u ncti o n i n disease-free 
s ur vi v ors of c hil d h o o d ac ute l y m p h oc ytic le u ke mia gi v e n C N S pr o p h yl a xis wit h or 
wit h o ut  1, 8 0 0 c G y cra nial irra diati o n. J. Cli n. O nc ol. 1 9 8 8; 6: 3 1 5- 3 2 0. 
 1 3 0.  
M ul her n R K, Ar mstr o n g F D, T h o m ps o n SJ. F u ncti o n-s pecific ne ur o ps yc h ol o gical 
assess me nt. Me d. Pe diatr. O nc ol. 1 9 9 8; S u p pl 1: 3 4- 4 0. 
 1 3 1.  Nat ha n P C, Patel S K, Dille y K et al. G ui deli nes f or i de ntificati o n of, a d v o cac y f or, a n d 
i nter ve nti o n i n ne ur oc o g niti ve pr o ble ms i n s ur vi v ors of c hil d h o o d ca n cer: a re p ort fr o m 
t he C hil dre n's O n c ol o g y Gr o u p. Arc h. Pe di atr. A d oles c. Me d. 2 0 0 7; 1 6 1: 7 9 8- 8 0 6. 
 1 3 2.  H oc ke n berr y M, Kr ull K, M o ore K et al. L o n git u di nal e val uati o n of fi ne m ot or s kills i n 
c hil dre n wit h le u ke mia. J. Pe diatr. He mat ol. O nc ol. 2 0 0 7; 2 9: 5 3 5- 5 3 9. 
 1 3 3.  
M ulle n E M. M ulle n Scales of Earl y Lear ni n g. Cir cle Pi nes, M N: A m erica n G ui da nce 
Ser vice; 1 9 9 2. 
 1 3 4.  B ur g u n d E D, Ka n g H C, Kell y J E et al. T he feasi bilit y of a c o m m o n stere otactic s pace f or 
c hil dre n a n d a d ults i n f M RI st u dies of de vel o p me nt. Ne ur oi ma ge. 2 0 0 2; 1 7: 1 8 4- 2 0 0. 
 1 3 5.  Ka n g H C, B ur g u n d E D, L u gar H M, Peters e n S E, Sc hla g gar B L. C o m paris o n of f u ncti o nal 
acti vati o n f oci i n c hil dre n a n d a d ults usi n g a c o m m o n stere otactic s pace. Ne ur oi ma ge. 
2 0 0 3; 1 9: 1 6- 2 8. 
 1 3 6.  C he n g C. Al m ost-s ure u nif or m err or b o u n ds of ge neral s m o ot h esti mat ors of q ua ntile 
de nsit y f u ncti o ns. Statistics & Pr o ba bilit y Letters 2 0 0 2; 5 9: 1 8 3- 1 9 4. 
 1 3 7.  Kal bfleisc h J D, Pre ntice R L. T he Statistical A nal ysis of Fail ure Ti me Data. H o b o ke n, NJ: 
J o h n Wile y & S o ns, I nc.; 2 0 0 2. 
 1 3 8.  Gra y, R. J. A class of K-sa m ple tests f or c o m pari n g t he c u m ulati ve i nci de nce of a 
c o m peti n g ris k. A n n Stat 1 6( 3), 1 1 4 1- 1 1 5 4. 1 9 8 8. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
P a ge 1 1 2  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 1 3 9.  Fi ne, J. P. a n d Gra y, R. J. A Pr o p orti o nal Hazar ds M o del f or t he S u b distri b uti o n of a 
C o m peti n g Ris k. J. A mer. Statistical Ass oc. 9 4( 4 4 6), 4 9 6- 5 0 9. 1 9 9 9. 
 1 4 0.  C he n g Q, Ya n g W, Rai m o n di S C et al. Kar y ot y pic a b n or malities create disc or da nce of 
ger mli ne ge n ot y pe a n d ca ncer cell p he n ot y pes. Nat. Ge net. 2 0 0 5; 3 7: 8 7 8- 8 8 2. 
 1 4 1.  C he n g C, P o u n ds S B, B o yett J M et al. Statistical si g nifica n ce t hr es h ol d crit eria f or 
a nal ysis of micr oarra y ge ne e x pressi o n data. Stat A p pl. Ge net. M ol. Bi ol. 2 0 0 4; 3: Article 3 6. 
 1 4 2.  P o u n ds S, C he n g C. R o b ust esti mati o n of t he false disc o ver y rate. Bi oi nf or matics. 
2 0 0 6; 2 2: 1 9 7 9- 1 9 8 7. 
 1 4 3.  Be nja mi ni Y, Kri e ger A M, Ye k utieli D. A da pti ve li near ste p- u p pr oce d ures t hat c o ntr ol 
t he false disc o ver y rat e. Bi o metri ka 2 0 0 6; 9 3: 4 9 1- 5 0 7. 
 1 4 4.  P o u n ds S, C he n g C. R o b ust esti mati o n of t he false disc o ver y rate. Bi oi nf or matics 
2 0 0 6; 2 2: 1 9 7 9- 1 9 8 7. 
 1 4 5.  P o u n ds S, C he n g C. Sa m ple siz e deter mi nati o n f or t he false disc o ver y rate. Bi oi nf or matics 
2 0 0 5; 2 1: 4 2 6 3- 4 2 7 1. 
 1 4 6.  C he n g C. Micr o arra y ge n e c o-e x pressi o n a n al ysis a n d vali dati o n b y a se q ue ntial cl usteri n g 
al g orit h m [a bstract]. J oi nt Statistical Meeti n gs of t he A merica n Statistical Ass ociati o n 
2 0 0 7; Salt La ke Cit y, U T: 
 1 4 7.  De Pa u w B, Wals h T, D o n nell y J et al. Re vise d Defi niti o ns of I n vasi ve F u n gal Dise ase 
fr o m t he E ur o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer/I n vasi ve F u n gal 
I nfecti o ns C o o perati ve Gr o u p a n d t he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases 
M yc os es St u d y Gr o u p ( E O R T C/ M S G) C o nse ns us Gr o u p. Cli nical I nfecti o us Diseases 
2 0 0 8; 4 6: 1 8 1 3- 1 8 2 1. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
A P P E N DI X I:  T R E A T M E N T/ E V A L U A TI O N C A L E N D A R S  
 
Re missi o n I n d ucti o n Pretreat me nt - See Pre- Pri nte d Or der s heets.  Offer e nr oll me nt f or i nstit uti o nal 
tiss ue ba n ki n g pr ot oc ol ( T B A N K). 
 
1  
L P , I T M H A, L V 
resc ue  
P R E D ( D E X f or 
E T P π ) 
V C R  
D A U N O §  
P E, C B C diff, Uric 
Aci d,  U A, C he m. 
1 8[ 1, 2, 3, 4, 8 ]  
2  
P R E D ( D E X 
f or E T Pπ ) 
P E, C B C diff, 
Uric Aci d, 
l ytes, Ca, P, 
M g,  
 
3  
P R E D ( D E X 
f or E T Pπ ) 
P E G -A S P  
P E, C B C diff, 
Uric Aci d, 
l ytes, Ca, P, 
M g,  
[ 6, 7]  
4  
L P, I T M H A( *), 
L V resc ue  
P R E D ( D E X f or 
E T P π ) 
P E, C B C diff, 
Uric Aci d, l ytes, 
Ca, P, M g  
C S F St u dies *  
5  
P R E D ( D E X f or 
E T P π ) 
P E, C B C diff, 
U R A, l ytes, Ca, P, 
M g  
bili, S G P T  
 
6  
P R E D ( D E X 
f or E T Pπ ) 
P E, C B C diff, 
U R A, l ytes, Ca, 
P, M g,  
 
 
7  
P R E D ( D E X 
f or E TP π ) 
C B C, diff, 
U R A, l ytes, 
Ca, P, M g  
 
 
 
 
8  
P R E D ( D E X f or 
E T P π ) 
V C R  
D A U N O §  
( *)I T M H A, L V 
resc ue 
M R D  
C S F St u dies *[ 3, 4]  
9  
P R E D ( D E X 
f or E T Pπ ) 
 
1 0  
P R E D ( D E X 
f or E T Pπ ) 
 
1 1  
P R E D ( D E X f or 
E T P π ) 
( *)I T M H A, L V 
resc ue 
C S F St u dies *  
1 2  
P R E D ( D E X f or 
E T P π ) 
C B C diff  
 
 
1 3  
P R E D ( D E X 
f or E T Pπ ) 
 
 
 
1 4  
P R E D ( D E X 
f or E T Pπ ) 
 
 
 
1 5  
L P, I T M H A, L V 
resc ue  
† B M  
P R E D ( D E X f or 
E T P π ) 
V C R  
() P E G-A S P  
T M P -S M Z  
M R D  
C S F St u dies * [ 3, 4, 
5]  
1 6  
P R E D ( D E X 
f or E T Pπ ) 
T M P -S M Z  
1 7  
P R E D ( D E X 
f or E T Pπ ) 
T M P -S M Z  
 
1 8  
P R E D ( D E X f or 
E T P π ) 
 
1 9  
P R E D ( D E X f or 
E T P π ) 
C B C diff  
 
2 0  
P R E D ( D E X 
f or E T Pπ ) 
 
2 1  
P R E D ( D E X 
f or E T Pπ ) 
 
 
2 2  
† B M  
( *)I T M H A, L V 
resc ue  
P R E D ( D E X f or 
E T P π ) 
V C R  
C Y C L O ( ) 
T G ( 6 M P f or 
H E T/ deficie nc y) ∞ 
Cl o/ C y/ V P ( ) 
‡ D as ati ni b  
T M P -S M Z  
C S F St u dies *  
M R D  
2 3  
P R E D ( D E X 
f or E T Pπ ) 
A R A -C  
T G ( 6 M P f or 
H E T/ defici e n
c y)  
C Y C L O ( ) 
Cl o/ C y/ V P 
() 
‡ D as ati ni b  
T M P -S M Z  
 
 
2 4  
P R E D ( D E X 
f or E T Pπ ) 
A R A -C  
T G ( 6 M P f or 
H E T/ deficie n
c y)  
Cl o/ C y/ V P 
() 
‡ D as ati ni b  
T M P -S M Z  
 
 
2 5  
P R E D ( D E X f or 
E T P π ) 
A R A -C  
T G ( 6 M P f or 
H E T/ deficie nc y)  
Cl o/ C y/ V P ( ) 
‡ D as ati ni b  
 
 
 
2 6  
P R E D ( D E X f or 
E T P π ) 
A R A -C   
T G ( 6 M P f or 
H E T/ deficie nc y)  
Cl o/ C y/ V P ( ) 
‡ D as ati ni b  
C B C diff  
2 7  
P R E D ( D E X 
f or E T Pπ ) 
T G ( 6 M P f or 
H E T/ deficie nc
y)  
‡ D as ati ni b  
2 8  
P R E D ( D E X 
f or E T Pπ ) 
T G ( 6 M P f or 
H E T/ deficie
nc y)  
‡ D as ati ni b  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
2 9  
St o p Pre d nis o ne 
(st o p De x f or 
E T P)  
T G ( 6 M P f or 
H E T/ deficie nc y)  
‡ D as ati ni b  
T M P -S M Z  
3 0  
A R A -C  
T G ( 6 M P f or 
H E T/ deficie n
c y)  
‡ D as ati ni b  
T M P -S M Z  
 
3 1  
A R A -C  
T G ( 6 M P f or 
H E T/ deficie n
c y  
‡ D as ati ni b  
T M P -S M Z  
 
3 2  
A R A -C  
T G ( 6 M P f or 
H E T/ deficie nc y)  
‡ D as ati ni b  
3 3  
A R A -C  
T G ( 6 M P f or 
H E T/ deficie nc y)  
‡ D as ati ni b  
C B C diff, bili, 2 4 -
h o ur uri ne, S p ot 
uri ne  
3 4  
T G ( 6 M P f or 
H E T/ deficie nc
y)  
‡ D as ati ni b  
3 5  
T G ( 6 M P f or 
H E T/ deficie
nc y)  
‡ D as ati ni b  
3 6  
‡ D as ati ni b  
T M P -S M Z  
 
 
3 7  
‡ D as ati ni b  
T M P -S M Z  
 
3 8  
‡ D as ati ni b  
T M P -S M Z  
 
3 9  
‡ D as ati ni b  
4 0  
‡ D as ati ni b  
C B C diff  
 
4 1  
‡ D as ati ni b  
 
4 2  
‡ D as ati ni b  
† B M (see 
c o ns oli dati o n 
cale n dar)  
M R D  
 
N otes: 
* I T met h otre xate + h y dr oc ortis o ne + c ytara bi ne (I T M H A) all partici pa nts Da y 1 a n d 1 5; ( *) P artici pa nts wit h t he 
f oll o wi n g feat ures will recei ve d a d diti o nal tri ple i ntrat hecal treat me nt o n da ys 8 a n d 2 2: W B C > 1 0 0 x 1 0 9/ L at 
prese ntati o n, Prese nce of P hil a d el p hia c hr o m os o me, M L L  re arra n ge me nt or h y p o di pl oi d y.  P artici pa nts wit h t he 
f oll o wi n g feat ures will recei ve a d diti o nal tri ple i ntrat hecal tr eat me nt o n da ys 4, 8, 1 1, a n d 2 2:  T-cell A L L, t 
( 1; 1 9)/E 2 A- P B X 1,  C N S- 3 stat us (i.e., > 5 W B C/L of C S F wit h blasts or cra nial ner ve pals y, C N S- 2 stat us ( < 
5 W B C/ L C S F wit h blasts, or tra u matic stat us ( > 1 0 R B C/ L of C S F wit h blasts.  Le uc o v ori n resc ue ( 5 m g/ m 2/ d ose) 
P O will be gi ve n at 2 4 a n d 3 0 h o urs after eac h tri ple i ntrat he cal treat me nt d uri n g i n d ucti o n.  F oll o w plas ma 
met h otre xate le vels (starti n g 2 4 h o urs after I T t hera p y a n d u ntil le vels bec o me u n detecta ble) i n patie nts wit h re nal 
d ysf u ncti o n or e xtra fl ui d i n t hir d s pace, a n d resc ue wit h le uc o v ori n acc or di n g t o P har m D r ec o m me n dati o n.  C S F 
St u dies t o be d o ne wit h eac h I T M H A treat me nt. 
§    First d ose of Da u n or u bici n ma y be dela ye d t o da y 2 i n patie nts wit h or at hi g h ris k of t u m or l ysis s y n dr o me.  Sec o n d 
d ose of da u n or u bici n c o ul d be dela ye d u p t o o ne wee k if cli nicall y i n dicate d. 
 Sec o n d d ose of P E G-as para gi nase t o be gi ve n as s o o n as M R D >/ = 1 % is c o nfir me d a n d n o later t ha n da y 2 1. 
 P artici pa nts wit h Da y 1 5 M R D < 5 %, will recei ve c ycl o p h os p ha mi de 1 0 0 0 m g/ m2 I V Da y 2 2 f or 1 d ose; P artici pa nts 
wit h Da y 1 5 M R D > 5 % (e xcl u di n g M L L + I nfa nts) will rec ei ve c ycl o p h os p ha mi de 3 0 0 m g/ m 2 e ver y 1 2 h o urs o n Da ys 
2 2 - 2 3 f or a t otal of 4 d oses. 
 
Cl ofara bi ne/c ycl o p h os p ha mi de/et o p osi de i n M L L + I nfa nts o nl y. M L L + I nfa nts will c o nti n ue pre d nis o ne b ut will n ot 
recei ve da y 2 2 vi ncristi ne, t hi o g ua ni ne, or c ytara bi ne i n i n d ucti o n. 
† 
All b o ne marr o w sa m ples f or M R D; B M E val uati o ns re q uir e d o n Da y 1 5, 2 2, a n d E n d of I n d ucti o n ( Da y 3 8- 4 2)  
‡ 
P hila del p hia p ositi ve ( P h +) partici pa nts o nl y 
π 
De xa met has o ne f or E T P i m m u n o p he n ot y pe o nl y.  See Secti o n 5. 2. 1, 1 0 m g/ m 2 P O da ys 1- 2 1, 4 m g/ m2 da ys 2 2- 2 4, a n d 
2 m g/ m 2 P O da ys 2 5-2 8  
∞ T P M T H E T/ deficie nt p atie nts will recei ve merca pt o p uri ne as per T O T X V d uri n g i n d ucti o n i nstea d of t hi o g ua ni ne.  
W T patie nts will recei ve T G, b ut will be cl osel y m o nit ore d f or si g ns or s y m pt o ms of V O D. 
 
S pecial st u dies: 
 
( 1) C B C wit h diff re q uire d dail y f or first 7 da ys, a n d t he n at least wee kl y ( 2) bl o o d c he mistries ( C h e m 
1 8 pr ofile) ( 3) bl o o d f or as para gi nase ( o btai n pre- aspara gi nase, d a y 8, da y 1 5, a n d 2- 3 a d diti o nal 
sa m ples after first d ose b ut bef ore a n y 2 n d d ose  ( 4) C S F As para gi n e – Secti o n 1 0. 3 c ollecte d pri or t o 
IT M H A treat me nts o n D a y 1 a n d 1 5 (a n d 8 if a p plica ble). A d diti o nal sa m ple re q uire d o n d a y of 
dia g n osis of sa gital si n us t hr o m b osis or D V T ( 5) Ser u m bi o mar kers, (e. g.., ser u m li pi ds a n d c ortis ol) 
( 6) bl o o d f or D N A ( % _ D N A sa m ple) ( 7) Re d Bl o o d cell T hi o p uri ne c o n ce ntrati o n – Secti o ns 8. 0 a n d 
1 0. 2.  ( 8) Q C T f or b o n e de nsit y   
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
M R D st u dies: 
 
S a m ples re q uire d f or M R D st u dies d uri n g re missi o n i n d ucti o n  
Ti me p oi nt  
B -li nea ge A L L 
T -li nea ge A L L 
  Da y 8  
P B  
P B  
  Da y 1 5  
B M  
B M a n d P B  
 ( Da y 2 2 if M R D+  o n Da y 1 5)  
B M  
B M a n d P B  
  Da y 4 3  
B M  
B M a n d P B  
P B; peri p heral bl o o d; B M: b o ne marr o w 
 
C o ns oli dati o n 
 
E n d of I n d ucti o n- M R D res p o nse: B M as pir ate will be perf or m e d ar o u n d d a y 3 8- 4 2 of re missi o n 
i n d ucti o n w he n A N C has rec o vere d t o > 3 0 0/ m m3 a n d platelet c o u nt t o > 5 0 x 1 09/ L.  If t he dat e falls 
o n a wee k-e n d or h oli da y, t he pr oce d ure ma y b e p erf or me d o n t h e cl osest w or ki n g d a y.  M R D le vel 
will be deter mi ne d i n t his b o ne marr o w s a m ple.  P o or res p o nse will be defi ne d as M R D le vel  0. 0 1 % 
ly m p h o blasts b y eit her i m m u n ol o gic or m olec ular assa y.  If b ot h assa ys are u ns uccessf ul or t he 
sa m ple is i na de q uate, t he M R D will be ass u me d t o be ne gati ve.  If t he res ult s h o ul d bec o me a vaila ble 
later a n d discl ose a le vel  0. 0 1 %, t he pr o visi o nal l o w-ris k case will t he n be classifie d as sta n d ar d-ris k 
or hi g h-ris k acc or di n gl y, a n d will recei v e s u bse q ue nt H D M T X at a hi g h er d osa ge (i.e., 5 g m/ m 2). 
 
1  
* I T M H A, L V resc ue 
H D M T X # 1  
6 M P  
‡ D as ati ni b  
C B C diff, [ 1, 2, 3, 4, 5, 6] 
2  
6 M P,  
‡ D as ati ni b  
3  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
4  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
5  
6 M P  
‡ D as ati ni b  
6  
6 M P  
‡ D as ati ni b  
7  
6 M P  
‡ D as ati ni b  
8  
6 M P  
‡ D as ati ni b  
C B C diff  
9  
6 M P  
‡ D as ati ni b  
1 0  
6 M P  
‡ D as ati ni b  
1 1  
6 M P  
‡ D as ati ni b  
1 2  
6 M P  
‡ D as ati ni b  
1 3  
6 M P  
‡ D as ati ni b  
1 4  
6 M P  
‡ D as ati ni b  
1 5  
*I T M H A, L V  
H D M T X # 2  
6 M P  
‡ D as ati ni b  
C B C, diff,  [ 2, 3, 7] 
1 6  
6 M P  
‡ D as ati ni b  
1 7  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
1 8  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
1 9  
6 M P  
‡ D as ati ni b  
2 0  
6 M P  
‡ D as ati ni b  
2 1  
6 M P  
‡ D as at i ni b  
2 2  
6 M P  
‡ D as ati ni b  
C B C, diff  
2 3  
6 M P  
‡ D as ati ni b  
2 4  
6 M P  
‡ D as ati ni b  
2 5  
6 M P  
‡ D as ati ni b  
2 6  
6 M P  
‡ D as ati ni b  
2 7  
6 M P  
‡ D as ati ni b  
2 8  
6 M P  
‡ D as ati ni b  
2 9  
*I T M H A, L V resc ue  
H D M T X # 3  
6 M P  
‡ D as ati ni b  
C B C, diff,[ 1, 2, 3]  
3 0  
6 M P  
‡ D as ati ni b  
3 1  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
3 2  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
3 3  
6 M P  
‡ D as ati ni b  
3 4  
6 M P  
‡ D as ati ni b  
3 5  
6 M P  
‡ D as ati ni b  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
3 6  
6 M P  
‡ D as ati ni b  
C B C, diff,  
3 7  
6 M P  
‡ D as ati ni b  
3 8  
6 M P  
‡ D as ati ni b  
3 9  
6 M P  
‡ D as ati ni b  
4 0  
6 M P  
‡ D as ati ni b  
4 1  
6 M P  
‡ D as ati ni b  
4 2  
6 M P  
‡ D as ati ni b  
4 3  
*I T M H A, L V resc ue  
H D M T X # 4  
6 M P  
‡ D as ati ni b  
C B C, diff [ 1, 2, 3]  
4 4  
6 M P  
‡ D as ati ni b  
4 5  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
4 6  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
4 7  
6 M P  
‡ D as ati ni b  
4 8  
6 M P  
‡ D as ati ni b  
4 9  
6 M P  
‡ D as ati ni b  
5 0  
6 M P  
‡ D as ati ni b  
C B C, diff  
5 1  
6 M P  
‡ D as ati ni b  
5 2  
6 M P  
‡ D as ati ni b  
5 3  
6 M P  
‡ D as ati ni b  
5 4  
6 M P  
‡ D as a ti ni b 
5 5  
6 M P  
‡ D as ati ni b  
5 6  
6 M P  
‡ D as ati ni b  
 
N otes: 
*I T met h otrex ate + hy dr oc ortis o ne + cyt ar a bi ne, t o be give n o n d ays 1, 1 5, 2 9, a n d 4 3; I T t her a py s h o ul d be 
give n o n s a me d ay as H D M T X a d mi nistr ati o n (c o ns ult PI or P K if t he I T a n d H D M T X bec o me se p ar ate d by 
m ore t h a n 1 2 h o urs. 
‡  O nly P h + p atie nts 
P hysic al Ex a m every 3- 7 d ays d uri n g C o ns oli d ati o n.  C B C wit h differe nti al nee de d weekly.   
 
S pecial st u dies:  
 
( 1) bl o o d c he mistries ( C he m 1 8 pr ofile); ( 2) C S F St u dies wit h eac h I T M H A ( 3) H D M T X 
P har mac o ki netics – Secti o n 1 0. 1 ( 4) ger mli ne D N A/ R N A ( o btai n sa m ple at re missi o n, bef ore first a n d 
t hir d H D M T X); ( 5) As p ara gi nase A nti b o dies/ Acti vit y – Secti o n 1 0. 3, ser u m a n d plas ma o btai ne d o n 
da ys 1 c o ns oli dati o n ( 6) C S F As para gi ne – d a y 1 c o ns oli dati o n ( 7) Ser u m bi o mar k ers (e. g. li pi ds, 
cortis ol) – Da y 1 5 c o ns oli dati o n  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T R E A T M E N T S C H E M A a n d s pecial la b orat or y tests d uri n g c o nti n uati o n t hera p y 
 
Sta n dar d/ Hi g h Ris k  
L o w Ris k  
 
W ee k  
 
S pecial 
St u dies  
 
S pecial 
St u dies  
 1  
D E X + D O X O + V C R + 6 M P + 
P E G -A S P + ‡ Dasati ni b  
 
6 M P + D E X  + V C R  
 
 2  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
 3  
( *) 6 M P + P E G-A S P + 
‡ Dasati ni b  
 
( *) 6 M P + M T X 
 
 4  
D E X + D O X + V C R + 6 M P + 
‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
 5  
 6 M P + P E G - A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
 6  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
 7  
*( †) Rei n d ucti o n I  
( D E X + D O XO + V C R + P E G -
A S P + ‡ Dasati ni b)  
[ 1, 2, 4, 5, 
6, 7, 8, 9, 
1 0, 1 1]  
*( †) Rei n d ucti o n I  
( D E X + V C R + D O X O + P E G-As p)  
[ 1, 2, 4, 5, 6, 9, 
1 0, 1 1]  
 8  
Rei n d ucti o n I  
( D O X O + V C R ‡ Dasati ni b) 
[ 1, 4, 6, 
1 3, 1 4, 
1 5]  
Rei n d ucti o n I  
( V C R) 
[ 1, 4, 6, ] 
 9  
Rei n d ucti o n I  
(D E X + V C R + P E G -
A S P + ‡ Dasati ni b)  
[ 1, 4] 
Rei n d ucti o n I  
( D E X + V C R + P E G-A S P)  
[ 1, 4] 
1 0  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1  
D O X + V C R + 6 M P + P E G -
A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 2  
* 6 M P + ‡ Dasati ni b  
[ 8] 
* 6 M P + M T X  
[ 8] 
1 3  
6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 4  
D E X + D O X + V C R + 6 M P + 
‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
1 5  
 6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 6  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 7  
*( †) Rei n d ucti o n II  
 ( D E X + V C R + P E G-
A S P + ‡ Dasati ni b)  
[ 1, 3, 4, 6, 
1 1 ] 
*( †) Rei n d ucti o n II  
( D E X + V C R + P E G-A S P)  
[ 1, 3, 4, 6, 1 1 ] 
1 8  
Rei n d ucti o n II  
 ( V C R + ‡ Dasati ni b) 
 
Rei n d ucti o n II  
( V C R) 
 
1 9  
Rei n d ucti o n II  
( D E X + V C R + H D Ara-C + 
P E G -A S P + ‡ Dasati ni b)  
[ 1, 4] 
Rei n d ucti o n II  
( D E X + V C R + P E G-A S P)  
[ 1, 4] 
2 0  
‡ Dasati ni b  
 
6 M P + M T X  
 
2 1  
6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 2  
6 M P + ‡ Dasati ni b  
[ 8] 
6 M P + M T X  
[ 8] 
2 3  
6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 4  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 5  
* D E X + V C R + P E G -A S P + 
Dasati ni b  
 
* 6 M P + D E X + V C R  
 
2 6  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 7  
6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 8  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 9  
* D E X + V C R + P E G -
A S P + ‡ Dasati ni b  
 
( *) 6 M P + D E X + V C R 
 
3 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 2  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
Sta n dar d/ Hi g h Ris k  
L o w Ris k  
 
W ee k  
 
S pecial 
St u dies  
 
S pecial 
St u dies  
3 3  
* D E X + V C R + ‡ Dasati ni b  
 
* 6 M P + D E X + V C R  
 
3 4  
6 M P + M T X + ‡ D asati ni b  
 
6 M P + M T X  
 
3 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 6  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 7  
* D E X + V C R + ‡ Dasati ni b  
 
( *) 6 M P + D E X + V C R 
 
3 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 0  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 1  
* D E X + V C R + ‡ Dasati ni b  
 
* 6 M P + D E X + V C R  
 
4 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 4  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 5  
* D E X + V C R + ‡ Dasati ni b  
 
( *) 6 M P + D E X + V C R 
 
4 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 7  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 8  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 9  
*( †) D E X + V C R + ‡ Dasati ni b  
 
* 6 M P + D E X + V C R  
 
5 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 2  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 3  
D E X + V C R + ‡ Dasa ti ni b 
 
6 M P + D E X + V C R  
 
5 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 6  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 7  
( *) D E X + V C R + ‡ Dasati ni b 
 
6 M P + D E X + V C R  
 
5 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 0  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 1  
D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
6 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 4  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 5  
( *)D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
6 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 7  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 8  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 9  
D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
7 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 3  
( *) 6 M P + D E X + 
V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
7 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 7  
6 M P + D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
7 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 1  
( *)6 M P + D E X + 
V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
Sta n dar d/ Hi g h Ris k  
L o w Ris k  
 
W ee k  
 
S pecial 
St u dies  
 
S pecial 
St u dies  
8 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 5  
6 M P + D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
8 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 7  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 9  
( *) 6 M P + D E X + 
V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
9 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 3  
6 M P + D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
9 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 7  
( *)6 M P + D E X + 
V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
9 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 1  
6 M P + D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
1 0 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 5  
6 M P + M T X ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 7  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 9  
6 M P + M T X ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 7  
6 M P + M T X ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 2 0  
† 6 M P + M T X + ‡ Dasati ni b  
[ 7, 8, 9, 
1 0 ] 
6 M P + M T X  
[ 7, 8, 9, 1 0 ] 
N otes:  
*I T met h otrex ate + h y dr oc ortis o ne + cyt ar a bi ne: 
 ( *) Tri ple i ntr at hec al tre at me nt will be give n t o l o w-risk c ases wit h C N S- 1 st at us ( n o i de ntifi a ble bl asts i n C S F) o n 
weeks 7, 1 2, 1 7, 2 5, 3 3, 4 1, a n d 4 9. 
 Tri ple i ntr at hec al tre at me nt will be give n t o l o w-risk c ases wit h C N S- 2, tr a u m atic C S F wit h bl asts st at us, or W B C  
1 0 0 x 1 0 9/ L o n weeks 3, 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5 a n d 4 9. 
 Tri ple i ntr at hec al tre at me nt will be give n t o st a n d ar d/ hi g h-risk c ases o n weeks 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5 a n d 4 9. 
 Tri ple i ntr at hec al tre at me nt will be give n t o ot her st a n d ar d/ hi g h-risk c ases wit h W B C 1 0 0 x 1 0 9/ L, T-cell A L L, , t 
( 1; 1 9)/ E 2 A- P B X 1, prese nce of P hil a del p hi a c hr o m os o me, M L L re arr a n ge me nt, hy p o di pl oi dy < 4 4, C N S- 2 or C N S-3 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
st at us, or tr a u m atic l u m b ar p u nct ure wit h bl asts o n weeks 3, 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5, 4 9, 5 7, 6 5, 7 3, 8 1, 8 9 a n d 
9 7.  
 S urveill a nce cere br os pi n al fl ui d ex a mi n ati o n wit h e ac h I T M H A a n d t he n a p pr oxi m ately every 1 6 weeks. 
 
† B o ne m arr o w ex a mi n ati o n; s a m ple f or M R D ( See Secti o n 1 1. 2) 
C B C wit h differe nti al is nee de d weekly, p hysic a n ex a m every 4 weeks, a n d c he mistries as cli nic ally i n dic ate d.  
D uri n g Re-I n d ucti o ns I a n d II: P E re q uire d every 3- 7 d ays, C B C weekly, c he m 1 8 o n D ay 1 Weeks 7, 8, 9, 
1 7. 1 9 
‡ O nly P h + p atie nts 
S urveill a nce cere br os pi n al fl ui d ex a mi n ati o n 
 
S pecial st u dies:   
 
1) Bl o o d c he mistries ( C he m 1 8) ( 2) R B C T G N – Da y 1 Wee k 7 ( 3) R B C T P M T – Da y 1 wee k 1 7 ( 4) 
As para gi nase A nti b o dies/ Acti vit y – Da y 1 Wee k 7, 8, 9, 1 7, a n d 1 9.  ( 5) C S F As para gi ne – Da y 1 Wee k 7 ( 6) 
Ser u m bi o mar kers (e. g. li pi ds, c ortis ol) – Wee k 7, 8, a n d 1 7.  ( 7) Q C T f or b o ne de nsit y – Wee k 1 2 0.  ( 8) M RI 
hi ps/ k nees a n d P T/ O T e val uati o n ( partici pa nts > 9 years of a ge) –  After eac h Re-I n d ucti o n ( wee ks 1 2- 1 4 a n d 
2 2- 2 4, a n d Wee k 1 2 0 or later), ( 9) Ps yc h ol o gical Testi n g, ( 1 0) M RI Brai n.   M R s h o ul d be ac q uire d bef ore 
D E X.  Partici pa nts wit h a b n or mal i ma gi n g e val uati o ns at wee k 1 2 0 will ha ve a n e xtra e xa m at 2 years off 
t hera p y t o reassess brai n str uct ure. ( 1 1) Plas ma f or meas ure me nt of de xa met has o ne c o nce ntrati o ns t o be 
o btai ne d wit h Da y 8 la bs d uri n g Rei n d ucti o ns I a n d II ( wee ks 7 a n d 1 7).  
 
Sa m ples re q uire d f or M R D st u dies p ost-re missi o n i n d ucti o n 
Ti me p oi nt  
B -li nea ge A L L 
T -li nea ge A L L 
Da y 4 3 
M R D +  
Da y 4 3 
M R D - 
Da y 4 3 
M R D + ( or 
“at y pical” T -
A L L)  
Da y 4 3 
M R D - 
Da y 1 ( Wee ks 7, 1 7, 4 9)  
B M  
N o ne  u nless 
cli nicall y 
i n dicate d or 
M L L +  
B M a n d P B  
P B  
Wee k 1 2 0 ( off t hera p y)  
B M  
B M  
B M  a n d P B 
B M a n d P B  
P B; peri p heral bl o o d; B M: b o ne marr o w   
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X II: D R U G I N F O R M A TI O N 
 
1.  
P R E D NI S O N E, P R E D NI S O L O N E 
 
S o urce a n d p h ar mac ol o g y: Pre d nis o ne is a s y nt hetic c o n ge ner of h y dr oc ortis o ne, t he nat ural a dre n al 
h or m o ne.  Pre d nis o ne is a w hite or yell o wis h cr ystalli ne p o w der.  It bi n ds wit h ster oi d rece pt ors o n 
n uclear me m bra nes, i m p airs cell ular mit osis a n d i n hi bits pr otei n s y nt h esis.  Pre d nis o ne als o has p ote nt 
anti-i nfla m mat or y effects a n d s u p presses t he i m m u ne s yste m. Pre d nis o ne is well a bs or be d orall y.  It is 
c o n verte d t o pr e d nis ol o ne, t he p har mac ol o gicall y acti ve meta b olite, i n t he li ver.  Pre d nis ol o ne is 
f urt her meta b olize d t o i nacti ve c o m p o u n ds i n t he li ver. T he meta b olites are e x crete d mai nl y i n t he 
uri ne. 
 
F or m ulati o n a n d sta bilit y: Pre d nis o ne is a vaila ble as vari o us stre n gt h ta blets a n d oral s ol uti o n fr o m 
m ulti ple ma n ufact urers. All d osa ge f or ms c a n be st ore d at r o o m te m perat ure. At St. J u de C hil dre n’ s 
Researc h H os pital, pre d nis ol o ne oral s ol uti o n ma y be s u bstit ute d f or pre d nis o ne li q ui d at e q ual d oses 
d ue t o its s u peri or palata bilit y. 
 
S u p plier: c o m merciall y a vaila ble 
 
T o xicit y: Si de effects of pre d nis o ne var y de pe n di n g o n t he d urati o n of its use. Si de effects t hat ca n 
occ ur wit h s h ort ter m use i ncl u de s o di u m a n d water rete nti o n wit h ass ociat e d h y perte nsi o n, pe ptic 
ulcer wit h p ossi ble perf orati o n a n d he m orr h a ge, i ncreas e d s usce pti bilit y t o i nfecti o ns, e m oti o nal 
i nsta bilit y, i ns o m nia, i ncrease d a p p etite, wei g ht gai n, ac ne a n d h y p er gl yce mia. Si de effects m ore 
c o m m o nl y ass oci ate d wit h pr ol o n ge d use i ncl u de cataracts, i ncrease d i ntra oc ular press ure a n d 
ass ociate d gla u c o ma, de v el o p me nt of a “c us hi n g oi d” state, c o m pr essi o n fract ures, me nstr ual 
irre g ularities, s u p pressi o n of gr o wt h i n c hil dre n, s ec o n dar y a dre n oc ortical a n d pit uitar y 
u nres p o nsi ve ness partic ularl y i n ti mes of stress as i n tra u ma, s ur ger y or ill ness, oste o p or osis a n d 
m uscle wasti n g. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
2.  
V I N C RI S TI N E ( O n c o vi n) 
 
S o urce a n d p h ar mac ol o g y:  Vi ncristi ne is a n al kal oi d o btai ne d fr o m t he peri wi n kle ( Vi n c a r ose a) 
pla nt.  It r e versi bl y bi n ds t o micr ot u b ule a n d s pi n dle pr otei ns ca usi n g meta p hase arrest. Vi ncristi ne 
has p o or pe netrati o n i nt o t he C S F.  It is a p pr o xi matel y 7 5 % pr otei n b o u n d. E xte nsi ve meta b olis m 
occ u rs i n t he li ver. E x creti o n is pri maril y i n t he bile. A d osa ge d ecrease is r ec o m me n de d i n patie nts 
wit h ele vate d bilir u bi n (s ee secti o n 7. 3) 
 
F or m ulati o n a n d sta bilit y: Vi ncristi ne is s u p plie d i n m ulti ple- d ose 1 m g/ ml vials c o ntai ni n g 1 ml, 2 ml 
a n d 5 ml. T he i ntact vials s h o ul d be st ore d u n der refri gerati o n a n d pr otecte d fr o m li g ht. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y: D ose li miti n g t o xicit y is ne ur ot o xicit y.  T his ca n be c h aracterize d b y c o nsti pati o n a n d/ or 
paral ytic ile us, pt osis, v ocal c or d paral ysis, wea k n ess, ja w pai n, a b d o mi nal pai n, peri p heral 
ne ur o pat hies, l oss of dee p te n d o n refle x es a n d “f o ot dr o p”. Peri p heral ne ur o pat h y is ofte n t h e first 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
si g n of ne ur ot o xicit y a n d is i nitiall y re versi ble.  Ot her t o xicities re p orte d i ncl u de al o pecia, mil d 
na usea a n d v o miti n g, SI A D H, m yel os u p pressi o n, ort h ostatic h y p ote nsi o n, o ptic atr o p h y, tra nsie nt 
c ortical bli n d ness, a n d a u dit or y da ma ge.  Ac ut e s h ort ness of breat h a n d se v ere br o nc h os pas ms has 
be e n re p orte d f oll o wi n g t he a d mi nistrati o n of vi nca al kal oi ds.  M yel os u p pressi o n is rare at us ual 
d ose s.  Vi ncristi ne is a vesica nt a n d ma y ca use se v ere tiss ue da ma ge if e xtra vasati o n occ urs. N O T E:  
d ose re d ucti o n ma y b e necessar y i n patie nts < 1 year of a ge, or < 1 0 k g wei g ht. D osi n g o n a p er k g 
(rat her t h a n per m2) basis has bee n a d v ocate d f or i nfa nts i n or der t o decreas e t o xicit y. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
3.  
D A U N O R U BI CI N ( Da u n o m yci n, Cer u bi di ne ) 
 
S o urce a n d p h ar mac ol o g y:  Da u n or u bici n is a n a nt hrac ycli ne a nti bi otic deri ve d fr o m Stre pt o myces 
c oer ule or u bi d us . Da u n or u bici n i ntercalates b et wee n base pairs of D N A ca usi n g steric o bstr ucti o n, 
disr u pti o n of D N A f u ncti o n a n d i n hi biti o n of R N A s y nt hesis.  I n a d diti o n, da u n or u bici n i n hi bits 
t o p ois o merase II, a n e nz y m e res p o nsi ble f or all o wi n g stra n ds of D N A t o pass t hr o u g h o n e a n ot her as 
t hey u n wi n d.  E v e n t h o u g h da u n or u bici n e xerts its maj or effects i n t he S p hase, it is c o nsi dere d t o b e 
cell c ycle p h ase n o n-s p ecific.  Da u n or u bici n is wi del y distri b ute d i n tiss ues b ut d oes n ot cr oss t he 
bl o o d brai n barrier.  It is meta b olize d t o da u n or u bici n ol, w hic h is t he maj or acti ve meta b olite a n d 
agl yc o nes (i nacti ve). T h e maj or r o ute of eli mi nati o n is t hr o u g h t he bile ( 4 0 %) wit h a d diti o nal 
eli mi nati o n t hr o u g h t he uri ne.  D osa ges s h o ul d be re d uce d i n p atie nts wit h li ver d ysf u ncti o n (as i n 
secti o n 7. 3) or re nal d ysf u ncti o n (creati ni ne > 3 m g/ d L). 
 
F or m ulati o n a n d sta bilit y:  Da u n or u bici n is s u p plie d i n vials c o ntai ni n g 2 0 m g of re d dis h c ol ore d 
l y o p hiliz e d p o w der a n d 1 0 0 m g of ma n nit ol.  T he i ntact vials s h o ul d be st ore d at r o o m te m perat ure. 
Eac h vial ca n be rec o nstit ute d wit h 4 ml of sterile water f or i njecti o n t o gi v e a fi nal c o nce ntr ati o n of 5 
m g/ ml.  Rec o nstit ute d s ol uti o ns are sta ble f or 2 4 h o urs at r o o m te m perat ure a n d 4 8 h o urs if 
refri gerate d. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y: D ose-li miti n g t o xicities of da u n or u bici n i ncl u de m yel os u p pressi o n a n d car di ot o xicit y. T w o 
f or ms of car diac t o xicit y ca n occ ur. Ac ut e t o xicit y ma y ta ke t he f or m of arr h yt h mias, heart bl oc k or 
pe ricar ditis a n d ma y b e fatal. T he c hr o nic f or m of   car di ot o xicit y is r elate d t o t otal c u m ulati ve d ose 
a n d is c haracteriz e d b y h eart fail ure. Me diasti nal ra di ot hera p y a n d/ or ot her car di ot o xic dr u gs ma y 
i ncreas e t he ris k of car di ot o xicit y.  I n ge n eral, t ot al lifeti me d osa ges of 4 5 0- 5 5 0 m g/ m2 s h o uld n ot be 
e x cee de d. Ot her t o xicities i ncl u de na usea a n d v o miti n g, m uc ositis, al o pecia, diarr hea a n d re d 
disc ol orati o n of t he uri ne a n d ot her b o d y fl ui ds. Se vere tiss ue da ma ge a n d necr osis ca n o cc ur u p o n 
e xtra vasati o n.  Ra diati o n recall reacti o ns ca n occ ur a n d ca n b e se vere.  Rarel y, aller gi c reacti o ns ha v e 
occ urre d.  T y p hlitis ca n occ ur w h e n c o m bi ne d wit h c ytara bi ne. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
4.  
P E G - L- A S P A R A GI N A S E ( Pe gas par gase, O ncas p ar) 
 
S o urce a n d p h ar mac ol o g y:  P E G-as p ara gi n ase is a m o difie d versi o n of t he e nz y me, L- as para gi nase.  
L- as para gi nase is m o difi e d b y c o vale ntl y c o nj u gati n g u nits of p ol yet h yl e n e gl yc ol ( P E G) t o t he 
e nz y me.   T he as par a gi nase use d i n t he ma n ufact uri n g of P E G-as para gi nase is deri ve d fr o m 
Esc heric hi a c oli.  As para gi nase h y dr ol yzes s er u m as para gi n e (a n a mi n o aci d re q uire d t o s y nt hesize 
pr otei ns a n d D N A) t o as partic aci d a n d a m m o nia, a n d is t heref ore let hal t o cells t hat ca n n ot s y nt hesi ze 
as para gi n e.  As para gi nas e is acti ve d uri n g all p has es of t he cell c ycle. As p ara gi nase is n ot a bs or b e d 
fr o m t he GI tr act a n d m ust be gi ve n p are nt erall y.  P E G- as para gi nase h as a plas ma half-life of 
ap pr o xi matel y 6 da ys, b ut is meas ura ble f or at least 1 5 da ys f oll o wi n g t he i nitial treat me nt.  It ca n n ot 
be detect e d i n t he uri ne. 
 
F or m ulati o n a n d sta bilit y:  P E G-as para gi n ase is a v aila ble i n si n gle- use vials c o ntai ni n g 5 ml of P E G-
as para gi n ase as a cle ar s ol uti o n.  Eac h vial c o ntai ns 3 7 5 0 u nits of dr u g at a c o nce ntr ati o n of 7 5 0 
u nits/ ml.  T he i ntact vials s h o ul d be st ore d u n der refri gerati o n. Freezi n g d estr o ys its acti vit y, w hic h 
ca n n ot be det ecte d vis uall y.  It s h o ul d n ot be use d if it is cl o u d y or a preci pitate is prese nt. 
 
S u p plier:   C o m mercia ll y a vaila ble 
 
T o xicit y: Ac ute t o xicit y i ncl u des a na p h ylactic reacti o ns w hic h occ ur m ost c o m m o nl y w he n t h e dr u g 
is gi ve n I V. T hese ca n be c haracteriz e d b y lar y n geal c o nstricti o n, h y p ot e nsi o n, dia p h oresis, fe v er, 
c hills, e de ma a n d l oss of c o nsci o us ness.  Aller gic reacti o ns at t he site of I M i njecti o n i ncl u de pai n, 
s welli n g a n d er yt he ma. T he i nci de nce of h y perse nsiti vit y reacti o ns t o P E G- as para gi n ase ma y be l ess 
t ha n wit h c o n ve nti o nal E. c oli deri ve d as p ara gi nas e alt h o u g h cr oss- s e nsiti vit y ca n o cc ur.  Ot her 
ad verse effects i ncl u de n e utr o pe nia a n d ass ociate d i m m u n os u p pressi o n, mil d na usea a n d v o miti n g, 
malaise, a n ore xia, ele vate d L F T’s, p a ncreatitis a n d h y per gl yce mia.  A decrease i n pr otei n s y nt hesis 
i ncl u di n g al b u mi n, fi bri n o ge n a n d ot her c oa g ulati o n fact ors ma y o cc ur w hic h ca n res ult i n t hr o m b osis 
or p u l m o nar y e m b olis m.  Less c o m m o n si de effects i ncl u de re nal d ysf u ncti o n a n d C N S c o m plicati o ns 
i ncl u di n g s o m n ole nce, w ea k ness, let har g y, c o ma a n d seiz ures. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
5.  
E R W I NI A L- A S P A R A GI N A S E ( Er wi n aze) 
 
S o urce a n d p h ar mac ol o g y: Er wi nia as para gi nase is a n e nz y me.  It is deri ve d fr o m Er wi ni a 
c hrys a nt he mi a n d ma y b e usef ul i n patie nts wit h a n aller g y t o t he E. c oli deri ve d pr o d u ct. 
As para gi nas e h y dr ol yz es ser u m as para gi ne (a n a mi n o aci d re q uir e d t o s y nt h esiz e pr otei ns) t o as partic 
aci d a n d a m m o nia, a n d is t heref ore let hal t o cells t hat ca n n ot s y nt hesize as p ara gi ne. As p ara gi n ase is 
acti ve d uri n g all p has es of t he cell c ycl e. As para gi nas e is n ot a bs or be d fr o m t he GI tract a n d m ust be 
gi ve n p are nterall y.  As para gi nase d o es n ot cr oss i nt o t he C S F. T he plas ma half-life of er wi nia 
as para gi n ase w he n gi ve n I M is a p pr o xi matel y 1 6 h o urs. O nl y mi ni mal uri n ar y a n d biliar y e x creti o n 
occ urs. Cleara nc e is u naffecte d b y a ge, re nal f u n cti o n or he patic f u ncti o n. 
 
F or m ulati o n a n d sta bilit y: Er wi nia as para gi nase is a vaila ble i n vials c o ntai ni n g 1 0, 0 0 0 u nits of 
l y o p hiliz e d dr u g.  U n us e d vials s h o ul d be refri gerate d. T he c o nt e nts of eac h vial s h o ul d be dil ute d 
wit h 1 ml of preser vati ve-free n or mal sali ne, gi vi n g a res ulta nt s ol uti o n of 1 0, 0 0 0 u nits/ ml. O nce i n 
s ol uti o n, it is rec o m me n de d t hat it be use d wit hi n 8 h o urs as n o pres er vati v e is a d de d.  Occasi o nall y a 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
s mall n u m ber of gelati n o us-li ke fi bers ma y de v el o p u p o n sta n di n g.  If t his occ urs, t he s ol uti o n ca n b e 
filtere d t hr o u g h a 5 micr o n filter t o re m o ve t he p articles wit h n o c ha n ge i n p ote nc y. 
 
S u p plier:   c o m merciall y a vaila ble. 
 
T o xicit y: Ac ute t o xicit y i ncl u des a na p h ylactic reacti o ns t hat occ ur m ost c o m m o nl y w he n t he dr u g is 
gi ve n I V.  T hes e ca n b e c haract erize d b y lar y n geal c o nstricti o n, h y p ote nsi o n, dia p h oresis, fe v er, 
c hills, e de ma a n d l oss of c o nsci o us ness.  Aller gic reacti o ns at t he site of I M i njecti o n i ncl u de pai n, 
s welli n g a n d er yt he ma.  Ot her a d verse effects i ncl u de ne utr o pe nia a n d ass ociate d i m m u n os u p pressi o n, 
mil d na usea a n d v o miti n g, malaise, a n ore xia, ele vate d L F Ts, p a ncreatitis a n d h y per gl yce mia.  A 
decrease i n pr otei n s y nt h esis i ncl u di n g al b u mi n, fi bri n o ge n a n d ot her c oa g ulati o n fact ors ma y occ ur 
w hic h ca n res ult i n he m orr ha ge. T hr o m b osis a n d/ or p ul m o nar y e m b olis m ca n als o oc c ur.   Less 
c o m m o n si de effects i ncl u de re nal d ysf u ncti o n a n d C N S c o m plicati o ns i ncl u di n g s o m n ole nce, 
wea k ness, let h ar g y, c o m a a n d seiz ures. 
 
G ui deli nes f or a d mi nistrati o n : See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
F or a d diti o nal i nf or mati o n a b o ut t his dr u g, please see pac k a ge i nsert. 
 
6.  
D O X O R U BI CI N ( A dria m yci n ) 
 
S o urce a n d p h ar mac ol o g y:  D o x or u bici n is a n a nt hrac ycli ne a nti bi otic pr o d uce d b y Stre pt o myces 
pe uceti us .  D o x or u bici n e x erts its a nti-t u m or effects i n se veral differe nt w a ys. D o x or u bici n 
i ntercalates b et wee n b ase pairs of D N A ca usi n g st eric o bstr ucti o n, disr u pti o n of D N A f u ncti o n a n d 
i n hi biti o n of R N A s y nt h esis.  I n a d diti o n, d o x or u bici n i n hi bits t o p ois o merase II, a n e nz y me 
res p o nsi ble f or all o wi n g stra n ds of D N A t o pass t hr o u g h o n e a n ot her as t h e y u n wi n d.  Lastl y, 
d o x or u bici n u n der g oes e nz y m atic electr o n re d u cti o n t o ge n erate hi g hl y reacti ve s pecies, i ncl u di n g t he 
h y dr o x yl free ra dic al, w hic h is t h o u g ht t o be res p o nsi ble f or t he dr u g’s car diac t o xicit y, b ut ma y pla y 
a r ole i n its a nti-t u m or acti vit y as well.   D o x or u bici n is cell-c ycle, p hase n o n-s pecific.  D o x or u bici n is 
wi del y distri b ute d i n t he tiss ues a n d plas ma, b ut d oes n ot cr oss t he bl o o d brai n barri er t o a n 
a p preci a ble e xte nt. It is meta b olize d t o d o x or u bici n ol, w hic h is t h o u g ht t o be t he maj or acti ve 
meta b olite, a n d a gl yc o nes. D o x or u bici n a n d its meta b olites are e x crete d m ai nl y i n t he bile a n d feces 
(a p pr o xi matel y 8 0 %).  T he re mai n der is e x crete d i n t he uri ne.  D osa ge s h o ul d be re d uce d i n patie nts 
wit h li ver d ysf u n cti o n (secti o n 7. 3) or re nal d ysf u ncti o n (creati ni ne > 3 m g/ dl). 
 
F or m ulati o n a n d sta bilit y: D o x or u bici n is a vaila ble i n vials c o ntai ni n g 1 0 m g, 2 0 m g, 5 0 m g a n d 2 0 0 
m g as a 2 m g/ ml re d- ora n ge s ol uti o n.  It is als o a vaila ble i n vials c o ntai ni n g 1 0 m g, 2 0 m g, 5 0 m g, 1 0 0 
m g a n d 1 5 0 m g of d o x or u bici n as a re d- ora n ge l y o p hilize d p o w der.  I nt act vials of d o x or u bici n 
s ol uti o n s h o ul d be st ore d u n der refri gerati o n w hile t he l y o p hilize d pr o d uct s h o ul d be st ore d at r o o m 
te m perat ur e.  B ot h pr o d u cts s h o ul d be pr otecte d fr o m li g ht. L y o p hilize d d o x or u bici n ca n be 
rec o nstit ute d b y a d di n g 5, 1 0, 2 5, 5 0 or 7 5 ml of 0. 9 % Na Cl res pecti vel y t o t he 1 0, 2 0, 5 0, 1 0 0 a n d 
1 5 0 m g vials t o pr o d uce a fi nal c o nc e ntrati o n of 2 m g/ ml.  Bacteri ostatic dil ue nts are n ot 
rec o m me n de d.  After rec o nstit uti o n, t he res ulta nt s ol uti o n s h o ul d be pr otecte d fr o m li g ht a n d is sta ble 
f or 7 da ys at r o o m te m p erat ure a n d 1 5 da ys if refri gerate d. 
 
S u p plier:  C o m merciall y a vaila ble 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T o xicit y: D ose-li miti n g t o xicities i ncl u de m yel os u p pressi o n a n d car di ot o xicit y. T w o f or ms of car diac 
t o xicit y ca n o cc ur.  Ac ut e t o xicit y ma y ta ke t he f or m of arr h yt h mias, heart bl oc k or pericar ditis a n d 
ma y b e fatal.  T h e c hr o ni c f or m of   car di ot o xicit y is relate d t o t otal c u m ulati ve d ose a n d is 
c haracteriz e d b y heart fail ure. Me diasti nal ra di ot h era p y a n d/ or ot her car di ot o xic dr u gs ma y i n crease 
t he ris k of car di ot o xicit y.  I n ge neral, t otal lifeti me d osa ges of 4 5 0- 5 5 0 m g/ m 2 s h o ul d n ot be e x cee de d.  
Ot he r t o xicities i ncl u de na usea a n d v o miti n g, m uc ositis, al o pecia, diarr h ea a n d re d disc ol orati o n of 
t he uri ne a n d ot her b o d y fl ui ds. Se vere tiss ue da m a ge a n d n ecr osis ca n occ ur u p o n e xtra vasati o n. 
Ra diati o n recall reacti o ns ca n occ ur a n d ca n be s e v ere. Rarel y, all er gic reacti o ns ha ve occ urre d. 
T y p hlitis ca n occ ur w h e n c o m bi ne d wit h c yt ara bi n e. 
 
7.  
C Y C L O P H O S P H A MI D E ( C yt o x a n ) 
 
S o urce a n d p h ar mac ol o g y:  C ycl o p h os p ha mi de is a nitr o ge n m ustar d deri vati ve.  It acts as a n 
al k ylati n g a ge nt t hat ca us es cr oss-li n ki n g of D N A stra n ds b y bi n di n g wit h n ucleic aci ds a n d ot her 
i ntracell ular str uct ures, t h us i nterferi n g wit h t he n or mal f u ncti o n of D N A. C ycl o p h os p ha mi de is c ell-
c ycle, p has e n o n-s pecific. C ycl o p h os p ha mi de is w ell a bs or be d fr o m t he GI tract wit h a bi oa vaila bilit y 
of > 7 5 %.  C ycl o p h os p ha mi de is a pr o dr u g t hat re q uires acti vati o n.  It is meta b olize d b y mi x e d-
f u ncti o n o xi dases i n t he li ver t o 4- h y dr o x yc ycl o p h os p ha mi de, w hic h is i n e q uili bri u m wit h 
al d of osfa mi de.  Al d of osfa mi de s p o nta ne o usl y s plits i nt o c ycl o p h os p ha mi de m ustar d, w hic h is 
c o nsi dere d t o be t h e maj or acti ve meta b olite, a n d acr olei n.  I n a d diti o n, 4- h y dr o x yc ycl o p h os p ha mi d e 
ma y b e e nz y m aticall y m eta b oliz e d t o 4- ket oc ycl o p h os p ha mi de a n d al d of osfa mi de ma y be 
e nz y maticall y meta b olize d t o car b o x y p h os p h a mi de, w hic h are ge n erall y c o nsi dere d t o be i nacti ve.  
C ycl o p h os p ha mi de a n d its meta b olites are e x cret e d mai nl y i n t he uri ne.  D osa ge a dj ust me nts s h o ul d be 
ma de i n patie nts wit h a creati ni ne cle ara n ce of < 5 0 ml/ mi n. 
 
F or m ulati o n a n d sta bilit y:  C ycl o p h os p ha mi de is a vaila bl e i n 2 5 a n d 5 0 m g ta blets. 
C ycl o p h os p ha mi de is als o a vaila ble i n vials c o ntai ni n g 1 0 0, 2 0 0, 5 0 0, 1 0 0 0 a n d 2 0 0 0 m g of 
l y o p hiliz e d dr u g a n d 7 5 m g ma n nit ol per 1 0 0 m g of c ycl o p h os p ha mi de.  B ot h f or ms of t he dr u g ca n 
be st ore d at r o o m te m perat ure.  T he vi als are rec o nstit ute d wit h 5, 1 0, 2 5, 5 0 or 1 0 0 ml of sterile wat er 
f or i njecti o n res p ecti vel y t o yiel d a fi n al c o nce ntrati o n of 2 0 m g/ ml.  Rec o nstit ute d s ol uti o ns ma y be 
f urt her dil ute d i n eit her 5 % de xtr ose or 0. 9 % Na Cl c o ntai ni n g s ol uti o ns.  Dil ute d s ol uti o ns are 
p h ysicall y sta ble f or 2 4 h o urs at r o o m te m perat ure a n d 6 da ys if refri gerate d, b ut c o ntai n n o 
preser vati ve, s o it is rec o m me n de d t hat t he y be us e d wit hi n 2 4 h o urs of pre parati o n. 
 
S u p plier:  C o m merciall y a vaila ble  
 
T o xicit y:  D ose li miti n g t o xicities of c ycl o p h os p ha mi de are b o ne m arr o w s u p pressi o n a n d car diac 
t o xicit y.  Car diac t o xicit y is t y picall y ma nifeste d as c o n gesti ve heart fail ure, car diac necr osis or 
he m orr ha gic m y o car ditis a n d ca n b e fatal.  He m orr ha gic c ystitis ma y o cc ur a n d necessitates 
wit h h ol di n g t hera p y.  T h e i nci de nce of he m orr ha gic c ystitis is relate d t o c ycl o p h os p ha mi de d ose a n d 
d urati o n of t hera p y.  F orce d fl ui d i nta ke a n d/ or t he a d mi nistrati o n of mes n a decreas e t he i nci de nce 
a n d se verit y of he m orr ha gic c ystitis.  Ot her t o xicities re p orte d c o m m o nl y i ncl u de na usea a n d 
v o miti n g ( ma y be mil d t o se vere d e pe n di n g o n d os a ge), diarr hea, a n ore xia, al o pecia, 
i m m u n os u p pressi o n a n d sterilit y.  P ul m o nar y fi br osis, SI A D H, a na p h yla xis a n d sec o n dar y ne o plas ms 
ha ve bee n re p orte d rarel y. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
8.  
C Y T A R A BI N E ( Ara- C) ( C yt osar- U ) 
 
S o urce a n d p h ar mac ol o g y:  C yt ara bi n e is a de o x yc yti di ne a nal o g ue.  It m ust be tri- p h os p h or yl ate d t o 
its acti ve f or m, A R A- C T P, b y de o x yc yti di ne ki nase a n d ot her n u cle oti de ki nases. Ara- C T P i n hi bits 
D N A p ol y m eras e. I n a d diti o n, ara- C T P is i nc or p orate d i nt o D N A as a false base, ca usi n g i n hi biti o n of 
D N A s y nt hesis.  It is cell c ycle, S p hase s p ecific. C yt ara bi ne d oes pe n etrat e t he bl o o d brai n barrier.  It 
is c o n verte d t o its i nacti ve f or m, uracil ara bi n osi de, b y p yri mi di ne n ucle osi de dea mi nase.  
A p pr o xi matel y 8 0 % of t he d ose is rec o vere d i n t he uri ne, m ostl y as uracil ara bi n osi de (ara- U). 
 
F or m ulati o n a n d sta bilit y: C yt ara bi n e is a vaila ble i n m ulti- d ose vials c o ntai ni n g 1 0 0, 5 0 0, 1 0 0 0 a n d 
2 0 0 0 m g of l y o p hiliz e d dr u g.  I nta ct vials ca n b e st ore d at r o o m te m perat ur e.  F or I V us e, eit her st erile 
water f or i njecti o n or bacteri ostatic water f or i njecti o n ca n be use d t o r ec o nstit ute t he l y o p hilize d 
dr u g.  F or i ntr at hecal us e, o nl y sterile water f or i njecti o n s h o ul d be use d f or rec o nstit uti o n.  T he 1 0 0 
a n d 5 0 0 m g vials are rec o nstit ute d wit h 2 a n d 1 0 ml res pecti vel y res ulti n g i n a fi nal c o nce ntrati o n of 
5 0 m g/ ml.  T he 1 0 0 0 a n d 2 0 0 0 m g vials are rec o nstit ute d wit h 2 0 ml a n d 4 0 ml res pecti vel y res ulti n g i n 
a fi nal c o nce ntrati o n of 5 0 m g/ ml.  After rec o nstit uti o n, t he dr u g is sta ble f or 8 da ys at r o o m 
te m perat ur e. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  M yel os u p pressi o n is t he d ose li miti n g a d verse effect, wit h le u k o pe nia a n d 
t hr o m b oc yt o pe ni a bei n g pre d o mi na nt.  Ot her a d verse effects r e p orte d c o m m o nl y i ncl u de na us ea a n d 
v o miti n g ( ma y be se v ere at hi g h d oses), diarr h ea, m uc ositis, a n ore xia, al o pecia, s ki n ras h a n d li ver 
d ysf u n cti o n.  A fl u-li ke s y n dr o me c haract erize d b y fe ver, m uscl e a n d b o ne ac hes is c o m m o n. Less 
c o m m o n si de effects i ncl u de aller gic reacti o ns a n d cell ulitis at t he i njecti o n site. Hi g h d oses of 
c yt ara bi ne ca n ca use c o nj u ncti vitis, he patitis, a n d a gr o u p of C N S s y m pt o ms i ncl u di n g s o m n ole nce, 
peri p heral ne ur o pat h y, ata xia, a n d pers o nalit y c ha n ges. C N S s y m pt o ms are us uall y re versi ble a n d are 
m ore c o m m o n i n patie nts w h o ha ve recei v e d pre vi o us cra nial irra diati o n.  I n a d diti o n, a s y n dr o m e of 
s u d de n res pirat or y distress pr o gressi n g t o p ul m o n ar y e de m a has occ urre d. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol.  
 
9.  
C Y T A R A BI N E ( Hi g h D ose A R A- C)  
 
S o urce a n d p h ar mac ol o g y:  C yt ara bi n e is a de o x yc yti di ne a nal o g ue.  It m ust be tri- p h os p h or yl ate d t o 
its acti ve f or m, AR A - C T P, b y de o x yc yti di ne ki nase a n d ot her n u cle oti de ki nases. Ara- C T P i n hi bits 
D N A p ol y m eras e. I n a d diti o n, ara- C T P is i nc or p orate d i nt o D N A as a false base, ca usi n g i n hi biti o n of 
D N A s y nt hesis.  It is cell c ycle, S p hase s p ecific. C yt ara bi ne d oes pe n etrat e t he bl o o d brai n barrier.  It 
is c o n verte d t o its i nacti ve f or m, uracil ara bi n osi de, b y p yri mi di ne n ucle osi de dea mi nase.  
A p pr o xi matel y 8 0 % of t he d ose is rec o vere d i n t he uri ne, m ostl y as uracil ara bi n osi de (ara- U). 
 
F or m ulati o n a n d sta bilit y: C yt ara bi n e is a vaila ble i n m ulti- d ose vials c o ntai ni n g 1 0 0, 5 0 0, 1 0 0 0 a n d 
2 0 0 0 m g of l y o p hiliz e d dr u g.  I nta ct vials ca n b e st ore d at r o o m te m perat ur e.  F or I V us e, eit her st erile 
water f or i njecti o n or bacteri ostatic water f or i njecti o n ca n be use d t o r ec o nstit ute t he l y o p hilize d 
dr u g.  F or i ntr at hecal us e, o nl y sterile water f or i njecti o n s h o ul d be use d f or rec o nstit uti o n.  T he 1 0 0 
a n d 5 0 0 m g vials are rec o nstit ute d wit h 2 a n d 1 0 ml res pecti vel y res ulti n g i n a fi nal c o nce ntrati o n of 
5 0 m g/ ml. T he 1 0 0 0 a n d 2 0 0 0 m g vials are rec o nstit ute d wit h 2 0 ml a n d 4 0 ml res pecti vel y res ulti n g i n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
a fi nal c o nce ntrati o n of 5 0 m g/ ml.  After rec o nstit uti o n, t he dr u g is sta ble f or 8 da ys at r o o m 
te m perat ur e. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  M yel os u p pressi o n is t he d ose li miti n g a d verse effect, wit h le u k o pe nia a n d 
t hr o m b oc yt o pe ni a bei n g pre d o mi na nt.  Ot her a d verse effects r e p orte d c o m m o nl y i ncl u de na us ea a n d 
v o miti n g ( ma y be se v ere at hi g h d oses), diarr h ea, m uc ositis, a n ore xia, al o pecia, s ki n ras h a n d li ver 
d ysf u n cti o n.  A fl u-li ke s y n dr o me c haract erize d b y fe ver, m uscl e a n d b o ne ac hes is c o m m o n. Less 
c o m m o n si de effects i ncl u de aller gic reacti o ns a n d cell ulitis at t he i njecti o n site. Hi g h d oses of 
c yt ara bi ne ca n ca use c o nj u ncti vitis, he patitis, a n d a gr o u p of C N S s y m pt o ms i ncl u di n g s o m n ole nce, 
peri p heral ne ur o pat h y, ata xia a n d pers o nalit y c ha n ges.  C N S s y m pt o ms are us uall y re versi ble a n d are 
m ore c o m m o n i n patie nts w h o ha ve recei v e d pre vi o us cra nial irra diati o n.  I n a d diti o n, a s y n dr o m e of 
s u d de n res pirat or y distress pr o gressi n g t o p ul m o n ar y e de m a has occ urre d. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 0.  
T H I O G U A NI N E ( 6- T G) 
 
S o urce a n d p h ar mac ol o g y:  T hi o g ua ni ne is a p uri ne a nti meta b olite.  It is i ntracell ularl y c o n v erte d t o 
ri b o n ucle oti des w hic h are i nc or p orate d i nt o D N A a n d R N A.  A bs or pti o n of t hi o g ua ni ne is varia ble 
a n d p o or a n d is decrease d b y f o o d. T hi o g u a ni ne u n der g oes e xte nsi ve meta b olis m i n t he li ver a n d 
ot her tiss ues t o t he i nacti ve, met h yl ate d deri v ati ve a n d t o 6-t hi o uracil b y x a nt hi ne o xi dase.  
T hi o g ua ni ne is e x crete d i n t he uri ne al m ost c o m pletel y as meta b olites. 
 
F or m ulati o n a n d sta bilit y: T hi o g ua ni ne is a v aila ble as a 4 0 m g sc ore d ta blet.  It ma y be st or e d at r o o m 
te m perat ur e. 
 
S u p plier:  Ta blets are c o m merciall y a vail a ble.  
 
T o xicit y:  T he maj or d os e-li miti n g t o xicit y is m yel os u p pressi o n. Na usea a n d v o miti n g are us u all y 
mil d. Ot her t o xicities re p orte d i ncl u de diarr hea, ras h, a n ore xia, st o matitis, a n d h y per urice mia.  
J a u n dice a n d ele vate d li v er f u ncti o n tests ha ve bee n re p orte d rarel y 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 1.  
C L O F A R A BI N E ( Cl- F- Ara- A, C A F d A, 2- C hl or o- 9- ( 2-d e o x y- 2-fl u or o- beta- D- 
ara bi n of ura n os yl)- 9 H- p uri n- 6-a mi ne, Cl ofare x, Cl olar) 
 
S o urce a n d p h ar mac ol o g y: Cl ofara bi ne is se q ue ntiall y meta b olize d i ntracell ularl y t o t he 5’- 
m o n o p h os p hate meta b olite b y d e o x yc yti di ne ki nase a n d m o n o- a n d di- p h os p h o ki nases t o t he acti ve 
5’-tri p h os p hate meta b olit e. Cl ofara bi ne has hi g h affi nit y f or t he acti vati n g p h os p h or ylati n g e nz y me, 
de o x yc yti di ne ki nase, e q ual t o or great er t ha n t hat of t he nat ural s u bstrat e, de o x yc yti di ne. Cl ofara bi ne 
i n hi bits D N A s y nt hesis b y decreasi n g cell ular d e o x y n ucl e oti de tri p h os p hat e p o ols t hr o u g h a n 
i n hi bit or y acti o n o n ri b o n ucle oti de re d u ctase, a n d b y ter mi nati n g D N A c hai n el o n gati o n a n d 
i n hi biti n g re pair t hr o u g h i nc or p orati o n i nt o t he D N A c hai n b y c o m p etiti ve i n hi biti o n of D N A 
p ol y merases. T he affi nit y of cl ofara bi ne tri p h os p hate f or t hes e e nz y m es is si milar t o or greater t h a n 
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I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t hat of de o x ya de n osi n e tri p h os p hate. I n precli nical m o dels, cl ofara bi n e has de m o nstrate d t he a bilit y t o 
i n hi bit D N A re pair b y i n c or p orati o n i nt o t he D N A c hai n d uri n g t he re pair pr ocess. Cl ofara bi ne 5’- 
tri p h os p hate als o disr u pts t he i nte grit y of mit oc h o n drial me m bra ne, l ea di n g t o t he releas e of t he pr o-
a p o pt otic mit oc h o n drial pr otei ns, c yt o c hr o me C a n d a p o pt osis-i n d uci n g fact or, lea di n g t o 
pr o gra m me d cell deat h. Cl ofara bi ne is c yt ot o xic t o ra pi dl y pr oliferati n g a n d q uiesce nt ca n cer cell 
t y pes i n vitr o. 
 
T he p o p ulati o n p har ma c o ki netics of cl ofara bi ne was st u die d i n 4 0 pe diatric patie nts a ge d 2 t o 1 9 years 
( 2 1 males/ 1 9 fe males) wit h rela pse d or refract or y A L L or A M L. At t he gi v e n 5 2 m g/ m 2 d ose, si milar 
c o nce ntr ati o ns were o bt ai ne d o ver a wi d e ra n ge of B S As. Cl ofara bi n e was 4 7 % b o u n d t o plas ma 
pr otei ns, pre d o mi na ntl y t o al b u mi n. Base d o n n o n-c o m part me ntal a nal ysis, s yste mic cl eara nce a n d 
v ol u me of half-life was esti mate d t o be 5. 2 h o urs. N o a p pare nt differe nce i n p har mac o ki netics was 
o bser ve d bet w ee n p atie nts wit h A L L a n d A M L or bet wee n mal es a n d fe mal es. Bas e d o n 2 4- h o ur 
uri ne c ollecti o ns i n t he p e diatric st u dies, 4 9- 6 0 % of t he d ose is e x crete d i n t he uri ne u nc ha n ge d. I n 
vitr o st u dies usi n g is olate d h u ma n he pat oc ytes i n dicate ver y li mite d meta b olis m ( 0. 2 %), t heref ore t h e 
pat h wa ys of n o n-re nal eli mi nati o n re mai n u n k n o w n. 
 
Alt h o u g h n o cli nical dr u g- dr u g i nteracti o n st u dies ha ve bee n c o n d uct e d t o date, o n t he basis of t he i n 
vitr o st u dies, c yt oc hr o me p 4 5 0 i n hi bit ors a n d i n d ucers are u nli kel y t o affect t he meta b olis m of 
cl ofara bi ne. T he effect of cl ofara bi ne o n t he meta b olis m of c yt oc hr o m e p 4 5 0 s u bstrates has n ot bee n 
st u die d. T he p har mac o ki netics of cl ofara bi ne has n ot bee n e val u ate d i n patie nts wit h re nal or he p atic 
d ysf u n cti o n. 
 
F or m ulati o n a n d sta bilit y: Cl ofara bi ne ( 1 m g/ m L) is s u p plie d i n a 2 0 m L, si n gle- us e vial. T h e 2 0 m L 
vial c o ntai ns 2 0 m g cl of ara bi ne f or m ulate d i n 2 0 m L u n b uffere d n or m al sali ne (c o m prise d of Water 
f or I njecti o n, U S P, a n d S o di u m C hl ori de U S P). T he p H ra n ge of t he s ol uti o n is 4. 5 t o 7. 5. St ore at 
2 5° C ( 7 7° F); e x c ursi o ns per mitte d t o 1 5- 3 0° C ( 5 9- 8 6° F). 
 
T o xicit y:  T he m ost c o m m o n t o xicities of cl ofara bi ne are v o miti n g, n a usea, diarr hea, a n e mia, 
le u k o pe nia, t hr o m b oc yt o pe nia, ne utr o pe ni a, fe brile ne utr o pe nia, a n d i nfecti o n.  Greater t ha n 1 0 % of 
pa tie nts recei vi n g cl ofara bi ne ha ve t he f oll o wi n g a d verse e v e nts: tac h ycar di a, a b d o mi nal pai n, 
c o nsti pati o n, gi n gi val ble e di n g, s or e t hr oat, e de ma, fati g u e, i njecti o n site pai n, let har g y, m u c osal 
i nfla m mati o n, pai n, p yre xia, ri g ors, he pat o me gal y, ja u n dice, wei g ht l oss, a n ore xia, art hral gia, 
m yal gia, b ac k pai n, li m b pai n, dizzi ness, hea dac he, s o m n ole nce, tre m or, a n xiet y, de pressi o n, 
irrita bilit y, he mat uria, c o u g h, d ys p nea, e pista xis, ple ural eff usi o n. Res pirat or y distress, c o nf usi o n, 
der matitis, dr y s ki n, er yt he ma, pal mar- pla ntar er yt hr o d ysest h esia s y n dr o m e, petec hi ae, pr urit us, 
fl us hi n g, h y perte nsi o n, h y p ote nsi o n, i ncreases i n A L T, A S T, a n d bilir u bi n, tra nsie nt left ve ntric ular 
s yst olic d ysf u ncti o n, a n d i ncreas e d ser u m creati ni n e. F o ur of 1 1 3 pe diatric patie nts e x perie nce d 
ca pillar y lea k s y n dr o me or SI R S lea di n g t o m ulti- or ga n fail ure. 
 
Fetal a n d t erat o ge ni c effects ha ve bee n n ote d i n a ni mals.  It is n ot k n o w n w het her cl of ara bi n e or its 
meta b olites are e x crete d i n h u ma n mil k. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. Filter 
cl ofara bi ne t hr o u g h a sterile 0. 2 μ m s yri n ge filter a n d t he n f urt her dil ute wit h 5 % de xtr ose i njecti o n 
U S P or 0. 9 % s o di u m c hl ori de i njecti o n U S P t o a c o n ve nie nt v ol u me a n d i nf use o ver 2 h o urs. T he 
res ulti n g a d mi xt ure ma y be st ore d at r o o m te m perat ure, b ut m ust be use d wit hi n 2 4 h o urs of 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
pre parati o n. 
 
T o re d uce t he effects of t u m or l ysis a n d ot her a d v erse e v e nts it is rec o m me n de d t hat c o nti n u o us I V 
fl ui ds be gi ve n t hr o u g h o ut t he 5 da ys of cl ofara bi ne a d mi nistrati o n. See A p pe n di x II f or S u p p orti ve 
Care G ui deli nes. 
 
Si nce cl ofara bi ne is pri m aril y e x crete d t hr o u g h t h e ki d ne ys, dr u gs wit h k n o w n re nal t o xicit y s h o ul d be 
a v oi de d d uri n g t he 5 da ys of cl ofara bi ne a d mi nistrati o n. I n a d diti o n, si nce t he li ver is a k n o w n t ar get 
or ga n f or cl ofara bi ne t o xicit y, c o n c o mita nt use of me dicati o ns k n o w n t o i n d uce he p atic t o xicit y 
s h o ul d be a v oi de d. 
 
S u p plier:  C o m merciall y a vaila ble 
 
1 2.  
M E T H O T R E X A T E 
 
S o urce a n d p h ar mac ol o g y:  Met h otre x ate is a f ol ate a nal o g ue t hat acts b y i n hi biti n g di h y dr of olate 
re d uctas e.  Di h y dr of olat e re d uctas e is a n e nz y m e i m p orta nt i n t he c o n versi o n of f olic aci d t o 
tetra h y dr of olic aci d, w hi c h is necessar y i n t he s y nt hesis of p uri ne n ucle oti d es a n d t h y mi d ylate.  B y 
i n hi biti n g t he pr o d ucti o n of tetra h y dr of olic aci d, m et h otre x ate i nterferes wit h D N A, R N A a n d pr otei n 
s y nt hesis.  Met h otre x ate is p o orl y a n d v aria bl y a bs or be d orall y, wit h a n a v era ge of > 4 0 % f or d oses of 
< 3 0 m g/ m 2.  At hi g her d osa ges, t he e xte nt of a bs or pti o n decreases. Met h otre x ate is a p pr o xi matel y 
5 0 % pr otei n b o u n d.  It distri b utes wi del y i nt o b o d y tiss ues a n d fl ui ds wit h s ustai ne d c o nce ntr ati o ns i n 
t he ki d ney a n d t he li ver.  Met h otre x ate u n der g oes meta b olis m b y c yt os olic al de h y de o xi dase t o 
h y dr o x y m et h otre x ate.  It is e x crete d mai nl y i n t he uri ne as u nc h a n ge d dr u g wit h s mall a m o u nts bei n g 
e x crete d i n t he bile a n d feces. T h e perce nt r ec o vere d as u nc ha n ge d dr u g i n t he uri ne is hi g h er wit h 
s h ort i nf usi o ns t ha n wit h pr ol o n ge d i nf usi o ns.  Met h otre x ate has a bi p hasic eli mi nati o n wit h a n i nitial 
half-life of a p pr o xi matel y 2 - 3 h o urs a n d a t er mi nal half-life of 1 0- 1 2 h o urs. Met h otre x ate ma y b e 
“se q uestere d” i n b o d y fl ui d c ollecti o ns a n d eli mi nate d sl o wl y fr o m t hese areas. Patie nts wit h eff usi o ns 
or GI o bstr ucti o n s h o ul d ha ve plas ma le vels m o nit ore d cl osel y f or dela ye d e x creti o n f oll o wi n g hi g h-
d ose met h otre x ate. 
 
F or m ulati o n a n d sta bilit y: Met h otre x ate is s u p plie d i n si n gle- d ose vials c o ntai ni n g 5 0 m g, 1 0 0 m g, 
2 0 0 m g, a n d 2 5 0 m g of m et h otre x ate as a 2 5 m g/ ml preser vati ve-free s ol uti o n a n d i n vials c o ntai ni n g 
2 0 m g, 5 0 m g, 1 0 0 m g, 2 5 0 m g a n d 1 0 0 0 m g of l y o p hilize d dr u g.  It is als o a vaila ble i n 2. 5 m g ta blets. 
Met h ot re x ate preser vati ve-free s ol uti o n a n d l y o p hilize d dr u g s h o ul d be st or e d at r o o m te m perat ure 
a n d pr otecte d fr o m li g ht.  Met h otre x ate ta blets ca n als o be st ore d at r o o m te m perat ure. T h e vials 
c o ntai ni n g 2 0, 5 0, 1 0 0 a n d 2 5 0 m g of l y o p hilize d pr o d uct ca n b e rec o nstit ute d b y a d di n g sterile wat er, 
0. 9 % Na Cl or D 5 W t o a fi nal c o nce ntrati o n n ot e x cee di n g 2 5 m g/ ml.  T he 1 0 0 0 m g vials c o ntai ni n g 
l y o p hiliz e d pr o d uct are rec o nstit ute d t o a fi nal c o nce ntrati o n of 5 0 m g/ ml. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y: 
T he d ose li miti n g t o xicities of met h otre x ate are ge nerall y b o ne marr o w s u p pressi o n, 
ulcerati ve st o matitis, se vere diarr hea or ac ute ne p hr ot o xicit y. T o xicities re p orte d fre q u e ntl y i n cl u de 
na usea a n d v o miti n g, diarr hea, a n ore xia, al o pecia, he patic t o xicit y a n d al o p ecia.  Less c o m m o n si de 
effects i ncl u de bl urre d visi o n, p h ot ose nsiti vit y, a n a p h yl a xis, hea dac he, p n e u m o nitis, s ki n 
de pi g me nt ati o n or h y p er pi g me ntati o n, ras h, v asc ulitis a n d e nce p hal o pat h y. 
St. J u d e
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I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
D uri n g hi g h- d os e met h otre x ate t hera p y, m ost pati e nts e x perie nce a tra nsie nt decrease i n G F R, b ut 
re nal f ail ure ca n occ ur, partic ularl y if t he p atie nt d oes n ot recei ve uri nar y al kali nizati o n a n d 
a g gressi ve h y drati o n bef ore, d uri n g a n d after recei vi n g hi g h d os e met h otre x ate.  Le uc o v ori n res c ue 
s h o uld be i nitiate d wit hi n 4 8 h o urs of starti n g hi g h- d ose met h otre x ate a n d a dj uste d base d o n M T X 
le vels t o pre ve nt b o ne m arr o w t o xicit y a n d m uc ositis.  Le uc o v ori n ma y als o be necessar y after I T 
a d mi nistrati o n, es peciall y if I T m et h otre x ate t hera p y is gi ve n t o patie nts wit h re nal d ysf u ncti o n.  
Patie nts wit h D o w n s y n dr o me ha ve a te n de n c y t o ha ve dela ye d met h otre x ate cleara nce a n d a great er 
ris k of t o xicit y, des pite i ncreas e d le uc o v ori n res c ue. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 3.  
L E U C O V O RI N (f oli nic aci d) 
 
S o urce a n d p h ar mac ol o g y:  Le u c o v ori n is a race mic mi xt ure of tetra h y dr of olic aci d, w hic h is i n v ol ve d 
as a c ofact or f or 1- car b o n tra nsfer reacti o ns i n t he s y nt hesis of p uri n e a n d p yri mi di nes. Le u c o v ori n is 
a p ote nt a nti d ote f or b ot h t he he mat o p oietic a n d retic ul oe n d ot helial t o xic effects of f olic aci d 
a nta g o nists b y re ple nis hi n g re d uce d f olate p o ols.  It is p ost ulate d t hat i n s o me ca ncers, le u c o v ori n 
e nters a n d “res c ues” n or mal cells fr o m t he t o xic effects of f olic aci d a nta g o nists, i n prefere n ce t o 
t u m or cells, beca us e of differe n ces i n me m br a ne tra ns p ort a n d affi nit y f or p ol y gl uta m yl ati o n. 
Le u c o v ori n is c o n verte d i n t he i ntesti nal m uc osa a n d t he li ver t o 5- met h yl- tetra h y dr of olat e, w hic h is 
als o acti ve as a re d u ce d f olate.  It is e x crete d pri m aril y i n t he uri ne wit h mi n or e x creti o n occ urri n g i n 
t he feces. 
 
F or m ulati o n a n d sta bilit y:  Le u c o v ori n is s u p plie d i n 5, 1 5 a n d 2 5 m g ta blets a n d vials c o ntai ni n g 5 0, 
1 0 0 or 3 5 0 m g of l e uc o v ori n as a l y o p hilize d p o w der.   T he ta bl ets a n d t he l y o p hilize d p o w der ca n b e 
st ore d at r o o m te m perat ure.  T he 5 0 m g a n d 1 0 0 vials ca n be rec o nstit ute d b y a d di n g 5 or 1 0 ml of 
sterile water or bacteri ost atic water f or i njecti o n res pecti vel y t o yiel d a fi nal c o nce ntr ati o n of 1 0 
m g/ ml.  T he 3 5 0 m g vi als ca n be rec o nstit ute d wit h 1 7 ml of sterile water or bacteri ostatic water f or 
i njecti o n t o yiel d a fi n al c o nce ntr ati o n of 2 0 m g/ ml.   T he rec o nstit ute d s ol uti o n is sta ble f or at least 7 
da ys at r o o m te m perat ure.  Le u c o v ori n ma y b e f urt her dil ute d i n 5 % de xtr ose or 0. 9 % Na Cl 
c o ntai ni n g s ol uti o ns. Le u c o v ori n is als o a vaila ble as a 1 m g/ ml or al s ol uti o n. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  Le u c o v ori n is ge n erall y w ell t olerate d.  T o xicities t hat ha ve bee n re p orte d u n c o m m o nl y 
i ncl u de ras h, mil d na usea, hea dac he, a n d w heezi n g ( p ossi ble aller gic reacti o n). I ntrat hecal le uc o v ori n 
is c o ntrai n dicate d a n d has ca use d ne ur ot o xic deat hs.  T here ha v e bee n rare re p orts of le u c o v ori n 
pr o m oti n g seiz ures. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 4.  
M E R C A P T O P U RI N E ( 6- M P) ( P uri net h ol ) 
 
S o urce a n d p h ar mac ol o g y:  Merca pt o p uri ne is a p uri ne a nti meta b olite.  It m ust be c o n verte d 
i ntracell ularl y t o 6-t hi o g ua ni ne n ucle oti des ( 6- T G Ns), t he acti ve f or ms of t he dr u g. T he 6- T G Ns are 
t he n i nc or p orat e d i nt o D N A a n d R N A a n d ca use i n hi biti o n of D N A a n d R N A s y nt h esis. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Merca pt o p uri n e is cell c ycle, S p hase s pecific. A bs or pti o n is varia ble a n d i n c o m plete ( 5- 3 7 %) a n d is 
decrease d b y t he prese n ce of f o o d i n t he g ut.  Merca pt o p uri ne d oes distri b ute i nt o t he C S F, wit h C S F 
c o nce ntr ati o ns of a p pr o xi matel y 2 7 % of plas ma c o nce ntrati o ns w he n gi v e n b y c o nti n u o us i nf usi o n.  
Merca pt o p uri n e u n der g o es first pass meta b olis m i n t he GI m uc osa a n d t he li ver.   It is meta b olize d i n 
he mat o p oeitic tiss ues b y H P R T t o t he acti ve n ucle oti de f or ms.  It is i na cti vate d t o met h yl ate d 
meta b olites b y T P M T (t hi o p uri ne met h yl tra nsferase) a n d t o 6-t hi o uric aci d b y x a nt hi ne o xi dase.  
T P M T is a ge n eticall y re g ulate d, p ol y m or p hicall y distri b ute d e nz y m e a n d is deficie nt i n a b o ut 1 i n 
3 0 0 pers o ns w h o ca n n ot t olerate us ual d oses of 6- M P.  Merca pt o p uri ne is eli mi nate d t hr o u g h t he uri ne 
as b ot h u nc ha n ge d dr u g a n d meta b olites. 
 
F or m ulati o n a n d sta bilit y: Merca pt o p uri ne is c o m merciall y a vaila bl e as a 5 0 m g ta blet a n d a 2 0 
m g/ m L oral s us pe nsi o n. T he ta blets s h o ul d be st ore d at r o o m te m perat ur e a n d pr otecte d fr o m li g ht. 
 
S u p plier:  C o m merciall y a vaila ble. 
 
T o xicit y:  T he d ose-li miti n g t o xi cit y of merca pt o p uri ne is m yel os u p pressi o n. Merca pt o p uri ne ca n 
ca use i ntra h e patic c h ol estasis a n d f ocal ce ntral o b ular necr osis a n d is us uall y ma nifeste d b y 
h y per bilir u bi ne mia a n d i ncreas e d li ver f u n cti o n tests.  Ot her t o xicities i ncl u de mil d na usea a n d 
v o miti n g, s ki n ras h, h y per urice mia, a n d mil d diarr hea. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 5.  
D E X A M E T H A S O N E ( Deca dr o n ) 
 
S o urce a n d p h ar mac ol o g y: De x a met has o ne is a s y nt hetic c o n ge ner of h y dr oc ortis o ne, t he nat ur al 
a dre nal h or m o ne.  De x a met has o ne is a w hite or yell o wis h cr ystalli ne p o w der.  It bi n ds wit h ster oi d 
rece pt ors o n n uclear me m bra nes, i m pairs cell ular mit osis a n d i n hi bits pr otei n s y nt hesis. 
De x a met has o ne als o has p ote nt a nti-i nfla m mat or y effects a n d s u p presses t he i m m u ne s yste m. 
De x a met has o ne is well a bs or be d orall y.  It is meta b olize d i n t he li ver a n d t he meta b olites are e x cret e d 
mai nl y i n t he uri ne. 
 
F or m ulati o n a n d sta bilit y:  De x a met has o ne is a vaila ble as vari o us stre n gt h t a blets a n d as a n eli xir. It is 
als o a vaila ble as a s ol uti o n f or pare nteral use.  All f or m ulati o ns of t he dr u g ca n be st or e d at r o o m 
te m perat ur e.  T he i nject a ble f or m ma y be f urt her dil ute d i n 5 % de xtr ose or 0. 9 % Na Cl c o ntai ni n g 
s ol uti o ns a n d is sta ble f or at least 2 4 h o urs at r o o m te m perat ur e. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y: Si de effects of de x a met has o ne var y d e p e n di n g o n t he d urati o n of its use. Si de effects t hat 
ca n occ ur wit h s h ort ter m use i ncl u de pe ptic ulcer wit h p ossi ble perf orati o n a n d he m orr h a ge, 
i ncreas e d s usce pti bilit y t o i nfecti o ns, e m oti o nal i nsta bilit y, i ns o m nia, i ncrease d a p petite, wei g ht gai n, 
ac ne, a n d h y per gl yce mia. Si de effects m ore c o m m o nl y ass oci ate d wit h pr ol o n ge d us e i ncl u de 
cataracts, i ncrease d i ntra oc ular press ure a n d ass ociate d gl a uc o ma, d e vel o p me nt of a “c us hi n g oi d” 
state, c o m pressi o n fract ures, me nstr ual irre g ulariti es, s u p pressi o n of gr o wt h i n c hil dre n, sec o n d ar y 
a dre n oc ortical a n d pit uitar y u nres p o nsi ve ness p arti c ularl y i n ti mes of stress as i n tra u ma, s ur ger y or 
ill ness, oste o p or osis a n d m uscle wasti n g. 
 
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 6.  
H Y D R O C O R TI S O N E, s yste mic ( C ort ef, S ol u- C ortef ) 
 
S o urce a n d p h ar mac ol o g y: H y dr oc ortis o ne is a s y nt hetic ster oi d a ki n t o t he nat ural a dre nal h or m o ne 
c ortis ol.  H y dr oc ortis o ne decreases i nfla m mati o n b y s u p pressi o n of mi grati o n of p ol y m or p h o n u clear 
le u k oc yt es a n d re vers al of i ncrease d ca pillar y per mea bilit y.  It is e x crete d i n t he uri ne a n d cata b olize d 
i n t he li ver. 
 
F or m ulati o n a n d sta bilit y:  S ol u- C ortef sterile p o w der is s u p plie d i n t he f oll o wi n g pac ka ges:  1 0 0 m g 
plai n, a n d 1 0 0 m g, 2 5 0 m g, 5 0 0 m g, a n d 1 0 0 0 m g A C T- O- VI A L ( MI X- O- VI A L). St ore l y o p hilize d 
pr o d uct at c o ntr olle d r o o m te m perat ure 1 5- 3 0° C ( 5 9- 8 6° F). St ore rec o nstit ute d s ol uti o n i n t he 
refri gerat or a n d pr ote ct fr o m li g ht.  U n use d s ol uti o n s h o ul d be discar de d aft er 3 da ys. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  H y per p ha gia, o besit y, striae, ac n e, cat aracts, i m m u n os u p pressi o n, electr ol yte dist ur ba n ces, 
e de ma, h y perte nsi o n, oste o p or osis, pers o nalit y c h a n ges, i ns o m nia, hea d ac h es, dia betes a n d 
C us hi n g oi d S y n dr o me.  Pa ncreatitis, pe ptic ulcer a n d/ or GI blee di n g h a ve als o bee n n ote d.  
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 7.  
E T O P O SI D E ( V P- 1 6) ( Ve pesi d ) 
 
S o urce a n d p h ar mac ol o g y:  Et o p osi de is a n e pi p o d o p h yll ot o xi n deri ve d fr o m P o d o p hyll u m pel at at u m. 
It is t h o u g ht t o act mai nl y b y i n hi biti n g t o p ois o merase II, ca usi n g d o u ble a n d si n gle stra n d D N A 
brea ks.  Et o p osi de is cell c ycle, p has e-s pecific, wit h acti vit y i n t he G 2 a n d S p hases. A bs or pti o n of 
et o p osi de is a p pr o xi matel y 3 0- 4 0 % a n d is hi g hl y varia ble a n d s o m e w hat d ose- de pe n d e nt.  It is 
exte nsi vel y b o u n d t o s er u m pr otei ns a n d is meta b olize d i n t he li ver, i ncl u di n g c yt oc hr o me P 4 5 0 3 A 
me ta b olis m t o se veral m oieties t hat i ncl u de a reacti ve o xi dize d s pecies.  Et o p osi de a n d its meta b olites 
are e x crete d mai nl y i n t h e uri ne wit h a s maller a m o u nt e xcrete d i n t he feces.  D osa ge a dj ust me nts 
s h o ul d be c o nsi dere d i n p atie nts wit h li ver d ysf u ncti o n, ki d ne y d ysf u ncti o n or h y p o al b u mi ne mia. 
 
F or m ulati o n a n d sta bilit y:  Et o p osi de is a vaila ble i n m ulti- d ose vials c o ntai ni n g 1 0 0 m g, 1 5 0 m g, 
5 0 0 m g a n d 1 0 0 0 m g of et o p osi de as a 2 0 m g/ ml s ol uti o n a n d 3 0 % alc o h ol.   Et o p osi de is als o a vaila ble 
as a 5 0 m g ca ps ule. T h e i ntact vials of et o p osi de s ol uti o n s h o ul d be st ore d at r o o m te m perat ur e. T he 
ca ps ules s h o ul d be st ore d u n der refri gerati o n.  Et o p osi de s ol uti o n s h o ul d be dil ute d i n D 5 W or 0. 9 % 
Na Cl pri or t o a d mi nistrati o n.  S ol uti o ns wit h a fi nal c o nce ntr ati o n of 0. 2 a n d 0. 4 m g/ ml are sta bl e at 
r o o m te m perat ur e f or 9 6 h o urs a n d 2 4 h o urs res pecti vel y. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  D ose li miti n g t o xicit y is m yel os u p pressi o n. Na usea a n d v o miti n g ( us uall y of l o w t o 
m o derate se v erit y), diarr hea, m uc ositis ( partic ularl y wit h hi g h d os es), al o p ecia a n d a n ore xia are fairl y 
c o m m o n.  H y p ote nsi o n ca n occ ur wit h ra pi d i nf usi o ns. Ot her si de effects r e p orte d less c o m m o nl y 
i ncl u de he patitis, fe ver a n d c hills, a na p h yl a xis a n d peri p heral ne ur o pat h y. Sec o n dar y le u ke mia has 
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
bee n re p orte d. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 8.  
D A S A TI NI B ( S P R Y C E L ®) 
 
F O R P H + A L L P A TI E N T S O N L Y  
 
S o urce a n d p h ar mac ol o g y: Das ati ni b (a n a mi n ot hiaz ole a nal o g ue) is a n i n hi bit or of m ulti ple t yr osi ne 
ki nases. It is a p pr o ve d f or t he treat me nt of c hr o nic m yel o ge n o us le u k e mia ( C M L) a n d f or t he 
treat me nt of a d ults wit h P hila del p hia c hr o m os o me- p ositi ve A L L wit h resista nce or i nt olera nce t o 
pri or t hera p y. It is bei n g i n vesti gate d as a br oa d-s p ectr u m a ntit u m or a ge nt a gai nst s oli d t u m ors. 
Dasati ni b is a p ote nt, br o a d s pectr u m A T P-c o m petiti ve i n hi bit or of 5 critical o nc o ge nic t yr osi ne 
ki nase fa milies: B C R- A B L, S R C fa mil y ki nases, c- KI T, e p hri n ( E P) rece pt or ki nases, a n d P D G F β 
rece pt or. Eac h of t hese pr otei n ki nases has bee n str o n gl y li n ke d t o m ulti ple f or ms of h u ma n 
mali g na n cies. I n a d ults, t he ma xi m u m plas ma c o nce ntrati o n of d asati ni b after oral a d mi nistrati o n is 
o bser ve d bet w ee n 0. 5 a n d 6 h o urs. T he o bser ve d effects fr o m f o o d were n ot cli nicall y rele va nt.  T h e 
o ve rall ter mi nal half-life is 3- 5 h o urs. T he dr u g e x hi bits d ose pr o p orti o nal i ncreas es i n A U C a n d 
li near eli mi nati o n c haract eristics o ver t he d ose ra n ge of 1 5 m g t o 2 4 0 m g/ d a y i n a d ults.  Dasati ni b is 
pri maril y met a b olize d i n t he li ver b y t h e h u ma n C Y P 3 A 4 e nz y me, is a si g nifica nt i n hi bit or of 
C Y P 3 A 4. Dasati ni b ma y decrease t he m eta b olic cl eara n ce of dr u gs t hat are si g nifica ntl y meta b olize d 
b y t he C Y P 3 A 4 e nz y me. D ue t o t he p ote ntial of d asati ni b t o pr ol o n g t he Q T/ Q Tc, ca uti o n m ust be 
use d w he n a d mi nisteri n g it wit h ot her p ote ntial Q Tc pr ol o n gi n g m e dicati o ns. D ue t o t he p ossi bilit y of 
gastr oi ntesti nal, c ar diac, a n d c uta ne o us h e m orr ha ge, a v oi d usi n g me di cati o ns t hat i n hi bit platelet 
f u ncti o n or a ntic oa g ul a nts i n c o nj u ncti o n wit h Dasati ni b. Dasati ni b is n ot a p - gl yc o pr otei n i n hi bit or. 
 
F or m ulati o n a n d sta bilit y: Dasati ni b is a vaila ble as ta blets of 2 0 m g, 5 0 m g, or 7 0 m g. T h e c ore ta blet 
is s urr o u n de d b y a fil m c oati n g t o pre v e nt e x p os ure t o t he acti ve dr u g s u bst a nce d uri n g h a n dli n g. If 
ta blets are c ut or cr us h e d, pr oce d ures t o pre v e nt e x p os ure t o t he acti ve dr u g s u bsta nce s h o ul d be 
f oll o we d. Pre g na nt w o m e n or breastfee di n g m ot h ers s h o ul d n ot ha n dle cr us he d a n d/ or br o k e n 
dasati ni b ta blets. 
 
T he i ntact dasati ni b ta blets ca n be place d (a n d all o we d t o diss ol ve) i n 1 o u nce of le m o na de (a d o u ble 
stre n gt h j uic e is rec o m m e n de d t o o bsc ure t he bitter taste), or 1 o u nce of preser vati ve-free a p pl e j uice, 
or 1 o u nce of preser vati v e-free ora n ge j uice. 
 
T he f oll o wi n g (i.e., ste ps 1 t hr o u g h 7) is t he pr oce d ure f or t he pre p arati o n of t he le m o na de d osi n g 
s ol uti o n. F or preser vati ve-free a p pl e j uice or pres er vati ve-free ora n ge j uice, ste ps 2 t hr o u g h 7 s h o ul d 
be f oll o we d. 
 
Mi x t he c o nte nts of o ne 1 2 o u nce ca n of Mi n ute Mai d Pre mi u m Fr oze n C o nce ntrate wit h 2 ca ns (i. e. 
t he e m ptie d le m o na de c o ntai ner) of water. T his will pr o d uce le m o na de t h at is a little m ore t ha n t wice 
as c o nce ntrate d as t he i nstr ucti o ns o n t he ca n wit h a s weeter taste. Pleas e kee p t he le m o na de s ol uti o n 
refri gerate d w he n n ot i n use. 
 
Place 1 o u nce ( 3 0 m L) of t his le m o na de s ol uti o n i nt o a dri n ki n g glass. 
 
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I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Place t he pr o per d ose of i ntact ta blets i nt o t he le m o na de. Please b e s ure t o al wa ys wear pr otecti ve 
gl o ves w h e n ha n dli n g t he me dicati o n. A mas k is n ot re q uire d w he n ha n dli n g t he me di cati o n.  
 
Al wa ys use t he 1 oz of le m o na de. D o n ot i n creas e t he le m o na de v ol u me. Start ti mi n g f or 2 0 mi n utes. 
At a p pr o xi matel y t he 5 mi n ute mar k, s wirl t he c o nte nts of t he gl ass well f or a b o ut 3 sec o n ds. 
 
At a p pr o xi matel y t he 1 5 mi n ute mar k, s wirl t he c o nte nts of t he gl ass a sec o n d ti me. At t he 2 0 mi n ute 
mar k, s wirl t he c o nte nts of t he gl ass o ne last ti me. I m me diat el y a d mi nister t he e ntire c o nte nts of t h e 
glass. 
 
I n or der t o e ns ure a d mi nistrati o n of t he e ntire me dicati o n d ose, a ri nsi n g ste p is necessar y. A d d 0. 5 
o u nce ( 1 5 m L) of le m o na de i nt o t he sa me glass t hat has j ust bee n e m ptie d. S wirl t he c o nte nts t o 
re m o ve a n y re mai ni n g si g ns of ta bl ets fr o m t he si des or b ott o m of t he gl ass. 
 
A d mi nister t he was hi n g l e m o na de t o t he patie nt. T he i ntact b ottles s h o ul d be st ore d at c o ntr olle d r o o m 
te m perat ur e ( 1 5°- 2 5° C or 5 9°- 7 7 °F) a n d pr otecte d fr o m li g ht. 
 
S u p plier: C o m merciall y a vaila ble  
 
T o xicit y: T he m ost fre q u e ntl y re p orte d a d verse e v e nts i ncl u de fl ui d rete nti o n ( ple ural eff usi o n), 
diarr hea, na usea, a b d o mi nal pai n, ras h, hea dac he, fati g u e, v o miti n g, blee di n g e v e nts a n d 
m yel os u p pressi o n. T he m ost fre q ue ntl y re p ort e d seri o us a d verse e v e nts i ncl u de p yre xia, fe brile 
ne utr o pe nia, gastr oi ntesti nal blee di n g, p ne u m o nia, t hr o m b oc yt o pe ni a, d ys p nea, a n e mia a n d car diac 
fail ure ( 3 %).  Less c o m m o nl y re p orte d are a n ore xia, de h y drati o n, a b d o mi nal diste nsi o n a n d 
flat ule nce, fl us hi n g, pr uritis, ele vate d creati ni ne, a n d ne ur o pat h y. Ele v ati o ns i n tra nsa mi nases a n d 
bilir u bi n ca n us uall y b e ma na ge d wit h d ose re d ucti o ns or d ose i nterr u pti o n. H y p o calce mia d uri n g 
dasati ni b t hera p y ca n be ma na ge d wit h oral calci u m s u p ple me ntati o n. 
 
1 9.  
IM A TI NI B ( Glee v ec ®, i mati ni b mes yl ate, f or merl y k n o w n as S TI 5 7 1) F or P h + A L L p atie nts 
o nl y.  See p ac ka ge i nsert f or a d diti o nal i nf or mati o n 
 
S o urce a n d p h ar mac ol o g y:  i mati ni b mes ylat e is a p he n yl a mi n o p yri mi di ne deri vati ve a n d is a 4- [( 4-
Met h yl- 1- pi perazi n yl) met h yl- N- [ 4- met h yl- 3-[[ 4-( 3-p yri di n yl)- 2- p yri mi d-i n yl] a mi n o]- 
p he n yl] be nza mi de met ha nes ulf o nate.  It is a pr ot ei n-t yr osi n e ki nase i n hi bit or t hat i n hi bits t he Bcr- A bl 
t yr osi ne ki nas e, t he c o nstit uti ve a b n or mal t yr osi ne ki nase create d b y t he P hila del p hia c hr o m os o me 
a b n or malit y. 
 
F or m ulati o n a n d sta bilit y:  Eac h fil m-c oat e d ta blet c o ntai ns 1 0 0 m g or 4 0 0 m g of i mati ni b free bas e.  
T he dr u g s h o ul d be st ore d at 2 5° C ( 7 7° F); e x c ursi o ns per mitte d t o 1 5° C- 3 0° C ( 5 9° F- 8 6° F).  T he 
ta blets s h o ul d be dis pe nse d i n a ti g ht c o nt ai ner, U S P, a n d pr otecte d fr o m m oist ure. 
 
T he prescri be d d ose s h o ul d be a d mi nistere d orall y, wit h a meal a n d a l ar ge glass of water.  I n 
c hil dre n, t he dail y d ose ma y b e s plit i nt o t w o – o nce i n t he m or ni n g a n d o nce i n t he e v e ni n g.  F or 
pa tie nts u na ble t o s wall o w t he fil m-c oate d t a blets, t he ta blets ma y b e dis perse d i n a gl ass of wat er or 
a p ple j uice.  T he re q uir e d n u m ber of ta blets s h o ul d be place d i n t he a p pr o priate v ol u me of be v era ge 
(a p pr o xi matel y 5 0 m L f or a 1 0 0- m g ta blet, a n d 2 0 0 m L f or a 4 0 0- m g ta blet) a n d stirre d wit h a s p o o n.  
T he  s us pe nsi o n s h o ul d be a d mi nistere d i m me diat el y after c o m plete disi nte grati o n of t he ta blet. 
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I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
S u p plier: C o m merciall y a vaila ble 
 
T o xicit y:  C o m m o n t o xicities i ncl u de d ys pe psia/ h eart b ur n, n a usea/ v o miti n g, hea dac he, 
m yel os u p pressi o n, a n d fati g ue.  O ccasi o nal t o xicities i ncl u de fe v er, e d e ma i n li m bs, face, peri or bital 
area, wei g ht gai n, i ncreas e d S G O T/ S G P T, al kali ne p h os p hatase, bilir u bi n, a b d o mi nal pai n a n d 
cra m pi n g, m yal gia, art hral gia, d ecreas e d b o ne marr o w cell ularit y, l y m p h o pe nia, ecze ma der matitis, 
ras h, m uscle pai n a n d cra m pi n g, a n ore xia, a n d pi g me ntati o n c ha n ges ( h y p o- vitili g o).  Rare t o xicities 
i ncl u de cere bral e de ma, mele na/ GI blee di n g, a ne mia, diarr hea, d ys p h a gia, es o p ha gitis, o d y n o p ha gi a, 
he m orr ha ge/ blee di n g wit h o ut gra d e 3 or 4 t hr o m b oc yt o p e nia, p ne u m o nitis/ p ul m o nar y i nfiltrat es, late 
he pat ot o xicit y a n d decrease i n t he heart’s a bilit y t o p u m p bl o o d.  
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I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X III: D E FI NI TI O N S R E L A T E D T O I N F E C TI O U S DI S E A S E S 
 
I. 
A S S E S S M E N T S 
 
A.  Fe ver: A si n gl e te m perat ure of > 3 8. 3° C ( 1 0 1° F) or > 3 8. 0° C ( 1 0 0. 4° F) o n t w o 
occasi o ns wit hi n 1 2 h o urs.  T he meas ure me nt m ust be oral wit h gl ass or I V A C  
t her m o meters or at t he t y m pa nic me m bra ne b y i nfrare d i nstr u me nts ( T h er m osca n). 
T he sa me met h o d s h o ul d be use d t hr o u g h o ut t he fe brile e pis o de f or eac h p atie nt. 
B.  Ne utr o pe nia: N e utr o p hil c o u nt < 5 0 0/ m m 3 or < 1, 0 0 0/ m m3 wit h pre dicte d decli ne 
t o < 5 0 0/ m m 3. 
C.  D urati o n of fe ver ( f or e pis o des of fe ver wit h ne utr o pe nia): T he i nitial te m perat ur e 
is t he o ne i m me diatel y b ef ore t h e first d ose of a nti bi otics a n d G C S F.  T his is 
desi g nat e d as zer o h o ur.  T he e n d of a fe brile peri o d is at t he ti me of t he first 
te m perat ur e of 3 8. 0°C or less w hic h is s ustai ne d at t his le vel o ver a peri o d of 2 4 
h o urs or l o n ger wit h o ut a nti p yretic i nter ve nti o n.  T he d urati o n of fe ver is t he 
n u m ber of h o urs fr o m zer o h o ur t o t he e n d of t he fe brile peri o d. 
D.  A nti bi otic t hera p y:  A n y s yste mic a nti bacterial dr u g will be c o nsi dere d as a nti bi otic 
t hera p y w het h er gi ve n orall y or pare nt erall y.  T o pical a nti bi otics will n ot be 
i ncl u de d. 
E.  A ntif u n gal t hera p y:  A n y a ntif u n gal dr u g a d mi nistere d orall y or pare nterall y will 
be c o nsi dere d a ntif u n gal t hera p y.  A ntif u n gal t hera p y will be cate g orize d f or 
a nal ysis as: 
1.  Treat me nt f or oral ca n di diasis 
N ystati n 
Cl otri maz ole tr oc hes 
Micaf u n gi n Fl uc o n az ole 
V oric o naz ole 
 
2.  Treat me nt f or s yst e mic m yc oses (i ncl u des e m piri cal use) 
S yste mic a m p h oteri ci n B (sta n dar d a n d li p os o mal) 
Fl uc o naz ole 
V oric o naz ole 
P osac o naz ole  
Itr ac o n az ole  
Micaf u n gi n 
 
II. 
B A C T E RI A L 
 
1.  Bact ere mia o nl y: D efi ne d as a gr o wt h of a n or ga nis m t hat is j u d ge d n ot t o be a c o nta mi na nt 
i n a bl o o d c ult ure dra w n d uri n g a fe brile e pis o de. Or ga nis ms are c o nsi dere d c o nta mi na nts if 
t he y are p art of s ki n fl ora (e. g., di p ht her oi ds ot her t ha n C ory ne b acteri u m jei kei u m , B acill us 
s p p. n ot B. cere us, Pr o pi o ni b acteri u m s p p., c o a g ul ase- ne g ative st a p hyl oc occ us ( C N S) or 
Micr oc occ us s p p. ) a n d if t he y are is olate d fr o m o nl y o ne c ult ure rece ptacle. All ot her 
or ga nis ms are re gar de d as pat h o ge ns.  ( S pecif y cat heter-relate d or n ot.) 
2.  Bact erial se psis:  p ositi ve bl o o d c ult ure f or a n y b acteri u m pl us cli nical e vi d e nce of 
i nfecti o n (fe v er, c hills, h y p ote nsi o n, etc.).  ( S pecif y cat heter-relate d or n ot.) 
 
St. J u d e
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
3.  Uri nar y tract i nfecti o n: uri ne c ol o n y c o u nt of 1 0 0, 0 0 0 or great er of a si n gle or ga nis m 
pl us s y m pt o ms, d ys uria, fla n k pai n, etc.  As y m pt o matic bacti uria is t he sa m e c ol o n y 
c o u nt wit h o ut s y m pt o ms. 
4.  P ne u m o nia ( bacterial):  ra di o gra p hic discer ni ble i nfiltrate pl us is olati o n of p ote ntiall y 
ca usati ve bacteria fr o m br o nc h oal ve olar la va ge, bl o o d or bi o ps y s peci me n.  If p ositi ve 
bl o o d c ult ure, c o de as bacterial se psis wit h p ne u m o nia. 
5.  Me ni n gitis:  p ositi ve c ult ure of ca usati ve bacteria fr o m C S F pl us s y m pt o ms c o m pati ble 
wit h me ni n gitis. 
6.  Oste o m yelitis:  ra di o gra p hic lesi o ns pl us p ositi ve bl o o d or b o ne as pirate/ bi o ps y c ult ures. 
7.  Ac ute Otitis Me dia:  p h ysicia n dia g n osis pl us a nti bi otic treat me nt. 
8.  P har y n gitis:  o nl y if gr o u p A beta he m ol ytic stre pt oc occ us is is olate d fr o m t hr oat c ult ure i n 
patie nt wit h s y m pt o ms. A p ositi ve ra pi d stre pt oc occal test is acce pta bl e i n place of c ult ure.  
Ot her t y p es of p h ar y n gitis will n ot be c o nsi dere d. 
9.  Cell ulitis:  er yt he m a a n d i n d urati o n pl us is olati o n of bacteria fr o m as pirate or drai na ge. 
 
III. 
F U N G A L I N F E C TI O N S 
 
A.  Ca n di diasis 
 
1.  Oral: prese n ce of t y pi cal w hitis h lesi o ns o n t he m uc osal s urface wit h yeast or 
pse u d o m ycelia o n gra m stai n or K O H pre parati o n or is olati o n of C a n di d a s pecies i n 
c ult ure fr o m t he m o ut h. 
2.  Es o p ha geal or uri nar y bl a d der: e vi de n ce of tiss ue i n v ol ve me nt pr o ve n b y e n d osc o p y 
a n d bi o ps y pl us is olati o n of f u n g us i n c ult ure.   
 
B.   
I n v asi ve F u n gal I nfecti o ns1 4 7 
 
1.  
P r o ve n i n vasi ve f u n gal i nfecti o n ( n ot e n de mic m yc osis) 
 
A nal ysis a n d s p eci me n  
M ol ds
a 
Yeasts a 
Micr osc o pic a n al ysis: 
sterile material 
Hist o pat h ol o gic, 
c yt o p at h ol o gic, or dire ct 
micr osc o pic e x a mi nati o n b 
of a s peci me n o bt ai ne d b y 
nee dle as pir ati o n or bi o ps y 
i n w hic h h y p h ae or 
mela nize d yeast -li ke f or ms 
are see n acc o m pa nie d b y 
e vi de nce of ass ociat e d 
tiss ue da ma ge 
Hist o pat h ol o gic, 
c yt o p at h ol o gic, or direct 
micr osc o pic e x a mi nati o n b 
of a s peci me n o bt ai ne d b y 
nee dle as pir ati o n or bi o ps y 
fr o m a n or mall y sterile site 
( ot her t ha n m uc o us 
me m bra nes) s h o wi n g yeast 
cells –  f or e x a m ple, 
Cry pt oc occ us s pecies 
i n dicate d b y e nca ps ulate d 
b u d di n g yeasts or C a n di d a 
s pecies s h o wi n g 
pse u d o h y p h ae or tr ue 
h y p hae c 
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
C ult ure  
Sterile material  
Rec o ver y of a m ol d or 
“ blac k yeast” b y c ult ure of 
a s peci me n o btai ne d b y a 
sterile pr oce d ure fr o m a 
n or mall y sterile a n d 
cli nicall y or 
ra di o gra p hicall y a b n or m al 
site c o nsiste nt wit h a n 
i nfecti o us disease pr ocess, 
e x cl u di n g br o nc h oal v e olar 
la va ge fl ui d, a cra nial si n us 
ca vit y s p eci me n, a n d uri ne  
 
 
Rec o ver y of a yeast b y 
c ult ure of a s a m ple 
o btai ne d b y a sterile 
pr oce d ure (i ncl u di n g a 
fres hl y place d [ < 2 4 h a g o] 
drai n) fr o m a n or mall y 
sterile site s h o wi n g a 
cli nical or ra di o gra p hical 
a b n or malit y c o nsiste nt wit h 
a n i nfecti o us diseas e 
pr ocess  
Bl o o d  
Bl o o d c ult ure t hat yiel ds a 
m ol d d (e. g. F us ari u m 
s pecies) i n t he c o nt e xt of a 
c o m pati ble i nfecti o us 
disease pr ocess  
Bl o o d c ult ure t hat yiel ds 
yeast (e. g. Cry pt oc occ us  or 
C a n di d a  s pecies) or yeast-
li ke f u n gi ( e. g. 
Tric h os p or o n s pecies) 
Ser ol o gic al a nal ysis:  C S F  
N ot a p plica ble  
Cr y pt oc occal a nti ge n i n 
C S F i n dicates disse mi nate d 
c yr o pt oc occ osis  
a  If c ult ure is av ail a ble, a p pe n d t he i de ntific ati o n at t he ge n us or s pecies level fr om t he c ult ure res ults.  
b Tiss ue a n d cells s u b mitte d f or hist o p at h ol o gic or cyt o p at h ol o gic st u dies s h o ul d be st ai ne d by 
Gr oc ott ‐G o m orri met he n a mi ne silver st ai n or by peri o dic aci d Sc hiff st ai n, t o f acilit ate i ns pecti o n of f u n g al 
str uct ures. W he never p ossi ble, wet m o u nts of s peci me ns fr o m f oci rel ate d t o i nv asive f u n g al dise ase s h o ul d 
be st ai ne d wit h a fl u oresce nt dye (e. g., c alc ofl u or or bl a nk o p h or).  
c C a n di d a, Tric h os p or o n,  a n d ye ast ‐like Ge otric h u m  s pecies a n d Bl ast osc hiz o myces c a pit at us  m ay als o f or m 
pse u d o hy p h ae or tr ue hy p h ae.  
e Rec overy of As per gill us  s pecies fr o m bl o o d c ult ures i nv ari a bly re prese nts c o nt a mi n ati o n  
 
2.  Pr o ba ble i n vasi ve f u n gal i nfecti o n ( n ot e n de mic m yc osis)  
 
H ost fact ors a 
 R ece nt hist or y of ne utr o p e nia ( < 0. 5 x 1 0 9 ne utr o pils/ m m 3) f or > 1 0 da ys) 
te m p orall y relate d t o t he o nset of f u n gal diseas e 
 R ecei pt of a n all o ge neic ste m cell tra ns pla nt 
 P r ol o n ge d use of c ortic oster oi ds (e x cl u di n g a m o n g patie nts wit h aller gic 
br o nc h o p ul m o nar y as p er gill osis) at a mea n mi ni m u m d ose of 0. 3 m g/ k g/ da y of 
pre d nis o ne e q ui val e nt f or > 3 wee ks. 
 Tr eat me nt wit h ot her rec o g nize d T cell i m m u n us u p pressa nts, s uc h as c ycl os p ori ne, 
T N F- α bl oc kers, s pecific m o n ocl o nal a nti b o dies (s uc h as ale mt uz u ma b), or 
ne ucle osi de a n al o g ues d uri n g t he past 9 0 da ys. 
 I n h erite d se v ere i m m u n o deficie nc y (s uc h as c hr o nic gra n ul o mat o us disease or se vere 
c o m bi ne d i m m u n o deficie nc y) 
 
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Cli nical criteria b 
 L o w er res pirat or y tr act f u n gal disease c 
o  T he  prese n ce of 1 of t he f oll o wi n g 3 si g ns o n C T: 
 De nse, w ell-circ u mscri be d lesi o n(s) wit h o ur wit h o ut a hal o si g n 
 Air -cresce nt si g n 
 C a vit y 
 Tr ac h e o br o nc hitis 
o  Tr ac h e o br o nc hial ulcerati o n, n o d ule, pse u d o me m bra ne, pla q ue, or es c har see n o n 
br o nc h osc o pic a nal ysis 
 S i n o nasal i nfecti o n 
o  Ima gi n g s h o wi n g si n usitis pl us at leas 1 of t he f oll o wi n g 3 si g ns: 
 Ac ute l ocalize d pai n (i ncl u di n g pai n ra di ati n g t o t he e ye) 
 Na sal ulcer wit h blac k es c har 
 E x te nsi o n fr o m t he para n asal si n us acr oss b o n y barriers, i ncl u di n g i nt o t he or bit 
 C N S i nfecti o n 
o  1 of t he  f oll o wi n g 2 si g ns: 
 F ocal lesi o ns o n i ma gi n g 
 Me ni n geal e n ha n ce me nt o n M RI or C T 
 D isse mi nate d ca n di diasisd 
o  At lea st 2 of t he f oll o wi n g 2 e ntities after a n e pis o de of ca n di d e mia wit hi n t he 
pre vi o us 2 wee ks: 
 S mall, tar get-li ke a bscess es ( b ull’s e ye lesi o ns) i n li ver or s plee n 
 Pr o gressi ve reti nal e x u dates o n o p ht hal m ol o gic e x a mi nati o n 
 
M yc ol o gic al criteri a 
 Dire ct test (c yt ol o g y, dir ect micr osc o p y, or c ult ure) 
o  M ol d  i n s p ut u m, br o nc h oal ve olar la v a ge fl ui d, br o nc hial br us h, or si n us as pirate 
sa m ples, i n dicate d b y 1 of t he f oll o wi n g 
 Prese nce of f u n gal ele me nts i n dicati n g a m ol d 
 Rec o ver y b y c ult ure of a m ol d (e. g. As p er gill us, F us ari u m, Zy g o mycetes, or 
Sce d os p ori u m  s peci es) 
 In dir ect tests ( det ecti o n of a nti ge n or cell- wall c o nstit ue nts) e 
o  As pe r gill osis 
 Galact o ma n n a n a nti ge n d etecte d i n plas ma, ser u m, br o nc h oal ve olar la va ge, or 
C S F 
o  In v asi ve f u n gal disease ot her t ha n cr y pt o c occ osis a n d z y g o m yc oses 
 β- D - gl uca n d etecte d i n ser u m 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
N O T E:  Pr o b a ble I F D re q uires t he prese nce of a h ost f act or, a cli nic al criteri a o n, a n d a myc ol o gic al criteri o n.  
C ases t h at meet t he criteri a f or a h ost f act or a n d a cli nic al criteri o n b ut f or w hic h myc ol o gic al criteri a are a bse nt 
are c o nsi dere d p ossi ble I F D. 
a H ost f act ors are n ot sy n o ny m o us wit h risk f act ors a n d are c h ar acteristics by w hic h i n divi d u als pre dis p ose d t o 
I F Ds c a n be rec o g nize d.  T hey are i nte n de d pri m arily t o a p ply t o p atie nts give n tre at me nt f or m ali g n a nt dise ase 
a n d t o reci pie nts of all o ge n eic he m at o p oietic ste m m cell a n d s oli d- or g a n tr a ns pl a nts.  T hese f act ors are als o 
a p plic a ble t o p atie nts w h o receive c ortic oster oi ds a n d ot her T-cell s u p press a nts as well as t o p atie nts wit h 
pri m ary i m m u n o deficie n cies. 
b M ust be c o nsiste nt wit h t he myc ol o gic al fi n di n gs, if a ny, a n d m ust be te m p or ally rel ate d t o c urre nt e pis o de 
St. J u d e
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I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9


T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c Every re as o n a ble atte m pt s h o ul d be m a de t o excl u de a n alter n ative eti ol o gy 
d T he prese nce of si g ns a n d sy m pt o ms c o nsiste nt wit h se psis sy n dr o me i n dic ates ac ute disse mi n ate d dise ase, 
w here as t heir a bse n ce de n otes c hr o mic disse mi n ate d dise ase 
e T hese tests are pri m arily a p plic a ble t o as per gill osis a n d c a n di di asis a n d are n ot usef ul i n di a g n osi n g i nfecti o ns 
d ue t o Cry pt oc o cc us s pecies or Zy g o mycetes (e. g. R hiz o p us, M uc or, or A bsi di a s pecies).  Detecti o n of n ucleic 
aci d is n ot i ncl u de d, bec a use t here are as yet n o v ali d ate d or st a n d ar dize d met h o ds. 
 
3.  
P o ssible i n vasi ve f u n gal i nfecti o n ( n ot e n de mic m yc osis) 
 
I n t he t a ble a b o v e, cas es t hat meet t he criteri a f or a h ost fact or a n d a cli nical criteri o n 
b ut f or w hic h m yc ol o gical criteria are a bse nt are c o nsi dere d p ossi ble I F D. 
 
C.   
Hist o plas m osis:  a dia g n osis of disse mi nate d disease ma y be esta blis he d b y a p ositi ve 
Hist o pl as m a  a nti ge n test o n C S F, uri ne or ser u m b y EI A, or t he prese n ce of 
c haracteristic i ntracell ular yeast f or ms i n a p eri p heral bl o o d s mear or i n b o n e marr o w. 
 
Criteria f or t he dia g n osis of e n de mic m yc os es  
Dia g n osis a n d criteri a  
Pr o ve n e n de mic m yc osis  
I n a h ost wit h a n ill ness c o nsiste nt wit h a n e n de mic m yc osis, 1 of t he f oll o wi n g 
 Re oc o ver y i n c ult ur e fr o ma  s peci me n o btai ne d fr o m t he affecte d 
site or fr o m bl o o d 
 Hist o pat h ol o gi c or direct micr osc o pic de m o nstrati o n of a p pr o pri ate 
m or p h ol o gic f or ms wit h a tr ul y disti ncti ve a p p eara nce 
c haracteristic of di m p or p hic f u n gi, s u c h as C occi di o des  s pecies 
s p her ules, Bl ast o myces d er m atitis  t hic k-walle d br oa d -base d 
b u d di n g yeasts, P ar acci di o i des br asile nsis m ulti ple b u d di n g yeast 
cells, a n d, i n t he cas e of hist o plas m osis, t he prese nce of 
c haracteristic i ntracell ular yeast f or ms i n a p h a g oc yt e i n a 
peri p heral bl o o d s mear or i n tiss ue macr o p ha ges  
 F or c o cci di oi d o m yc osis, de m o nstrati o n of c occi di oi dal a nti b o d y i n 
C S F, or a 2 -dil uti o n rise meas ure d i n 2 c o ns ec uti v e bl o o d sa m ples 
teste d c o nc urre ntl y i n t he setti n g of a n o n g oi n g i nf ecti o us disease 
pr ocess.  
 F or parac o cci di oi d o m yc osis, de m o nstrati o n i n 2 c o nsec uti ve ser u m 
sa m ples of a preci piti n ba n d to parac occi di oi di n c o nc urre ntl y i n 
t he setti n g of a n o n g oi n g i nfecti o us disease pr ocess 
Pr o ba ble e n de mic m yc osis  
 Prese nce of a h ost fact or, i ncl u di n g b ut n ot li mite d t o t h ose 
s pecifie d i n # 2 Ta ble a b o ve, pl us a cli nical pict ure c o nsiste nt wit h 
e n de mic m yc osis a n d m yc ol o gical e vi de nce, s uc h as p ositi ve 
Hist o plas ma a nti ge n t est res ult fr o m uri ne, bl o o d, or C S F  
 
N ote:  E n de mic myc osies i ncl u des hist o pl as m osis, bl ast o myc osis, c occi di oi d o myc osis, 
p ar ac o cci di oi d o myc osis, s p or otric h osis, a n d i nfecti o n d ue t o Pe nicilli u m m ar neffei.  O nset wit hi n 3 
m o nt hs after prese nt ati o n defi nes a pri m ary p ul m o n ary i nfecti o n.  T here is n o c ate g ory of p ossi ble 
e n de mic myc osis, as s uc h, bec a use neit her h ost f act ors n or cli nic al fe at ures are s ufficie ntly s pecific; 
s uc h c ases are c o nsi dere d t o be of v al ue t o o li mite d t o i ncl u de i n cli ncic al tri als, e pi de mi ol o gic al 
st u dies, or ev al u ati o ns of di a g n ostic tests. 
St. J u d e
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
D.   
Ot hers:  t he i n vesti gat or ma y i ncl u d e certai n ot her i nfecti o us diseases of u ni q ue nat ure.  
Acce pt a nce re q uir es decisi o n bef ore dec o di n g occ urs a n d wit h t he a gree me nt of t he 
pri nci pal i n vesti gat or a n d a n atte n di n g fr o m t he I nfecti o us Diseas e De p art me nt. 
 
I V.  
P R O T O Z O A N 
 
A.  
P ne u m ocystis c ari nii  P ne u m o nia:  discer ni ble ra di o gra p hic lesi o n pl us i de ntificati o n of P. 
cari nii  i n br o nc h oal ve olar la va ge fl ui d, bi o ps y or i n d uce d s p ut u m. 
B.  
C ry pt os p ori di osis:  C. p ar u m  i de ntifie d i n st o ol pl us diarr hea. 
C.  
T ox o pl as m osis:   see A C T G pr ot oc ol 2 5 4.  
 
V.  
T O P O G R A P HI C A L 
 
A.   
T he f oll o wi n g di a g n oses are acce pta ble f or o bjecti vel y i de ntifie d i nfecti o ns wit h o ut 
c o nfir mati o n of eti ol o g y. 
1.   
P ne u m o nia:  lesi o n o n ra di o gra p h 
2.   
Oste o m yelitis:  ra di ol o gical dia g n osis 
3.   
Si n usitis:  ra di ol o gical di a g n osis ( x-ra y, C T, M RI) 
4.   
Cell ulitis:  p h ysicia n dia g n osis 
 
VI.  
F E V E R O F U N D E T E R MI N E D E TI O L O G Y 
 
B.   
Fe ver wit h o ut a n y f oc us or eti ol o g y i de ntifie d b y cli nical hist or y, p h ysic al 
e x a mi nati o n, ra di ol o gical or micr o bi ol o gic fi n di n g.  I d e ntif y as: 
1.  
ne utr o pe nic = A N C < 5 0 0/ m m 3  
2.   
n o n ne utr o pe nic =  A N C > 5 0 0/ m m3 
 
VII. 
C U L T U R E N E G A TI V E S E P SI S 
 
I n t he I n t he a bs e nce of a p ositi ve c ult ure, a s yste mic res p o nse t o a p ossi ble i nfecti o n b y 
he m o d y n a mic i nsta bilit y, f ocal or m ulti ple or ga n i n v ol ve me nt s uc h as p o or s ki n perf usi o n, 
oli g uria, h y p o x e mia, a n d/ or altere d me ntal stat us or let har g y. 
 
 
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T O T X VI 
 
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D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X I V: C O M M O N S U B S T R A T E S, I N HI BI T O R S A N D I N D U C E R S O F 
C Y P 3 A 4/ 3 A 5 
 
T he f oll o wi n g lists descri be me dicati o ns w hic h are c o m m o n C Y P 3 A 4 s u bstrates, i n hi bit ors a n d 
i n ducers. T his list s h o ul d n ot be c o nsi dere d all i ncl usi ve. C o ns ult P har mace utical Ser vices f or 
s pecific i nf or mati o n o n meta b olis m b y  C Y P 3 A 4/ C Y P 3 A 5. 
S u bstr ates  
Macr oli de a nti bi otics  
clarit hr o m yci n  
er yt hr o m yci n  
N O T  azit hr o m yci n  
A nti -arr h yt h mics 
q ui ni di ne  
Be nz o diaze pi nes  
al praz ola m  
diaze pa m  
mi daz ola m 
triaz ola m 
I m m u ne m o d ulat ors 
c ycl os p ori ne  
tacr oli m us ( F K 5 0 6) 
sir oli m us 
HI V  a ntivirals  
i n di na vir 
nelfi na vir  
rit o na vir 
sa q ui na vir 
A nti hista mi nes  
aste miz ole 
c hl or p he nira mi ne 
terfe ni di ne 
Calci u m  c ha n nel  bl oc kers  
a ml o di pi ne 
diltiaze m  
fel o di pi ne 
lerca ni di pi ne 
nife di pi ne  
nis ol di pi ne 
nitre n di pi ne  
vera pa mil  
H M G  C o A re d uctase i n hi bit ors at or vastati n 
ceri vastati n  
l o vastati n 
N O T  pra vastati n  
Si m vastati n  
 
 
 
 
 
 
 
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T O T X VI 
 
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I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
S u bstrates  - c o nti n ue d 
Ster oi d  6 beta -O H  
estra di ol  
h y dr oc ortis o ne  
pr o gester o ne  
test oster o ne 
Ot her  
alfe nta n yl  
b us pir o ne 
cafer g ot  
caffei ne = > T M U  
c ocai ne 
da ps o ne  
c o dei ne-N -de met h yl  
de xtr o met h or p ha n  
e plere n o ne 
fe nta n yl 
fi nasteri de 
i mati ni b 
hal o peri d ol  (i n part)  
iri n oteca n 
Li d ocai ne  met ha d o ne  
o n da nsetr o n  
pi m ozi de pr o pra n ol ol  
q ui ni ne 
sal metrer ol 
sil de nafil 
ta m o xife n 
paclita xel  
traz o d o ne 
vi ncristi ne  
zale pl o n 
z ol pi de m 
I n hi bit ors 
HI V  a nti virals 
dela viri di ne  
i n di na vir 
nelfi na vir  
rit o na vir 
sa q ui na vir 
 
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Ot her  
a mi o dar o ne N O T azit hr o m yci n  
ci meti di ne 
ci pr ofl o x aci n  
clarit hr o m yci n  
diet h yl -dit hi ocar ba mate  
diltiaze m  
er yt hr o m yci n  
fl uc o naz ole 
fl u v o x a mi ne 
gest o de ne  
gra pefr uit  j uice 
itrac o naz ole 
ket oc o naz ole  
mife prist o ne  
nefaz o d o ne  
n orfl o xaci n  
n orfl u o x eti ne  
mi befra dil  
vera pa mil  
v oric o naz ole  
I n d ucers 
 
HI V  a nti virals 
efa vire nz  
ne vira pi ne  
Ot her  
bar bit urates  
car ba maze pi ne  
gl uc oc ortic oi ds  
m o dafi nil  
p he n o bar bital  
p he n yt oi n  
rifa m pi n 
St.  J o h n’s w ort  
tr o glitaz o ne 
p i o glitaz o ne 
rifa b uti n 
 
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
A P P E N DI X V - T O T X VI R A N D O MI Z A TI O N F O R M 
T O T X VI  R A N D O MI Z A TI O N  F O R M  
 
Please fa x t he c o m plete d f or m t o t he St. J u de Ce ntral P har mac y at 
.  
Please call t he St. J u de p har mac y at 
 t o let t he m k n o w y o u’ ve faxe d a re q uest f or T O T X VI 
ra n d o mizati o n.  If y o u are u na ble t o se n d t his f or m b y F A X , t he i nf or mati o n ma y be gi ve n b y p h o ne a n d se nt b y 
F A X  later. 
 
M R N:                                                           I nitials:                               Date:                                    
                                                                                                                                M M          D D          Y Y                              
Na me:                                                                                                                                
 
Has partici pa nt/ L A R si g ne d i nf or me d c o nse nt, a greei n g t o partici pate i n P E G -as para gi nase r a n d o mizati o n? 
 
 
  
Y es 
 
 
N o ( Partici pa nt will n ot be ra n d o mize d -d o N O T fa x t he f or m t o p har mac y)  
 
N ote:  P artici p a nts wit h D o w n sy n dr o me will N O T be r a n d o mize d - D O N O T f ax t he f or m t o p h ar m acy . 
 
Stratificati o n fact ors ( p lease c hec k o nl y o ne i n eac h cate g or y) 
 
1.  Ris k stat us at start of co nti n uati o n p hase ( see secti o n 4. 0): 
 
 
 L o w  
 Sta n dar d  
 
 Hi g h  
 
2.  F or  st a n d ar d ris k partici pa nts o nl y:  
 
 
 T -Li nea ge  
 B -Li nea ge  
 U n k n o w n  
 
3.  F or St a n d ar d r is k, T-Cell li ne a ge partici pa nts o nl y:  
 
 
 Da y 1 5 M R D ne gati ve   
 Da y 1 5 M R D p ositi ve  
 U n k n o w n  
P h ysicia n:  
 
 
( pri nt na me) 
 
C o ntact na me if n ot t he p h ysicia n:   
 
Tele p h o ne c o n t act n u m b er f or q uesti o ns: 
 
P har macist :  Please  e mail d ose assi g n me nt t o e mail gr o u p T O T X VI R a n d o miz ati o n Res ults  
I n cl u de patie nt’s n a me, me dical rec or d n u m ber a n d P E G-as para gi nase d os e assi g n m e nt.   
P ri nt a c o p y of y o ur e mail messa ge a n d place it i n t he n ote b o o k wit h t his f or m 
 
 
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X VI: P S Y C H O L O GI C A L T E S T B A T T E R Y F O R C HI L D R E N O V E R T H R E E 
Y E A R S O F A G E 
D o m ai n  
Me as ure  
Br o a d skill  
T as k c h ar acteristics  
A ge  
ra n ge  
Ti me  
I ntelli ge n ce 
S B -V 1  
R o uti n g S u btests  
Gl o bal C o g niti ve 
F u ncti o n  
O bject Series/ Matrices a n d  
V oca b ular y s u bt ests  
3 +  
2 0  
Atte nti o n & 
E x ec uti ve 
F u ncti o n  
Di git S pa n 2, 3 
A u dit or y Atte nti o n  
& W or ki n g M e m or y  
F or war d - re peat ra n d o m di git 
stra n ds of i ncreasi n g le n gt h 
Bac k war d - re p eat r a n d o m 
di git stra n ds i n re v erse or der  
6 +  
 
5  
 
S patial S pa n 2, 3 
S patial At te nti o n 
& W or ki n g M e m or y  
F or war d - re peat ra n d o m bl oc k 
ta ps of i ncreasi n g l e n gt h  
Bac k war d - re p eat r a n d o m 
bl oc k ta ps i n re verse or der  
6 +  
5  
 
A u dit or y 
Atte nti o n 4  
A u dit or y Selecti ve 
Atte nti o n  
P oi nt t o a pict ure i n dicate d b y  
a s p o ke n w or d; bac k gr o u n d 
n oise is  i ncrease d o v er ti me 
3 +  
5  
 
C P T 5, 6  
S ustai ne d Vis ual 
Atte nti o n  
Selecti vel y res p o n d t o tar gets 
o n a c o m p uter scree n, W hile 
i n hi biti n g res p o nse t o n o n-
tar gets 
4 +  
2 0  
 
A u dit or y W or ki n g 4   
Me m or y  
A u dit or y W or ki n g 
Me m or y  
Re peat w or ds a n d n u m bers 
after or ga nizi n g bas e d o n r ule  
4 +  
5  
 
Retrie val Fl ue n c y 4  
Ver bal Fl ue nc y  
Ge nerate na me of f o o ds, 
pe o ple & a ni mals  
3 +  
5  
( Pare nt 
Meas ures)  
B RI E F 6  
E x ec uti ve F u ncti o n  
Q uesti o n naire ass essi n g 
e x ec uti ve d ysf u ncti o n  
2 +  
1 5  
Me m or y  
C V L T 8, 9  
Ver bal List Lear ni n g  
Lear n ver bal list o ver wit h 
m ulti ple prese ntati o ns, 
i nterfere nce, d ela y & 
rec o g niti o n 
5 +  
1 5  
 
St or y Me m or y 1 0  
St or y Recall  
Recall st ories after si n gl e 
prese ntati o n a n d f oll o wi n g  a 
dela y; rec o g niti o n c uei n g 
pr o vi de d after free recall  
5 +  
1 5  
 
Bea d M e m or y 1 1  
Vis ual Me m or y  
Recrea te bea d patter ns of 
i ncreasi n g le n gt h  
3 +  
5  
 
Re y Fi g ure 1 2  
Vis ual Me m or y  
& Or ga nizati o n  
C o p y a c o m ple x fi g ure 
f oll o we d b y dra wi n g fr o m 
me m or y after s h ort a n d l o n g 
dela ys  
6 +  
2 0  
Pr ocessi n g 
S pee d  
 
 
Vis ual Matc hi n g 4  
Pr ocessi n g S pee d  
Fi n d matc hi n g pairs  
3 +  
3  
 
Decisi o n S pee d 4  
Pr ocessi n g S pee d  
Fi n di n g t w o c o nce pt u all y 
si milar pairs 
3 +  
3  
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Vis ual S patial/ 
Vis ual M ot or  
S patial Relati o ns 4  
Me ntal R otati o n  
& S patial I nte grati o n  
Pic k o bject t hat matc hes 
p uzzle pieces p ut t o get her  
3 +  
5  
 
V MI 1 3  
 
Vis ual Perce pti o n &  
V is ual-M ot or I nte grati o n  
Matc h s ha pes of decreasi n g 
siz e; Dra w s ha pes of 
i ncreasi n g c o m ple xit y 
3 -2 1  
1 5  
M ot or  
P ur d ue Pe g b o ar d 1 4  
Fi ne M ot or S pee d & 
De xterit y  
Place pe gs usi n g d o mi na nt, 
n o n d o mi na nt & b ot h ha n ds  
3 +  
3  
A da pti ve  
A B A S -II1 5  
A da pti ve F u n cti o ni n g  
Pa re nt q uesti o n naire of 
a da pti ve s kills  
Birt h +  
1 5  
S ocial -
E m oti o nal  
B A S C -II1 6  
Ps yc h o -s o cial 
A dj ust me nt  
Pare nt q uesti o n naire of 
be ha vi oral d o mai ns.  
2 -2 1  
1 5  
(1 ) St a nf or d- Bi net, Fift h E diti o n; (2 ) Wec hsler I ntelli ge nce Sc ale f or C hil dre n, F o urt h E diti o n; (3 ) Wec hsler A d ult 
I ntelli ge n ce Sc ale, T hir d E diti o n; (4 ) W o o dc o ck J o h ns o n, T hir d E diti o n; (5 ) C o n ners’ C o nti n u o us Perf or m a nce Test, 
Sec o n d E diti o n; ( 6 ) C o n ners’ Ki d die Perf or m a nce Test; (7 ) Brief R ati n g I nve nt ory of Exec utive F u ncti o n; (8 ) C alif or ni a 
Ver b al Le ar ni n g Test- C hil dre n’s Versi o n; ( 9 ) C alif or ni a Ver b al Le ar ni n g Test, Sec o n d E diti o n; (1 0 ) C hil dre n’s Me m ory 
Sc ale; ( 1 1 ) St a nf or d- Bi net, F o urt h E diti o n; (1 2 ) Rey- Osterriet h C o m plex Fi g ure; (1 3 ) Beery- B ukte nic a Test of Vis u al-
M ot or I nte gr ati o n; ( 1 4 ) P ur d ue Pe g b o ar d Test; (1 5 ) A d a ptive Be h avi or Assess me nt Syste m-II; (1 6 )Be h avi or Assess me nt 
Syste m f or C hil dre n- II. 
 
Refere nces: 
 
1.  R oi d G. Sta nf or d- Bi net I ntelli ge nce Scales, Fift h E diti o n ( S B- V). R olli n g Mea d o ws, I L: T he Ri versi de P u blis hi n g 
C o m pa n y 2 0 0 3. 
2.  W ec hsler D. W ec hsler I nt elli ge nce Scale f or C hil dre n, F o urt h E diti o n, I nte grate d ( WI S C- I V-I). Sa n A nt o ni o, T X: 
Harc ort Assess me nt, I nc or p orate d 2 0 0 4. 
3.  W ec hsler D. W ec hsler A d ult I ntelli ge nce Scale, T hir d E diti o n 
4.  W o o dc oc k R, Mc Gre w K, Mat her N. W o o dc oc k-J o h ns o n III ( WJIII). Itasca, I L: Ri versi de P u blis hi n g 2 0 0 1.  
5.  C o n ners C K. C o n ners’ C o nti n u o us P erf or ma nce T est II. N ort h T o na wa n da, N Y: M ulti- He alt h S yste ms, I nc.; 2 0 0 1. 
6.  C o n ners C K. C o n ners’ C o nti n u o us P erf or ma nce T est; Ki d die Versi o n V. 5. N ort h T o na wa n da, N Y: M ulti- Healt h 
S yste ms, I nc.; 2 0 0 5. 
7.  Gi oia G A, Is q uit h P K, G u y S G, Ke n w ort h y L. T he Be ha vi or Rati n g I n ve nt or y of E xec uti ve F u ncti o n ( B RI E F).  L utz, 
F L: Ps yc h ol o gical Assess me nt Res o urces, I nc or p orate d 2 0 0 1. 
8.  Delis D C, Kra mer J H, Ka pla n E, O ber B A. Calif or nia Ver bal Lear ni n g T est -  C hi l dre n’s E diti o n ( C V L T-C ). Sa n 
A nt o ni o, T X: Harc o urt Assess me nts, I nc or p orate d 1 9 9 4.  
9.  Delis D C, Kra mer J H, Ka pla n E, O ber B A. Calif or nia Ver bal Lear ni n g T est, Sec o n d E diti o n.. Sa n A nt o ni o, T X: 
Harc o urt Assess me nts, I nc or p orate d 2 0 0 0.  
1 0.  C o he n M. C hil dre n’s Me m or y Scale ( C M S). Sa n A nt o ni o, T X: Harc o urt Assess me nts, I nc or p orate d 1 9 9 7. 
1 1.  T h or n di ke R L, Ha ge n E P, Sattler J S. Sta nf or d- Bi net I ntelli ge nce Scale, F o urt h E diti o n ( S B-I V). Itasca, I L: Ri versi de 
P u blis hi n g 1 9 8 6.  
1 2.  Me yers S E, Me yers K R. Re y- Osterreit h C o m ple x Fi g ure ( Re y- O). L utz, F L: Ps yc h ol o gical Assess me nt Res o urces, 
I nc or p orate d 1 9 9 5. 
1 3.  B eer y K E. T he B eer y- B u kte ni ca De vel o p me ntal T est of Vis ual- M ot or I nte grati o n: A d mi nistrati o n, Sc ori n g a n d 
T eac hi n g Ma n ual ( 4 t h e d.; B eer y V MI). P arsi p pa n y, NJ: M o der n C urric ul u m Press 1 9 9 7.  
1 4.  Tiffi n J, As her EJ. T he P ur d ue P e g b oar d: N or ms a n d st u dies of relia bilit y a n d vali dit y. J o ur nal of A p plie d Ps yc h ol o g y 
1 9 4 8; 3 2: 2 3 4- 2 4 7.  
1 5.  Harris o n P, Oa k T. A da pti ve B e ha vi or Assess me nt S yste m, Sec o n d E diti o n ( A B A S- II) 
1 6.  Re y n ol ds C R, Ka m p ha us R W. B e ha vi or Assess me nt S yste m f or C hil dre n, Sec o n d E diti o n ( B A S C-II). Bl o o mi n gt o n, 
M N: P ears o n Assess me nts Res o urces, I nc or p orate d 2 0 0 4. 
St. J u d e
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X VII: S C H E M A 
 
St. J u d e
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T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X VII I: T E S T S P E R F O R M E D F O R G O O D C LI NI C A L C A R E A N D F O R 
R E S E A R C H 
 
T he sta n dar d of care ser vices i n t his st u d y are as f oll o ws: 
 
 Hist or y & p h ysical e x a ms  
 He mat ol o g y:  C B C wit h diff, c oa g ulati o n scree n  
 All bl o o d a n d uri ne c he mistries, li pi d scree n, plas ma 1, 2 5- di h y dr o x y vita mi n D, oste ocalci n, 
t h yr oi d f u n cti o n tests 
 C hest x-ra ys  
 B o ne marr o w f or m or p h ol o g y, c yt oc he mistr y, i m m u n o p he n ot y pi n g, c yt o ge netics, D N A i n d e x, 
m olec ular st u dies, a n d M R D st u dies  
 Peri p heral bl o o d f or M R D  
 L u m bar p u nct ures wit h C S F e x a mi nati o n a n d a d mi nistrati o n of i ntrat hecal c he m ot hera p y  
 Ot he r st u dies as cli nicall y i n dicat e d (e. g. sic kl e cell pre p, he m o gl o bi n el ectr o p h oresis a n d 
G 6 P D scree n f or bla c k c hil dre n, varicella titer, he patitis B a nti ge n, HI V, E B V, T O X O, C M V 
titers) 
 M R I of hi ps a n d k n ees a n d P T/ O T e val uati o ns 
 Me t h otre x ate p har mac o ki netics 
 Q C T f or b o ne de nsit y  
 Ur i nal ysis 
 A m m o ni a le vels  
 T P M T D N A ( T P M T ge n ot y pi n g)  
 T P M T R B C acti vit y a n d 6 T G N R B C testi n g  
 
 
T he rese arc h ser vices are as f oll o ws: 
 
 B o ne marr o w sa m ple f or bi ol o g y st u dies (ta ke n at sa me ti me b o ne marr o w pr oce d ure is d o ne 
f or r o uti ne care at dia g n osis – pre-trial b o ne marr o w) 
 Ge r mli ne D N A/ R N A  
 Ne ur o ps yc h ol o gic al testi n g 
 M R I brai n (i ncl u des se d ati o n) a n d f u ncti o nal M RI brai n 
 P las ma h o m oc ystei ne 
 S er u m a n d C S F f or as p ara gi n ase a n d a nti-as para gi nase a nti b o dies  
 M R D – ali q u ot of C S F sa m ples se nt t o T B A N K 
 S er u m bi o mar kers 
 As para gi nas e a n d d e x a met has o ne acti vit y 
 N K cell rece pt or st u dies 
 I ntesti nal micr o bi o me res earc h – st o ol s peci me ns 
 
  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9