Conditions: Recurrent B-Cell Childhood Acute Lymphoblastic Leukemia Recurrent Childhood B-Lymphoblastic Lymphoma
Keywords: leukemia lymphoma Non-Hodgkins
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
The overall objective of this protocol is to improve the cure rate of relapsed precursor B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma.

This phase II trial is studying risk-directed therapy for B-lymphoblastic leukemia or lymphoma in first relapse. Standard risk (SR) and high risk (HR) participants will receive different therapy. Treatment will consist of chemotherapy for SR participants, and chemotherapy followed by hematopoietic stem cell transplant (HSCT) for HR in first relapse. Induction therapy consists of three blocks of chemotherapy. The first block is a novel immunotherapy regimen that includes chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. SR participants will continue to receive chemotherapy for a total duration of approximately 2 years. HR participants will be candidates for HSCT and will proceed to transplant once a suitable donor is found and their minimal residual disease (MRD) is negative.

Detailed description:
Primary objective

* To estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk-directed therapy.

Secondary objectives

* To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17
* To estimate levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of remission induction therapy for relapsed precursor B-cell ALL.

STUDY DESCRIPTION:

The general treatment plan will consist of chemotherapy for standard-risk participants and chemotherapy followed by HSCT for high risk participants in first relapse of B-precursor ALL or lymphoblastic lymphoma. Remission induction for all participants consists of three blocks of therapy, wherein the first block is a novel immunotherapy regimen that includes cytotoxic chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. Standard-risk patients will continue to receive chemotherapy for a total duration of approximately 2 years. High-risk patients will be candidates for HSCT and will proceed to transplant once a suitable donor is found and the patient achieves negative MRD.

Participants will be assigned to the standard arm if they experience late relapse (\> or = 6 months after completion of frontline therapy) AND maximum residual disease (MRD) is \<0.01% at the end of Block II of remission induction therapy. Provisional standard risk participants (i.e., late relapse) will be re-assigned to high risk if MRD is \> or = 0.01% at the end of Block II. Participants with lymphoma must be in complete remission at the end of Block III.

High risk participants will meet one of the following criteria:

* Early relapse (on therapy or \<6 months after completion of frontline therapy), OR
* Any relapse after hematopoietic stem cell transplant, OR
* MRD \> or = 0.01% at the end of Block II of remission induction therapy, OR
* Re-emergence of MRD at any time after attaining negative MRD on this clinical trial.

Natural killer (NK) cell collection: Donors who meet eligibility criteria will undergo apheresis once. The cells obtained will be purified for CD56+ cells utilizing the CliniMACS selection system. The NK cell product will undergo quality control testing following standard operating procedures of the St. Jude Human Applications Laboratory.

OUTLINE (STANDARD RISK):

REMISSION INDUCTION:

BLOCK I: Patients receive dexamethasone orally (PO) or intravenously (IV) thrice daily (TID) on days 1-8 and 21-28; vincristine sulfate IV on days 1, 21, 28, and 35; rituximab IV on days 4, 13, 20, and 27; clofarabine, cyclophosphamide, and etoposide IV on days 6-10; aldesleukin subcutaneously (SC) once every other day (QOD) on days 11-19; and pegaspargase IV on days 21 and 35. Patients also undergo natural killer (NK) cell infusion on day 12. Patients may receive triple intrathecal therapy comprising methotrexate, therapeutic hydrocortisone, and cytarabine on days 1, 5, 8, 11, 21, and 28. Patients continue on to Block II after count recovery.

BLOCK II: Patients receive methotrexate IV over 24 hours on days 1 and 8 and mercaptopurine PO on days 1-21. Patients also receive triple intrathecal therapy on day 1. High-risk patients with negative MRD continue on to transplantation. All patients with positive MRD continue on to Block III after count recovery.

BLOCK III: Patients receive cytarabine IV over 2 hours twice daily (BID) on days 1-4 and mitoxantrone hydrochloride IV over 1 hour on days 3-5. Patients also receive triple intrathecal therapy on day 7.

INTERIM CONTINUATION (for patients unable to tolerate dose intensive chemotherapy): Patients receive etoposide and cyclophosphamide IV on day 1, methotrexate IV on day 8, mercaptopurine PO on days 8-14, teniposide and cytarabine IV on day 15, dexamethasone PO TID on days 22-26, and vinblastine IV on day 22.

RE-INDUCTION THERAPY: Patients receive clofarabine, cyclophosphamide, and etoposide IV on days 1-5; dexamethasone PO on days 1-6; and pegaspargase on days 6 and 20 and vincristine sulfate IV on days 6, 13, and 20. Patients may also receive triple intrathecal therapy on days 1 and 15. Patients continue on to continuation treatment after count recovery.

CONTINUATION TREATMENT: Patients receive methotrexate IV over 2 hours on day 1 and mercaptopurine PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide and cytarabine IV on day 1 of weeks 3 and 7; vincristine sulfate IV on day 1 of week 4; dexamethasone PO TID on days 1-5 of weeks 4 and 8; and vinblastine IV on day 1 of week 8. Treatment repeats every 8 weeks for up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients may also receive triple intrathecal therapy on day 1 of week 1 of all courses and day 1 of week 5, courses 1-5.

Due to the unavailability of the drug Teniposide (VM-26), etoposide (VP-16) will be substituted for the remaining doses for patients currently on this study. The protocol Section 5.1.3 allows this substitution.

OUTLINE: GROUP 2 (high risk defined as participants not meeting the standard risk criteria noted above):

Patients receive Remission Induction (Blocks I, II, and III) treatment as described above for Group 1. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT) as soon as they have negative MRD. Patients with negative MRD may continue chemotherapy until a suitable donor is found.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 1 year, and then yearly for up to 10 years.

Arms:
arm 1: Interventions: dexamethasone, vincristine sulfate, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, teniposide, vinblastine, natural killer cell infusion, laboratory biomarker analysis, therapeutic hydrocortisone

Cells for infusion are prepared using the CliniMACS System. arm 2: Interventions: dexamethasone, vincristine, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, natural killer cell infusion, allogeneic hematopoietic stem cell transplantation, laboratory biomarker analysis, therapeutic hydrocortisone

Cells for infusion are prepared using the CliniMACS System.

Interventions: intervention 1: dexamethasone intervention 2: vincristine sulfate intervention 3: rituximab intervention 4: clofarabine intervention 5: cyclophosphamide intervention 6: etoposide intervention 7: aldesleukin intervention 8: pegaspargase intervention 9: methotrexate intervention 10: mercaptopurine intervention 11: cytarabine intervention 12: mitoxantrone intervention 13: teniposide intervention 14: vinblastine intervention 15: natural killer cell infusion intervention 16: laboratory biomarker analysis intervention 17: therapeutic hydrocortisone intervention 18: allogeneic hematopoietic stem cell transplantation intervention 19: CliniMACS
Intervention descriptions: intervention 1: given intravenously or orally intervention 2: given intravenously intervention 3: given intravenously intervention 4: given intravenously intervention 5: given intravenously intervention 6: given intravenously intervention 7: given subcutaneously intervention 8: given intravenously intervention 9: given intrathecally or intravenously intervention 10: given orally intervention 11: given intrathecally or intravenously intervention 12: given intravenously intervention 13: given intravenously intervention 14: given intravenously intervention 15: undergo allogeneic natural killer cell infusion intervention 16: correlative studies intervention 17: given intrathecally intervention 18: undergo allogeneic HSCT intervention 19: The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.

Protocol document:
Prot_SAP_000.pdf: 
ALLR18 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
Amendment 3.0, dated 03-19-2018. Resubmitted to IRB 6-12-2018(IRB approved: 6-13-2018) 
St. Jude 
 
Initial version, dated: 11-22-2011, Resubmitted to CT-SRC 01-18-2012 and 02-16-2012, 
Resubmitted to IRB 03-28-2012 and 04-12-2012. (IRB approved: April 19, 2012). 
Amendment 1.0, dated 06-14-2012. Resubmitted to IRB 08-20-2012 (IRB approved: 09-05-2012). 
Revision 1.1, dated 09-18-2012. IRB Approved: 10-18-2012. Activation date: 10-19-12 
Amendment 2.0, dated 12-02-2014. Resubmitted to IRB 02-12-2015. IRB approved: 02-24-2015. 
Revision 2.1, dated 03-10-2015. Resubmitted to IRB 04-20-2015 (IRB approved: 04-24-2015) 
Activated: 06-22-2015 
 
 
 
 
 
 
A PHASE II STUDY OF THERAPY FOR PEDIATRIC RELAPSED OR REFRACTORY 
PRECURSOR B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA AND LYMPHOMA 
 
IDE 11,533 (CliniMACSTM System) 
 
Principal Investigator 
Sima Jeha, M.D. 
Department of Oncology 
 
Co-Investigators 
 
Patrick Campbell, M.D., Ph.D.1 
Brandon Triplett, M.D.6 
Cheng Cheng, Ph.D.3 
Monika Metzger, M.D.1 
John K. Choi, M.D., PhD.4 
Charles G. Mullighan, MBBS (Hons), MSc, M.D.4 
Kristine R. Crews, Pharm.D., BCPS2 
Jennifer L. Pauley, Pharm.D.2 
William E. Evans, Pharm.D.2 
Ching-Hon Pui, M.D.1 
Aditya H. Gaur, M.D.5 
Mary V. Relling, Pharm.D.2 
Charles Gawad, MD, PhD1 
Terrence Geiger, M.D.4 
Tanja A. Gruber, M.D., Ph.D.1 
Raul C. Ribeiro, M.D.1 
Jeffrey E. Rubnitz, M.D., Ph.D.1 
Hiroto Inaba. M.D., Ph.D.1 
John T. Sandlund, M.D.1 
Jun J. Yang, Ph.D.2 
 
 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, Tennessee 38105-3678 
Telephone: (901) 595-3300 
 
 
Departments of Oncology1, Pharmaceutical Sciences2, Biostatistics, 3 Pathology4, Infectious 
Diseases5, and Bone Marrow Transplantation & Cellular Therapy6 
 
 
Contents of this document may not be extracted without permission from the Principal Investigator. 
CM1, dated 8-3-18 (IRB Approved: 8-7-18) 
Activated: 6-25-2018 
CTG# - NCT01700946 
ALLR18 


ALLR18 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
Collaborating Investigators/Institutions 
 
Deborah Schiff, MD 
Pediatric Hematology/Oncology/Blood and Marrow Transplant 
Children's Hospital San Diego/UCSD 
3020 Children's Way 
San Diego, CA 92123 
Phone: 
Fax: 
 
 
Kenneth M. Heym, MD 
Cook Children’s Medical Center 
Hematology and Oncology Center 
901 Seventh Ave., Ste. 220 
Ft. Worth, TX 78104 
Phone: 
 
 
External Collaborating Scientists/Institutions 
 
Dario Campana, MD, PhD 
Elaine Coustan-Smith, MSc 
National University of Singapore 
21 Lower Kent Ridge Road 
Singapore 119077 


St. Jude 
IRB NUMBER: Pro12817 
IRB APPROVAL DATE: 03/18/2019 
 
 
 
 
 
August 3, 2018 
To: 
IRB 
From: Sima Jeha, MD 
 
RE: 
ALLR18, A Phase II Study of Therapy for Pediatric Relapsed or Refractory 
Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma. 
 
Clarification Memo 
 
Due to the unavailability of the drug Teniposide (VM-26), etoposide (VP-16) will be substituted 
for the remaining doses for patients currently on this study. The protocol Section 5.1.3 allows 
this substitution. Participants will be informed of the substitution verbally, and this will be 
documented in the medical record. The substitution of VP-16 will continue until 46 participants 
are enrolled to ensure that 40 evaluable patients are enrolled. 
 
1. During Interim Continuation (Section 5.3), Week 3 teniposide will be substituted with 
Etoposide 300 mg/m2 on Day 1 
 
Week Agent 
Dosage and 
route 
# Doses Schedule 
1 
VP16 
(etoposide) 
300 mg/m2 IV 
1 
Day 1 
CYCLO 
(cyclophosphamide) 
300 mg/m2 IV 
1 
Day 1 
2 
MTX 
(methotrexate) 
40 mg/m2 IV 
1 
Day 1 
6MP 
(mercaptopurine) 
75 mg/m2 PO 
7 
Days 1-7 
3 
VP16 
(etoposide) 
300 mg/m2 IV 
1 
Day 1 
ARA-C 
(cytarabine) 
300 mg/m2 IV 
1 
Day 1 
4 
DEX 
(dexamethasone) 
12 mg/m2 PO 
15 
Days 1-5 TID 
VINBLAST 
(vinblastine) 
6 mg/m2 IV 
1 
Day 1 


St. Jude 
IRB NUMBER: Pro22817 
IRB APPROVAL DATE: 03/18/2019 
 
 
2. During Continuation Treatment (Sections 5.5.1 and 5.5.2), Weeks 3 and 7 teniposide will 
be substituted with etoposide 300 mg/m2 on Day 1. 
 
 
Week 
Agents 
1 
MTX + 6MP 
2 
MTX + 6MP 
3 
VP16 + ARA-C 
4 
DEX + VCR 
5 
MTX + 6MP 
6 
MTX + 6MP 
7 
VP16 + ARA-C 
8 
DEX + VINBLAST 
 
5.5.2 Drug dosages, schedules and routes – Continuation treatment 
 
MTX (methotrexate) 
6MP (mercaptopurine) 
VP16 (etoposide) 
VCR (vincristine) 
40 mg/m2 
75 mg/m2 
300 mg/m2 
2 mg/m2 
1 dose, IV* day 1 (weeks 1, 2, 5 & 6) 
days 1-7, PO (weeks 1, 2, 5 & 6) 
1 dose, IV day 1 (weeks 3 & 7) 
(max 2 mg), 1 dose, IV push day 1 (week 4) 
ARA-C (cytarabine) 
300 mg/m2 
1 dose, IV day 1 (weeks 3 & 7) 
DEX (dexamethasone) 
12 mg/m2 
15 doses, PO day 1-5 TID (weeks 4 & 8) 
VINBLAST (vinblastine) 
6 mg/m2 
1 dose, IV day 1 (week 8) 


ALLR18 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
 
Protocol and Title: ALLR18, A PHASE II STUDY OF THERAPY FOR PEDIATRIC 
RELAPSED OR REFRACTORY PRECURSOR B-CELL ACUTE LYMPHOBLASTIC 
LEUKEMIA AND LYMPHOMA 
Principal Investigator: Sima Jeha, M.D. 
IDE holder: St. Jude Children’s Research Hospital, IDE 11,533 (CliniMACS system) 
Brief overview: This phase II trial is studying risk-directed therapy (standard and high risk 
participants will receive different therapy) for precursor B-cell acute lymphoblastic leukemia or 
lymphoma in first relapse. 
Interventions: 
Biologicals: rituximab, Interleukin-2 
Drugs: vincristine, dexamethasone, clofarabine, cyclophosphamide, etoposide, PEG- 
asparaginase, Erwinia asparaginase, methotrexate, mercaptopurine, leucovorin, cytarabine, 
mitoxantrone, teniposide, vinblastine, imatinib, dasatinib, nilotinib 
Device: CliniMACS™ System 
Procedure: Intrathecal chemotherapy (ITMHA), NK cell infusions, allogeneic hematopoietic 
stem cell transplant (HSCT) 
Other: CNS irradiation, testicular irradiation 
Brief outline of treatment plan: The general treatment plan will consist of chemotherapy for 
standard-risk participants and chemotherapy followed by HSCT for high risk participants in first 
relapse of B-precursor ALL or lymphoblastic lymphoma. Remission induction for all 
participants consists of three blocks of therapy, wherein the first block is a novel 
immunotherapy regimen that includes cytotoxic chemotherapy, rituximab and infusion of 
haploidentical NK cells. Standard-risk patients will continue to receive chemotherapy for a total 
duration of approximately 2 years. High-risk patients will be candidates for HSCT and will 
proceed to transplant once a suitable donor is found and the patient achieves negative MRD. 
Study design: Phase II multi-center, non-randomized trial. Primary outcome measure is 3- 
year survival rate. 
Sample size: 40 evaluable participants over 6 years. 
Data management: Data management and statistical analysis will be provided locally by the 
Hematological Malignancies Program clinical research staff, Leukemia/Lymphoma Division 
and Biostatistics Department at St. Jude Children’s Research Hospital. 
Human subjects: The primary risk to participants in this research study is toxicity from the 
multi-modality therapies. For patients with relapsed ALL, there is no salvage regimen that offers 
a good cure rate. The current standard of care is intensive chemotherapy using different 
regimens, and allogeneic transplant for those who have a suitable donor. The primary objective 
of this study is to increase the 3-year survival rate. Rituximab and NK cell therapy has been 
shown to be safe and effective in similar pediatric malignancies, but both are investigational 
therapies for ALL in first relapse. As such, an additional risk to patients participating in this trial 
may be that rituximab and NK cell therapy increase incidence of side effects. Potential benefits 
for patients who participate in this study include a possible increase in progression free survival. 
Since the standard of care is intensive chemotherapy and allogeneic transplant, participants will 
be receiving the standard of care. 


ALLR18 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
Table of Contents 
1.0 
OBJECTIVES ......................................................................................................... 1 
1.1 
Primary Objective ............................................................................................... 1 
1.2 
Secondary Objectives .......................................................................................... 1 
1.3 
Exploratory Secondary Objectives ...................................................................... 1 
2.0 
BACKGROUND AND RATIONALE ................................................................... 2 
2.1 
Remission Induction ........................................................................................... 2 
2.2 
Re-Induction ....................................................................................................... 8 
2.3 
Continuation and Interim Continuation .............................................................. 8 
2.4 
MRD to Determine Indication and Timing of HSCT ......................................... 8 
2.5 
Background and Rationale for Biologic and Ancillary Studies .......................... 9 
3.0 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT ............................... 13 
3.1 
Inclusion Criteria for Participant....................................................................... 13 
3.2 
Exclusion Criteria for Participant ..................................................................... 15 
3.3 
Screening criteria for NK cell donors ............................................................... 15 
3.4 
Inclusion criteria for Selected NK cell donor ................................................... 16 
3.5 
Research Participant Recruitment and Screening ............................................. 16 
3.6 
Enrollment on Study at St. Jude ........................................................................ 16 
3.7 
Enrollment on Study at Collaborating Sites ...................................................... 16 
4.0 
RISK ASSIGNMENT ........................................................................................... 17 
4.1 
Standard Risk .................................................................................................... 17 
4.2 
High Risk .......................................................................................................... 17 
5.0 
TREATMENT PLAN ........................................................................................... 17 
5.1 
General Overview ............................................................................................. 17 
5.2 
Remission Induction ......................................................................................... 19 
5.3 
Interim Continuation (4 weeks) ........................................................................ 29 
5.4 
Re-Induction Therapy ....................................................................................... 30 
5.5 
Continuation Treatment .................................................................................... 31 
5.6 
Plan for HSCT................................................................................................... 33 
5.7 
Prophylaxis and Treatment for CNS Disease ................................................... 34 
5.8 
Participation of St. Jude Collaborating Sites in the Treatment Plan ................. 34 
5.9 
Participation of St. Jude Affiliates the Treatment Plan ..................................... 34 
5.10 
Summary of Intrathecal Therapy on ALLR18 .................................................. 35 
6.0 
TREATMENT MODIFICATIONS ...................................................................... 36 
6.1 
Philadelphia Chromosome-Positive (Ph+) ALL ............................................... 36 
6.2 
PEG-Asparaginase Allergies/Hypersensitivity ................................................. 37 
6.3 
Irradiation for Participants with CNS Disease .................................................. 37 
6.4 
Treatment for Testicular Involvement .............................................................. 38 
6.5 
Obesity .............................................................................................................. 38 
6.6 
Infants ............................................................................................................... 38 
6.7 
Down Syndrome Participants ........................................................................... 38 
6.8 
Participants with Renal Dysfunction ................................................................ 39 
6.9 
Participants with Hepatic Dysfunction ............................................................. 39 
6.10 
Cardiotoxicity ................................................................................................... 40 
6.11 
Vinca Alkaloid Neurotoxicity ........................................................................... 40 
6.12 
Pancreatitis ........................................................................................................ 40 
6.13 
TPMT Status and Thiopurine Dosage ............................................................... 41 


ALLR18 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
7.0 
SUPPORTIVE CARE GUIDELINES .................................................................. 41 
7.1 
Management of Tumor Lysis Syndrome .......................................................... 41 
7.2 
Management of Hyperleukocytosis .................................................................. 42 
7.3 
Prophylaxis for Pneumocystis Jiroveci Pneumonia (REQUIRED) ................. 42 
7.4 
Prophylaxis for Fungal Infections (REQUIRED .............................................. 42 
7.5 
Prophylaxis for Bacterial Infections (REQUIRED) .......................................... 43 
7.6 
Management of Febrile Neutropenia ................................................................ 44 
7.7 
Growth Factors .................................................................................................. 44 
7.8 
Management of Capillary Leak Syndrome Related to Clofarabine .................. 44 
7.9 
Etoposide Reactions .......................................................................................... 45 
7.10 
Drug Interactions .............................................................................................. 46 
7.11 Cytokine Release Syndrome Related to Administration of IL-2 and NK cells 46 
8.0 
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION .................................... 47 
9.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ..................... 48 
9.1 
Response Evaluations ....................................................................................... 50 
9.2 
Suggested Long-Term Follow-up Evaluations ................................................. 50 
10.0 
EVALUATION CRITERIA ................................................................................. 51 
10.1 
Response Criteria for Leukemia ....................................................................... 51 
10.2 
Response Criteria for Lymphoblastic Lymphoma ............................................ 51 
10.3 
Toxicity Evaluation Criteria .............................................................................. 52 
10.4 Acceptable Percentage of Missed Doses for Commercially Available Drugs . 52 
11.0 
OFF THERAPY AND OFF STUDY CRITERIA ................................................ 52 
11.1 
Off-Study Criteria ............................................................................................. 52 
11.2 
Off-Treatment Criteria ...................................................................................... 53 
12.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS ............. 53 
12.1 
Reporting Adverse Experiences (AEs) and Deaths on Treatment .................... 53 
12.2 
Recording AEs and SAEs ................................................................................. 56 
12.3 
Reporting Requirements to the FDA ................................................................ 56 
12.4 
Reporting to St. Jude Regulatory Affairs Office (RAO) .................................. 57 
12.5 
Reporting AEs to and from St. Jude and Collaborating Sites/Affiliates ........... 57 
13.0 
DATA COLLECTION, MONITORING AND CONFIDENTIALITY ............... 58 
13.1 
Data Collection ................................................................................................. 58 
13.2 
Data Collection Instructions for Collaborating Sites ........................................ 58 
13.3 
Study Monitoring .............................................................................................. 59 
13.4 
Confidentiality .................................................................................................. 60 
14.0 
STATISTICAL CONSIDERATIONS .................................................................. 60 
14.1 
Accrual .............................................................................................................. 60 
14.2 
Monitoring of Induction Toxicities and Short-Term Efficacy .......................... 60 
14.3 
Primary Objective ............................................................................................. 61 
14.4 
Secondary Objectives ........................................................................................ 63 
14.5 
Exploratory Objectives ..................................................................................... 64 
15.0 
OBTAINING INFORMED CONSENT ............................................................... 65 
15.1 
Consent/Assent at Enrollment ........................................................................... 65 
15.2 
Consent at Age of Majority ............................................................................... 66 
15.3 
Consent When English is Not the Primary Language ....................................... 66 
16.0 
REFERENCES ..................................................................................................... 67 


ALLR18 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
APPENDICES: 
 
Appendix I: Tests performed for good clinical care and for research 
Appendix II: Pediatric rituximab infusion guidelines 
Appendix III: Drug/device/biologic agent information 
Appendix IV: ALLR18 schema 
Appendix V: Treatment and evaluation calendars 
Appendix VI: Definitions related to infectious diseases 
Appendix VII:  Common substrates, inhibitors and inducers of CYP3A4/3A5 
Appendix VIII: HDMTX administration and monitoring guidelines, Induction Block II 


ALLR18 
Page 1 of 67 
Amendment 3.0, dated: 03-19-2018 
IRB Approval date: 06-13-2018 
St. Jude 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
1.0 
OBJECTIVES 
 
The overall objective of this protocol is to improve the cure rate of relapsed 
precursor B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. 
 
1.1 
Primary Objective 
 
To estimate the 3-year survival rate of participants with first relapse or primary 
refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk- 
directed therapy. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To determine minimal residual disease (MRD) levels at the end of 
remission induction therapy for participants with relapsed precursor B-cell 
ALL and compare the results with those in ALLR17. 
 
1.2.2 
To estimate levels of CD20 expression at baseline, during treatment with 
dexamethasone-containing chemotherapy and following rituximab treatment 
in Block 1 of remission induction therapy for relapsed precursor B-cell ALL. 
 
1.3 
Exploratory Secondary Objectives 
 
1.3.1 
To assess donor natural killer (NK) cell immunoglobulin-like receptor 
(KIR) repertoire and explore the efficacy of NK cell infusions followed by 
rituximab in relapsed ALL. 
 
1.3.2 
To study whether pre-existing or emerging development of serum 
antibodies to asparaginase is related to hypersensitivity reactions or 
exposure to asparaginase or to anti-leukemic or adverse effects of therapy, 
in participants with relapsed ALL. 
 
1.3.3 
To describe the effect of prophylactic antibiotics on: 
 
a. The evolution of antibiotic resistance in peri-rectal swab isolates of 
Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, 
Streptococcus mitis and enterococci. 
b. Resistance patterns of bacterial isolates from all sterile site cultures. 
 
Completed with amendment 3.0 
 
1.3.4 
To characterize global gene expression and copy number changes in 
leukemic cells at relapse and to compare to initial diagnosis (when 
available) to improve knowledge of mechanisms of relapse. 


ALLR18 
Page 2 of 67 
Amendment 3.0, dated: 03-19-2018 
IRB Approval date: 06-13-2018 
St. Jude 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
1.3.5 
To determine in vitro sensitivity of pretreatment relapsed leukemic cells to 
anti-leukemic agents and compare to in vitro sensitivity at diagnosis (when 
available). 
 
1.3.6 
To engraft freshly harvested relapsed ALL cells into murine models of 
ALL to gain insights into therapy resistance. 
 
1.3.7 
To study the development of resistant clones during therapy for relapsed ALL. 
 
2.0 
BACKGROUND AND RATIONALE 
 
Cure rates for newly diagnosed ALL have improved dramatically over the past 50 
years. In the recent St Jude Total XV study, the estimated 5-year event-free survival 
(EFS) and overall survival (OS) rates for all 498 patients were 85.6% and 93.5% 
respectively.1 On the other hand, for children who relapse outcome is generally poor 
despite intensified therapy.2 In particular, outcome for those who relapse while still 
on therapy is dismal across multiple co-operative group and single institution studies 
(5-year OS between 11% and 29%).3,4 Preliminary analyses of the St Jude ALLR16 
study, which utilized an upfront topotecan window treatment followed by intensive 
multi-agent chemotherapy, demonstrated a 5-year OS of 40% while in the subsequent 
ALLR17 study with an etoposide and teniposide based regimen 3-year OS estimate is 
49% for all patients. Hence, there is a need for novel therapeutic approaches. The 
outcome for patients with primary induction failure is also poor.5 The 10-year 
survival rate is estimated at 32%. Thus, these patients will be eligible for ALLR18. 
An exception is children < 6 years of age with induction failure and favorable 
cytogenetics (hyperdiploidy or ETV6-RUNX1). This group of patients has a higher 
survival rate of approximately 72% with chemotherapy alone and will be excluded 
from ALLR18. 
 
2.1 
Remission Induction 
 
MRD is an excellent surrogate marker for relapse free survival.4 Interim analyses of 
ALLR17 revealed that 71% of participants continue to be MRD positive at the end 
of remission induction therapy and the outcome of these participants is poor. 
Similar results have been reported by the Children’s Oncology Group.5 Thus, in 
ALLR18, we will attempt to decrease this rate of MRD positivity by utilizing a 
novel immunotherapy regimen of rituximab, cytotoxic chemotherapy and 
haploidentical NK cells. The hypotheses for the induction regimen in ALLR18 are: 
 
1) Immunotherapy with the anti-CD20 monoclonal antibody rituximab can 
be given safely in children with relapsed precursor B-cell ALL in 
combination with cytotoxic chemotherapy. 
2) Pre-treatment with dexamethasone will cause up-regulation of CD20 
expression in relapsed ALL blasts leading to increased rituximab mediated 
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3) NK cell infusions from a haploidentical donor in addition to direct anti- 
leukemia effects will enhance efficacy of rituximab. 
4) Cytotoxic chemotherapy will be synergistic with rituximab and will also 
augment NK cell function by induction of neutropenia. 
5) This strategy will lower MRD levels, improve complete remission (CR) 
rates and ultimately event free survival. 
 
2.1.1 Rationale for rituximab 
 
The CD20 antigen is a B-cell specific marker which is expressed on the surface of 
B-lymphocytes from the pre B-cell stage through the memory cell stage. 
Rituximab, a chimeric anti-CD20 monoclonal antibody is approved by the FDA 
for the treatment of patients with non-Hodgkin lymphoma and chronic 
lymphocytic leukemia. In the pediatric setting, rituximab is shown to be safe and 
efficacious in immune mediated disorders and non-Hodgkin lymphoma.6-8 Though 
all its mechanisms of action are not completely understood, rituximab’s anti-tumor 
effects are attributed to direct inhibition of signaling pathways, complement 
mediated cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC).9 
Studies have also demonstrated synergy with cytotoxic chemotherapy.9 Rituximab 
has been extensively used for the treatment of lymphomas but its use in ALL is 
limited. Nevertheless, a recent study in adult patients with ALL incorporated 
rituximab in a backbone of multi-agent chemotherapy (HyperCVAD) and 
demonstrated a survival benefit in patients less than 60 years (3-year overall 
survival rates of 75% versus 47% with standard HyperCVAD alone).10 The 
potential therapeutic role of rituximab in childhood ALL is not defined but interest 
in this agent was ignited by a study showing that pretreatment of leukemic blasts 
with steroids either in vitro or in vivo caused up-regulation of CD20 and increased 
their susceptibility to rituximab in vitro.11 At diagnosis, 52% of patients expressed 
CD20 on their peripheral blood blasts while on Day 8 of therapy, CD20 expression 
was noted in 75% of patients. These finding, which we have confirmed in 
preliminary results at St Jude, suggest that rituximab therapy could be incorporated 
in the treatment of ALL and can potentially augment leukemic cell kill. 
 
2.1.2 Rationale for the choice of chemotherapeutic agents in the first induction block 
 
Cytotoxic chemotherapy will include clofarabine, a highly active nucleoside 
analog approved by the FDA for children with relapsed/refractory ALL.12,13 
Clofarabine was rationally designed as a hybrid molecule to improve the activity 
and overcome the toxicities associated with fludarabine and cladribine. The 
cytotoxic effects of clofarabine are due to its inhibition of DNA synthesis and 
repair, induction of apoptosis and possibly other mechanisms.14 In the pediatric 
phase 1 study, the maximum tolerated dose (MTD) was determined to be 52 
mg/m2/day for 5 days. Of the 17 ALL patients enrolled, 4 achieved CR and one 
PR, resulting in an overall response rate of 29%.12 Dose limiting toxicities were 
reversible elevations in transaminases and skin rash. In the pediatric phase II 
study, 61 patients with ALL were enrolled and the overall response rate was 


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30%.15 In vitro studies have demonstrated synergy between clofarabine and the 
alkylator cyclophosphamide.16 Cells treated with clofarabine impede repair of 
cyclophosphamide induced DNA damage. In the multicenter pediatric phase I 
CLO-218 study, clofarabine was given in combination with cyclophosphamide 
and etoposide.17 Dose escalation was performed for all three drugs. An MTD was 
not reached, but the recommended phase II doses for the three agents were 40, 
440 and 100 mg/m2/day respectively for 5 consecutive days. The overall response 
rate for the 20 ALL patients enrolled was 55% (9 CR and 2 CRp). Treatment 
related toxicities were mainly infectious with documented infections in 72% of 
patients. Elevation in transaminases was commonly noted. This combination of 
agents has been subsequently used for patients with relapsed and refractory ALL 
by multiple centers. Three reports are available: a study of 25 patients from 
Italy18, a retrospective review of 18 patients from the UK19 and the St Jude 
experience of 11 patients with relapsed or refractory ALL.20 All three reports 
concluded that the regimen was efficacious with an acceptable safety profile even 
in patients who had received a prior transplant and in infants. Supportive care, 
especially prophylaxis against infectious diseases was imperative. The St Jude 
frontline ALL study Total XVI incorporates this regimen for high-risk patients 
and for infants. NKHEM is another ongoing St Jude study that utilizes the same 
combination followed by infusion of haploidentical natural killer cells. In 
ALLR18, we will add non- myelosuppressive agents such as vincristine, 
dexamethasone and PEG-asparaginase in induction block I while awaiting count 
recovery. Prophylaxis against infectious agents (bacterial and fungal) will be 
required. Due to anticipated risk of increased hepatotoxicity, myelosuppression 
and infections in patients with prior hematopoietic stem cell transplant, these 
patients will be evaluated in a separate stratum for toxicity. 
 
2.1.3 Rationale for the addition of NK cells 
 
NK cells are normal lymphocytes that can kill target cells without the need for 
prior sensitization or activation. The ability of NK cells to perceive alterations in 
target cells is mediated by a balance of signals through many surface receptors 
including KIRs and activating receptors such as CD16a. CD16a is a low-affinity 
transmembrane Fragment c gamma receptor IIIA (FcγRIIIA) found predominantly 
in NK cells and is essential for ADCC.21 The FcγRIIIA binds clustered IgG 
molecules bound to antigens on the cell surface of target cells and does not bind 
circulating monomeric IgG. Therefore, ADCC is highly specific and occurs only 
when the target cells are coated with antibody. The CD16b (FcγRIIIB) GPI-linked 
form on neutrophils binds to IgG but is inefficient in inducing any signal or 
functional effect.21 Because one of the primary mechanisms of action of rituximab 
is primarily through ADCC, strategies to optimize NK cell mediated ADCC will 
be crucial to improve the outcomes of patients treated with rituximab. 
 
Four strategies may be used to optimize NK cell therapy. First is to adoptively 
transfer normal NK cells from a healthy donor to the patients. This is particularly 
important in this protocol, as the patient’s NK cell number and function are 


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expected to be low after chemotherapy. Using the St. Jude NKCELL protocol, we 
performed 12 consecutive purifications of NK cells from 12 normal volunteers. The 
system uses a two-step procedure.22 First, mononuclear cells obtained by 
leukapheresis are depleted of T cells by CD3+ cell depletion using the CliniMACS. 
Second, the CD3-depleted product is enriched for CD56+ cells using the 
CliniMACS. The final products contained a median of 1.6 x 108 mononuclear cells 
and 91% CD3-CD56+ cells. In addition, the final products had minimal 
contamination with T cells (at or below the lower limit of detection in 10 of the 12 
products) or B cells (median 0.2%). Thus, recipients are expected to be at low risk 
for GVHD or EBV lymphoproliferative disease. We also found that the expression 
of KIRs, adhesion molecules, intracellular cytokines, perforin, and granzyme B in 
NK cells was not significantly different before and after cell purification. Extensive 
proliferative capacity and potent antitumor activity of the NK cells were 
demonstrated by using an immunodeficient mouse model.23 In addition, GVHD 
developed in all mice transplanted with unpurified mononuclear cells, but in none 
of the 10 mice transplanted with purified NK cells. 
 
Based on these preclinical data, four clinical protocols have been opened at St. 
Jude to transplant normal NK cells from parents into leukemia patients. The data 
from the first cohort of 10 patients from the NKAML protocol (FDA IDE 11533) 
were published recently.24 This study demonstrated that haploidentical NK cell 
infusions were safe, feasible, and efficacious. The conditioning, IL-2, and NK cell 
transplantation were all well tolerated. The median NK cell dose was 27 x 106/kg 
(range, 5 to 80 x 106/kg). The average hospital stay was only 2 days. None of the 
patients have acute or chronic graft-versus-host disease. Correlative laboratory 
studies showed that all patients had transient donor NK cell engraftment for a 
median of 10 days. NK cell cytotoxicity against K562 cells normalized in all 
patients by Day 7 after NK cell transplantation. Importantly, there was a 
significant expansion of KIR mismatched cells in the blood, from a median of 
only 210/ml on Day 2 to a median of 5,800/ml on day 14. 
 
The second strategy to optimize NK cell therapy in this protocol is the use of 
chemotherapy that is efficacious in ALL to induce cytopenia and to up-regulate 
stress ligand expression before rituximab and NK cell administration. We have 
shown that T cell activity may dominate NK cell activity; thus, T-cell 
lymphopenia may facilitate NK cell function.25,26 Furthermore, we have recently 
shown that blood DCs may suppress NK cell through IL-6 and IL-10.27 Taken 
together, these data suggest that giving chemotherapy before NK cell 
administration may augment NK cell function and expansion by induction of 
leukopenia. Furthermore, DNA damage is known to be able to trigger ATM and 
ATR pathways to up-regulate genotoxic stress ligands such as NKG2D ligand 
expression.28 NKG2D is a potent NK cell activating receptor and signals through 
DAP10 for degranulation and IF-γ production. 
 
The third approach to augment NK cell cytotoxicity towards ALL is to capitalize 
on the unique ability of St. Jude in selecting an optimal KIR mismatched donor.29 


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The laboratory of Dr. Leung has set up comprehensive KIR typing assays for the 
highly polymorphic KIR genes.30 In humans, KIRs are encoded by a gene family 
on chromosome 19q13 and recognize specific HLA class I alleles in HLA-A, -B 
and -C. The receptors specific for MHC class I molecules on target cells inhibit 
NK effector functions such as cytotoxicity and cytokine production. Clinical data 
suggest that KIR2DL2 and KIR2DL3 that recognize an epitope shared by HLA-C 
group 1 allotypes, KIR2DL1 that recognizes an epitope shared by HLA-C group 2 
allotypes, and KIR3DL1 that recognizes an epitope shared by HLA-Bw4 
allotypes are important determinants of anti-tumor effect. In hematopoietic stem 
cell transplantation (SCT), the NK cells of the donor may exert potent anti- 
leukemia effects if the cognate MHC class I epitope is absent on the patient’s 
leukemia cells for the donor’s inhibitory KIRs.31 This potency has been 
demonstrated in both mouse models and in clinical transplantation. In a study of 
51 patients at the St. Jude Children’s Research Hospital with direct measurement 
of the donor KIR repertoire, patients with a KIR matched donor had a 4-fold 
higher risk of relapse than those with a KIR mismatched donor.29 
 
The fourth strategy to optimize NK cell therapy is the use of IL2. In the four 
clinical trials at St. Jude using haploidentical NK cell transplantation, all patients 
received low dose IL-2 (1 million units/m2/dose SQ) every other day starting the 
night before NK cell transplantation. The purpose of the low dose IL-2 
administration is to expand NK cells in vivo and to augment their cytotoxicity. 
Correlative laboratory studies in the first cohort of participants showed that all 
patients had expansion of donor NK cells with a median peak at Day 14 and 
normalization of NK cell cytotoxicity against K562 cells by Day 7 after NK cell 
transplantation.24 Importantly, there was a significant expansion of KIR 
mismatched cells in the blood in the first 2 weeks after transplantation. The IL2 
was well tolerated - there was no associated grade II-IV toxicity, no patients 
required hospitalization, and no patients required discontinuation of IL-2. 
 
2.1.4 Induction Block II 
 
Two doses of HDMTX 5 g/m2 will be given a week apart together with 6MP. This 
regimen was used in Total XIV and will provide good CNS coverage. The second 
dose of methotrexate will be targeted to achieve a steady-state plasma 
concentration of 65 µM as has been done in our frontline studies since Total XV. 
Our goals are to continue to avoid unacceptably low concentrations (albeit in a 
small % of courses), minimize unacceptably high concentrations and avoid GI 
toxicity. Using this approach, we had only 5.1% of courses with grade 3-4 
mucositis (compared to as high as 44% of courses with BFM’s administration of 5 
g/m2 without targeting). In patients who have experienced renal dysfunction, 
require concurrent drugs that might affect MTX clearance, or who are otherwise 
unstable, we will employ intra-course targeting of HDMTX. 
 
Rationale for change in administration of mercaptopurine (revision 2.1) 


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Prior studies assessing the pharmacological and therapeutic impact of giving oral 
mercaptopurine (MP) with food or with dairy products, or giving 6MP at different 
times of day have produced variable results. All of the early studies32-34 enrolled 
small numbers of patients and revealed trends in differences in peak plasma 
concentrations of parent drug or plasma area-under-the-concentration-time curve 
(AUC), but these results were not statistically significant. Other studies35,36 reported 
statistically significant differences in time of maximum drug concentration in 
plasma (tmax) and AUC in the fasting state of parent drug35 or changes in ALL 
disease free survival36 associated with time of day of oral 6MP administration (with 
better results reported for nighttime drug administration in that the risk of relapse 
was 4.6 times greater with the morning administration schedule). 
 
However, these older studies did not assess these variables in the context of 
treatment protocols that utilize erythrocyte thioguanine nucleotides (TGN) levels 
to guide therapy adjustments, nor did they include thiopurine dosing as part of 
multivariate analyses for outcome predictors. A more recent study of 532 patients 
by Schmiegelow (2014) used a Cox multivariate model to show that the circadian 
schedule (morning vs. evening vs. mixed) of MTX/6MP was not of prognostic 
significance for the risk of relapse, and the 10-year cumulative relapse risk was 
below 20% in all groups.37 
 
A separate recent study assessed the effects of “pill-taking” habits on treatment 
adherence, erythrocyte TGN levels & relapse risk in 441 children enrolled on the 
COG AALL03N1 study.38 This study reported no association between relapse risk 
and whether 6MP was taken with food (p=0.5), with dairy (p=0.2), whether tablets 
were swallowed whole vs. crushing/chewing (p=0.7); IV), or time of day: 
evening/night vs. morning/mid-day (p=0.9), varying times vs. non-varying times 
(p=0.9). The 6MP taking habits were also not associated with DI- and age-adjusted 
TGN levels. The authors concluded that the commonly practiced restrictions 
concerning administration with food or at bedtime did not significantly influence 
outcome in their protocol and patient cohort. 
 
Based on these larger and newer studies, that include more careful attention to 
6MP dosing than was true in the earlier studies, and on the fact that 6MP dose is 
adjusted to desired blood counts, we propose to lift the restrictions concerning 
administering MP at bedtime and on an empty stomach to allow patients to take 
6MP at a time of day which is most likely to yield full adherence to the prescribed 
daily dosing of 6MP. As for any daily drug, we recommend that parents 
administer and/or patients take 6MP at a consistent time every day. We also 
strongly recommend that erythrocyte TGN levels continue to be monitored to 
guide 6MP therapy (detect non-adherence and/or inappropriate dosing). Likewise, 
TPMT phenotype/genotype should continue to be assessed for each patient to 
guide the selection of optimal 6MP dosages for each patient. Finally, ALL 
continuation therapy should continue to be guided by measurement of WBC 
throughout therapy, with dosage adjusted made as stipulated in the primary ALL 
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2.1.5 Induction Block III 
 
High dose cytarabine and mitoxantrone will be used. This combination is well 
tolerated in multiple AML regimens.41,42 In the recent UK ALLR3 study for ALL 
in first relapse, mitoxantrone was shown to be beneficial.43 The estimated 3-year 
overall survival was 69% in patients who received mitoxantrone in induction 
versus 45.2% in patients randomized to receive idarubicin. In addition, patients 
are not exposed to mitoxantrone in frontline studies for ALL and it is anticipated 
that the use of this agent will circumvent drug resistance. High dose cytarabine 
will provide good CNS coverage. 
 
2.2 
Re-Induction 
 
A five day course of clofarabine, cyclophosphamide and etoposide along with 
non-myelosuppressive agents dexamethasone, vincristine and PEG-asparaginase, 
similar to Block I induction (without rituximab and NK cells) will be used to 
consolidate remission. 
 
2.3 
Continuation and Interim Continuation 
 
These phases are similar to ALLR17 with the use of rapidly rotating drug pairs 
(modeled after Total XI and ALLR11). This continuation regimen is well 
tolerated in an outpatient setting. Four weeks of this regimen will be used as 
interim continuation between the induction Block III and re-induction phases to 
allow time for recovery from intensive chemotherapy. During continuation 
cyclophosphamide and etoposide will be omitted as patients would have received 
these agents during the induction and re-induction blocks. We will use vinblastine 
in interim continuation and alternating with vincristine in weeks 4 and 8 of each 
cycle of continuation. There are in vitro data showing sensitivity of ALL to 
vinblastine.44 Considering the hematological toxicity of vinblastine, the dose will 
be adjusted according to the patient’s ANC. 
 
Additional interim continuation weeks of chemotherapy will also be given to the 
occasional patients who are deemed unable to tolerate intensive therapy as 
prescribed by the study. Criteria include but are not limited to systemic fungal 
infection, severe thrombosis or grade 3 or 4 hepatic or renal dysfunction. 
 
2.4 
MRD to Determine Indication and Timing of HSCT 
 
Bone marrow MRD will be done at the end of each block of induction therapy. 
Provisional standard-risk patients (i.e. late relapse) with positive MRD (≥0.01%) 
at the completion of Block II will be re-assigned to the high-risk group. Multiple 
studies in first relapse have demonstrated the prognostic implication of positive 
MRD (≥ 0.01%) at the end of 4-6 weeks of therapy.45 In the COG AALL01P2 
study, the 12 month EFS was 80% versus 48% in patients with positive versus 


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negative MRD at the end of the first block of remission induction therapy.5 In the 
UKALLR3 study, patients with MRD ≥ 0.01% at week 5 were candidates for 
stem cell transplant.43 
 
MRD status immediately prior to HSCT is predictive of outcome in precursor B- 
cell ALL. In a report from the BFM group, the cumulative incidence of 
subsequent relapse was 57% in patients with ≥10-4 leukemic cells versus 13% in 
patients with ≤10-4 leukemic cells prior to HSCT.46 Thus, patients with positive 
MRD (≥0.01%) at the end of induction Block II will receive Block III (+/- interim 
continuation) prior to HSCT. If MRD is still detectable or they are not candidates 
for HSCT, they may continue to re-induction therapy or be offered alternate 
studies. They will receive HSCT as soon as MRD is negative and a suitable donor 
is available. 
 
2.5 
Background and Rationale for Biologic and Ancillary Studies 
 
2.5.1 Minimal residual disease (MRD) 
 
MRD is an excellent surrogate marker for response and survival in childhood 
ALL at initial diagnosis.4 At first relapse, studies at St Jude and other institutions 
have also demonstrated the prognostic implication of positive MRD (≥ 0.01%) at 
the end of 4-6 weeks of therapy. In St Jude ALLR11 and ALLR15 studies, the 
cumulative incidence of second relapse was 70.2% for MRD positive patients (≥ 
0.01%) versus 28% for MRD negative patients (p=0.008).45 In the COG 
AALL01P2 study, the 12 month EFS was 80% versus 48% in patients with 
positive versus negative MRD at the end of the first block of remission induction 
therapy.5 The proportion of patients who are MRD positive at the end of re- 
induction therapy is relatively high: 68% in AALL01P2 and 71% in ALLR17. 
Thus, in ALLR18, we will attempt to decrease the rate of MRD positivity by 
utilizing a novel induction regimen. It remains unclear whether patients with 
insufficient reduction of MRD can be salvaged by more intensive treatment. 
 
2.5.2 CD20 expression 
 
The CD20 antigen is expressed on the surface of peripheral blood B-lymphoblasts 
in approximately 50% of patients with precursor B-cell ALL.11 The 
administration of steroids increased this proportion to 75% by day 8 of therapy. 
Up-regulation of CD20 expression sensitizes cells to the cytotoxic effects of 
rituximab.11 Post rituximab, the number of CD20-positive cells is expected to 
diminish rapidly. Thus, we will measure CD20 expression by flow cytometry 
frequently during the first three weeks of induction Block I to study the kinetics of 
CD20 expression in relation to the various components of therapy. 
 
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In humans, NK cells are regulated by KIRs that are encoded by a gene family on 
chromosome 19q13 and recognize specific HLA class I alleles.47 KIRs includes 
receptors with activating as well as inhibitory potential, receptors that have no 
known ligand, and receptors with specificity for MHC class I such as HLA-A, -B 
and -C. The receptors specific for MHC class I molecules on target cells inhibit 
NK effector functions such as cytotoxicity and cytokine production. Each NK cell 
generally expresses at least one inhibitory receptor that recognizes a self HLA 
molecule, thus preventing autoimmunity. Fourteen members of the KIR family 
have been identified on human NK cells thus far.48 The NK cells of the donor may 
exert potent anti-leukemia effects if the cognate MHC class I epitope is absent on 
the patient’s leukemia cells for the donor’s inhibitory KIRs. In a landmark article 
evaluating NK cell alloreactivity in 57 adult patients with AML, none of the 34 
patients who received a KIR-ligand mismatched haploidentical HSCT had a 
disease relapse.49 In an analysis of 130 patients with hematologic malignancies 
undergoing unrelated donor SCT, those with KIR-ligand incompatibility (including 
patients with ALL, CML, and MDS) had higher probabilities of overall survival 
and disease free survival and lower rates of transplant-related mortality and 
relapse.50 In an exclusively pediatric study, with 51 research participants at St. 
Jude, the effect of KIR mismatch on myeloid leukemia was confirmed and a KIR 
mismatch effect was also noted in pediatric lymphoid leukemias.31 In this study, 
with direct measurement of the donor KIR repertoire, participants with a KIR 
matched donor had a 4-fold higher risk of relapse than those with a KIR 
mismatched donor. In contrast to KIR mismatch, KIR-ligand mismatch was not a 
significant factor for the prediction of relapse. The absence of beneficial effects of 
KIR-ligand mismatch has also been observed in additional studies.51 Taken 
together, these data underscore the importance of direct assessment of donor KIR 
repertoire rather than donor KIR-ligands. Peripheral blood will be obtained from 
the donor and the patient prior to Induction Block 1 and on Day 19 for 
immunophenotyping and genotyping for NK cell receptors as described 
previously.31 We will assess NK cell receptors including KIRs, NCRs, NKG2D, 
DNAM-1, 2B4, and NTBA. 
 
2.5.4 Asparaginase antibodies 
 
Because patients have been treated previously with asparaginase, we expect there 
will be variability in both pre-existing asparaginase antibodies and in the 
development of antibodies on ALLR18. We will incorporate single serum 
samples to measure antibodies to asparaginase as well as to measure asparaginase 
activity in serum (which may be affected by changes in immune response). 
Antibodies against native E. coli (Elspar), PEGylated E. coli (Oncaspar), and 
Erwinia asparaginase are measured by an ELISA. Those with possible allergic 
reactions will also have measurement of anti-asparaginase antibodies and 
asparaginase at the time of the reaction and, if re-challenged, after the next dose. 
Asparaginase will be measured using a spectrophotometric assay based on 
conversion of asparagine to aspartic acid.52 These measures will be available to 
use as covariates in analyses of objectives 1.1.1 and 1.2.1. 


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2.5.5 Surveillance for antibiotic resistance (completed with amendment 3.0) 
 
A COG study evaluating a 3-block platform of intensive chemotherapy for 
children with first marrow relapse noted the rate of febrile neutropenia and 
clinically or microbiologically documented infections to be 59.7%, 39.6% and 
79.4% per block of therapy.5 Studies of the use of prophylactic antibiotics in 
neutropenic adult oncology patients conducted over the last 30 years have 
consistently shown efficacy in reducing the incidence of fever and 
microbiologically documented bacterial infections.53 What is less well documented 
is the evolution of antibiotic resistance in colonizing and invasive bacterial isolates 
in recipients of such antibiotic prophylaxis. Showing that antibiotic exposure can 
increase the rate of resistance among colonizing organisms is not an absolute 
confirmation that colonization by a resistant organism can result in infection. 
There have, however, been a number of studies in patients with acute leukemia and 
those receiving HSCT that illustrate that invasive infection is often linked to 
previously noted colonization by the same organism.54-56 Resistance not only to the 
antibiotic that a patient is being exposed to for antibiotic prophylaxis but cross- 
resistance to other antibiotic classes remains a major concern and needs to be 
systematically tracked. We will determine whether ciprofloxacin or cefepime 
prophylaxis will result in the selective emergence of colonization with Gram 
negative organisms resistant to fluoroquinolones, higher generation of 
cephalosporins or other unrelated antimicrobial agents such as carbapenems. 
Additionally, we will define whether fluoroquinolone or cefepime prophylaxis will 
result in the emergence of colonization or invasive infections with S. mitis that are 
resistant to fluoroquinolones, higher generation cephalosporins or penicillin. 
Finally, we will assess the impact of antibiotic prophylaxis on colonization with 
vancomycin resistant enterococci and incidence of C. difficle infections. Peri-rectal 
swabs will be collected pre and post antibiotic prophylaxis during inductions 
Blocks I, III and re-induction. 
 
2.5.6 Global gene expression and copy number changes 
 
Matched diagnosis and relapse leukemic samples from the same patient offer an 
excellent resource to study the mechanisms of relapse and to identify potential new 
therapeutic targets. Global changes in gene expression have been studied on 
Affymetrix microarrays and have demonstrated that pathways involved in cell 
cycle and DNA repair to be predominant in early relapse.57 Survivin, an anti- 
apoptotic gene was up-regulated at relapse and these findings have led to the 
initiation of a phase I study of survivin antagonists in relapsed ALL. Studies of 
DNA changes (copy number variations, loss of heterozygosity) at St Jude have 
provided insights into the clonal evolution of relapse58 and a recent re-sequencing 
effort identified novel mutations including those in the CREBBP gene at relapse.59 
Another study of matched samples from the Children’s Oncology group identified 
deletions of the MSH6 gene in a subset of patients specifically at relapse.60 The 
studies mentioned above had a limited number of patient samples and thus it was 


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not possible to investigate changes specific to various ALL subtypes at relapse and 
correlate to multiple clinical features and response. In addition, recent discoveries 
of genomic aberrations (e.g. rearrangements of CRLF2, activating mutations of 
JAK2) in high risk ALL have not been studied in detail in relapsed ALL.61-64 In 
ALLR18, we will collect bone marrow samples at the time of relapse and retrieve 
cells from initial diagnosis from the tissue bank (if available). Consent for TBANK 
is required for participation in these studies. 
 
 
2.5.7 Drug sensitivity studies 
 
In newly diagnosed ALL, ex vivo drug sensitivity predicts long-term relapse risk, 
is associated with drug-specific gene expression patterns, and is being coupled 
with preclinical studies in cell lines and murine models to identify determinants of 
drug sensitivity.65-67 Not much data is available for in vitro drug resistance in 
relapsed ALL though it is well known clinically that relapsed blasts are relatively 
chemo-resistant. In 1995, Klumper et al68 demonstrated that relapsed blasts 
(N=137) were highly resistant to glucocorticoids, L-asparaginase, anthracyclines 
and thiopurines, but not to other agents like vincristine, and epipodophyllotoxins 
when compared to samples from initial diagnosis (N=141). In this study, matched 
samples were only available for 16 patients which showed de novo as well as 
acquired drug resistance. At St Jude, in vitro drug resistance profiles of leukemic 
blasts at diagnosis to a panel of chemotherapeutic agents have been performed in 
Studies Total XIII-XVI and have led to the identification of genes correlating with 
sensitivity to single agents as well as combination chemotherapy.66,67 Findings also 
point to previously unrecognized potential targets for therapeutic intervention. 
Profiles at relapse are available in a subset of patients too. In ALLR18, we will 
continue to study ex vivo sensitivity of primary ALL blasts to multiple anti 
leukemic agents (e.g., mercaptopurine, thioguanine, prednisolone, dexamethasone, 
vincristine, L-asparaginase, cytarabine, and daunorubicin) and/or chemo- 
sensitivity modulators (e.g., rolipram, a PDE4B inhibitor that improves sensitivity 
to glucocorticoids). 
 
2.5.8 Xenograft models of ALL 
 
Establishing xenografts of primary human ALL samples has proven to be a 
powerful tool to establish bio-repositories of human leukemic cells to examine the 
genetic and biologic basis of treatment failure, to examine clonal heterogeneity and 
to use as a platform for the testing of novel therapeutic agents ex vivo and in vivo. 
At St Jude, several investigators have performed xenotransplants of B-progenitor 
ALL, including CRLF2-rearranged ALL, infant leukemia and hypodiploid ALL, 
and have achieved up to 80% engraftment rates with remarkable reproducibility 
between the tempo of engraftment between replicate mice transplanted with the 
same tumor. Moreover, for CRLF2 rearranged and hypodiploid ALL downstream 
genomic assays demonstrated that the genomic alterations in the relapsed tumor 


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recapitulate those present in the primary leukemia. The use of xenograft models 
has also proven valuable in determining the genetic basis of the aggressiveness of 
disease, and the basis of relapse.62,69,70 At St Jude, these studies have been 
performed with cryopreserved viable cells stored by the St Jude Biorepository. 
Cells harvested from patients in ALLR18 will be used for engraftment into murine 
models and will contribute to the ongoing efforts at SJCRH to establish a panel of 
xenografts of high risk acute leukemia samples to serve as a resource for a range of 
studies of the biologic basis of relapse in acute leukemia, as well as establishing a 
platform for the preclinical testing of novel therapeutics. 
 
 
2.5.9 Resistant clones during therapy for relapsed ALL 
 
Recent genomic profiling studies from our group and others identified somatic 
mutation within the NT5C2 gene directly related to drug resistance in relapsed ALL 
(~15-20% in T and B-lineage ALL at relapse).71,72 Cells with NT5C2 gain-of- 
function mutation are extremely resistant to thiopurine therapy compared to those 
with wildtype NT5C2, and we expect a substantial proportion of patients in this trial 
would be NT5C2 mutant. Therefore, this protocol offers a unique opportunity to 
examine the dynamics of NT5C2 mutation during therapy (e.g., the change of % 
mutant cells at a function of time), especially as patients progress through various 
blocks of therapy. Therefore, it is important to determine the feasibility of 
monitoring NT5C2 mutation during ALL therapy. Our ultimate goal is to examine 
the clinical value of prospectively identifying NT5C2 mutant patients and possibility 
of implementing NT5C2-guided treatment individualization. Bone marrow samples 
will be collected for this objective to coincide with the timing of MRD evaluations. 
Consent for TBANK is required for participation in these studies. 
 
3.0 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT 
 
According to institutional and NIH policy, the study will accession research 
participants regardless of gender and ethnic background. Institutional 
experience confirms broad representation in this regard. 
 
3.1 
Inclusion Criteria for Participant 
 
3.1.1 
Must have relapsed or refractory precursor B-cell acute lymphoblastic 
leukemia or acute lymphoblastic lymphoma. 
 
3.1.1.1 Participants with leukemia must meet one of the following: 
 
1) In first hematologic relapse*, or 
 
2) Refractory to one or two courses of frontline induction therapy 
(≥ 5% blasts in the bone marrow or peripheral blood confirmed 
by flow cytometric analysis). 


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Note: see Exclusion Criterion 3.2.1. Participants aged 1 to 5 
years with induction failure and favorable cytogenetics (i.e., 
hyperdiploid or ETV6-RUNX1) will not be eligible for this 
protocol. Other patients younger than 6 years will be eligible. 
 
3.1.1.2 Participant with lymphoma must meet one of the following: 
 
1) In first relapse, or 
 
2) Refractory to one or two courses of frontline induction therapy 
with measurable disease 
*Relapse in ALL is defined as the reappearance (in a patient who 
has previously achieved remission) of leukemic blasts in the bone 
marrow or peripheral blood. 
 
o Should flow cytometric analyses suggest relapse (by the 
reappearance of a similar immunophenotype to the original 
leukemia) in the presence of <5% blasts morphologically, a 
repeat bone marrow test is recommended to confirm relapse. 
 
o Molecular or genetic relapse is characterized by the 
reappearance of a cytogenetic or molecular abnormality. 
 
o Early relapse is defined as relapse on therapy or < 6 months 
after completion of frontline therapy. Late relapse is defined 
as relapse occurring ≥ 6 months after completion of frontline 
therapy. 
 
3.1.2 
Participants age is < 22 years at time of enrollment (e.g., participant is 
eligible until 22nd birthday). 
 
3.1.3 
Prior therapy 
 
3.1.3.1 There is no waiting period for participants who relapse while 
receiving frontline therapy and are free from acute side effects 
attributable to such therapy. 
 
3.1.3.2 Emergent radiation therapy, one dose of intrathecal chemotherapy, 
and up to 7 days of steroids for treatment of relapse are permitted 
before start of treatment in participants who relapse after 
completion of frontline therapy. 
 
3.1.3.3 At least 90 days have elapsed since bone marrow transplant and 
participant is off immune suppression for > 2 weeks, if applicable. 


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Participants with ALL or NHL who were transplanted in first 
remission are eligible for this study. 
 
3.1.4 
Organ function requirements 
 
3.1.4.1 Hepatic: Total bilirubin < ULN for age, or if total bilirubin is 
>ULN, direct bilirubin is < 1.4 mg/dL. 
3.1.4.2 Cardiac: Shortening fraction > 28%. 
 
3.1.4.3 Renal: Glomerular filtration rate >50cc/min/1.73 m2, OR serum 
creatinine based on age as follows: 
 
 
Age (years) 
Maximum serum creatinine (mg/dL) 
Male Female 
1 to 2 years 
0.6 
0.6 
2 to 6 years 
0.8 
0.8 
6 to 10 years 
1 
1 
10 to <13 years 
1.2 
1.2 
13 to 16 years 
1.5 
1.4 
> 16 years 
1.7 
1.4 
 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
 
3.2 
Exclusion Criteria for Participant 
 
3.2.1 
Leukemia participants aged 1 to 5 years with induction failure and 
favorable cytogenetics (i.e., ETV6-RUNX1 or hyperdiploidy defined as 
DNA Index > 1.16 or modal chromosome number > 51). 
 
3.2.2 
Hepatitis B or HIV infection. 
 
3.2.3 
Pregnant or breast-feeding. 
 
3.2.4 
Inability or unwillingness or research participant or legal 
guardian/representative to give written informed consent. 
 
3.3 
Screening criteria for NK cell donors 
 
3.3.1 
Donor is at least 18 years of age. 
 
3.3.2 
Donor is a family member. 


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Potential donor(s) will first be screened for eligibility and suitability (e.g., HIV 
testing, pregnancy, and blood samples to Pathology & BMT&CT to select the 
optimal donor(s). This will be accomplished using the donor eligibility checklist 
and donor consent. The BMT&CT and Oncology teams will then select the best 
donor(s) based on established institutional practice, among the screened donor(s) 
who meet the eligibility criteria listed in Section 3.3. Only the selected donor(s) 
will proceed to the donor procedures. This will not require a re-consent or re- 
enrollment, although donors may withdraw consent at any time before the 
apheresis procedure is completed. 
 
3.4 
Inclusion criteria for Selected NK cell donor 
 
3.4.1 
Donor is not pregnant or breast-feeding. 
 
3.4.2 
Donor is HIV negative. 
 
3.4.3 
Donor does not have any other medical condition that, in the opinion of an 
independent physician, precludes performance of an apheresis procedure. 
 
3.5 
Research Participant Recruitment and Screening 
 
Three institutions will collaborate in the proposed project: St. Jude Children's 
Research Hospital (SJCRH); Rady Children’s Hospital in San Diego, CA and 
Cook Children’s Medical Center in Fort Worth, TX. It is anticipated that 
additional sites will be added as new collaborations are established. 
 
3.6 
Enrollment on Study at St. Jude 
 
A member of the study team will confirm potential participant eligibility as 
defined in Section 3.1-3.2, complete and sign the ‘Participant Eligibility 
Checklist’. The study team will enter the eligibility checklist information into the 
St. Jude Clinical Trials Management System (CTMS). Eligibility will be reviewed, 
and a research participant-specific consent form and assent document (where 
applicable) will be generated. The complete signed consent / assent form(s) must 
be faxed or emailed to the CPDMO at 
to complete the enrollment 
process. 
 
The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A staff 
member from the St. Jude Cerner Millennium (MILLI) helpline is on call 
Saturday, Sunday, and holidays from 8:00 am to 6:00 pm. If you have a 
prospective research enrollment and need assistance releasing your consent, please 
call the MILLI helpline 
on call number. 
 
3.7 
Enrollment on Study at Collaborating Sites 


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All participants must receive Block I therapy at St. Jude (includes NK cell 
infusions). Therefore, all participants will be consented and enrolled at St. Jude. 
Collaborating sites will assess preliminary eligibility on-site and will refer 
potentially eligible participants to St. Jude for final eligibility determination and 
work-up for NK cell infusions. 
 
4.0 
RISK ASSIGNMENT 
 
Provisional risk assignment will be based on timing of relapse. Final risk 
assignment will incorporate MRD measurements after Block II of remission 
induction therapy. 
 
4.1 
Standard Risk 
 
1) Late relapse (≥ 6 months after completion of frontline therapy) AND 
2) MRD < 0.01% at the end of Block II of remission induction therapy. 
 
Provisional standard risk participants (i.e., late relapse) will be re-assigned 
to High risk if MRD > 0.01% at the end of Block II. 
 
Participants with lymphoma must be in complete remission at the end of 
Block III. 
 
4.2 
High Risk 
 
1) Early relapse (on therapy or < 6 months after completion of frontline 
therapy), OR 
2) Any relapse after hematopoietic stem cell transplant, OR 
3) MRD ≥ 0.01% at the end of Block II of remission induction therapy, OR 
4) Re-emergence of MRD at any time after attaining negative MRD on 
ALLR18 
 
Biopsy of residual mass should be attempted (if feasible) for participants 
with lymphoma who are not in complete remission at the end of Block III. 
 
5.0 
TREATMENT PLAN 
 
5.1 
General Overview 
 
Refer also to Appendix V 
 
The general treatment plan will consist of chemotherapy for standard-risk patients 
and chemotherapy followed by HSCT for high risk patients. Remission induction 
for all patients comprises of three blocks of therapy wherein the first block is a 
novel immunotherapy regimen that includes cytotoxic chemotherapy, rituximab 
and infusion of haploidentical NK cells. Standard-risk patients will continue to 


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receive chemotherapy for a total duration of approximately 2 years. High-risk 
patients will be candidates for HSCT and will proceed to transplant once a 
suitable donor is found and the patient achieves negative MRD. 
 
As the chemotherapy is intensive and participants with ALL will require 
supportive care measures and the majority of the participants will receive HSCT, 
placement of double-lumen Hickman line before starting the treatment is strongly 
recommended. 
 
All participants with ALL receive remission induction. All high-risk participants 
will be offered HSCT, which will be performed after a suitable donor is identified 
and preferably after MRD becomes negative (see section 5.5). Standard-risk 
participants continue chemotherapy if MRD is negative after Block II of induction. 
If the assay is unsuccessful or the specimen is inadequate, the MRD will be 
assumed negative for purposes of treatment decisions and it will be handled as 
missing data for data analysis of MRD. Repeat MRD should be obtained as soon as 
possible. 
 
Interim continuation treatment will be given to the occasional participants who are 
deemed unable to tolerate dose intensive chemotherapy. Specific criteria to use 
interim continuation therapy include disseminated fungal infection, recent 
development of cerebral thrombosis, or grade 3 or 4 renal or hepatic dysfunction. 
Interim treatment will consist of the plan for “interim continuation” as per section 
5.3. Protocol specified therapy will be resumed when the participant’s physical 
condition improves. 
 
5.1.1 
General assumptions regarding chemotherapy administration for all treatment 
phases: 
 
• The timing and duration for administration for all commercially available 
agents are provided in the treatment phase sections as guidelines only. 
Variations in the timing and duration of chemotherapy infusions according to 
institutional practice or variations based on patient care needs are acceptable, 
as long as the treating investigator and/or PI determines that there was no 
impact on patient safety. These variations will not be considered protocol 
deviations, as long as the total dose is given within 10% of protocol specified 
dose. 
• The term “day” does not refer to an absolute calendar day. It refers to a 
general 24-hour period as per St. Jude Nursing P&P. 
• Medication dosing may be modified for research recipients based upon actual 
body weight or adjusted ideal body weight when clinically indicated. Criteria 
for medication calculations based on body weight/body surface area can be 
found in any version of the St. Jude Formulary. Medication doses may be 
rounded to the nearest integer or to the nearest appropriate quantity when 
clinically or pharmaceutically indicated as per the M.D. and Pharm.D. 


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5.1.2 
NK cell therapy for collaborating site participants 
 
NK cell therapy for participants from collaborating sites will be done at St. Jude. The 
patient and donor will need to travel to Memphis and stay for about 3 weeks. St. Jude 
will cover travel costs for the patient, donor and one parent, housing for up to 4 
family members, and all medical costs during this time. St. Jude will also cover the 
travel costs for the NK cell donor. 
 
5.1.3 
Guidance during times of drug shortages and unavailability: 
 
Treating investigators are urged to consult with the PI and to use their best clinical 
judgment in optimizing therapeutic intent and ensuring patient safety in managing 
the protocol-specified therapy. Although these decisions may constitute “Protocol 
Violations,” they are unavoidable and made in consideration of the best interest of 
an individual patient. These will not be considered monitoring/audit findings if 
appropriately documented. All protocol deviations must be noted in the research 
database and the alterations in therapy due to the agent shortage will be captured. 
This should be accomplished by entering “dose modified” and details noted in the 
comments field. These deviations will also be noted in the Deviation Log with the 
notation “Drug substitution/reduction due to unavoidable drug 
shortage/unavailability”. 
 
5.2 
Remission Induction 
 
Required baseline evaluations: 
 
• History and physical exam 
• CBC with diff 
• CMP, LDH, uric acid 
• Coagulation screen 
• Urine analysis 
• Hepatitis and HIV screen 
• EBV, CMV. HSV, varicella, histoplasma and toxoplasma titres 
• Bone marrow aspirate for MRD, mutant cells, cytogenetics, biology and 
molecular studies 
• Serum for asparaginase and anti-asparaginase antibodies 
• CSF cell count, diff and cytology 
• Chest X-ray 
• CT scan of involved areas (lymphoma participants only) 
• ECHO and EKG (can be performed within 1 week of initiation of therapy) 
• QCT for bone density 
• Peri-rectal swab for infectious disease research 
• HLA typing 
• KIR genotyping and NK cell phenotyping 


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• VNTR or variable nucleotide tandem repeat (chimerism studies) 
• Pregnancy test of female adolescent patient 


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5.2.1 
Block I - (approximately 5 weeks, until count recovery). Block I therapy 
must be administered at St. Jude. 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
VCR 
DEX 
ITMHA 
DEX 
DEX 
RITUX 
DEX 
DEX 
(ITMHA) 
CLO 
CYCLO 
VP16 
DEX 
CLO 
CYCLO 
VP16 
DEX 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
CLO 
CYCLO 
VP16 
DEX 
ITMHA 
CLO 
CYCLO 
VP16 
CLO 
CYCLO 
VP16 
IL-2 
(ITMHA)* 
NK cell 
infusion 
RITUX 
IL-2 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
IL-2 
IL-2 
IL-2 
RITUX 
PEG-ASP 
VCR 
DEX 
(ITMHA) 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
DEX 
DEX 
DEX 
DEX 
DEX 
RITUX 
DEX 
VCR 
DEX 
ITMHA 
Day 29 
Day 30 
Day 31 
Day 32 
Day 33 
Day 34 
Day 35 
PEG-ASP 
VCR** 
RITUX (rituximab) - 375 mg/m2/dose IV: Days 4, 13, 20, 27 
CLO (clofarabine) - 40 mg/m2/day IV: Days 6-10 
CYCLO (cyclophosphamide) - 300 mg/m2/day IV: Days 6-10 
VP16 (etoposide) - 100 mg/m2/day IV: Days 6-10 
DEX (dexamethasone) - 8 mg/m2/day divided TID PO or IV: Days 1-8 and Days 21-28 
(Avoid dexamethasone for at least 3 days prior to NK cell infusion) 
PEG-ASP (PEG-asparaginase) - 2500 units/m2/dose IV: Day 21 and 35 
VCR (vincristine) - 1.5 mg/m2/dose (max. 2 mg) IV: Day 1, 21, 28, 35 
IL-2 (interleukin-2) - 1 x 106 units/m2 SQ QOD for 5 doses (Day 11-19) 
*ITMHA will be repeated on Day 11 if Day 8 CSF is not clear. Additional ITMHA on 
Days 5 and 21 for participants with CNS2, CNS3 or traumatic taps with blasts. See 
Sections 5.2.1.2 and 5.10 for details of IT. 
**Day 35 PEG-ASP and VCR may be skipped if counts recover sooner than Day 35. 


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See table 9 and appendix 5 for required research studies. 


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5.2.1.1 Enrollment of initial 5 participants 
 
Enrollment of the initial participants will be done in a staggered fashion to ensure 
safety of the experimental treatment. For the first 5 enrollments, participants must 
be enrolled one at a time and each participant must complete therapy through 
Block I with recovery of counts prior to the next enrollment. If the safety profile 
is acceptable for the first 5 participants, enrollment will proceed as planned. 
 
Recovery of counts is defined as: WBC ≥ 1500/mm3, ANC ≥300/mm3 and 
platelet count ≥ 50 x 109/L 
 
5.2.1.2 Triple Intrathecal therapy (ITMHA) – Block I 
 
• CNS1: Days 1, 8 and 28 
 
• CNS2 and CNS3 and traumatic tap with blasts: Days 1, 5, 8, 21 and 28. 
 
o If CNS blasts are not cleared by Day 8, additional ITMHA will 
be given on day 11. 
 
5.2.1.3 Bone marrow aspirate and MRD – Block I 
 
Bone marrow aspirate/MRD will be performed after count recovery (WBC ≥ 
1500/mm3, ANC ≥ 300/mm3 and platelet count ≥ 50 x 109/L 
 
5.2.1.4 Participants who do not receive NK cell therapy for any reason (e.g., 
donor found to be ineligible after workup): IL-2 will NOT be given and 
chemotherapy Day 21 onwards may be moved up by a week to Day 14. 
 
5.2.1.5 NK cell therapy – Block I 
 
Note: When scheduling needs warrant, Day 11 of therapy onwards may be 
delayed for 1-3 days if necessary. Please contact PI or the transplant team for 
scheduling questions. 
 
Donor selection and testing 
 
1) HLA-typing in the HLA laboratory to confirm that the donor is greater 
than or equal to 3 of 6 HLA match to recipient. 
 
2) KIR phenotyping and genotyping in Dr. Leung’s laboratory (Mnemonic: 
NK TYPING). The results of these assays will not be used for donor 
selection (i.e., KIR matched or mismatched donors will be able to donate 
NK cells). 


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3) Donors are required to undergo screening, examination, and testing as 
described in 21 CFR 1271 and the Guidance "Eligibility Determination for 
Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products 
(HCT/Ps)" to determine eligibility. This includes the following: 
 
a) Medically approved by a non-Department of Bone Marrow 
Transplantation and Cellular Therapy (St. Jude or non- St. Jude) to 
serve as an NK cell donor. Medical evaluation must be done within 
60 days of NK cell collection (i.e. apheresis procedure). 
b) Medically cleared by the Blood Donor Center physician or designee 
to undergo apheresis within 7 days of apheresis procedure. 
c) Infectious disease testing within 7 days of apheresis procedure 
 
Participants with ALL will receive NK cell transplantation from an adult family 
member who shares at least one HLA-haplotype with the recipient if available. 
Specific exclusion criteria include pregnancy and any other medical condition 
that, in the opinion of an independent physician, precludes performance of an 
apheresis procedure. If a suitable donor is not available, NK cell therapy as well 
as IL2 administration will be omitted. Subsequent chemotherapy can be initiated a 
week earlier (i.e., chemotherapy planned day 20 onwards can begin on day 14). 
 
Histocompatibility testing is performed in a CLIA-certified, ASHI- and CAP- 
inspected laboratory of the Department of Pathology, SJCRH. Molecular techniques 
will be utilized to characterize donor and recipient HLA Class I gene content to the 
level sufficient to determine the ligand repertoire for KIR recognition. 
 
NK cell collection and selection 
 
On day 11 the donor will undergo apheresis once. The cells obtained will be 
purified for CD56+ cells by the two-step procedure described previously.22 The 
CliniMACS selection column will be operated using the Standard Operating 
Procedures of the Human Applications Laboratory. For this protocol, our goal is 
to infuse immediately after processing on Day 12 all the NK cells collected to 
give >2x106 CD56+ cells/kg of recipient body weight, but allowing for a 
CD3+CD56− cell dose of no greater than 0.05x106 /kg. The maximum dose of 
cells that would be infused is 400 x 106 CD56+ cells/kg. The minimum dose that 
would be infused is 0.1 x 106 cells/kg. The NK cell product will undergo quality 
control testing that includes assays for viability, sterility and purity before release 
for infusion following standard operating procedures of the Human Applications 
Laboratory. 


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Quality assurance for cellular products 
 
The Department of Therapeutic Production and Quality has established an 
independent division of Quality Assurance (QA). This group is responsible for the 
management of Quality Control, Quality Assurance and Quality Improvement 
processes for the Human Applications Laboratory. Production and QA Systems 
that are in place include: 
 
• Standard Operation Procedures (SOPs) for production and quality processes 
• Documentation of Donor Eligibility 
• Documentation of processes captured in Batch Records. 
• In-process quality control testing including sterility 
• Release Specifications established for all products. 
• Out of Specification Reporting and Investigation Process 
• Authorization by QA for the release of all products after review of records 
and release specification test results. 
• Product labeling procedures with multiple person review. 
• Variance Management Process 
• Personnel Competence and Proficiency Program 
• Inventory control and documentation of product history through patient 
infusion. 
 
Test results that are out of specification for products that are needed on a clinically urgent 
basis will be evaluated by the laboratory medical director. The patient's physician or 
attending transplant physician will be informed of the test result prior to infusion of the 
product. Notification regarding positive sterility results before or after infusion will be 
given to the primary attending physician and patient and/or parent/guardian. Notification 
to the FDA and St. Jude IRB will be given and will include testing results or adverse 
events and any required intervention. An investigation following TPQ/HAL SOPs will be 
completed, reviewed by TPQ Quality Assurance and outcomes of the investigation 
reported. 


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5.2.2 
Induction Block II (duration 3 weeks) 
 
Note: patients with high-risk relapse who will require cranial irradiation 
prior to transplant will NOT receive this block of therapy in order to prevent 
neurological toxicity. 
 
5.2.2.1 Drug dosages – Block II 
 
Agent 
Dosage and route 
# Doses 
Schedule 
HDMTX 
(high dose methotrexate) 
5 g/m2 IV or targeted 65 µM 2 
Days 1 and 8 
6MP 
(mercaptopurine) 
50 mg/m2/day PO 
21 
Days 1 to 21 
 
Block II will begin after count recovery from Block I (i.e., WBC ≥ 1500/mm3, 
ANC ≥ 300/mm3 and platelet count ≥ 50 x 109/L). 
 
5.2.2.2 Intrathecal therapy – Block II 
 
• ITMHA on day 1 
 
5.2.2.3 Bone marrow aspirate/MRD – Block II 
 
Bone marrow aspirate and MRD will be performed on Day 22, provided counts are 
satisfactory (WBC ≥ 1500/mm3, ANC ≥ 300/mm3 and platelet count ≥ 50 x 109/L. 
 
High-risk participants will proceed to BMT once MRD is negative. They may 
continue to receive protocol directed therapy while awaiting transplant workup. 
All participants with positive MRD will proceed to receive Block III. 
 
5.2.2.4 Mercaptopurine administration – Block II 
 
Mercaptopurine should be given daily at a consistent time that maximizes 
adherence with the prescribed treatment. If a dose is inadvertently missed, then it 
should be given as soon as the omission is noted, as long as it is at least 6 hours 
prior to the next scheduled dose of MP. 
 
In participants for whom high dose methotrexate treatment is delayed, 
mercaptopurine may be continued until 7 days after the last course of high dose 
methotrexate. Mercaptopurine may be held in the presence of ANC < 300/mm3, WBC 
< 1,500/mm3, platelet count < 50 x 109/L or grade 3 or 4 mucositis. Dosage of 
mercaptopurine may be reduced to 25 mg/m2/day in participants who have developed 
neutropenia after the first high dose methotrexate and mercaptopurine treatment. See 
section 6.13 for modifications of mercaptopurine based on TPMT status. 


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IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
 
5.2.2.5 HDMTX Administration – Block II 
 
Patients will receive 5 gram/m2 (or a dose targeted to achieve a steady-state 
plasma concentration of 65 µM) administered over 24 hours intravenously. The 
subsequent dose of high dose methotrexate and mercaptopurine will be delayed if 
ANC <300/mm3, WBC < 1500/mm3, platelet count < 50 x 109/L, SGPT >500 
U/L, total bilirubin >2 mg/dl and direct bilirubin >1.4 mg/dl, or mucositis is 
present. For patients with Down syndrome, high dose methotrexate administration 
will be modified (see section 6.7.1) 
 
HDMTX pre-hydration 
 
At least two hours before high dose methotrexate, pre-hydration IV fluid (D5W + 
40 mEq NaHCO3/L + 20 mEq KCl/L) will be administered at the rate of 200 
ml/m2/hr. At start of pre-hydration, one IV dose of NaHCO3 (25 mEq/m2) diluted in 
50 ml D5W will be given over 15 minutes. Pre-hydration fluid may also be given 
overnight at a rate of at least 125 ml/m2/hr. High dose methotrexate treatment will 
follow, provided that urinary pH is ≥ 6.5; exceptions must be cleared with the 
pharmacokinetics service and the attending physician. 
 
HDMTX infusion 
 
Methotrexate loading dose will be given over 1 hour, followed immediately by 
maintenance infusion over 23 hours. During the methotrexate infusion, 
participants should receive hydration fluid with D5W + 40 mEq/L NaHCO3 + 20 
mEq KCl/L at 125-150 ml/m2/hr. Urine pH will be monitored with each void 
during infusion. An IV bolus of 12 mEq/m2 NaHCO3 will be given if urine pH is 
6.0; and 25 mEq/m2 will be given if urine pH is <6.0. Acetazolamide 500 mg/m2 
orally every 6 to 8 hours may be used if systemic alkalosis limits the 
administration of bicarbonate for urinary alkalinization. Participants with 
evidence of renal dysfunction or delayed clearance during the methotrexate 
infusion may receive less than a 24 hour methotrexate infusion. Blood samples for 
methotrexate pharmacokinetics will be drawn as described below. 
 
HDMTX leucovorin rescue 
 
Leucovorin, 15 mg/m2 (IV or PO) will be started at 42 hours after the start of 
methotrexate and repeated every 6 hours for a total of three to five doses, as 
determined by primary physician and Pharm D based on patient’s prior treatment 
history or present condition. The dosage of leucovorin will be increased in 
participants with high plasma methotrexate concentrations (>1.0 µM at 42 hours) 
and continued until the methotrexate concentration is less than 0.10 µM. 
Additional measures, such as hydration, hemoperfusion, or carboxypeptidase will 
be considered in participants with 42-hour methotrexate levels > 10µM. 
Participants with a history of delayed Grade 3 or 4 gastrointestinal toxicity with 


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IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
prior methotrexate or a history of typhlitis with any chemotherapy should have 
leucovorin continue for 5 doses; those with early toxicity should have leucovorin 
begin at 36 hours with subsequent methotrexate; if toxicity recurs, the baseline 
leucovorin dosage should also be increased. 
 
See Appendix VIII, “HDMTX administration and monitoring guidelines, 
Induction Block II” for additional information. 
 
5.2.3 
Induction Block III (approximately 3 weeks until count recovery) 
 
Block III will begin when WBC ≥ 1500/mm3, ANC ≥ 300/mm3 and platelet count 
≥ 50 x 109/L. 
 
5.2.3.1 High dose mitoxantrone and cytarabine (MA) – Block III 
 
Agent 
Dosage and route 
# Doses 
Schedule 
ARA-C 
(cytarabine) 
1 g/m2 IV over 2 hours every 
12 hours 
8 
Days 1-4 
MITO 
(mitoxantrone) 
12 mg/m2 (0.4 mg/kg for 
participants < 10 kg) IV over 
1 hour 
3 
Days 3-5 
 
5.2.3.2 Drug dosages, schedules and routes – Block III 
 
ARA-C (cytarabine): 1 g/m2 IV over 2 hours every 12 hours on days 1-4 (8 doses) 
 
MITO (mitoxantrone: 12 mg/m2 (0.4 mg/kg for participants less than 10 kg) IV 
over 1 hour on days 3-5 (3 doses) 
 
5.2.3.3 Intrathecal treatment – Block III 
 
• ITMHA on Day 7 
 
5.2.3.4 Conjunctivitis prophylaxis – Block III 
 
Dexamethasone ophthalmic solution (0.1%), 2 drops to both eyes four times per day, or 
artificial tears (e.g., hydroxymethylcellulose, hypromellose, polyvinyl alcohol), 2 drops 
to both eyes every 2-6 hours, may be used during HDAC administration and for 24 hours 
after completion to prevent conjunctival irritation. 
 
5.2.3.5 Bone marrow aspirate/MRD – Block III 
 
Bone marrow aspirate and MRD will be performed after count recovery (WBC ≥ 
1500/mm3, ANC ≥ 300/mm3 and platelet count ≥ 50 x 109/L. 


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IRB Approval date: 06-13-2018 
St. Jude 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
5.3 
Interim Continuation (4 weeks) 
 
Interim continuation will begin when WBC ≥ 1500/mm3, ANC ≥ 300/mm3 and 
platelet count ≥ 50 x 109/L 
 
Week Agent 
Dosage and 
route 
# Doses Schedule 
1 
VP16 
(etoposide) 
300 mg/m2 IV 
1 
Day 1 
CYCLO 
(cyclophosphamide) 
300 mg/m2 IV 
1 
Day 1 
2 
MTX 
(methotrexate) 
40 mg/m2 IV 
1 
Day 1 
6MP 
(mercaptopurine) 
75 mg/m2 PO 
7 
Days 1-7 
3 
VM26 
(teniposide) 
200 mg/m2 IV 
1 
Day 1 
ARA-C 
(cytarabine) 
300 mg/m2 IV 
1 
Day 1 
4 
DEX 
(dexamethasone) 
12 mg/m2 PO 
15 
Days 1-5 TID 
VINBLAST 
(vinblastine) 
6 mg/m2 IV 
1 
Day 1 
 
5.3.1 
Intrathecal therapy – Interim Continuation 
ITMHA on Day 1 of week 1. 
5.3.2 
Mercaptopurine administration 
 
Mercaptopurine should be given daily at a consistent time that maximizes 
adherence with the prescribed treatment. If a dose is inadvertently missed, then it 
should be given as soon as the omission is noted, as long as it is at least 6 hours 
prior to the next scheduled dose of 6MP 
 
5.3.3 
Dose modifications and delays – Interim Continuation 
 
Chemotherapy except dexamethasone may be delayed or the dose will be reduced 
as follows: 
• WBC >1,500/mm3 and ANC >300/mm3; give full dose 
• WBC > 1,000/mm3 but <1,500/mm3 and ANC >300/mm3; reduce dose by 50% 
• WBC < 1000/ mm3 or ANC <300/ mm3; hold chemotherapy 
• Participants with a variant TPMT allele should receive no more than 60 
mg/m2 of 6MP 


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IRB Approval date: 06-13-2018 
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IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
5.3.3 Bone marrow/aspirate/MRD – Interim Continuation 
 
Bone marrow aspirate and MRD will be performed at the end of week 4 provided 
counts are satisfactory (WBC ≥ 1500/mm3, ANC ≥ 300/mm3 and platelet count ≥ 
50 x 109/L). 
 
5.4 
Re-Induction Therapy 
 
Approximately 3 weeks until count recovery. 
 
5.4.1 
Overview - Re-Induction treatment will begin when WBC ≥ 1500/mm3, 
ANC ≥ 300/mm3 and platelet count ≥ 50 X 109/L 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
CLO 
CYCLO 
VP16 
DEX 
ITMHA 
CLO 
CYCLO 
VP16 
DEX 
CLO 
CYCLO 
VP16 
DEX 
CLO 
CYCLO 
VP16 
DEX 
CLO 
CYCLO 
VP16 
DEX 
PEG-ASP 
VCR 
DEX 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
VCR 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
(ITMHA) 
PEG-ASP 
VCR 
 
5.4.2 
Drug dosages, schedules and routes – Re-Induction therapy 
 
CLO (clofarabine) 
40 mg/m2/day: IV Days 1-5 
CYCLO (cyclophosphamide) 
300 mg/m2/day: IV Days 1-5 
VP16 (etoposide) 
100 mg/m2/day: IV Days 1-5 
DEX (dexamethasone) 
8 mg/m2/day: PO Days 1-6 
PEG-ASP (PEG-asparaginase) 
2500 units/m2/dose: IV Day 6 and 20 
VCR (vincristine) 
1.5 mg/m2/dose (max. 2 mg): 
IV push Day 6, 13, 20 
 
5.4.3 
Intrathecal treatment – Re-Induction therapy 
 
• CNS1: ITMHA on Day 1 


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IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
• CNS 2, 3 and traumatic tap with blasts: ITMHA on Days 1,15 
5.4.4 
Bone marrow aspirate/MRD – Re-induction therapy 
 
Bone marrow aspirate and MRD will be performed after count recovery (WBC ≥ 
1500/mm3, ANC ≥ 300/mm3 and platelet count ≥ 50 x 109/L. 
 
5.5 
Continuation Treatment 
 
5.5.1 Overview of Continuation treatment 
 
Continuation treatment begins after completion of Re-Induction, provided that the 
ANC  300/mm3, WBC  1500/mm3 and platelet count  50 x 109/L as well as no 
evidence of grade 3 or 4 mucositis. Duration of continuation: 10 cycles of 8-week 
rotations for a total of 80 weeks. Entire duration of treatment is approximately 2 
years. 
 
Week 
Agents 
1 
MTX + 6MP 
2 
MTX + 6MP 
3 
VM26 + ARA-C 
4 
DEX + VCR 
5 
MTX + 6MP 
6 
MTX + 6MP 
7 
VM26 + ARA-C 
8 
DEX + VINBLAST 
 
5.5.2 Drug dosages, schedules and routes – Continuation treatment 
 
MTX (methotrexate) 
6MP (mercaptopurine) 
VM26 (teniposide) 
VCR (vincristine) 
40 mg/m2 
75 mg/m2 
200 mg/m2 
2 mg/m2 
1 dose, IV* day 1 (weeks 1, 2, 5 & 6) 
days 1-7, PO (weeks 1, 2, 5 & 6) 
1 dose, IV day 1 (weeks 3 & 7) 
(max 2 mg), 1 dose, IV push day 1 (week 4) 
ARA-C (cytarabine) 
300 mg/m2 
1 dose, IV day 1 (weeks 3 & 7) 
DEX (dexamethasone) 
12 mg/m2 
15 doses, PO day 1-5 TID (weeks 4 & 8) 
VINBLAST (vinblastine) 
6 mg/m2 
1 dose, IV day 1 (week 8) 
 
*MTX should be given IM or as a 2 hour IV infusion if the participant has had 
previous cranial irradiation. Mercaptopurine should be given daily at a 
consistent time that maximizes adherence with the prescribed treatment. If a dose 


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IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
is inadvertently missed, then it should be given as soon as the omission is noted, 
as long as it is at least 6 hours prior to the next scheduled dose of MP 


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Amendment 3.0, dated: 03-19-2018 
IRB Approval date: 06-13-2018 
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IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
5.5.3 Intrathecal therapy – Continuation treatment 
 
• CNS1: ITMHA on Day 1 of week 1 of all cycles 
• CNS2, 3 and traumatic tap with blasts: 
o Cycles 1-5: ITMHA on Day 1 of week 1 and Day 1 of week 5 
o Cycles 6-10: ITMHA on Day 1 of week 1 
o Participants who are candidates for cranial irradiation will receive 4-5 
ITMHAs during radiation therapy. These patients will not receive 
additional ITMHA following completion of radiation therapy. Lumbar 
puncture will be done every 16 weeks for surveillance only. See section 
6.3.3.3 for details 
 
5.5.4 Dose modifications and delays – Continuation treatment 
 
Dexamethasone and vincristine can be given regardless of counts. For all other 
drugs, dose will be reduced as follows: 
 
• WBC >1,500/mm3 and ANC >300 /mm3; give full dose 
• WBC > 1,000/mm3 but <1,500/mm3 and ANC > 300 /mm3; reduce the 
dose by 50% 
• WBC < 1,000/mm3 or ANC <300/mm3; hold chemotherapy 
• Participants with a variant TPMT allele should receive no more than 60 
mg/m2 of 6MP 
 
5.5.5 Bone marrow aspirate/MRD – Continuation treatment 
 
Bone marrow aspirate/MRD will be performed for all participants in week 1 of every 2 
cycles (i.e. every 16 weeks) and at the end of therapy. 
 
5.5.6 End of therapy evaluations 
 
• CBC with diff 
• CMP, LDH, uric acid 
• Bone marrow aspirate and MRD 
• CSF cell count, differential and cytology 
• ECHO/EKG 
 
5.6 
Plan for HSCT 
 
All high-risk participants are eligible for HSCT. HSCT will be performed as soon 
as MRD becomes negative (<0.01%). If MRD becomes negative and a donor has 
not been found, the patient will continue chemotherapy phases until a suitable 
donor is found. All attempts will be made to attain a negative MRD prior to 
HSCT. If MRD is persistently positive, the plan will be discussed with the PI and 
the transplant team. Donor will be selected according to institutional practices and 


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IRB APPROVAL DATE: 03/18/2019 
Protocol document date: 06-12-2018 
 
 
 
transplant regimens will be used according to institutional HSCT protocols and 
guidelines. 
 
5.7 
Prophylaxis and Treatment for CNS Disease 
 
All participants will receive ITMHA. Irradiation will be given to some participants 
with CNS involvement at relapse, see section 6.3. 
 
5.7.1 Criteria for CNS status 
 
• CNS-1: No blasts in CSF 
• CNS-2: < 5 WBC/µL of CSF with blasts 
• CNS-3: ≥ 5 WBC/µL of CSF with blasts or cranial nerve palsy 
• Traumatic tap with blasts: > 10 RBC/µL of CSF with blasts 
 
5.7.2 Dosage of ITMHA 
 
Age 
< 1 year 
1-2 years 
2-3 years 
> 3 years 
methotrexate 
6 mg 
8 mg 
10 mg 
12 mg 
hydrocortisone 
12 mg 
16 mg 
20 mg 
24 mg 
cytarabine 
18 mg 
24 mg 
30 mg 
36 mg 
total volume 
6 ml 
8 ml 
10 ml 
12 ml 
 
Leucovorin 5 mg/m2/dose, max 5 mg will be given PO or IV at 24 and 30 
hours after each intrathecal treatment during induction Block I, Block III 
and Re-induction. Leucovorin may be given during other phases of 
therapy if the patient has an adverse reaction with previous intrathecal 
treatments or methotrexate treatment or is neutropenic. 
 
5.8 
Participation of St. Jude Collaborating Sites in the Treatment Plan 
 
Block I Induction therapy will be administered at St. Jude. After 
completion of Block I Induction therapy, participants will return to 
collaborating site to complete the remainder of ALLR18 therapy. 
 
5.9 
Participation of St. Jude Affiliates the Treatment Plan 
 
St. Jude participants may return to affiliate to receive some parts of 
ALLR18. Blocks I, II, III of induction and Re-induction therapies, and 
HSCT must be given at St. Jude. Participants may return to affiliates to 
receive interim continuation and continuation treatments. 


St. Jude 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
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IRB Approval date: 06-13-2018 
 
 
ALLR18 
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5.10 
Summary of Intrathecal Therapy on ALLR18 
 
CNS Status 
Induction- 
Block I 
Induction – 
Block II 
Induction – 
Block III 
Interim 
continuation 
Re-induction 
Continuation 
All phases 
CNS-1 
Days 
Total 
Day 
Total 
Day 
Total 
Day 
Total 
Days 
Total 
Days 
Total 
Total –all 
phases 
1, 8, 
28 
3 
1 
1 
7 
1 
1 
1 
1 
1 
Cycles 1-10: 
Day 1 of Week 1 
10 
17 
CNS-2, 
1, 5, 8, 
5 or 
1 
1 
7 
1 
1 
1 
1, 15 
2 
Cycles 1-5: 
15 
25 
(26 if 
given on 
Day 11 
Block I) 
CNS-3, & 
(11*), 
6* 
Day 1, Week 1 
Traumatic tap 
21, 28 
& Day 1, week 5 
w/blasts 
Cycles 6-10: 
Day 1, week 1 
*If CNS blasts are not cleared by Day 8, additional ITMHA will be given on Day 11 
 
Those patients receiving CNS irradiation should receive 4-5 ITHMA during radiation. They will not receive subsequent ITMHA following 
radiation therapy. See section 6.3.3.3 - Concurrent chemotherapy with irradiation. Consult with PI and radiation oncologist. 


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St. Jude 
IRB Approval daIRteB: 0N6U-1M3B-E20R1:8Pro00002817 
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Protocol document date: 06-12-2018 
 
 
6.0 
TREATMENT MODIFICATIONS 
 
6.1 
Philadelphia Chromosome-Positive (Ph+) ALL 
 
The use of tyrosine kinase inhibitors has improved the outcome of children with Ph- 
positive ALL73. Imatinib and dasatinib are the agents used most frequently in 
frontline therapy. Unfortunately, resistance develops commonly due to point 
mutations within the kinase binding domain of BCR-ABL. By using sensitive 
detection methods such as denaturing high-performance liquid chromatography, 
these mutations can be detected in a small sub-clone of leukemic cells in 40% of 
newly diagnosed patients, but in the dominant clone in 90% at relapse, thus 
implying selective pressure of the resistant clone after treatment with tyrosine 
kinase inhibitors.74 
 
Ph-like ALL is a high-risk subtype of ALL with a gene expression profile similar to 
Ph-positive ALL, but lacking the Philadelphia chromosome.75 Recent studies have 
demonstrated that a subset of these cases harbor a diverse range of genomic 
alterations that activate tyrosine kinases such as ABL1, ABL2, CSF1R and 
PDGFR.76,77 In preclinical studies, Ph-like leukemic cells with targetable lesions are 
highly sensitive to tyrosine kinase inhibitors.76,77 Various case reports also 
demonstrate that patients with Ph-like ALL respond well to TKIs despite resistance 
to standard chemotherapeutic agents.78 In view of compelling preclinical data, TKIs 
will be added to frontline therapy for patients with Ph-like ALL in Total XVII as 
well as ongoing COG studies. 
 
In addition to patients with Philadelphia chromosome (Ph)-positive ALL, patients 
with the Ph-like subtype of ALL and a targetable lesion will also receive a tyrosine 
kinase inhibitor. Testing for specific mutations will be done in a CLIA-approved 
laboratory and patients with fusions predicted to respond to ABL1 inhibitor will 
receive a TKI (ex. imatinib, dasatinib, nilotinib). Please discuss individual cases 
with the PI. 
 
The choice of tyrosine kinase inhibitor in ALLR18 will be at the discretion of the 
treating physician and principal investigator dependent on prior exposure and 
resistance patterns. Examples include imatinib, dasatinib and nilotinib. 
 
Tyrosine kinase inhibitors should be introduced after Day 20 of Induction Block I 
therapy to avoid drug interactions and interference with NK cell function. Consider 
holding during HDMTX in induction Block II to avoid cumulative toxicity. Dose 
should be adjusted to avoid myelosuppression to enable administration of therapy 
without interruption. Please discuss with the PI. 


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St. Jude 
IRB Approval daIRteB: 0N6U-1M3B-E20R1:8Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
6.2 
PEG-Asparaginase Allergies/Hypersensitivity 
 
Participants with allergic reactions or intolerance to PEG-asparaginase will be given 
Erwinia L-asparaginase intramuscularly or intravenously over 30-60 minutes 
duration.79 Each dose of PEG-asparaginase will be replaced by Erwinia at 25,000 
units/m2/dose thrice weekly (2 to 3 days apart, e.g. Monday, Wednesday and Friday). 
 
Participants with possible allergic reactions should have measurements of anti- 
asparaginase antibodies and asparaginase at the time of the reaction and if re- 
challenged, after the next dose. Native E. coli L-asparaginase (L-asparaginase, 
Elspar®) may be given when clinically indicated, but this should be discussed and 
approved by the PI. 
 
6.3 
Irradiation for Participants with CNS Disease 
 
6.3.1 Participants with CNS3 disease 
 
Craniospinal irradiation will be given for participants whose first CR was less than 
18 months and only cranial irradiation will be given for those whose CR was more 
than 18 months. The doses are 18 Gy cranial and 12 Gy spinal. 
 
6.3.2 Participants with CNS2 disease 
 
Not all participants with CNS2 disease will require irradiation. These cases will be 
discussed individually with the radiation oncologist and PI. 
 
6.3.3 Timing of cranial/craniospinal irradiation 
 
6.3.3.1 Participants who will not undergo HSCT (i.e. standard-risk participants): 
After completion of the 3rd course of continuation therapy (i.e. approximately one 
year from diagnosis of relapse). These participants will resume the protocol at cycle 
4 of continuation after completion of irradiation but will not receive subsequent 
intrathecal chemotherapy. A lumbar puncture will be done every four months for 
surveillance only. 
 
Methotrexate should be given IM or as a 2 hour IV infusion if the participant has 
had previous cranial irradiation. 
 
6.3.3.2 Participants who will undergo HSCT (i.e. high-risk participants): 
Participants who will receive total body irradiation (TBI) for pre-transplant 
conditioning will receive a cranial irradiation boost (6 Gy) just prior to the TBI. 
Participants who will not receive TBI conditioning will receive cranial or 
craniospinal irradiation as per section 6.3.1 just prior to HSCT. 


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St. Jude 
IRB Approval daIRteB: 0N6U-1M3B-E20R1:8Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
6.3.3.3 Concurrent chemotherapy with irradiation 
 
Those participants receiving cranial irradiation should only receive 4 to 5 triple 
intrathecal therapy with leucovorin rescue during irradiation. Mercaptopurine and 
methotrexate will be withheld for at least one week prior to and during irradiation; 
systemic chemotherapy during irradiation will include dexamethasone and 
vincristine with or without PEG-asparaginase. 
 
6.4 
Treatment for Testicular Involvement 
 
The plan for testicular irradiation for participants with testicular involvement will 
be discussed with the radiation oncologist and PI at the time of diagnosis of relapse 
and at the end of induction therapy. The need for testicular radiation will be 
determined for individual participants based on response to therapy, ultrasound 
findings and possibly testicular biopsy. 
 
6.5 
Obesity 
 
Actual body weight will be used to calculate body surface area in all participants 
and used for dosage calculations (with the exception that vincristine dosage is 
capped at 2 mg). 
 
6.6 
Infants 
 
With the exception of vincristine and mitoxantrone, all dosages given to infants (< 1 
year) will be based on body surface area. For infants < 1 month of age, or for 
infants < 3 months of age born significantly prematurely (< 36 weeks gestation), a 
50% reduction in dosages of asparaginase, etoposide, methotrexate, thiopurines, 
cyclophosphamide, clofarabine, and cytarabine should be made. The vincristine 
dosage for participants < 12 months of age or < 10 kg weight is 0.05 mg/kg/dose. 
The mitoxantrone dose for participants less than 10 kg is 0.4 mg/kg/dose 
 
6.7 
Down Syndrome Participants 
 
Participants with Down syndrome should be closely monitored. Doses should be 
reduced (30% to 50%) as clinically indicated (especially dexamethasone and high- 
dose cytarabine, and for those who have higher than expected toxicity in earlier 
phases). 
 
6.7.1 HD-MTX 
 
Dosages of HD-MTX will be modified because participants with Down syndrome 
have altered MTX pharmacokinetics and enhanced tissue sensitivity to the effects of 
MTX. The hydration and alkalinization regimen should be the same as outlined in 
section 5.1.2. However, the dose of HD-MTX should be 500 mg/m2 (50 mg/m2 over 
1 h and 450 mg/m2 given over 23 h). Baseline leucovorin rescue will begin early (at 
hour 30 at 30 mg/m2 IV q 6 h × 2 doses, followed by 10 mg/m2 IV q6 h × 6 doses). 


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St. Jude 
IRB Approval daIRteB: 0N6U-1M3B-E20R1:8Pro00002817 
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Protocol document date: 06-12-2018 
 
 
If MTX plasma levels are elevated, increased leucovorin rescue will be 
recommended by the Pharmacokinetics Service. Vigorous hydration should be 
ensured until the 42-hr MTX level is known. 
 
6.7.2 Continuation low-dose MTX 
 
The low-dose weekly MTX (40 mg/m2) should be administered at full dosage if 
possible. If the patient has severe neutropenia or leucopenia (which delays 
subsequent therapy) or grade 4 mucositis (or mucositis which delays subsequent 
therapy) after being administered 40 mg/m2 low-dose MTX, the dosage should be 
decreased to 30 mg/m2, and further to 20 mg/m2 and finally to 10 mg/m2 if 
necessary. If 10 mg/m2 is also not tolerated, then leucovorin should be added at 5 
mg/m2 every 6 h for 4 doses, starting 42 h from the MTX dosage, with titration to 
acceptable toxicity. 
 
6.8 
Participants with Renal Dysfunction 
 
Subclinical renal impairment (normal serum creatinine but decreased GFR) may be 
present in participants receiving concurrent nephrotoxic drugs (e.g. IV acyclovir 
and vancomycin) which, if possible, should be held during and for 20 hours after 
HDMTX infusions or until adequate MTX clearance has been documented. 
Consideration to delaying MTX should be given if a patient's serum creatinine 
indicates renal impairment (e.g., glomerular filtration rate <50cc/min/1.73 m2, 
however this will be a clinical decision, please contact PI, and/or PharmD). 
 
In the event of toxicity secondary to high dose methotrexate, consider 
carboxypeptidase (glucarpidase). 
 
6.9 
Participants with Hepatic Dysfunction 
 
6.9.1 Mitoxantrone, clofarabine, etoposide and vincristine 
 
Dosages for mitoxantrone, clofarabine, etoposide and vincristine should be 
modified in participants with elevated direct bilirubin concentrations or other 
evidence of biliary obstruction. 
 
• Direct bilirubin 2-4 mg/dl: 50% dosage decrease 
• Direct bilirubin 4-6 mg/dl: 75% dosage decrease 
• Direct bilirubin >6 mg/dl: withhold dose 
 
6.9.2 PEG-Asparaginase 
 
PEG-asparaginase may need to be withheld in participants with elevated direct 
bilirubin concentrations, especially if there is evidence of mucositis. 


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6.9.3 HDMTX – High dose methotrexate 
 
HDMTX should be withheld if there is evidence of existing mucositis or if total 
bilirubin >2 mg/dl and direct bilirubin >1.4 mg/dl. 
 
Subclinical hypertransaminasemia (SGPT >500 IU/L) is an indication to delay only 
high dose methotrexate but no other chemotherapy. 
 
6.10 
Cardiotoxicity 
 
Hold mitoxantrone until fractional shortening is > 28%. Consultation with 
cardiologist is suggested if clinically indicated. 
 
6.11 
Vinca Alkaloid Neurotoxicity 
 
Mild vinca alkaloid toxicities are anticipated. These include jaw pain, constipation, 
decreased deep tendon reflexes. If there is persistent severe abdominal cramps, gait 
impairment, severe pain that requires narcotics or SIADH develops, the dose may 
be reduced to 50%. Motor paralysis or typhlitis will warrant temporary 
discontinuation of vinca alkaloids. 
 
6.12 
Pancreatitis 
 
Acute hemorrhagic pancreatitis is a contraindication to continue PEG-asparaginase 
treatment. In the case of mild to moderate pancreatitis, PEG-asparaginase should be 
held until symptoms and signs subside, and amylase and lipase levels return to 
normal and then resumed. Any participants with abdominal pain suspected of 
pancreatitis should have serum amylase and lipase measured as well as an 
abdominal sonogram or CT scan done. In the case of severe pancreatitis (i.e. 
abdominal pain of 72 hours or more, amylase and lipase level three times or more 
of the upper limit of normal, and sonographic or CT scan evidence of pancreatitis), 
PEG-asparaginase may be discontinued permanently when the possibility of 
glucocorticoid- or mercaptopurine induced pancreatitis is excluded. In cases with 
mild to moderate pancreatitis (abdominal pain less than 72 hours and amylase and 
lipase level less than three times the upper limit of normal), PEG-asparaginase 
should be held and resumed once symptoms and signs subsided. Call the PI to 
discuss the management if the patient is asymptomatic (without abdominal pain) 
and has only elevated amylase or lipase levels. Consideration should be given to use 
native asparaginase (10,000 units/m2 thrice weekly for 3 doses) for participants who 
are re-challenged. Consideration should also be given to dexamethasone- or 
mercaptopurine- related pancreatitis. Contact the PI to discuss the management if 
there is a possibility that the pancreatitis is due to either of these two drugs. 


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6.13 
TPMT Status and Thiopurine Dosage 
 
Participants who have at least one mutant TPMT allele often require dosage 
decreases of 6MP to avoid severe myelosuppression.80,81 In a setting in which 6MP 
dosage was preferentially adjusted in about 1/3 of participants with TPMT defects, 
overall leukemia-free survival was outstanding among participants with TPMT 
defects.82 Thus, we recommend that participants with phenotype or genotype 
consistent with at least one variant allele start mercaptopurine at 60 mg/m2 and 
adjust the subsequent doses according to blood count and red blood cell 6 
thioguanine nucleotide level (in consultation with Pharm D). For the participants 
who did not have TPMT testing in the frontline protocol, a blood sample (5-10 ml) 
will be drawn along with routine lab work at the start of induction Block B to allow 
for timely TPMT genotyping and/or phenotyping.83 In participants in whom TPMT 
genotype and phenotype are discordant, or in whom suspected noncompliance, 
problems with toxicities or high blood counts are present, samples for red blood 
6TGN and/or repeat TPMT activity may be measured. The dose of 6MP may be 
adjusted based on participants’ TPMT status, 6TGN levels and WBC in 
consultation with Pharmaceutical Sciences. 
 
7.0 
SUPPORTIVE CARE GUIDELINES 
 
These guidelines are provided to help physicians caring for participants treated on 
this protocol. They are guidelines and not protocol requirements. Nothing in these 
guidelines is intended to supplant the judgment of the treating physician regarding 
patient management. Current institutional practice may dictate other approaches to 
the management of the areas discussed in this section. 
 
7.1 
Management of Tumor Lysis Syndrome 
 
It is suggested that baseline serum chemistries (uric acid, urea, creatinine, 
electrolytes, Ca, Mg, and PO4) be obtained pre-treatment and frequently after 
therapy is started, and a central venous line (Double Lumen Hickman Catheter or 
DLHC) be inserted for fluid administration and monitoring. 
 
Preventative measures 
 
1. Give allopurinol 300 mg/m2 daily divided TID. Alternatively, rasburicase 
may be given daily until the lysis period is over. 
2. Intravenous fluids should be started at least 12 hours before chemotherapy, 
3000 mL/m2/day. NO ADDED POTASSIUM. 
3. 
Phosphate binder for hyperphosphatemia as per institution guidelines 
 
Suggested monitoring during Induction chemotherapy 
 
1. Strict monitoring of fluid balance is essential. 
2. Check blood pressure frequently. 
3. Daily weights. 


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4. Frequent measurement of serum chemistries 
7.2 
Management of Hyperleukocytosis 
 
In participants with WBC > 400 x 109/L or symptoms of hyperviscosity, 
leukapheresis or exchange transfusion may be used according to local institutional 
guidelines. 
 
7.3 
Prophylaxis for Pneumocystis Jiroveci Pneumonia (REQUIRED) 
 
All participants should receive TMP/SMZ (trimethoprim 150 mg/m2/day in 2 
divided doses on Monday, Tuesday, and Wednesday of each week). For those who 
cannot tolerate TMP/SMZ, monthly pentamidine may be substituted. Other options 
include atovoquone or dapsone. Please consult with clinical pharmacists and local 
institutional guidelines. 
 
7.4 
Prophylaxis for Fungal Infections (REQUIRED) 
 
Participants with relapsed ALL are at especially increased risk for fungal infections, 
most commonly candidiasis and aspergillosis. Although there is no national 
standard for antifungal prophylaxis of these participants, effective regimens include 
voriconazole and posaconazole. Micafungin and caspofungin are acceptable 
alternatives, but fluconazole and itraconazole are not recommended because of lack 
of activity against Aspergillus. Antifungal prophylaxis should be initiated when 
ANC < 500 or <1000 and falling or predicted to fall in induction blocks I, III and 
re-induction and continue until count recovery (ANC >100 and rising). 
 
All participants on ALLR18 must receive prophylactic antifungal therapy, 
although the agent(s) used may be based on local institutional guidelines. 
Acceptable antifungal prophylaxis options are listed below, in order of preference. 
Currently, we recommend voriconazole or posaconazole. Please consult with 
clinical pharmacists for therapeutic drug monitoring and refer to local institutional 
guidelines for voriconazole and posaconazole. Consult with the PI if other 
antifungal agents other than one listed below will be used. 
Voriconazole and other azoles should be avoided during administration of vinca 
alkaloids and high dose methotrexate. 
 
• Voriconazole 
≥ 1 – 11 years: 
7 mg/kg/dose PO BID (rounded up to 50 mg or 
100 mg dose increments) 
≥ 12 years, < 40 kg: 200 mg PO BID x 1 day then 100 mg PO BID 
>12 years, ≥ 40 kg: 
400 mg PO BID x 1 day then 200 mg PO BID 
• 
Posaconazole 
Oral suspension 40 mg/mL (recommend adequate oral intake or 
nutritional supplement with at least 14 g of fat and avoid H2 antagonist 
and proton pump inhibitors. 


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o Participants > 13 years old: 200 mg PO 3 times a day with meals 
o Participants < 13 years old: dose not established 
Delayed-release tablets (do not cut or crush tablets and may administer 
without regards to meals) 
o Participants ≥ 13 years old: 300 mg PO 2 times a day for 1 day, 
then 300 mg once daily 
o Participants < 13 years old: dose not established 
 
• 
Micafungin: 
o < 40 kg: 1 mg/kg/day IV (max 50 mg/day) or per local 
institutional guidelines 
o 40 kg: 50 mg/day IV 
• 
Liposomal amphotericin B IV: 3-5 mg/kg/day 
• 
Caspofungin: 1 mg/kg/day IV (max 50 mg/day) 
 
7.5 
Prophylaxis for Bacterial Infections (REQUIRED) 
 
Because patients with relapsed ALL are at high risk for bacterial sepsis, all 
participants on ALLR18 must receive prophylactic antibiotics. Prophylactic 
antibiotics should be started in induction blocks I, III and re-induction when 
the ANC < 500 or < 1000 and falling or predicted to fall, and continue until 
the ANC > 100 and rising. Antibiotics may be given by the parents or other 
caregivers at home, according to local institutional guidelines. Acceptable 
prophylactic regimens, in order of preference, include the following: 
 
• Levofloxacin 10 mg/kg PO/IV every 12 hours if < 5 years of every 
24 hours if > 5 years (maximum 500 mg per dose) 
 
• Vancomycin 400 mg/m2/dose IV every 12 hours (maximum 1 gram 
per dose) plus ciprofloxacin 250-350 mg/m2/dose PO every 12 hours 
(maximum 500 mg per dose) 
 
• Cefepime 1500 mg/m2/dose IV every 12 hours (maximum 2 gram 
per dose) 
 
• Vancomycin 400 mg/m2/dose IV every 12 hours (maximum 1 gram 
per dose) plus cefepime 1500 mg/m2/dose IV every 12 hours 
(maximum 2 gram per dose). Note that this regimen is not 
recommended by the PI, but is acceptable if preferred by the local 
institution or treating physician. 
 
• Please consult with the PI if you wish to use a prophylactic regimen 
other than one listed above. Because local infection rates, organisms, 
and susceptibilities vary, other prophylactic regimens will be 
allowed. However, regimens should be uniform at each collaborating 


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site and data on each regimen will be captured to explore the 
efficacy of each regimen. 
7.6 
Management of Febrile Neutropenia 
 
Episodes of fever and neutropenia should be managed according to institutional 
guidelines. Participants with fever (defined as a single oral temperature  38.3 C 
(101F) or temperature of  38.0 C (100.4 F) sustained over a one hour period 
and neutropenia (defined as ANC  500 cells/L) should be given IV antibiotics 
immediately. We recommend the following guidelines: 
 
• Participants who develop fever while receiving prophylactic levofloxacin or 
vancomycin and ciprofloxacin: 
o Begin cefepime (1500 mg/m2/dose IV every 8 hours) 
o Add or increase vancomycin to 400 mg/m2/dose IV every 8 hours 
o Discontinue ciprofloxacin or levofloxacin 
 
• Participants who develop fever while receiving prophylactic cefepime: 
o Begin meropenem (20 mg/kg/dose IV every 8 hours) 
o Add vancomycin (400 mg/m2/dose IV every 8 hours) if recent 
history of receiving intensive chemotherapy that produces substantial 
mucosal damage 
o Discontinue cefepime 
 
Participants who have suspected catheter-related infection, have evidence of sepsis 
(including shock, hypotension, rigors, septic emboli, unexplained respiratory 
distress or hypoxemia, or poor peripheral perfusion), or are known to be colonized 
by Pseudomonas aeruginosa, should also receive tobramycin, 60 mg/m2/dose IV 
every 6 hours. 
 
Participants who have severe abdominal pain or radiographic findings suggesting 
typhlitis, severe abdominal pain with evidence of sepsis, focal findings suggestive 
of intra-abdominal infection on physical examination, or known or suspected 
infection with Bacillus cereus should receive meropenem, 20 mg/kg/dose IV every 
8 hours, instead of cefepime. 
 
7.7 
Growth Factors 
 
Prophylactic use of hematopoietic growth factors (GM-CSF or G-CSF) is not 
recommended. However, GM-CSF (250 µg/m2/day) or G-CSF (5-10 µg/kg/day) 
may be considered for participants who have life threatening fungal infections or 
bacterial sepsis after discussion with PI. 
 
7.8 
Management of Capillary Leak Syndrome Related to Clofarabine 
 
In pediatric studies, during or shortly after clofarabine administration a few 
participants developed signs and symptoms consistent with capillary leak 


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syndrome. In these heavily pretreated participants, it has been difficult to separate 
potential drug-related cases of capillary leak syndrome from concurrent medical 
conditions such as infection/sepsis, progressive disease, or other underlying 
problems resulting from prior anti-leukemic therapies. For these reasons, during and 
after each dose of clofarabine investigators are to assess participants for the onset of 
the following signs or symptoms  grade 2: 
 
• Tachypnea or other evidence of respiratory distress; 
• Unexplained hypotension; and/or 
• Unexplained tachycardia. 
 
If one or more of these signs or symptoms occurs during study drug infusion, 
clofarabine administration is to be interrupted or held as clinically indicated. It is 
recognized that the total infusion time for this clofarabine dose in this circumstance 
may exceed 1 hour. Thus, if the patient’s condition stabilizes or improves, 
clofarabine administration may resume. Supportive care, strict monitoring of intake 
and output and investigation for other etiologies of the signs and symptoms, such as 
infection/sepsis, must be pursued. 
 
7.9 
Etoposide Reactions 
 
7.9.1 
Cardiovascular effects - Transient hypotension has occurred in about 1 to 2 % 
of participants following rapid IV administration of etoposide during clinical trials. 
However, hypotension has not been associated with cardiac toxicity or 
electrocardiogram changes. Blood pressure usually normalizes within a few hours 
after discontinuation of the infusion. To avoid this complication, etoposide should be 
infused over 30 – 60 minutes. If hypotension should occur, stop the infusion, and if 
necessary, give 10 mL/kg NS bolus over 15 minutes. Repeat as necessary. Once 
symptoms resolve, resume infusion at ½ the previous infusion rate until the full dose 
administered. If hypotension recurs, stop infusion and administer 10 mL/kg NS bolus 
as indicated. Once hypotension resolves, resume infusion at ½ previous infusion rate 
until complete. Consider infusing NS at 1 – 1.5 x maintenance during remainder of 
infusion. For all subsequent doses, further dilute and infuse over 2 hours. 
 
7.9.2 
Sensitivity reactions - Anaphylactoid reactions consisting principally of 
chills, rigors, diaphoresis, pruritis, loss of consciousness, nausea, vomiting, fever, 
bronchospasm, dyspnea, tachycardia, hypertension, and/or hypotension have 
occurred in 0.7 – 3% of patients receiving etoposide. Other manifestations include 
flushing, rash, substernal chest pain, lacrimations, sneezing, coryza, throat pain, 
back pain, abdominal cramps, and auditory impairment. Facial/lingual swelling, 
coughing, diaphoresis, cyanosis, tightness in the throat, and laryngospasm have also 
occurred. If an anaphylactoid reaction should occur: 
 
1. Stop the infusion immediately and notify H/O Fellow or Attending MD 
2. Administer the following as indicated: 
a) diphenhydramine 1mg/kg IV (max dose 50 mg) 


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b) hydrocortisone 50 – 100 mg/m2 IV 
c) epinephrine to be administered according to institutional policy 
d) fluid bolus 10 mL/kg NS infused over 15 minutes 
3. Once symptoms have resolved, resume infusion at ½ previous rate until 
infusion complete. Consider infusing NS at 1 – 1.5 x maintenance during 
remainder of infusion. 
4. If anaphylaxis recurs, stop the infusion and re-treat as above. Do not 
administer remainder of dose. Consider substituting etoposide with 
etoposide phosphate (Etopophos®) for all subsequent doses. 
5. If anaphylaxis does not recur, pre-medicate all subsequent doses with 
diphenhydramine 1mg/kg (max 50 mg) and hydrocortisone 50 – 100 mg/m2. 
Consider slowing the loading dose to be administered over 1 hour. 
6. Have at bedside all of the following for all subsequent infusions: 
a) Diphenhydramine 1mg/kg IV (max 50 mg) 
b) Hydrocortisone 50 – 100 mg/m2 IV 
c) epinephrine to be administered according to institutional policy 
 
Please note: anaphylactoid reactions are still possible with etoposide phosphate. If 
the patient cannot tolerate the substitution, drug is contraindicated and must be 
discontinued. 
 
7.10 
Drug Interactions 
 
Because concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, 
phenobarbital, and carbamazepine) with anti-leukemic therapy has recently been 
associated with inferior EFS, every effort should be made to avoid these agents, as 
well as rifampin, which also induces many drug metabolizing enzymes. Gabapentin 
does not induce hepatic drug metabolizing enzymes and may be a suitable 
alternative anticonvulsant. Azole antifungals (fluconazole, itraconazole, 
voriconazole, and ketoconazole) and the macrolide group of antibiotics (e.g. 
erythromycin, rifampin, and zithromax) may have potent inhibitory effects on drug- 
metabolizing enzymes, and the doses of some antileukemic drugs (e.g. vincristine, 
anthracyclines, steroids, etoposide) may need to be reduced in some patients on 
chronic azole antifungals or antibiotics. Consult Pharmacokinetics if long-term use 
of these interacting drugs is unavoidable. 
 
Penicillins interfere with tubular excretion of methotrexate, and it is recommended 
that an alternative non-penicillin antibiotic be used. 
 
Ph+ participants receiving tyrosine kinase inhibitors (e.g. imatinib, dasatinib and 
nilotinib) should not receive drugs known prolong the QT interval and should avoid 
strong CYP3A4 inhibitors. Participants should also avoid food 2 hours before and 1 
hour after taking dose. 
 
7.11 
Cytokine Release Syndrome Related to Administration of IL-2 and NK 
cells 


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Cytokine release syndrome is a disorder characterized by nausea, headache, 
tachycardia, hypotension, rash and shortness of breath. It is caused by the release of 
cytokines from the cells. IL-2 will be discontinued for cytokine release syndrome > 
grade 2. Supportive care with IV fluids, correction of hypoalbuminemia with albumin 
infusions and close monitoring should be performed. In severe cases, corticosteroids 
may be required. Corticosteroids should be avoided (if possible) during the 3 days 
prior to NK cell infusion or during the first 7 days after the infusion. 
 
8.0 
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION 
 
See Appendix III for information on the individual drugs to be used in this protocol. 


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9.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
Baseline 
Induction 
Block I 
Induction 
Block II 
Induction 
Block III 
Interim 
continuation 
Re-induction 
Continuation 
Off therapy 
H&P 
X 
Q 3-7 days 
Q 3-7 days 
Q 3-7 days 
Q week 
Q 3-7 days 
Q week 
X 
CBC with diff 
X 
Q 3-7 days 
Q 3-7 days 
Q 3-7 days 
Q week 
Q 3-7 days 
Q week 
X 
CMP 
X 
Q 3-7 days 
Q 3-7 days 
Q 3-7 days 
As indicated 
Q 3-7 days 
As indicated 
X 
Coagulation screen 
X 
Urine analysis 
X 
Hepatitis, HIV screen 
X 
EBV, CMV, HSV, 
varicella, histoplasma and 
toxoplasma titres 
X 
Bone marrow for 
MRD and mutant cells 
X 
End of block 
End of block 
End of block 
End of block 
End of block 
Every 16 
weeks 
X 
Bone marrow for biology 
studies 
X 
#Peripheral blood for 
MRD 
Day 6 
#Peripheral blood for 
CD20 
X 
Days 2, 4, 6, 
11, 14 and 21 
Serum for asparaginase 
and anti-asparaginase 
antibodies 
X 
Days 21 & 35 
(pre-PEG 
each day) 
Day 1 of week 
1 
Days 6 & 20 
(pre-PEG 
each day) 
*TPMT genotyping 
Day 3 
Germline DNA 
Day 3 
Day 1 
CSF cell count, diff, 
cytology 
with each IT 
with each IT 
with each IT 
with each IT 
with each IT 
with each IT 
with each IT 
with each IT 
Chest X-ray 
X 
ECHO/EKG 
X 
X 
QCT for bone density 
X 
5 years after completion 
of therapy 
CT scan of involved areas 
(lymphoma pts. only) 
X 
X (end of 
Block III) 
X 


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Baseline 
Induction 
Block I 
Induction 
Block II 
Induction 
Block III 
Interim 
continuation 
Re-induction 
Continuation 
Off therapy 
HLA typing of patient, 
parents and full siblings 
X 
KIR genotyping (recipient 
and donor) 
X 
NK cell phenotype 
(recipient) 
X 
Day 19 
NK cell phenotype (donors) 
X 
NK Chimerism (recipient) 
Day 19 
Variable nucleotide tandem 
repeat (recipient and donor) 
X 
Pregnancy test, if applicable 
Donor evaluations and 
services as per “NK Donor 
Pre-Evaluations and 
Scheduled Evaluations Prior 
to Cell Collection” standard 
order set 
X 
# Peripheral blood MRD and Peripheral blood CD20 evaluations will be discontinued for a patient following a negative MRD result (i.e., less than 0.01%) 
 
*TPMT genotyping will be sent if previous results are not available from frontline therapy 
 
 
Participants with possible allergic reactions to peg-asparaginase should have measurements of anti-asparaginase antibodies and asparaginase at the time of the reaction, and 
again if re-challenged (see Section 6.2) 
 
See Appendix I for listing of standard of care versus research studies 


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9.1 
Response Evaluations 
 
Bone marrow aspiration for microscopic evaluation and MRD by flow cytometry 
will be performed at the following time points: 
 
• End of block I of induction 
• End of block II of induction 
• End of Block III of induction 
• End of interim continuation 
• End of re-induction 
• Every 16 weeks during continuation 
• End of therapy 
• As clinically indicated to plan for transplant or for suspicion of relapse 
 
9.2 
Suggested Long-Term Follow-up Evaluations 
 
The following evaluations are recommended for participants who are off-treatment 
after completion of protocol specified therapy: 
 
• It is recommended that participants will be followed every 4 months for 1 year, 
every 6 months for 1 year and then yearly until the patient is in remission for 
10 years and is at least 18 years old. Thereafter, the patient will become alumni 
and will be followed according to the institution’s policy. 
• During the St. Jude visit, CBC with differential and other laboratory studies 
as clinically indicated will be obtained. 
• It is recommended that QCT for bone density be performed at 5 years off- 
therapy. 
• Participants will be considered off therapy 30 days after last treatment 
taken. Adverse events will not be reported while patient is off-therapy 
unless they are unanticipated problems (see Section 12.0) deemed related to 
therapy by the site PI. 
• After attaining continuous, complete remission for 5 years or more, SJCRH 
participants will be invited to participate in the long-term follow-up 
umbrella protocol and may be referred to the After Completion of Therapy 
Clinic (ACT). Collaborating sites will follow participants as per local 
guidelines. 
• When a SJCRH patient has been in remission for 10 years and is at least 18 
years of age, the patient will become SJCRH alumni and will be followed 
according to the SJCRH institutional policy. 
 
Note: Participants removed from therapy for other reasons (i.e., relapse, toxicity, 
etc.) before treatment is completed will be followed for survival only, and 
evaluations will be done as per treating physician’s/institution’s standard practice. 


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10.0 
EVALUATION CRITERIA 
 
10.1 
Response Criteria for Leukemia 
 
The response after each course of chemotherapy will be determined by the 
examination of the bone marrow. For the purposes of this protocol, MRD-negative 
is defined as < 0.01% blasts with a leukemia associated phenotype detected by 
flow cytometry. Because morphologic examination of the bone marrow during 
periods of hematopoietic recovery after intensive chemotherapy may be unreliable, 
response will be based on blast percentage by flow cytometry. Blast percentages 
determined by morphology will be used in cases that are not evaluable by flow 
cytometry. If the blast percentage is less than 5% in such cases, they will be 
classified as complete response, MRD not evaluable. 
 
10.1.1 Complete response (CR), MRD-negative 
< 0.01% blasts by flow cytometry 
 
10.1.2 Complete response (CRM), MRD-positive 0.01% to < 5% blasts by flow 
cytometry 
 
10.1.3 Partial response (PR) - A decrease of at least 50% in the percentage of 
blasts and 5% to 25% blasts by flow cytometry. 
 
10.1.4 No response (NR) - No change in clinical or laboratory status. 
 
10.1.5 Progressive disease (PD): Deterioration of initial disease status 
 
10.1.6 Relapse 
 
• Bone marrow relapse: Subsequent appearance, after achievement of 
CR, of ≥ 5% blasts in the bone marrow with confirmation by flow 
cytometry 
• CNS relapse: ≥ 5 WBC/µL of CSF with definite blasts on cytospin 
• Other extra-medullary relapse: Development of extra-medullary disease 
after achievement of CR. 
 
10.2 
Response Criteria for Lymphoblastic Lymphoma 
 
10.2.1 Complete response (CR) - No clinical or radiographic evidence of disease 
with M1 marrow (<5% blasts) status and with normal CSF and hemogram. 
 
10.2.2 Partial response (PR) - defined as >50% but <100% decrease in the sum of 
the product of the maximum perpendicular diameter of all lesions and 
decrease in bone marrow involvement by tumor cells by at least 50% 
 
10.2.3 No response (NR) - No change in clinical or laboratory status, response not 
qualifying for PR or Progressive disease 


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10.2.4 Progressive Disease (PD) - Worsening of disease, evidenced by >25% 
increase in the size of any lesion, increased organomegaly or appearance of 
new disease. 
 
10.3 
Toxicity Evaluation Criteria 
 
Common Terminology Criteria for Adverse Events v4 (CTCAE): This study will 
utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and 
performance reporting. A copy of the current version of the CTCAE can be 
downloaded from the Cancer Therapy Evaluation Program (CTEP) home page 
(http://ctep.info.nih.gov). Additionally, toxicities are to be reported on the 
appropriate data collection screens/forms. 
 
10.4 
Acceptable Percentage of Missed Doses for Commercially Available 
Drugs 
 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, 
the deviation must be reported to the IRB. However, it is expected that participants 
will occasionally miss some doses or receive the wrong dose of oral chemotherapy. 
Compliance with oral medication will be captured in the CRIS database and 
appropriately documented in the participants’ medical records. Appropriately 
documented doses of missed or wrong doses of chemotherapy will not constitute a 
deviation unless the amount in question is over 10% of the expected total dose due 
in the respective protocol cycles (these are specified in the CRIS ALLR18 
database). Missed doses do not include doses held or reduced for medical reasons 
(toxicity, illness) and will not be considered protocol deviations or violations. 
 
11.0 
OFF THERAPY AND OFF STUDY CRITERIA 
 
11.1 
Off-Study Criteria 
 
• Death 
• Withdrawal of consent 
• Found to be ineligible (e.g., incorrect diagnosis) 
• For St. Jude participants: completion of protocol-required evaluations and 
follow-up period (10 years), then survival outcomes will be followed per 
SJLTFU. For participants from collaborating sites, participants will be 
followed for survival status and relapse until one of the above criteria are 
met (e.g. death, withdrawal of consent, found to be ineligible). 
• For donors: 8 days after apheresis, or sooner if he/she is deemed ineligible 
after donor workup. 


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11.2 
Off-Treatment Criteria 
 
Off-treatment participants will continue to be followed for survival status until an 
off-study criterion is met. The first relapse/progression will be documented and 
grade 3-4 adverse events will be followed until they have resolved to < grade 2, or 
until the participant receives other anti-leukemia/lymphoma therapy. 
 
• Research participants who fail to achieve complete remission after 
induction block III of treatment. 
• Relapse as defined in section 10.1.6. 
• Second malignancy 
• Development of unacceptable toxicity during treatment (with concurrence 
of the PI) 
• Participant/family decision to withdraw from protocol treatment at any time 
for any reason 
• Discretion of the study PI, such as the following: 
o The researcher decides that continuing in the study would be harmful 
o A treatment is needed that is not allowed on this study 
o The participant misses so many appointments that the data cannot be 
used in the study 
o The participant’s condition gets worse 
o New information is learned that a better treatment is available, or that 
the study is not in the participant’s best interest 
• 30 days after completion of all protocol prescribed treatment, or if 
participant proceeds to transplant, off treatment date will be defined as the 
first day of conditioning therapy. 
 
12.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
 
12.1 
Reporting Adverse Experiences (AEs) and Deaths on Treatment 
 
Only “unanticipated problems involving risks to participants or others” referred to 
hereafter as “unanticipated problems” are required to be reported to the St. Jude 
IRB promptly, but in no event later than 10 working days after the investigator first 
learns of the unanticipated problem. Regardless of whether the event is internal or 
external (for example, an IND safety report by the sponsor pursuant to 21 CFR 
312.32), only adverse events that constitute unanticipated problems are reportable 
to the St. Jude IRB. As further described in the definition of unanticipated 
problem, this includes any event that in the PI’s opinion was: 
 
• Unexpected (in terms of nature, severity, or frequency) given (1) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document, as well as other relevant information available about the 
research; (2) the observed rate of occurrence (compared to a credible 


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baseline for comparison); and (3) the characteristics of the subject 
population being studied; and 
• Related or possibly related to participation in the research; and 
• Serious; or if not serious suggests that the research places subjects or others 
at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. 
 
Unrelated, expected deaths do not require reporting to the IRB. Though death is 
“serious”, the event must meet the other two requirements of “related or possibly 
related” and “unexpected/unanticipated” to be considered reportable. 
 
Deaths meeting reporting requirements are to be reported immediately to the St. 
Jude IRB, but in no event later than 48 hours after the investigator first learns of 
the death. 
 
The following definitions apply with respect to reporting adverse experiences: 
 
Serious Adverse Event: Any adverse event temporally associated with the 
subject’s participation in research that meets any of the following criteria: 
 
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the 
event as it occurred); 
• requires inpatient hospitalization or prolongation of existing 
hospitalization; 
• results in a persistent or significant disability/incapacity; 
• results in a congenital anomaly/birth defect; or 
• any other adverse event that, based upon appropriate medical judgment, 
may jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include: any substantial disruption of the ability 
to conduct normal life functions, allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse), a congenital 
anomaly/birth defect, secondary or concurrent cancer, medication 
overdose, or is any medical event which requires treatment to prevent any 
of the medical outcomes previously listed. 
 
Unexpected Adverse Event: 
 
• Any adverse event for which the specificity or severity is not consistent 
with the protocol-related documents, including the applicable investigator 
brochure, IRB approved consent form, Investigational New Drug (IND) or 
Investigational Device Exemption (IDE) application, or other relevant 
sources of information, such as product labeling and package inserts; or if it 


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does appear in such documents, an event in which the specificity, severity 
or duration is not consistent with the risk information included therein; or 
• The observed rate of occurrence is a clinically significant increase in the 
expected rate (based on a credible baseline rate for comparison); or 
• The occurrence is not consistent with the expected natural progression of 
any underlying disease, disorder, or condition of the subject(s) 
experiencing the adverse event and the subject’s predisposing risk factor 
profile for the adverse event. 
 
Internal Events: Events experienced by a research participant enrolled at a site 
under the jurisdiction of St. Jude IRB for either multicenter or single-center 
research projects. 
 
External Events: Events experienced by participants enrolled at a site external to 
the jurisdiction of the St. Jude Institutional Review Board (IRB) or in a study for 
which St. Jude is not the coordinating center or the IRB of record. 
 
Unanticipated Problem Involving Risks to Subjects or Others: An unanticipated 
problem involving risks to subjects or others is an event which was not expected to 
occur and which increases the degree of risk posed to research participants. Such 
events, in general, meet all of the following criteria: 
 
• unexpected; 
• related or possibly related to participation in the research; and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. An unanticipated problem involving risk 
to subjects or others may exist even when actual harm does not occur to 
any participant. 
 
Consistent with FDA and OHRP guidance on reporting unanticipated problems 
and adverse events to IRBs, the St. Jude IRB does not require the submission of 
external events, for example IND safety reports, nor is a summary of such 
events/reports required; however, if an event giving rise to an IND safety or other 
external event report constitutes an “unanticipated problem involving risks to 
subjects or others” it must be reported in accordance with this policy. In general, to 
be reportable external events need to have implications for the conduct of the study 
(for example, requiring a significant and usually safety-related change in the 
protocol and/or informed consent form). 
 
Although some adverse events will qualify as unanticipated problems involving 
risks to subjects or others, some will not; and there may be other unanticipated 
problems that go beyond the definitions of serious and/or unexpected adverse 
events. Examples of unanticipated problems involving risks to subjects or others 
include: 


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• Improperly staging a participant’s tumor resulting in the participant being 
assigned to an incorrect arm of the research study; 
• The theft of a research computer containing confidential subject 
information (breach of confidentiality); and 
• The contamination of a study drug. Unanticipated problems generally will 
warrant consideration of substantive changes in the research protocol or 
informed consent process/document or other corrective actions in order to 
protect the safety, welfare, or rights of subjects or others 
 
12.2 
Recording AEs and SAEs 
 
Adverse events (AEs) will be evaluated and documented by the clinical staff and 
investigators throughout inpatient hospitalizations and each outpatient visit. CRAs 
are responsible for reviewing documentation related to AEs and entering directly 
into CRIS protocol-specific database. The data to be recorded are 1) the event 
description, 2) the NCI CTCAE v4.0 code and grade, 3) the onset date, 4) the 
resolution date (or ongoing), 4) action taken for event, 5) patient outcome 6) 
relationship of AE to protocol treatment/interventions, 7) if AE was expected or 
unexpected, and 8) comments, if applicable. AEs that are classified as serious, 
unexpected, and at least possibly related will be notated as such in the database as 
“SAEs”. These events will be reported expeditiously to the St. Jude IRB within the 
timeframes as described above. 
 
Cumulative summary of Grades 1-5 events will be collected in Induction Block I; 
and Grade 3-5 events will be reported throughout rest of the protocol therapy as 
part of the progress reports to IRB at the time of continuing review. Hematological 
adverse events will not be collected in database. Specific data entry instructions for 
AEs and other protocol-related data will be documented in protocol-specific data 
entry guidelines, which will be developed and maintained by study team and 
clinical research informatics. 
 
The study team will meet regularly to discuss AEs (and other study progress as 
required by institutional DSMP). The PI will review Adverse Event reports 
generated from the research database, and corrections will be made if applicable. 
Once the information is final the PI will sign and date reports, to acknowledge 
his/her review and approval of the AE as entered in the research database. 
 
12.3 
Reporting Requirements to the FDA 
 
Any unexpected fatal or unexpected life-threatening event judged by the PI to 
possibly be due to the investigational agent, will be reported to the FDA by 
telephone or fax as soon as possible but no later than seven calendar days after 
notification of the event and followed by a written safety report as complete as 
possible within eight additional calendar days (i.e. full report 15 calendar days 
total after notification of event). 


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Unexpected, non-fatal and non-life-threatening SAEs, which occur in on-study 
participants during the time periods specified in Section 9.1 that are considered due 
to or possibly due to the investigational agent, will be reported to the FDA 
by written safety report as soon as possible but no later than 15 calendar days of 
the notification of the occurrence of the event. Expected SAEs, even unexpected 
fatal SAEs, considered by the PI to be not related to the study, will be reported to 
the FDA in the Annual Review Report along with non-serious AEs. All FDA 
correspondence and reporting will be conducted through the St. Jude Office of 
Regulatory Affairs. 
 
12.4 
Reporting to St. Jude Regulatory Affairs Office (RAO) 
 
Copies of all correspondence to the St. Jude IRB, including SAE reports, are 
provided to the St. Jude Regulatory Affairs office by the St. Jude study team. 
FDA-related correspondence and reporting will be conducted through the 
Regulatory Affairs office. 
 
12.5 
Reporting AEs to and from St. Jude and Collaborating Sites/Affiliates 
 
Adverse events from collaborating sites will also be reviewed by the PI and 
discussed in study team meetings as described above. SAE report from 
collaborating sites for AEs that are serious, unexpected, and at least possibly 
related to protocol treatment or interventions will be reported to site IRB and the 
St. Jude IRB within the reporting requirements described above. The PI will 
determine if this is an event that will need to be reported expeditiously to all 
participating sites, considering the following criteria: 
 
• Is the AE serious, unexpected, and related or possibly related to 
participation in the research? 
• Is the AE expected, but occurring at a significantly higher frequency or 
severity than expected? 
• Is this an AE that is unexpected (regardless of severity that may alter the 
IRB’s analysis of the risk versus potential benefit of the research and, as a 
result, warrant consideration of substantive changes in the research 
protocol or informed consent process/document? 
 
With the submission of the “Reportable Event” in St. Jude TRACKS application, 
the PI will indicate if all sites should be notified to report to their IRBs, and if the 
protocol and/or consent should be amended (consent will be amended if event is 
information that should be communicated to currently enrolled subjects). 
Generally, only events that warrant an amendment to the protocol and/or consent 
will be reported expeditiously to all sites. However, any event may be reported 
expeditiously to all sites at the discretion of the PI. 
 
A cumulative summary of Grades 1-5 adverse events that occur during Block I, 
Grade 3-5 AEs adverse events during remainder of protocol therapy, and 
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will be reported to all sites with study progress report at the time of continuing 
review. 
For collaborating sites: Serious AND unexpected events are to be reported to the 
St. Jude PI (Dr. Sima Jeha) within 48-72 hours via fax or email. 
 
Unexpected deaths must be reported to the St. Jude PI via phone call or email 
within 24 hours of the event. A written report must follow. 
 
All correspondence and reports must also be sent by email to ALLR18 study team. 
 
Sima Jeha, MD 
Department of Oncology 
Leukemia/Lymphoma Division 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
Memphis, TN 38105 
Phone: 
FAX: 
 
Email: 
Email: 
 
13.0 
DATA COLLECTION, MONITORING AND CONFIDENTIALITY 
 
13.1 
Data Collection 
 
Electronic case report forms (e-CRFs) will be completed by the SJCRH 
Leukemia/Lymphoma CRAs. Data will be entered from record directly into a 
secure CRIS database, developed and maintained by St. Jude Clinical Research 
Informatics. 
 
Data Management will be supervised by the Director of Clinical Trials 
Management, and Manager of Clinical Research Operations for the 
Leukemia/Lymphoma Division, working with Dr. Jeha or her designee. All 
protocol-specific data and all grade 3-5 adverse events will be recorded by the 
clinical research associates into the CRIS database, ideally within 2-4 weeks of 
completion of study phase. All questions will be directed to the attending physician 
and/or PI and reviewed at regularly-scheduled working meetings. The attending 
physicians (or their designees) are responsible for keeping up-to-date roadmaps in 
the patient’s primary SJCRH medical chart. 
 
Regular (at least monthly) summaries of toxicity and protocol events will be 
generated for the PI and the department of Biostatistics to review 
 
13.2 
Data Collection Instructions for Collaborating Sites 


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Collaborating sites will collect abstract data from medical records and submit by 
using e-CRFs via remote electronic data entry. All protocol-specific data and all 
grade 3-5 adverse events will be recorded by the clinical research associates into 
the CRIS database, ideally within 2-4 weeks of completion of study phase. 
13.3 
Study Monitoring 
 
This study is considered high risk (HR-3) for monitoring purposes. Protocol and 
regulatory compliance, including essential regulatory documentation, will be 
assessed as well as the accuracy and completeness of all data points relating to the 
primary and secondary objectives semi-annually. If the study design has strata, 
accrual will be tracked continuously. The first two enrollees will be monitored and 
15% of the study enrollees thereafter, semi-annually. 
 
The PI and study team are responsible for protocol and regulatory compliance, and 
for data accuracy and completeness. The study team will meet at appropriate 
intervals to review case histories or quality summaries on participants and retain 
copies of the minutes that are signed by the PI. 
 
The Eligibility Coordinators in the Central Protocol and Data Monitoring Office 
(CPDMO) will verify informed consent documentation and eligibility status on 
100% of St. Jude participants within 5 working days of enrollment completion. 
 
The Clinical Research Monitor (CRM) will verify informed consent documentation 
and eligibility status of all non-St. Jude participants and perform a quality 
verification of select St. Jude participants during routine monitoring intervals (every 
6 months). Overall study conduct, compliance with primary and secondary 
objectives, age of majority consenting, safety assessments and reporting, and the 
timeliness and accuracy of database entries are monitored routinely. 
 
Study documents routinely monitored on selected participants include medical 
records, database entries, study worksheets, and case report forms. Study 
documents are monitored for participant status, demographics, staging, subgroup 
assignment, treatments, investigational drug accountability, evaluations, responses, 
participant protocol status, off-study and off-therapy criteria, and for all other 
specifics as detailed in a separate study-specific monitoring plan. The study- 
specific monitoring plan may be revised over time, to adapt monitoring frequency 
and/ or intensity to a changing environment when appropriate (for example: new 
safety signals; positive history of compliance; all participants are in long term 
follow-up; or the enrollment period has ended). 
 
The recording and reporting of Adverse Events, Serious Adverse Events (SAEs), 
and Unanticipated Problems (UPs) to include type, grade, attribution, duration, 
timeliness and appropriateness will be reviewed by the Monitor/ CRM. The CRM 
will generate a formal report which is shared with the Principal Investigator (PI), 
study team and the Internal Monitoring Committee (IMC). 


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Continuing reviews by the Internal Review Board (IRB) and Clinical Trials- 
Scientific Review Committee (CT-SRC) will occur at least annually. In addition, 
unanticipated problems are reviewed in a timely manner by the IRB. 
 
St. Jude affiliates and domestic collaborating study sites will be monitored on-site 
by a representative of St. Jude as needed. 
13.4 
Confidentiality 
 
Study numbers will be used in place of an identifier such as a medical record 
number. No research participant names will be recorded on the data collection 
forms. The list containing the study number and the medical record number will be 
maintained in a locked file and will be destroyed after all data have been analyzed. 
The medical records of study participants may be reviewed by the St. Jude IRB, 
FDA, and St. Jude clinical research monitors. 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Accrual 
 
The institutional trial ALLR17 has been activated for 7 years and enrolled 41 
participants thus far. The first 6 participants were considered not evaluable due to an 
amendment to ALLR17. The previous trial ALLR16 opened in January 1997 and 
closed to accrual in September 2003 with 40 evaluable participants enrolled. Thus 
historically there would be on average 5 to 6 participants enrolled per year in our 
institution. Thus, at the institution’s historical rate, we expect 7 to 8 years accrual 
time for the desired sample size of 40. The ALLR18 trial will be a multi-institution 
study and it is predicted that the accrual rate will be higher, at approximately 10 
evaluable participants per year. Assuming this rate, we expect to accrue 40 evaluable 
participants in approximately 4 years for the primary objective. 
 
Update amendment 2.0: The first 5 patients were enrolled in a staggered manner 
(until completion of Block I) due to FDA stipulations to ensure safety of the 
experimental regimen. As a consequence, enrollment was slow for the first 2 years 
until the restricted enrollment period was completed on 7/28/14. Therefore, we will 
extend the accrual of the trial by 2 years (i.e., we expect to accrue 40 evaluable 
patients in approximately 6 years for the primary objective). 
 
14.2 
Monitoring of Induction Toxicities and Short-Term Efficacy 
 
The chemotherapy in the remission induction phase of this protocol is more 
intensive than the previous trials. We will closely monitor grade 4 or higher 
infections and toxic deaths during remission induction. 
 
Grade 4 infection or higher: The rate of grade 4 or higher infection during 
Induction of ALLR16 and R17 is 15% and 17.6% respectively. The following 
group sequential rule will be in place to monitor if there is sufficient evidence that 
the true probability of grade 4 or higher infection is higher than 20%. 


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Number of participants completing 
Induction 
Suspend trial if # Gr 4 Infection >= 
or toxic death during Block I 
10 
5 
20 
8 
30 
11 
Based on the Binomial distribution, the overall significance level is less than 0.091 
based on the inclusion-exclusion formula, and the statistical power to stop the trial at 
each look is 0.49, 0.74, and 0.86, respectively if the true probability is 45%. 
 
Toxic deaths during Induction Block I. All toxic deaths (not related to 
progressive disease) during Induction will be monitored closely. In ALLR16 and 
ALLR17, all disease-unrelated deaths were toxic deaths: 2/40 on ALLR16 and 
2/39 on ALLR17. Thus, on ALLR18, we will not tolerate more than 3 toxic deaths 
in the first block of induction therapy. If, at any time, the third toxic death occurs 
during the first block of induction, we will suspend the trial and re-evaluate the 
safety of the therapy. 
 
One-year event-free survival: The 1-year EFS rate of ALLR16 and R17 is about 
50%. For monitoring purpose failures we will exactly include death, failure to 
attain CR, relapse, second malignancy, excessive toxicity resulting in cessation of 
ALLR18 treatment, and lost to follow-up (but we fully expect to follow every 
patient for at least one year). The following binomial based group sequential rule 
will be in place to monitor if there is sufficient evidence that the true 1-year failure 
rate is higher than 55%. 
 
Number of participants completing 
one-year Tx 
Suspend trial if # failures >= 
15 
10 
30 
20 
 
Based on the binomial distribution, only when the number of failures greater than 
or equal to 12 and 22 at each look respectively can the overall significance level be 
controlled below 0.075, but these numbers are too high to be clinically acceptable. 
We thus set the boundary at 10 and 20. Based on the binomial distribution, if the 
probability of failure at one year is 0.7 (i.e. 0.2 higher than the historical 0.5 and 
0.15 higher than the monitoring target of 0.55), then the stopping boundary gives 
the probability to stop at the first look 0.73 and at the second look 0.72. [Note that 
based on the binomial distribution, only when the number of failures is greater 
than or equal to 12 and 22 at each look respectively can the overall type-I error 
(i.e., erroneously stop when the true 1-year failure rate is in fact 0.5) probability be 
controlled below 0.075, but these numbers are too high to be clinically acceptable. 
We thus set the boundary at 10 and 20.] 
 
14.3 
Primary Objective 


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To estimate the 3-year survival rate of participants with 1st relapse or primary 
refractory precursor B-cell ALL treated with risk-directed therapy 
 
Analysis and power: This is a phase-II clinical trial. The outcome will be analyzed 
in terms of overall survival (OS) since diagnosis of first relapse. Only death will be 
considered a failure for OS. Event-free survival (EFS) will also be estimated. For 
EFS, relapse and second malignancies will be considered as failures in addition to 
death in complete remission. The time to EFS will be set to 0 for participants who 
fail to achieve complete remission. Kaplan-Meier estimates of the OS and EFS 
functions will be computed, along with estimates of standard errors by the method of 
Peto. Three-year OS and EFS rates, as well as longer term survival rates (5 year and 
10 year) will be estimated with 95% confidence intervals. 
 
Additionally, EFS and OS will be estimated separately in two strata: participants 
with prior bone marrow transplant (BMT) and those never had any BMT because it 
is expected that participants with prior BMT may have worse survival. The follow- 
up time on each participant will be three years since enrollment. 
 
Kaplan-Meier estimates of EFS and OS in R16 and R17 are shown below: 
 


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The objective here is estimation instead of comparison. Comparisons to historical 
controls are considered exploratory. With the sample size n=40, the statistical 
power will be limited. Analysis will begin after 3 years of follow-up since the on- 
study date of the last enrolled patient. 
 
14.4 
Secondary Objectives 
 
1) To determine minimal residual disease (MRD) levels at the end of remission 
induction therapy and compare with ALLR17. 
 
Probability (proportion) of positive MRD will be compared with that from the 
ALLR17 trial using Fisher’s exact test. MRD will also be put into ordered 
categories such as negative (<0.01%), low (0.01% - 1%) and high (>=1%) and 
compared with those in ALLR17 using exact Chi-square test. We are aware that 
the power is limited given the small sample size, unless the true difference is 
unusually large. Analysis will begin no later than 1 year after the last enrollment. 
 
2) To estimate levels of CD20 expression at baseline, during treatment with 
dexamethasone-containing chemotherapy and following rituximab treatment in week 
1 of Block I of remission induction therapy for relapsed precursor B-cell ALL 
 
Mean and median of CD20 expression levels will be computed at each time point 
along with 95% confidence intervals. Trajectory of CD20 levels as a function of 
time will be modeled and predicted using a longitudinal data model, with time (and 
possibly other clinical and demographic variables) and an intra-patient random 
effect as factors; this analysis is considered exploratory. Analysis will begin no 
later than 1 year after the last enrollment. 


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14.5 
Exploratory Objectives 
 
1) To assess donor NK cell killer immunoglobulin-like receptor (KIR) repertoire 
and explore the efficacy of NK cell infusions followed by rituximab in relapsed ALL. 
 
The donor KIR repertoire will be described by summary statistics (counts and 
proportions). Three and five year EFS of participants who received NK cell 
infusion will be estimated by the KM estimator along with 95% confidence 
intervals. Analysis will begin no later than 1 year after the last enrollment. 
 
2) To study whether pre-existing or emerging development of serum antibodies to 
asparaginase is related to hypersensitivity reactions or exposure to asparaginase 
or to anti-leukemic or adverse effects of therapy, in participants with relapsed 
ALL. 
 
Due to heterogeneity among participants and prior therapy, we will use exploratory 
analytic tools to assess whether anti-asparaginase antibodies are related to clinical 
hypersensitivity reactions. Analysis will begin no later than 1 year after the last 
enrollment. 
 
3) To describe the effect of prophylactic antibiotics on the evolution of antibiotic 
resistance in peri-rectal swab isolates of Escherichia coli, Klebsiella pneumonia, 
Pseudomonas aeruginosa, Streptococcus mitis and enterococci and resistance 
patterns of bacterial isolates from all sterile site cultures (completed with 
amendment 3.0) 
 
Resistance of selected colonizing and invasive organisms to representative 
antibiotics from various classes (ex. Cephalosporins, carbapenems, 
fluoroquinolones) will be described pre and post antibiotic prophylaxis at baseline 
(pre-antibiotic prophylaxis) and post-antibiotic prophylaxis at any time point for 
the entire study population and separately based on type of antibiotic prophylaxis 
the patients received. All suspected or proven infections which occur while a 
patient is on antibiotic prophylaxis as well as C. difficle infections during and up to 
one month post antibiotic prophylaxis will be described. 
 
Analysis will begin no later than 1 year after the last enrollment. 
 
4) To characterize global gene expression and copy number changes in leukemic 
cells at relapse and to compare to initial diagnosis (when available) to improve 
knowledge of mechanisms of relapse 
 
The analyses will be performed using established methods.17-19 Analysis will begin 
no later than in 1 year after the last enrollment. 
 
5) To determine in vitro sensitivity of pretreatment relapsed leukemic cells to 
anti-leukemic agents and compare to in vitro sensitivity at diagnosis (when 
available) 


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Protocol document date: 06-12-2018 
 
 
 
 
Descriptive statistics of sensitivity such as IC50 will be calculated. Analysis will 
begin no later than 1 year after the last enrollment. 
 
6) To engraft freshly harvested relapsed ALL cells into murine models of ALL to 
gain insights into therapy resistance 
After engraftment, various downstream analyses will be done on the leukemic cells 
including immunophenotype, histologic and genomic studies. Analysis will begin 
no later than 1 year after the last enrollment. 
 
8) To study the development of resistant clones during therapy for relapsed ALL. 
 
NT5C2 mutation detection will be performed by targeted re-sequencing using next 
generation platforms. We plan to sequence NT5C2 coding regions on the Mi-seq 
platform, but are mindful of continuing evolvement of sequencing technologies to 
adopt the most cost-effective and efficient platforms for this study, with the help 
from Hartwell Center and PCGP. Analysis will begin no later than 1 year after the 
last enrollment. 
 
15.0 
OBTAINING INFORMED CONSENT 
 
15.1 
Consent/Assent at Enrollment 
 
The process of informed consent for ALLR18 will follow institutional policy. The 
informed consent process is an ongoing one that begins at the time of diagnosis and 
ends after the completion of therapy. Informed consent should be obtained by the 
attending physician or his/her designee, in the presence of at least one non-physician 
witness. Initially, informed consent will be sought for the institutional banking 
protocol (research study), blood transfusion and other procedures as necessary. After 
the diagnosis of relapse ALL is established, we will invite the patient to participate 
in the ALLR18 protocol. Consent/assent for initial enrollments will be done at St. 
Jude for all participants (including NK cell donors). 
 
Throughout the entire treatment period, participants and their parents receive 
constant education from health professionals at SJCRH and collaborating sites, and 
are encouraged to ask questions regarding alternatives and therapy. All families 
have ready access to chaplains, psychologists, social workers, and the St. Jude 
ombudsperson for support, in addition to that provided by the primary physician 
and other clinicians involved in their care. 
 
We will also obtain verbal assent from children 7 to 14 years old and written assent 
for all participants >14 years of age. Participants who reach the age of majority 
while on study will be re-consented for continued participation on ALLR18, 
according to Cancer Center and institutional policy. 


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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
 
15.2 
Consent at Age of Majority 
 
The age of majority in the state of Tennessee is 18 years old. Research participants 
must be consented at the next clinic visit after their 18th birthday. If an affiliate or 
collaborating site is located in a country or state where a different age of majority 
applies, that location must consent the participants according to their local laws. 
 
15.3 
Consent When English is Not the Primary Language 
 
When English is not the patient, parent, or legally authorized representative’s 
primary language, the Social Work department will determine the need for an 
interpreter. This information documented in the participant’s medical record. 
Either a certified interpreter or the telephone interpreter’s service will be used to 
translate the consent information. The process for obtaining an interpreter and for 
the appropriate use of an interpreter is outlined on the Interpreter Services, OHSP, 
and CPDMO websites. 
 
Collaborating Sites will follow institutional policy for consenting non-English 
speaking participants (and will provide institutional policy to St. Jude). 


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IRB Approval daIRteB: 0N6U-1M3B-E20R1:8Pro00002817 
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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
16.0 
REFERENCES 
 
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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
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Protocol document date: 06-12-2018 
 
 
 
48. Long EO: Regulation of immune responses through inhibitory receptors. Annu Rev 
Immunol 17:875-904, 1999 
49. Ruggeri L, Capanni M, Casucci M, et al: Role of natural killer cell alloreactivity in 
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formulation among children with newly diagnosed acute lymphoblastic leukemia. 
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64. Mullighan CG, Zhang J, Harvey RC, et al: JAK mutations in high-risk childhood acute 
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Protocol document date: 06-12-2018 
 
 
 
66. Holleman A, Cheok MH, den Boer ML, et al: Gene-expression patterns in drug- 
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351:533-42, 2004 
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chemotherapy crossresistance and treatment response in childhood acute 
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74. Pfeifer H, Wassmann B, Pavlova A, et al: Kinase domain mutations of BCR-ABL 
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Protocol document date: 06-12-2018 
 
 
 
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ALLR18 
Appendix I 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
APPENDIX I: TESTS PERFORMED FOR GOOD CLINICAL CARE AND FOR RESEARCH 
 
The standard of care services in this study are as follows: 
 
• History & physical exams 
• CBC with diff 
• Coagulation screen 
• Urine analysis 
• Hepatitis, HIV screen 
• NK cell recipient - EBV, CMV, HSV, varicella, histoplasma, and toxoplasma titres 
• Bone marrow aspirate and biopsy procedure and MRD 
• Peripheral blood for MRD 
• TPMT genotyping 
• CSF cell count, diff 
• Chest x-ray 
• ECHO and EKG 
• QCT for bone density 
• HLA typing of patient and potential donors 
• Pregnancy test for females of childbearing potential (patient) 
• All agents used in this trial are commercially available. Rituximab and IL-2 use are 
experimental 
 
The research services are as follows: 
 
• CliniMACS system and NK cell infusions 
• Bone marrow sample for biology studies (taken at same time bone marrow procedure 
is done for routine care to confirm relapse – baseline) 
• Peripheral blood for CD20 
• Bone marrow for mutant cells 
• Serum for asparaginase and anti-asparaginase antibodies (at specified time points – 
baseline, Induction Block I - Days 21, 28, 35 (pre-PEG each day); Interim 
continuation - Day 1 of week 1; Re-Induction – Days 6, 13, 20 (pre-PEG); and at time 
of reaction (if applicable); again if re-challenged with asparaginase (section 6.2) 
• Germline DNA sample Day 3 Induction Block I and Day 1 induction Block II 
• NK PHENO (patient) – baseline and Day 19 of Induction Block I 
• NK PHENO (donor) – baseline 
• Variable nucleotide tandem repeat (VNTR) and KIR typing for recipient participant 
• Donor testing – KIR typing, VNTR, serologic infectious disease testing, CBC, 
pregnancy test, complete metabolic panel; see NK Cell Donor Power Plan order set for 
full details 


ALLR18 
Appendix II 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
APPENDIX II: PEDIATRIC RITUXIMAB INFUSION GUIDELINES 
 
Dose = 375 mg/m2 
 
• Dilute in NS to final concentration 1 mg/ml for ease of administration. 
• Administer intravenously through a dedicated line 
Pre-medicate with: 
• Acetaminophen 15 mg/kg PO (max 650 mg) 
• Benadryl 1 mg/kg IV or PO (max 50 mg) 
 
FIRST INFUSION: Participants treated at St. Jude will be as per current St. Jude formulary 
from Intranet (collaborating sites will follow institutional formulary/policy) 
 
SUBSEQUENT INFUSIONS: Participants treated at St. Jude will be as per current St. Jude 
formulary from Intranet (collaborating sites will follow institutional formulary/policy) 
 
GENERAL GUIDELINES: 
 
1. Monitor blood pressure, pulse, respiration and temperature every 15 minutes for the 
first hour or until the participant is stable, then hourly until the infusion is complete. 
2. Have epinephrine and diphenhydramine available along with resuscitation equipment 
for the emergency management of anaphylactic reactions. 
3. If infusion related events occur, slow the infusion or stop the infusion until resolution, 
treating the participant if necessary. If it is determined that the participant can be 
safely re-challenged, begin the infusion at 50% of the rate at which the infusion was 
running when stopped. 
4. Verify that the participant has not taken antihypertensive medications within 12 hours 
of beginning the rituximab infusion. Hypotension may occur during the infusion. 
5. Participants with a high number of circulating cancer cells (> 25,000/mm3) may be at 
a higher risk for tumor lysis syndrome. These participants should receive allopurinol 
and intravenous hydration and should be monitored. 
6. Participants who experience severe infusional symptoms may need to be hospitalized 
for observation. Participants and families should be counseled to be seen in the 
emergency room if infusion-related symptoms occur again after the infusion is 
complete (i.e. at home at a later time). 
7. Monitor participants during and for a few weeks after receiving rituximab for the 
development of mucositis with a sore throat or mouth ulcers followed by a diffuse skin 
rash which can worsen rapidly and result in total body skin sloughing and can become 
life threatening. 
8. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of 
active HBV infection and for signs of hepatitis throughout their study participation. 


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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
APPENDIX III: DRUG/DEVICE/BIOLOGIC AGENT INFORMATION 
 
1. VINCRISTINE (Oncovin) 
 
Source and pharmacology: Vincristine is an alkaloid obtained from the periwinkle (Vinca 
rosea) plant. It reversibly binds to microtubule and spindle proteins to cause metaphase arrest. 
Vincristine has poor penetration into the CSF. It is extensively protein bound (~75%). 
Extensive metabolism occurs in the liver. Excretion is primarily in the bile. A dosage decrease 
is recommended in participants with elevated bilirubin (see section 7.3). 
 
Formulation and stability: Vincristine is supplied in multiple-dose 1 mg/mL vials containing 1 
mL, 2 mL and 5 mL. The intact vials should be stored under refrigeration and protected from 
light. 
 
Supplier: The drug is commercially available. 
 
Toxicity: Dose-limiting toxicity is neurotoxicity, which is characterized by constipation 
and/or paralytic ileus, ptosis, vocal cord paralysis, weakness, jaw pain, abdominal pain, 
peripheral neuropathies, loss of deep tendon reflexes, and “foot drop.” Peripheral neuropathy 
is often the first sign of neurotoxicity and is initially reversible. Other toxicities reported 
include alopecia, mild nausea and vomiting, SIADH, myelosuppression, orthostatic 
hypotension, optic atrophy, transient cortical blindness, and auditory damage. Acute shortness 
of breath and severe bronchospasm have been reported after administration of vinca alkaloids. 
Myelosuppression is rare at usual doses. Vincristine is a vesicant and may cause severe tissue 
damage if extravasation occurs. Note that dose reduction may be necessary in participants <1 
year of age or <10 kg in weight; dosing on a “per kg” (rather than per m2) basis has been 
advocated for infants in order to decrease toxicity. 
 
Guidelines for administration: intravenous, see Treatment section 5.2.1 (Remission induction 
Block I), section 5.4 (Re-Induction) and section 5.5 (Continuation). 
 
 
2. DEXAMETHASONE (Decadron®) 
 
Source and pharmacology: Dexamethasone is a synthetic congener of the natural adrenal 
hormone hydrocortisone. Dexamethasone is a white or yellowish crystalline powder. It binds 
with steroid receptors on nuclear membranes to impair cellular mitosis and inhibit protein 
synthesis. Dexamethasone also has potent anti-inflammatory effects and suppresses the 
immune system. Dexamethasone is absorbed well orally. It is metabolized in the liver, and the 
metabolites are excreted mainly in the urine. 
 
Formulation and stability: Dexamethasone is available as tablets of various strengths and as 
an elixir. It is also available as a solution for parenteral use. All formulations of the drug can 
be stored at room temperature. The injectable form may be further diluted in 5% dextrose or 
0.9% NaCl-containing solutions and is stable for at least 24 h at room temperature. 


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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
Supplier: The drug is commercially available. 
Toxicity: The side effects of dexamethasone vary depending on the duration of its use. Side 
effects that can occur with short-term use include peptic ulcers with possible perforation and 
hemorrhage, increased susceptibility to infections, emotional instability, insomnia, increased 
appetite, weight gain, acne, and hyperglycemia. Side effects more commonly associated with 
prolonged use include cataracts, increased intraocular pressure and associated glaucoma, 
development of a “cushingoid” state, compression fractures, menstrual irregularities, 
suppression of growth in children, secondary adrenocortical and pituitary unresponsiveness 
particularly in times of stress as in trauma, surgery or illness, osteoporosis and muscle wasting. 
 
Guidelines for administration: PO, see section 5.2.1 (Remission induction, Block I), section 
5.3 (Interim continuation), section 5.4 (Re-Induction), section 5.5 (Continuation) 
 
 
3. HYDROCORTISONE, Intrathecal (Cortef, Solu-Cortef) 
 
Source and pharmacology: Hydrocortisone is a synthetic steroid akin to the natural adrenal 
hormone cortisol. Hydrocortisone has phase-specific cytotoxicity, killing lymphoblasts 
primarily during S phase. It has catabolic effect on proteins and alters the kinetics of 
peripheral blood leukocytes. It is excreted in the urine and catabolized in the liver. 
 
Formulation and stability: Solu-Cortef sterile powder is supplied in the following package: 
100 mg plain, and 100 mg, 250 mg, 500 mg, and 1000 mg ACT-O-VIAL (MIX-O-VIAL). 
Store unreconstituted product at controlled room temperature 15-30C (59-86F). Store 
reconstituted solution in the refrigerator and protect from light. Unused solution should be 
discarded after 3 days. Use Solu-Cortef (plain vial) for intrathecal use, and reconstitute with 
0.9% sodium chloride, USP for injection. 
 
Supplier: Commercially available 
 
Toxicity: If given intrathecally, sterile arachnoiditis may occur. Headache, seizures, unusual 
feelings or sensations, loss of feeling or ability to move arms or legs, and difficulty with 
urination or bowel movements may also occur. 
 
Guidelines for administration: Intrathecal, see section 5.2.1 (Remission induction Block I), 
section 5.2.2 (Remission induction Block II), 5.2.3 (Remission induction Block III), section 
5.3 (interim continuation), section 5.4 (Re-induction), section 5.5 (Continuation), and 
5.7 (prophylaxis and treatment for CNS disease), 5.10 (summary of IT therapy). 
 
 
4. METHOTREXATE 
 
Source and pharmacology: Methotrexate is a folate analogue that acts by inhibiting 
dihydrofolate reductase. Dihydrofolate reductase is an enzyme important in the conversion of 
folic acid to tetrahydrofolic acid, which is necessary in the synthesis of purine nucleotides and 
thymidylate. By inhibiting the production of tetrahydrofolic acid, methotrexate interferes with 


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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
DNA, RNA and protein synthesis. Methotrexate is poorly and variably absorbed orally, with 
an average of  40% for doses of < 30 mg/m2. At higher dosages, the extent of absorption 
decreases. Methotrexate is approximately 50% protein bound. It distributes widely into body 
tissues and fluids with sustained concentrations in the kidney and the liver. Methotrexate 
undergoes metabolism by cytosolic aldehyde oxidase to hydroxy methotrexate. It is excreted 
mainly in the urine as unchanged drug with small amounts being excreted in the bile and 
feces. The percent recovered as unchanged drug in the urine is higher with short infusions 
than with prolonged infusions. Methotrexate has a biphasic elimination with an initial half-life 
of  2-3 hours and a terminal half-life of 10-12 hours. Methotrexate may be “sequestered” in 
body fluid collections and eliminated slowly from these areas. Patients with effusions or GI 
obstruction should have plasma levels monitored closely for delayed excretion following 
high-dose methotrexate. 
 
Formulation and stability: Methotrexate is supplied in single-dose vials containing 50mg, 
100mg, 200mg, and 250 mg of methotrexate as a 25 mg/ml preservative-free solution and in 
vials containing 20mg, 50 mg, 100mg, 250 mg and 1000mg of lyophilized drug. It is also 
available in 2.5 mg tablets. Methotrexate preservative-free solution and lyophilized drug 
should be stored at room temperature and protected from light. Methotrexate tablets can also 
be stored at room temperature. The vials containing 20, 50, 100 and 250 mg of lyophilized 
product can be reconstituted by adding sterile water, 0.9% NaCl or D5W to a final 
concentration not exceeding 25 mg/ml. The 1000mg vials containing lyophilized product are 
reconstituted to a final concentration of 50 mg/ml. 
 
Supplier: commercially available 
 
Toxicity: The dose limiting toxicities of methotrexate are generally bone marrow suppression, 
ulcerative stomatitis, severe diarrhea or acute nephrotoxicity. Toxicities reported frequently 
include nausea and vomiting, diarrhea, anorexia, alopecia, hepatic toxicity and alopecia. Less 
common side effects include blurred vision, photosensitivity, anaphylaxis, headache, 
pneumonitis, skin depigmentation or hyperpigmentation, rash, vasculitis and encephalopathy. 
During high-dose methotrexate therapy, most patients experience a transient decrease in GFR, 
but renal failure can occur, particularly if the patient does not receive urinary alkalinization and 
aggressive hydration before, during and after receiving high dose methotrexate. Leucovorin 
rescue should be initiated within 48 hours of starting high-dose methotrexate and adjusted based 
on MTX levels to prevent bone marrow toxicity and mucositis. Leucovorin may also be 
necessary after IT administration, especially if IT methotrexate therapy is given to patients with 
renal dysfunction. Patients with Down syndrome have a tendency to have delayed methotrexate 
clearance and a greater risk of toxicity, despite increased leucovorin rescue. 
 
Guidelines for administration: Intrathecal and intravenous, see section 5.2.1 (Remission 
induction Block I), section 5.2.2 (Remission induction Block II), 5.2.3 (Remission induction 
Block III), section 5.3 (interim continuation), section 5.4 (Re-induction), section 5.5 
(Continuation), and 5.7 (prophylaxis and treatment for CNS disease), 5.10 (summary of IT 
therapy). 


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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
5. CYTARABINE (Ara-C) (Cytosar-U) 
 
Source and pharmacology: Cytarabine is a deoxycytidine analogue. It must be tri- 
phosphorylated to its active form, ARA-CTP, by deoxycytidine kinase and other nucleotide 
kinases. Ara-CTP inhibits DNA polymerase. In addition, ara-CTP is incorporated into DNA 
as a false base, causing inhibition of DNA synthesis. It is cell cycle, S phase specific. 
Cytarabine does penetrate the blood brain barrier. It is converted to its inactive form, uracil 
arabinoside, by pyrimidine nucleoside deaminase. Approximately 80% of the dose is 
recovered in the urine, mostly as uracil arabinoside (ara-U). 
 
Formulation and stability: Cytarabine is available in multi-dose vials containing 100, 500, 
1000 and 2000mg of lyophilized drug. Intact vials can be stored at room temperature. For IV 
use, either sterile water for injection or bacteriostatic water for injection can be used to 
reconstitute the lyophilized drug. For intrathecal use, only sterile water for injection should be 
used for reconstitution. The 100 and 500 mg vials are reconstituted with 2 and 10 ml 
respectively resulting in a final concentration of 50mg/ml. The 1000 and 2000mg vials are 
reconstituted with 20ml and 40 ml respectively resulting in a final concentration of 50mg/ml. 
After reconstitution, the drug is stable for 8 days at room temperature. 
 
Supplier: commercially available 
 
Toxicity: Myelosuppression is the dose limiting adverse effect, with leukopenia and 
thrombocytopenia being predominant. Other adverse effects reported commonly include 
nausea and vomiting (may be severe at high doses), diarrhea, mucositis, anorexia, alopecia, 
skin rash and liver dysfunction. A flu-like syndrome characterized by fever, muscle and bone 
aches is common. Less common side effects include allergic reactions and cellulitis at the 
injection site. High doses of cytarabine can cause conjunctivitis, hepatitis, and a group of CNS 
symptoms including somnolence, peripheral neuropathy, ataxia and personality changes. 
CNS symptoms are usually reversible and are more common in patients who have received 
previous cranial irradiation. In addition, a syndrome of sudden respiratory distress progressing 
to pulmonary edema has occurred. 
 
Guidelines for administration: Intrathecal and intravenous; see section 5.2.1 (Remission 
induction Block I), section 5.2.2 (Remission induction Block II), 5.2.3 (Remission induction 
Block III), section 5.3 (interim continuation), section 5.4 (Re-induction), section 5.5 
(Continuation), and 5.7 (prophylaxis and treatment for CNS disease), 5.10 (summary of IT 
therapy). 
 
 
6. RITUXIMAB (Rituxan®) 
 
Source and pharmacology: Rituximab is a murine /human chimeric monoclonal antibody. It is 
specific for the CD20 antigen located on B-cells. Rituximab has been shown to mediate 
complement-dependent tumor cell lysis and antibody-dependent cellular cytotoxicity. Direct 
binding to the CD20 antigen is thought to play a role in inhibition of cell growth. Rituximab is 


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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
administered intravenously. The mean serum half-life after a single IV dose of 375 mg/m2 is 
59.8 hours (range 11.1-104.6 hours). 
Formulation and stability: Rituximab is available as 100 mg/10 ml single-use and 500 mg/50 
ml single-use vials. Each vial also contains sodium chloride 9 mg/ml, sodium citrate 7.35 
mg/ml, polysorbate 80 0.7 mg/ml and water for injection. Rituximab for injection 
concentration must be diluted with 5% Dextrose or 0.9% NaCl prior to administration. After 
dilution, unused drug is stable for 24 hours when refrigerated (2-8 degrees Celsius) and 12 
hours at room temperature. Vials should be protected from direct sunlight. 
 
Supplier: commercially available 
 
Toxicity: Hypersensitivity reactions may occur; therefore, premedication with acetaminophen 
and diphenhydramine should be considered before each infusion. The most common toxicities 
are infusion related and may include chills, fever, headache, nausea, vomiting, angioedema 
(13%), hypotension (10%), bronchospasm (8%), and arrhythmia. Other possible adverse 
reactions include thrombocytopenia, myalgias, arthralgias, asthenia, and throat irritation. 
 
Guidelines for administration: Do not administer as an intravenous push or bolus. Infusions 
should be initiated at 50 mg/hour for 30 minutes. If hypersensitivity or infusion-related events 
do not occur, subsequent infusions can be administered at an initial rate of 100 mg/hour and 
increased by 100 mg/hour every 30 minutes as tolerated. Infuse at a maximum rate of 400 
mg/hour. See section 5.2 (Remission Induction, Block I and Appendix II). 
 
 
7. CLOFARABINE (Clolar™, Clofarex) 
 
Source and pharmacology: Clofarabine is a purine nucleoside analog. It is intracellularly 
metabolized to the active metabolite clofarabine 5’-triphosphate which competes with 
deoxyadenosine triphosphate for binding to ribonucleotide reductase and DNA polymerase. It 
inhibits DNA synthesis, terminates DNA chain elongation and inhibits DNA repair. 
Clofarabine also disrupts the mitochondrial membrane which results in the release of proteins, 
cytochrome C and apoptosis-inducing factor leading to cell death. It is mainly excreted in the 
urine as unchanged drug. 
 
Formulation and stability: Clofarabine is available in the parenteral form as a preservative- 
free solution that is 1 mg/mL. It is available in 20 mL vials. The undiluted drug should be 
stored at room temperature. The diluted solution is stable for 24 hours at room temperature. 
Clofarabine injection should be filtered through sterile 0.2 micrometer syringe filter and then 
further diluted with 5% dextrose or 0.9% NaCl containing solutions. 
 
Supplier: The injection is commercially available. 
 
Toxicity: The most common side effects are nausea, vomiting, diarrhea, headache, fever and 
pruritus. Also reported are pericardial effusion, tachycardia, hypotension, left ventricular 
systolic dysfunction, edema, flushing, hypertension, fatigue, anxiety, pain, dizziness, 


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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
depression, irritability. Patients who receive clofarabine are at risk for tumor lysis syndrome 
and need to be monitored closely. 
 
Patients may also experience a systemic inflammatory response syndrome (SIRS) or capillary 
leak syndrome. Patients should be monitored for this during the infusion. 
 
Dosage and route of administration: Intravenous, see section 5.2.1 (Remission induction, 
Block I) and section 5.4 (Re-induction) 
 
 
8. CYCLOPHOSPHAMIDE (Cytoxan) 
 
Source and pharmacology: Cyclophosphamide is a nitrogen mustard derivative. It acts as an 
alkylating agent that causes cross-linking of DNA strands by binding with nucleic acids and 
other intracellular structures, thus interfering with the normal function of DNA. 
Cyclophosphamide is cell-cycle, phase non-specific. Cyclophosphamide is well absorbed 
from the GI tract with a bioavailability of > 75%. Cyclophosphamide is a prodrug that 
requires activation. It is metabolized by mixed-function oxidases in the liver to 4- 
hydroxycyclophosphamide, which is in equilibrium with aldofosfamide. Aldofosfamide 
spontaneously splits into cyclophosphamide mustard, which is considered to be the major 
active metabolite, and acrolein. In addition, 4-hydroxycyclophosphamide may be 
enzymatically metabolized to 4-ketocyclophosphamide and aldofosfamide may be 
enzymatically metabolized to carboxyphosphamide which are generally considered to be 
inactive. Cyclophosphamide and its metabolites are excreted mainly in the urine. Dosage 
adjustments should be made in patients with a creatinine clearance of < 50 ml/min. 
 
Formulation and stability: Cyclophosphamide is available in 25 and 50 mg tablets. 
Cyclophosphamide is also available in vials containing 100, 200, 500, 1000 and 2000mg of 
lyophilized drug and 75 mg mannitol per 100 mg of cyclophosphamide. Both forms of the 
drug can be stored at room temperature. The vials are reconstituted with 5, 10, 25, 50 or 100 
ml of sterile water for injection respectively to yield a final concentration of 20 mg/ml. 
Reconstituted solutions may be further diluted in either 5% dextrose or 0.9% NaCl containing 
solutions. Diluted solutions are physically stable for 24 hours at room temperature and 6 days 
if refrigerated, but contain no preservative, so it is recommended that they be used within 24 
hours of preparation. 
 
Supplier: commercially available 
 
Toxicity: Dose limiting toxicities of cyclophosphamide are bone marrow suppression and 
cardiac toxicity. Cardiac toxicity is typically manifested as congestive heart failure, cardiac 
necrosis or hemorrhagic myocarditis and can be fatal. Hemorrhagic cystitis may occur and 
necessitates withholding therapy. The incidence of hemorrhagic cystitis is related to 
cyclophosphamide dose and duration of therapy. Forced fluid intake and/or the administration 
of MESNA decreases the incidence and severity of hemorrhagic cystitis. Other toxicities 
reported commonly include nausea and vomiting (may be mild to severe depending on 


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Protocol document date: 06-12-2018 
 
 
 
dosage), diarrhea, anorexia, alopecia, immunosuppression and sterility. Pulmonary fibrosis, 
SIADH, anaphylaxis and secondary neoplasms have been reported rarely. 
 
Dosage and route of administration: Intravenous, see section 5.2.1 (Remission induction, 
Block I), section 5.3 (Interim continuation) and section 5.4 (Re-induction). 
9. ETOPOSIDE (VP-16) (Vepesid) 
 
Source and pharmacology: Etoposide is an epipodophyllotoxin derived from Podophyllum 
pelatatum. It is thought to act mainly by inhibiting topoisomerase II, causing double and 
single strand DNA breaks. Etoposide is cell cycle, phase-specific, with activity in the G2 and 
S phases. Absorption of etoposide is approximately 30-40% and is highly variable and 
somewhat dose-dependent. It is extensively bound to serum proteins and is metabolized in the 
liver, including cytochrome P450 3A metabolism to several moieties that include a reactive 
oxidized species. Etoposide and its metabolites are excreted mainly in the urine with a smaller 
amount excreted in the feces. Dosage adjustments should be considered in patients with liver 
dysfunction, kidney dysfunction or hypoalbuminemia. 
 
Formulation and stability: Etoposide is available in multi-dose vials containing 100mg, 
150mg, 500mg and 1000mg of etoposide as a 20mg/ml solution and 30% alcohol. Etoposide 
is also available as a 50 mg capsule. The intact vials of etoposide solution should be stored at 
room temperature. The capsules should be stored under refrigeration. Etoposide solution 
should be diluted in D5W or 0.9% NaCl prior to administration. Solutions with a final 
concentration of 0.2 and 0.4 mg/ml are stable at room temperature for 96 hours and 24 hours 
respectively. 
 
Supplier: commercially available 
 
Toxicity: Dose limiting toxicity is myelosuppression. Nausea and vomiting (usually of low to 
moderate severity), diarrhea, mucositis (particularly with high doses), alopecia and anorexia 
are fairly common. Hypotension can occur with rapid infusions. Other side effects reported 
less commonly include hepatitis, fever and chills, anaphylaxis and peripheral neuropathy. 
Secondary leukemia has been reported. 
 
Dosage and route of administration: Intravenous, see section 5.2.1 (Remission induction, 
Block I), section 5.3 (Interim continuation) and section 5.4 (Re-induction) 
 
 
10. ETOPOSIDE PHOSPHATE (Etopophos®) - To be used in case of etoposide reactions 
(see section 7.9). 
 
Source and pharmacology: Etoposide is an epipodophyllotoxin derived from Podophyllum 
pelatatum. It is thought to act mainly by inhibiting topoisomerase II, causing double and 
single strand DNA breaks. Etoposide is cell cycle, phase-specific, with activity in the G2 and 
S phases. Absorption of etoposide is approximately 30-40% and is highly variable and 
somewhat dose-dependent. It is extensively bound to serum proteins and is metabolized in the 
liver, including cytochrome P450 3A metabolism to several moieties that include a reactive 


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IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
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Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
oxidized species. Etoposide and its metabolites are excreted mainly in the urine with a smaller 
amount excreted in the feces. Dosage adjustments should be considered in patients with liver 
dysfunction, kidney dysfunction or hypoalbuminemia. 
 
Formulation and stability: Etoposide phosphate is a water-soluble ester of etoposide. The 
higher water solubility of etoposide phosphate than that of etoposide lessens the potential for 
precipitation following dilution and during administration. Etoposide phosphate is available in 
single-dose vials containing etoposide phosphate equivalent to 100mg etoposide. The intact 
vials of etoposide solution should be stored at 2 to 8 degrees Celsius. Etoposide phosphate 
solution should be diluted in D5W or 0.9% NaCl prior to administration. Solution is stable at 
room temperature for 24 hours. 
 
Supplier: commercially available. 
 
Toxicity: Dose limiting toxicity is myelosuppression. Nausea and vomiting (usually of low to 
moderate severity), diarrhea, mucositis (particularly with high doses), alopecia and anorexia 
are fairly common. Hypotension can occur with rapid infusions. Other side effects reported 
less commonly include hepatitis, fever and chills, anaphylaxis and peripheral neuropathy. 
Secondary leukemia has been reported. 
 
Guidelines for administration: Intravenous, see section 5.2.1 (Remission induction, Block I), 
section 5.3 (Interim continuation) and section 5.4 (Re-induction). 
 
 
11. CliniMACSTM System 
 
This system is described fully in the Investigators Brochure and is briefly described here. The 
mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated 
cell sorting. The CliniMACS device is a powerful tool for the isolation of many cell types 
from heterogeneous cell mixtures. For example, apheresis products can be separated in a 
magnetic field using an immunomagnetic label specific for the cell type of interest, such as 
CD34+ human hematopoietic cells enrichment, CD3+ T cell depletion, or CD56+ NK cell 
enrichment. 
 
The cells to be isolated or depleted are specifically labeled with super-paramagnetic particles 
by an antibody directed toward a cell surface antigen. After magnetic labeling, the cells are 
separated using a high-gradient magnetic separation column as described below. The 
magnetically labeled cells are retained in the magnetized column while the unlabeled cells 
flow through. The retained cells are eluted by removing the magnetic field from the column, 
washing the cells out and collecting them. 
 
The super-paramagnetic particles are small in size (about 50 nm in diameter) and are 
composed of iron oxide/hydroxide and dextran conjugated to monoclonal antibodies. These 
magnetic particles form a stable colloidal solution and do not precipitate or aggregate in 
magnetic fields. The CliniMACS device incorporates a strong permanent magnet and a 
separation column with a ferromagnetic matrix to separate the cells labeled with the magnetic 


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Protocol document date: 06-12-2018 
 
 
 
particles. The high-gradient system allows the application of strong magnetic forces and a 
rapid demagnetization. Small ferromagnetic structures, such as the column matrix, placed in a 
magnetic field, concentrate this homogenous field and thereby produce high magnetic 
gradients. In their immediate proximity, the ferromagnetic structures generate magnetic forces 
10,000-fold greater than in the absence of those structures enabling the retention of 
magnetically labeled cells. After removing the column from the magnet, the rapid 
demagnetization of the column matrix allows the release of retained cells. 
The CliniMACS device is comprised of a computer controlled instrument incorporating a 
strong permanent magnet, a closed-system sterile tubing set containing columns with a coated 
ferromagnetic matrix and a paramagnetic, cell specific, labeling reagent. The instrument will 
separate the cells in a fully automated process 
 
 
12. INTERLEUKIN-2 (IL-2, ALDESLEUKIN, PROLEUKIN) 
 
Source and pharmacology: Aldesleukin is a biosynthetic cytokine (a lymphokine) of 
recombinant DNA origin. It differs from human interleukin-2 by the absence of an N-terminal 
alanine, the replacement of cysteine with serine at position 125 of the sequence, and the 
absence of glycosylation. It is a biologic response modifier with complex antineoplastic and 
immunomodulating activities. 
 
Formulation and stability: Aldesleukin vials contain 22 million units of lyophilized 
recombinant interleukin. Each single use vial is reconstituted with 1.2 ml of sterile water for 
injection to give 18 million units/ml. Aldesleukin should be admixed with D5W for infusion, 
with albumin 0.1% added to decrease adsorption. Do not use an in-line filter. Do not mix in 
saline. 
 
Supplier: commercially available 
 
Toxicities: Aldesleukin is a highly toxic drug. Most adverse effects are dose related and 
schedule dependent, with fewer toxicities associated with low dose, subcutaneous or 
continuous IV infusions as compared to high dose, rapid IV infusions. Most adverse effects 
are self-limiting and reversible within 2 to 3 days of drug discontinuance. Many of the 
adverse effects of aldesleukin are related to capillary leak syndrome, which has been 
associated with this drug. The most frequently reported serious adverse effects include 
hypotension, renal dysfunction with oliguria/anuria, dyspnea or pulmonary congestion, and 
mental status changes (lethargy, somnolence, confusion, agitation). Additional serious adverse 
effects reported include myocardial ischemia, myocarditis, gangrene, respiratory failure 
leading to intubation, GI bleeding, intestinal perforation, ileus, coma, seizures, sepsis, and 
renal impairment requiring dialysis. Most patients receiving aldesleukin develop some degree 
of a flu-like syndrome that may include fever, chills, rigors, fatigue, weakness, malaise, 
arthralgia and myalgia. 
 
Guidelines for administration: Subcutaneous injection, for NK Cell transplant participants 
only, see section 5.2.1 (Remission induction, Block I). 


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Protocol document date: 06-12-2018 
 
 
 
 
13. PEG-L-ASPARAGINASE (Pegaspargase, Oncaspar) 
 
Source and pharmacology: PEG-asparaginase is a modified version of the enzyme, L- 
asparaginase. L-asparaginase is modified by covalently conjugating units of polyethylene glycol 
(PEG) to the enzyme. The asparaginase used in the manufacturing of PEG-asparaginase is 
derived from Escherichia coli. Asparaginase hydrolyzes serum asparagine (an amino acid 
required to synthesize proteins and DNA) to aspartic acid and ammonia, and is therefore lethal 
to cells that cannot synthesize asparagine. Asparaginase is active during all phases of the cell 
cycle. Asparaginase is not absorbed from the GI tract and must be given parenterally. PEG- 
asparaginase has a plasma half-life of approximately 6 days, but is measurable for at least 15 
days following the initial treatment. It cannot be detected in the urine. 
 
Formulation and stability: PEG-asparaginase is available in single-use vials containing 5 ml 
of PEG-asparaginase as a clear solution. Each vial contains 3750 units of drug at a 
concentration of 750 units/ml. The intact vials should be stored under refrigeration. Freezing 
destroys its activity, which cannot be detected visually. It should not be used if it is cloudy or 
a precipitate is present. 
 
Supplier: commercially available 
 
Toxicity: Acute toxicity includes anaphylactic reactions which occur most commonly when 
the drug is given IV. These can be characterized by laryngeal constriction, hypotension, 
diaphoresis, fever, chills, edema and loss of consciousness. Allergic reactions at the site of IM 
injection include pain, swelling and erythema. The incidence of hypersensitivity reactions to 
PEG-asparaginase may be less than with conventional E. coli derived asparaginase although 
cross-sensitivity can occur. Other adverse effects include neutropenia and associated 
immunosuppression, mild nausea and vomiting, malaise, anorexia, elevated LFT’s, 
pancreatitis and hyperglycemia. A decrease in protein synthesis including albumin, fibrinogen 
and other coagulation factors may occur which can result in thrombosis or pulmonary 
embolism. Less common side effects include renal dysfunction and CNS complications, 
including somnolence, weakness, lethargy, coma and seizures. 
 
Guidelines for administration: Intravenous or intramuscular injection, see section 5.2.1 
(Remission induction) and 5.4 (Re-induction). 
 
 
14. ERWINIA L-ASPARAGINASE (Erwinase) 
 
To be used in case of allergy or intolerance to PEG-Asparaginase. 
 
Source and pharmacology: Erwinia asparaginase is an enzyme. It is derived from Erwinia 
chrysanthemi and may be useful in patients with an allergy to the E. coli derived product. 
Asparaginase hydrolyzes serum asparagine (an amino acid required to synthesize proteins) to 
aspartic acid and ammonia, and is therefore lethal to cells that cannot synthesize asparagine. 
Asparaginase is active during all phases of th cell cycle. Asparaginase is not absorbed from 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
the GI tract and must be given parenterally. Asparaginase does not cross into the CSF. The 
plasma half-life of Erwinia asparaginase when given IM is approximately 16 hours. Only 
minimal urinary and biliary excretion occurs. Clearance is unaffected by age, renal function 
or hepatic function. 
 
Formulation and stability: Erwinia asparaginase is available in vials containing 10,000 units 
of lyophilized drug. Unused vials should be refrigerated. The contents of each vial should be 
diluted with 1 ml of preservative-free normal saline, giving a resultant solution of 10,000 
units/ml. Once in solution, it is recommended that it be used within 8 hours as no preservative 
is added. Occasionally a small number of gelatinous-like fibers may develop upon standing. If 
this occurs, the solution can be filtered through a 5 micron filter to remove the particles with 
no change in potency. 
 
Supplier: Commercially available 
 
Toxicity: Acute toxicity includes anaphylactic reactions that occur most commonly when the 
drug is given IV. These can be characterized by laryngeal constriction, hypotension, 
diaphoresis, fever, chills, edema and loss of consciousness. Allergic reactions at the site of IM 
injection include pain, swelling and erythema. Other adverse effects include neutropenia and 
associated immunosuppression, mild nausea and vomiting, malaise, anorexia, elevated LFTs, 
pancreatitis and hyperglycemia. A decrease in protein synthesis including albumin, fibrinogen 
and other coagulation factors may occur which can result in hemorrhage. Thrombosis and/or 
pulmonary embolism can also occur. Less common side effects include renal dysfunction and 
CNS complications including somnolence, weakness, lethargy, coma and seizures. 
 
Guidelines for administration: Intravenous or intramuscular injection, see section 5.2.1 
(Remission induction) and 5.4 (Re-induction). 
 
For additional information about this drug, please see package insert. 
 
 
15. MERCAPTOPURINE (6-MP) (Purinethol) 
 
Source and pharmacology: Mercaptopurine is a purine antimetabolite. It must be converted 
intracellularly to 6-thioguanine nucleotides (6-TGNs), the active forms of the drug. The 6- 
TGNs are then incorporated into DNA and RNA and cause inhibition of DNA and RNA 
synthesis. Mercaptopurine is cell cycle, S phase specific. Absorption is variable and 
incomplete (5-37%) and is decreased by the presence of food in the gut. Mercaptopurine does 
distribute into the CSF, with CSF concentrations of  27% of plasma concentrations when 
given by continuous infusion. Mercaptopurine undergoes first pass metabolism in the GI 
mucosa and the liver. It is metabolized in hematopoietic tissues by HPRT to the active 
nucleotide forms. It is inactivated to methylated metabolites by TPMT (thiopurine methyl 
transferase) and to 6-thiouric acid by xanthine oxidase. TPMT is a genetically regulated, 
polymorphically distributed enzyme and is deficient in about 1 in 300 persons who cannot 
tolerate usual doses of 6-MP. Mercaptopurine is eliminated through the urine as both 
unchanged drug and metabolites. 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
 
Formulation and stability: Mercaptopurine is commercially available as a 50 mg tablet and 20 
mg/mL oral suspension; store at room temperature and protect from light. 
 
Supplier: Tablets are commercially available. 
 
Toxicity: The dose-limiting toxicity of mercaptopurine is myelosuppression. Mercaptopurine 
can cause intrahepatic cholestasis and focal centralobular necrosis and is usually manifested 
by hyperbilirubinemia and increased liver function tests. Other toxicities include mild nausea 
and vomiting, skin rash, hyperuricemia, and mild diarrhea. 
Guidelines for administration: oral tablets or suspension, see section 5.2.2 (Remission 
induction, Block II), section 5.3 (Interim continuation), section 5.5 (Continuation). 
 
 
16. LEUCOVORIN (Folinic Acid) 
 
Source and pharmacology: Leucovorin is a racemic mixture of tetrahydrofolic acid, which is 
involved as a cofactor for 1-carbon transfer reactions in the synthesis of purines and 
pyrimidines. Leucovorin is a potent antidote for both the hematopoietic and 
reticuloendothelial toxic effects of folic acid antagonists by replenishing reduced folate pools. 
It is postulated that in some cancers, leucovorin enters and “rescues” normal cells from the 
toxic effects of folic acid antagonists, in preference to tumor cells, because of differences in 
membrane transport and affinity for polyglutamylation. Leucovorin is converted in the 
intestinal mucosa and the liver to 5-methyl-tetrahydrofolate, which is also active as a reduced 
folate. It is excreted primarily in the urine with minor excretion occurring in the feces. 
 
Formulation and stability: Leucovorin is supplied in 5, 15 and 25 mg tablets and vials 
containing 50, 100 or 350 mg of leucovorin as a lyophilized powder. The tablets and the 
lyophilized powder can be stored at room temperature. The 50 mg and 100 vials can be 
reconstituted by adding 5 or 10 ml of sterile water or bacteriostatic water for injection 
respectively to yield a final concentration of 10 mg/ml. The 350 mg vials can be reconstituted 
with 17 ml of sterile water or bacteriostatic water for injection to yield a final concentration of 
20 mg/ml. The reconstituted solution is stable for at least 7 days at room temperature. 
Leucovorin may be further diluted in 5% dextrose or 0.9% NaCl containing solutions. 
Leucovorin is also available as a 1 mg/ml oral solution. 
 
Supplier: commercially available 
 
Toxicity: Leucovorin is generally well tolerated. Toxicities that have been reported 
uncommonly include rash, mild nausea, headache, and wheezing (possible allergic reaction). 
Intrathecal leucovorin is contraindicated and has caused neurotoxic deaths. There have been 
rare reports of leucovorin promoting seizures. 
 
Guidelines for administration: oral or intravenous, see section 5.2.2 (Remission induction 
Block II after HDMTX, and section 5.7 (after ITHMA), section 5.7.2 (Down syndrome 
participants), and section 6.3.3.3 (ITHMA with CNS irradiation). 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
 
 
17. MITOXANTRONE (Novantrone) 
 
Source and pharmacology: Mitoxantrone is an anthracenedione that is structurally similar to 
the anthracyclines. It is thought to act by intercalating into DNA, causing template disorder, 
steric obstruction and inhibition of DNA and RNA synthesis. In addition, mitoxantrone 
inhibits the action of topoisomerase II. Mitoxantrone is active throughout the cell cycle. 
Mitoxantrone is about 78% protein bound and does cross the blood brain barrier. 
Mitoxantrone is metabolized in the liver to inactive metabolites. The parent drug and 
metabolites are excreted primarily via hepatobiliary excretion with small amounts excreted in 
the urine. Dosage adjustment is recommended for patients with severe hepatic dysfunction 
(total bilirubin > 3.4 mg/dl). 
 
Formulation and stability: Mitoxantrone is available in multi-dose vials containing 20 mg, 25 
mg or 30 mg of mitoxantrone as a dark blue, aqueous solution at a concentration of 2 mg/ml. 
The intact vials should be stored at room temperature. Refrigeration may result in 
precipitation of mitoxantrone, which will re-dissolve upon warming to room temperature. The 
drug should be further diluted to at least 50 ml in 5% dextrose or 0.9% NaCl prior to 
administration. These solutions are chemically stable for at least 7 days when stored at room 
temperature. 
 
Supplier: commercially available 
 
Toxicity: The major dose-limiting toxicity of mitoxantrone is leukopenia with 
thrombocytopenia and anemia occurring much less frequently. Nausea and vomiting are 
usually moderate in severity. Other side effects reported commonly include alopecia, diarrhea, 
headache, fever and stomatitis. Blue to green discoloration of urine and other body fluids 
occurs. Other side effects reported less commonly include elevated liver function tests, 
allergic reactions, seizures, jaundice and renal failure. Congestive heart failure has been 
reported, but is much less common than with doxorubicin. CHF has been reported primarily 
in patients receiving prior therapy with anthracyclines. Patients with an increased risk of 
cardiotoxicity include those having received prior therapy with anthracyclines, those with 
previous mediastinal radiotherapy and those with pre-existing cardiac conditions. 
 
Guidelines for administration: Intravenous, see section 5.2.3 (Remission induction, Block III). 
 
 
18. TENIPOSIDE (VM-26) (Vumon) 
 
Source and pharmacology: Teniposide is a semi-synthetic derivative of epipodophyllotoxin 
derived from Podophyllum peltatum. It is thought to act mainly by inhibiting topoisomerase II 
and thus causing double and single strand DNA breaks. Teniposide is cell cycle, phase- 
specific, with activity in the G2 and S phases. Teniposide is highly protein bound. It is 
extensively metabolized in the liver, including O-demethylation by cytochrome P450 3A4 to 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
reactive oxidative metabolites. It is excreted in the urine as parent drug and metabolite. Fecal 
excretion may account for a small amount of total excretion. 
 
Formulation and stability: Teniposide is available in clear glass ampules containing 50 mg of 
teniposide. Each ml of teniposide solution contains 10 mg of teniposide, 30 mg benzyl 
alcohol, 500 mg Cremophor EL and 43% dehydrated alcohol. Intact ampules should be 
stored under refrigeration and protected from light. Freezing does not adversely affect the 
product. Teniposide must be diluted in 5% dextrose or 0.9% NaCl containing solutions prior 
to administration to a final concentration between 0.1-1mg/ml. At these concentrations, 
solutions are stable for up to 24 hours at room temperature. Solutions of 1mg/ml should be 
used within 4 hours of preparation. Refrigeration of diluted solutions is not recommended. 
 
Supplier: Commercially available 
Toxicity: The major dose-limiting effect of teniposide is bone marrow suppression. Nausea 
and vomiting (moderate in severity), diarrhea, alopecia and mucositis are reported commonly. 
Hypotension may occur if the drug is given too rapidly. Hypersensitivity reactions and 
secondary leukemias have been reported. 
 
Guidelines for administration: Intravenous, see section 5.3 (Interim continuation) and section 
5.5 (Continuation). 
 
 
19. VINBLASTINE (Velban) 
 
Source and pharmacology: Vinblastine is an alkaloid extracted from the periwinkle plant 
(Vinca Rosea). It reversibly binds to microtubule and spindle proteins causing metaphase 
arrest. It may also block cellular utilization of glutamic acid, thereby inhibiting purine 
synthesis and urea formation via the citric acid cycle. Vinblastine is highly protein bound and 
poorly penetrates the CSF. Metabolism in the liver is extensive with one metabolite, deacetyl 
vinblastine, being more active than the parent drug. The major route of elimination is via the 
bile. Dosages should be adjusted for patients with impaired liver function (bilirubin > 3 
mg/dl). 
 
Formulation and stability: Vinblastine is available in 10 ml vials containing 1mg/ml of 
vinblastine in solution. Intact vials of vinblastine solution and lyophilized vinblastine should 
be stored under refrigeration. 
 
Supplier: Commercially available 
 
Toxicity: The dose limiting toxicity is myelosuppression. Other toxicities reported commonly 
include alopecia, mild nausea and vomiting and constipation. Vinblastine is a vesicant and 
may cause severe tissue damage if extravasation occurs. Vinblastine rarely produces 
neurotoxicity characterized by peripheral neuropathy, loss of deep tendon reflexes, weakness, 
jaw pain and “foot drop”. This toxicity is much less common than with vincristine. Acute 
shortness of breath and severe bronchospasm have been reported following the administration 
of vinca alkaloids. 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
 
Guidelines for administration: Intravenous, see section 5.3 (Interim continuation) and section 
5.5 (Continuation). 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
The following tyrosine kinase inhibitors may be used for participants with Ph+ ALL and 
Ph-like ALL as part of standard clinical management, at the discretion of the treating 
investigator. 
 
20. IMATINIB (Gleevec®, imatinib mesylate) 
 
Source and pharmacology: imatinib mesylate is a phenylaminopyrimidine derivative and is a 
4-[(4-Methyl-1-piperazinyl)methyl-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimid-inyl]amino]- 
phenyl]benzamidemethanesulfonate. It is a protein-tyrosine kinase inhibitor that inhibits the 
Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia 
chromosome abnormality. 
 
Formulation and stability: Each film-coated tablet contains 100 mg or 400 mg of imatinib free 
base. The drug should be stored at 25C (77F); excursions permitted to 15C-30C (59F - 
86F). The tablets should be dispensed in a tight container, USP, and protected from moisture. 
 
The prescribed dose should be administered orally, with a meal and a large glass of water. In 
children, the daily dose may be split into two – once in the morning and once in the evening. 
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass 
of water or apple juice. The required number of tablets should be placed in the appropriate 
volume of beverage (approximately 50 mL for a 100-mg tablet, and 200 mL for a 400-mg 
tablet) and stirred with a spoon. The suspension should be administered immediately after 
complete disintegration of the tablet. 
 
Supplier: Commercially available 
 
Toxicity: Common toxicities include dyspepsia/heartburn, nausea/vomiting, headache, 
myelosuppression, and fatigue. Occasional toxicities include fever, edema in limbs, face, 
periorbital area, weight gain, increased SGOT/SGPT, alkaline phosphatase, bilirubin, 
abdominal pain and cramping, myalgia, arthralgia, decreased bone marrow cellularity, 
lymphopenia, eczema dermatitis, rash, muscle pain and cramping, anorexia, and pigmentation 
changes (hypo-vitiligo). Rare toxicities include cerebral edema, melena/GI bleeding, anemia, 
diarrhea, dysphagia, esophagitis, odynophagia, hemorrhage/bleeding without grade 3 or 4 
thrombocytopenia, pneumonitis/pulmonary infiltrates, late hepatotoxicity and decrease in the 
heart’s ability to pump blood. 
 
 
21. DASATINIB (SPRYCEL®) 
 
Source and pharmacology: Dasatinib (an aminothiazole analogue) is an inhibitor of multiple 
tyrosine kinases. It is approved for the treatment of chronic myelogenous leukemia (CML) and 
for the treatment of adults with Philadelphia chromosome-positive ALL with resistance or 
intolerance to prior therapy. It is being investigated as a broad-spectrum antitumor agent against 
solid tumors. Dasatinib is a potent, broad spectrum ATP-competitive inhibitor of 5 critical 
oncogenic tyrosine kinase families: BCR-ABL, SRC family kinases, c-KIT, ephrin (EP) 
receptor kinases, and PDGFβ receptor. Each of these protein kinases has been strongly linked 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
to multiple forms of human malignancies. In adults, the maximum plasma concentration of 
dasatinib after oral administration is observed between 0.5 and 6 hours. The observed effects 
from food were not clinically relevant. The overall terminal half-life is 3-5 hours. The drug 
exhibits dose proportional increases in AUC and linear elimination characteristics over the 
dose range of 15 mg to 240 mg/day in adults. Dasatinib is primarily metabolized in the liver 
by the human CYP3A4 enzyme, is a significant inhibitor of CYP3A4. Dasatinib may decrease 
the metabolic clearance of drugs that are significantly metabolized by the CYP3A4 enzyme. 
Due to the potential of dasatinib to prolong the QT/QTc, caution must be used when 
administering it with other potential QTc prolonging medications. Due to the possibility of 
gastrointestinal, cardiac, and cutaneous hemorrhage, avoid using medications that inhibit 
platelet function or anticoagulants in conjunction with Dasatinib. Dasatinib is not a p - 
glycoprotein inhibitor. 
 
Formulation and stability: Dasatinib is available as tablets of 20 mg, 50 mg, or 70 mg. The 
core tablet is surrounded by a film coating to prevent exposure to the active drug substance 
during handling. If tablets are cut or crushed, procedures to prevent exposure to the active 
drug substance should be followed. Pregnant women or breastfeeding mothers should not 
handle crushed and/or broken dasatinib tablets. 
 
The intact dasatinib tablets can be placed (and allowed to dissolve) in 1 ounce of lemonade (a 
double strength juice is recommended to obscure the bitter taste), or 1 ounce of preservative-free 
apple juice, or 1 ounce of preservative-free orange juice. 
 
The following (i.e. steps 1 thru 7) is the procedure for the preparation of the lemonade dosing 
solution. For preservative-free apple juice or preservative-free orange juice, steps 2 thru 7 
should be followed. 
 
1. Mix the contents of one 12 ounce can of Minute Maid Premium Frozen Concentrate 
with 2 cans (i.e. the emptied lemonade container) of water. This will produce lemonade 
that is a little more than twice as concentrated as the instructions on the can with a 
sweeter taste. Please keep the lemonade solution refrigerated when not in use. 
2. Place 1 ounce (30 mL) of this lemonade solution into a drinking glass. 
3. Place the proper dose of intact tablets into the lemonade. Please be sure to always wear 
protective gloves when handling the medication. A mask is not required when handling 
the medication. Always use the 1 oz of lemonade. Do not increase the lemonade 
volume. 
4. Start timing for 20 minutes. At approximately the 5 minute mark, swirl the contents of 
the glass well for about 3 seconds. 
5. At approximately the 15 minute mark, swirl the contents of the glass a second time. At 
the 20 minute mark, swirl the contents of the glass one last time. Immediately 
administer the entire contents of the glass. 
6. In order to ensure administration of the entire medication dose, a rinsing step is 
necessary. Add 0.5 ounce (15 mL) of lemonade into the same glass that has just been 
emptied. Swirl the contents to remove any remaining signs of tablets from the sides or 
bottom of the glass. 
7. Administer the washing lemonade to the patient. 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
 
The intact bottles should be stored at controlled room temperature (15 - 25C (59 - 77F) 
and protected from light. 
 
Supplier: Commercially available 
 
Toxicity: The most frequently reported adverse events include fluid retention (pleural 
effusion), diarrhea, nausea, abdominal pain, rash, headache, fatigue, vomiting, bleeding 
events and myelosuppression. The most frequently reported serious adverse events include 
pyrexia, febrile neutropenia, gastrointestinal bleeding, pneumonia, thrombocytopenia, 
dyspnea, anemia and cardiac failure (3%). Less commonly reported are anorexia, dehydration, 
abdominal distension and flatulence, flushing, pruritis, elevated creatinine, and neuropathy. 
Elevations in transaminases and bilirubin can usually be managed with dose reductions or 
dose interruption. Hypocalcemia during dasatinib therapy can be managed with oral calcium 
supplementation. 
 
 
22. NILOTINIB (Tasigna™) 
 
Source and pharmacology: Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor that may 
be used in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome 
acute lymphoblastic leukemia (Ph+ALL). Nilotinib binds to and stabilizes the inactive 
conformation of the kinase domain of Abl protein. It is considered to be a “second generation” 
tyrosine kinase inhibitor and may be efficacious in patients who have becomes resistant to 
“first generation” drugs such as imatinib. Nilotinib is an analog of imatinib and features a 
more energetically favorable binding mode that contributes to its enhanced potency (twenty 
times higher than imatinib). The increased potency is hoped to allow lower dosages, which 
may limit side effects that would otherwise make this medication intolerable. 
 
Formulation and stability: Tasigna (nilotinib) capsules, for oral use, contain 150 mg or 200 
mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive 
ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate 
and polyoxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), iron 
oxide (black) and titanium dioxide. The capsules should be stored at 25°C, although 
excursions are permitted between 15-30°C. 
 
Supplier: Commercially available 
 
Toxicity: Its most common side effects, occurring in over 10% of patients, include peripheral 
edema, headache, rash, pruritis, fatigue, GI upset, increased lipids, neutropenia (grades 3/4, 
median duration 15 days), thrombocytopenia (grades 3/4, median duration 22 days), 
neuralgias, musculoskeletal pain, and upper respiratory tract infections. Other serious side 
effects include QT prolongation, depression, insomnia, electrolyte disturbances, pancytopenia, 
and elevated LFTs. Reports of sudden deaths from QTc prolongation has let the FDA to 
require a “Black Box” warning on Tasigna emphasizing the need to monitor electrolyte levels 
and co-administration of other medications in patients taking the drug. Nilotinib should not be 


ALLR18 
Appendix III 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
taken with drugs that prolong the QT interval or inhibitors or inducers of CYP3A4. It may 
induce other CYP enzymes, thus affecting the metabolism of other drugs. It also inhibits P- 
glycoprotein and is a substrate for its efflux transporter. The REMS (Risk Evaluation and 
Mitigation Strategy) approved in conjunction with the Black Box Warning requires that all 
patients receive specific oral and written counseling to take nilotinib on an empty stomach, 
time doses appropriately, get regular ECGs, avoid grapefruit products, and report all other 
medications to the prescribing physician. Nilotinib should be used with caution in patients 
with a history of pancreatitis or impaired hepatic function. 
 
Dosage and route of administration: Nilotinib is available as oral capsules in 150 mg and 200 
mg strengths. Nilotinib capsules should be taken twice daily (about 12 hours apart) with 
water. It must not be taken with food as this can significantly change adsorption; patients 
should not eat 2 hours prior or 1 hour after taking nilotinib. For patients unable to swallow 
capsules, the contents may be mixed with a small amount of pureed apple sauce and taken 
within 15 minutes. 


ALLR18 
Appendix IV 
St. Jude 
IRB Approval dateI:R0B6-N1U3-M2B01E8R: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
 
 


ALLR18 
Appendix V 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
APPENDIX V: TREATMENT AND EVALUATION CALENDARS 
 
Pretreatment - See order sheets. Offer enrollment for institutional banking and pharmacogenetic protocols 
 
Block I – must be given at St. Jude (including collaborating site participants) 
1 
ITMHA* 
VCR 
DEX 
*CSF cell count, diff 
and cytology 
2 
DEX 
#Peripheral blood 
CD20 
3 
DEX 
TPMT genotyping (if 
not available from 
frontline therapy) 
Germline DNA 
4 
RITUX 
DEX 
#Peripheral blood 
CD20 
5 
(ITMHA*) 
DEX 
(*CSF cell count, 
diff and cytology) 
6 
CLO 
CYCLO 
VP16 
DEX 
#Peripheral blood 
MRD and CD20 
7 
CLO 
CYCLO 
VP16 
DEX 
8 
ITMHA* 
CLO 
CYCLO 
VP16 
DEX 
9 
CLO 
CYCLO 
VP16 
10 
CLO 
CYCLO 
VP16 
11 
(ITMHA*) 
IL-2 
12 
NK cell infusion 
13 
RITUX 
IL-2 
14 
*CSF cell count, diff 
and cytology 
#Peripheral blood 
CD20 
(*CSF cell count, 
diff and cytology) 
#Peripheral blood 
CD20 
15 
IL-2 
16 
17 
IL-2 
18 
19 
IL-2 
20 
RITUX 
21 
PEG-ASP** 
VCR 
(ITMHA*) 
DEX 
(*CSF cell count, 
diff and cytology) 
#Peripheral blood 
CD20 
**Asp & antibodies 
NK Pheno (patient) 
***TKI Ph+ ALL & 
Ph-like ALL 
22 
DEX 
23 
DEX 
24 
DEX 
25 
DEX 
26 
DEX 
27 
RITUX 
DEX 
28 
ITMHA* 
VCR 
DEX 
*CSF cell count, diff 
and cytology 
29 
30 
31 
32 
33 
34 
35 
PEG-ASP** 
VCR 
**Asp & antibodies 
BM/MRD and 
mutant cells after 
count recovery 


ALLR18 
Appendix V 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
Notes: 
1. 
#Peripheral blood MRD and CD20 evaluations – will be discontinued following a negative MRD result (less than 0.01%) 
2. 
*CNS1: ITMHA Days 1, 8, 28 
CNS2 and CNS3 and traumatic tap with blasts: Days 1, 5, 8, 21 and 28. If CNS blasts not cleared by Day 8, additional ITMHA on Day 11 
3. 
**Asparaginase and anti-asparaginase antibodies: additional samples at time of reaction 
4. 
H&P, CBC diff, CMP every 3-7 days 
5. 
***For participants with Ph+ ALL and Ph-like ALL (see section 6.1), tyrosine kinase inhibitor (TKI) may be added at the discretion of the 
treating physician and principal investigator (e.g., imatinib, dasatinib and nilotinib). TKI’s should be introduced after day 20 of Induction 
Block I therapy to avoid drug interactions and interference with NK cell function. Treatment with TKI will be as per SOC or 
manufacturer’s recommendation. See package insert for specific drug for details. 


ALLR18 
Appendix V 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
Block II – HDMTX and 6MP 
 
1 
*ITMHA 
HDMTX 
6MP 
2 
6MP 
3 
6MP 
4 
6MP 
5 
6MP 
6 
6MP 
7 
6MP 
*CSF cell count, diff 
Germline DNA 
8 
HDMTX 
6MP 
9 
6MP 
10 
6MP 
11 
6MP 
12 
6MP 
13 
6MP 
14 
6MP 
15 
6MP 
16 
6MP 
17 
6MP 
18 
6MP 
19 
6MP 
20 
6MP 
21 
6MP 
22 
BMA/MRD/mutant 
cells day 21 
23 
24 
25 
26 
27 
28 
Notes: 
1. H&P, CBC diff, CMP every 3-7 days 


ALLR18 
Appendix V 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
Block III – ARAC and MITO 
 
1 
ARA-C 
ARA-C 
2 
ARA-C 
ARA-C 
3 
ARA-C 
ARA-C 
MITO 
4 
ARA-C 
ARA-C 
MITO 
5 
MITO 
6 
7 
*ITMHA 
*CSF cell count, diff 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
BMA/MRD/mutant 
after cell count 
recovery 
CT scan involved 
areas - lymphoma 
pts. 
 
Notes: 
 
1. H&P, CBC diff, CMP every 3-7 days 


ALLR18 
Appendix V 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
Interim Continuation 
 
1 
ITMHA* 
VP16 
CYCLO 
*CSF cell count, diff 
Asp & antibodies 
2 
3 
4 
5 
6 
7 
8 
MTX 
6MP 
9 
6MP 
10 
6MP 
11 
6MP 
12 
6MP 
13 
6MP 
14 
6MP 
15 
VM26 
ARA-C 
16 
17 
18 
19 
20 
21 
22 
VINBLAST 
DEX 
23 
DEX 
24 
DEX 
25 
DEX 
26 
DEX 
27 
28 
BMA/MRD/mutant 
cells upon count 
recovery 
 
Notes: 
 
1. H&P, CBC diff every week, CMP as clinically indicated 
2. Serum for asparaginase and anti-asparaginase antibodies 


ALLR18 
Appendix V 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
Re-Induction 
 
1 
ITMHA* 
CLO 
CYCLO 
VP16 
DEX 
*CSF cell count, diff, 
cytology 
2 
CLO 
CYCLO 
VP16 
DEX 
3 
CLO 
CYCLO 
VP16 
DEX 
4 
CLO 
CYCLO 
VP16 
DEX 
5 
CLO 
CYCLO 
VP16 
DEX 
6 
PEG-ASP** 
VCR 
DEX 
**Asp & antibodies 
7 
8 
9 
10 
11 
12 
13 
VCR 
14 
15 
(*ITMHA) 
16 
17 
18 
19 
20 
PEG-ASP** 
VCR 
21 
(*CSF cell count, 
diff, cytology) 
**Asp & antibodies 
BMA/MRD/mutant 
cells after count 
recovery 
 
Notes: 
 
1. *CNS1: ITMHA on Day 1 
CNS 2, 3 and traumatic tap with blasts: ITMHA on Days 1 and 15 
2. **Asp & antibodies: additional samples at time of reaction 
3. H&P, CBC diff and CMP every 3-7 days 


ALLR18 
Appendix V 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
CONTINUATION THERAPY 
Week 
Treatment 
Special Studies 
1 
MTX + 6MP + ITMHA 
CSF cell count, diff 
2 
MTX + 6MP 
3 
VM26 + ARA-C 
4 
DEX + VCR 
5 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
6 
MTX + 6MP 
7 
VM26 + ARA-C 
8 
DEX + VINBLAST 
9 
MTX + 6MP + ITMHA) 
CSF cell count, diff 
10 
MTX + 6MP 
11 
VM26 + ARA-C 
12 
DEX + VCR 
13 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
14 
MTX + 6MP 
15 
VM26 + ARA-C 
16 
DEX + VINBLAST 
17 
MTX + 6MP + ITMHA 
CSF cell count, diff 
18 
MTX + 6MP 
19 
VM26 + ARA-C 
20 
DEX + VCR 
21 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
22 
MTX + 6MP 
23 
VM26 + ARA-C 
24 
DEX + VINBLAST 
25 
MTX + 6MP + ITMHA 
CSF cell count, diff 
26 
MTX + 6MP 
27 
VM26 + ARA-C 
28 
DEX + VCR 
29 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
30 
MTX + 6MP 
31 
VM26 + ARA-C 
32 
DEX + VINBLAST 
33 
MTX + 6MP + ITMHA 
CSF cell count, diff 
34 
MTX + 6MP 
35 
VM26 + ARA-C 
36 
DEX + VCR 
37 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
38 
MTX + 6MP 
39 
VM26 + ARA-C 
40 
DEX + VINBLAST 
41 
MTX + 6MP + ITMHA 
CSF cell count, diff 
42 
MTX + 6MP 
43 
VM26 + ARA-C 
44 
DEX + VCR 
45 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
46 
MTX + 6MP 
47 
VM26 + ARA-C 
48 
DEX + VINBLAST 
49 
MTX + 6MP + ITMHA 
CSF cell count, diff 
50 
MTX + 6MP 
51 
VM26 + ARA-C 
52 
DEX + VCR 
53 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 


ALLR18 
Appendix V 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
Week 
Treatment 
Special Studies 
54 
MTX + 6MP 
55 
VM26 + ARA-C 
56 
DEX + VINBLAST 
57 
MTX + 6MP + ITMHA 
CSF cell count, diff 
58 
MTX + 6MP 
59 
VM26 + ARA-C 
60 
DEX + VCR 
61 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
62 
MTX + 6MP 
63 
VM26 + ARA-C 
64 
DEX + VINBLAST 
65 
MTX + 6MP + ITMHA 
CSF cell count, diff 
66 
MTX + 6MP 
67 
VM26 + ARA-C 
68 
DEX + VCR 
69 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
70 
MTX + 6MP 
71 
VM26 + ARA-C 
72 
DEX + VINBLAST 
73 
MTX + 6MP + ITMHA 
CSF cell count, diff 
74 
MTX + 6MP 
75 
VM26 + ARA-C 
76 
DEX + VCR 
77 
MTX + 6MP (+ ITMHA) 
(CSF cell count, diff) 
78 
MTX + 6MP 
79 
VM26 + ARA-C 
80 
DEX + VINBLAST 
*off therapy 
 
Notes: 
 
1. BMA/MRD/mutant cells every 16 weeks 
2. CNS1: Cycles 1-10, day 1 of week 1 
CNS2 and CNS3 and traumatic tap with blasts: 
a. 
Cycles 1-5: day 1 of week 1 and day 1 of week 5 
b. Cycles 6-10: day 1 of week 1 
3. H&P and CBC diff every week, CMP as clinically indicated 
4. *Off therapy evaluations: H&P, CBC diff, CMP, BMA/MRD, ECHO/EKG, CT scan involved areas 
(lymphoma pts.) 


ALLR18 
Appendix VI 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
APPENDIX VI: DEFINITIONS RELATED TO INFECTIOUS DISEASES 
 
I. 
ASSESSMENTS 
 
A. 
Fever: A single temperature of > 38.3oC (101oF) or >38.0oC (100.4oF) on two 
occasions within 12 hours. The measurement must be oral with glass or IVAC7 
thermometers or at the tympanic membrane by infrared instruments (Thermoscan7). 
The same method should be used throughout the febrile episode for each patient. 
B. 
Neutropenia: Neutrophil count < 500/mm3 or < 1,000/mm3 with predicted decline 
to <500/mm3. 
C. 
Duration of Fever (for episodes of fever with neutropenia): The initial 
temperature is the one immediately before the first dose of antibiotics and GCSF. 
This is designated as zero hour. The end of a febrile period is at the time of the 
first temperature of 38.0oC or less which is sustained at this level over a period of 
24 hours or longer without antipyretic intervention. The duration of fever is the 
number of hours from zero hour to the end of the febrile period. 
D. 
Antibiotic Therapy: Any systemic antibacterial drug will be considered as 
antibiotic therapy whether given orally or parenterally. Topical antibiotics will not 
be included. 
E. 
Antifungal Therapy: Any antifungal drug administered orally or parenterally will 
be considered antifungal therapy. Antifungal therapy will be categorized for 
analysis as: 
1. 
Treatment for oral candidiasis 
Nystatin 
Clotrimazole troches 
Micafungin 
Fluconazole 
Voriconazole 
2. 
Treatment for systemic mycoses (includes empirical use) 
Systemic amphotericin B (standard and liposomal) 
Fluconazole 
Voriconazole 
Posiconazole 
Itraconazole 
Micafungin 
 
II. 
BACTERIAL 
 
1. 
Bacteremia only: Defined as a growth of an organism that is judged not to be a 
contaminant in a blood culture drawn during a febrile episode. Organisms are 
considered contaminants if they are part of skin flora (e.g., diphtheroids other than 
Corynebacterium jeikeium, Bacillus spp. not B. cereus, Propionibacterium spp., 
coagulase-negative staphylococcus (CNS) or Micrococcus spp.) and if they are 
isolated from only one culture receptacle. All other organisms are regarded as 
pathogens. (Specify catheter-related or not.) 


ALLR18 
Appendix VI 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
2. 
Bacterial sepsis: positive blood culture for any bacterium plus clinical evidence of 
infection (fever, chills, hypotension, etc.). (Specify catheter-related or not.) 
3. 
Urinary tract infection: urine colony count of 100,000 or greater of a single 
organism plus symptoms, dysuria, flank pain, etc. Asymptomatic bactiuria is the 
same colony count without symptoms. 
4. 
Pneumonia (bacterial): radiographic discernible infiltrate plus isolation of 
potentially causative bacteria from bronchoalveolar lavage, blood or biopsy 
specimen. If positive blood culture, code as bacterial sepsis with pneumonia. 
5. 
Meningitis: positive culture of causative bacteria from CSF plus symptoms 
compatible with meningitis. 
6. 
Osteomyelitis: radiographic lesions plus positive blood or bone aspirate/biopsy 
cultures. 
7. 
Acute Otitis Media: physician diagnosis plus antibiotic treatment. 
8. 
Pharyngitis: only if group A beta hemolytic streptococcus is isolated from throat 
culture in patient with symptoms. A positive rapid streptococcal test is acceptable 
in place of culture. Other types of pharyngitis will not be considered. 
9. 
Cellulitis: erythema and induration plus isolation of bacteria from aspirate/ drainage. 
 
III. 
FUNGAL INFECTIONS 
 
A. 
Candidiasis 
1. 
Oral: presence of typical whitish lesions on the mucosal surface with yeast 
or pseudomycelia on gram stain or KOH preparation or isolation of 
Candida species in culture from the mouth. 
2. 
Esophageal or urinary bladder: evidence of tissue involvement proven by 
endoscopy and biopsy plus isolation of fungus in culture. 
 
B. 
Invasive fungal infections 
1. 
Proven invasive fungal infection (not endemic mycosis) 
Analysis and specimen 
Moldsa 
Yeastsa 
Microscopic analysis: 
Histopathologic, 
Histopathologic, 
sterile material 
cytopathologic, or direct 
cytopathologic, or direct 
microscopic examinationb 
microscopic examinationb 
of a specimen obtained by 
of a specimen obtained by 
needle aspiration or biopsy 
needle aspiration or biopsy 
in which hyphae or 
from a normally sterile site 
melanized yeast-like forms 
(other than mucous 
are seen accompanied by 
membranes) showing yeast 
evidence of associated 
cells – for example, 
tissue damage 
Cryptococcus species 
indicated by encapsulated 
budding yeasts or Candida 
species showing 
pseudohyphae or true 
hyphaec 


ALLR18 
Appendix VI 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
 
Culture 
Sterile material 
Recovery of a mold or 
“black yeast” by culture of 
a specimen obtained by a 
sterile procedure from a 
normally sterile and 
clinically or 
radiographically abnormal 
site consistent with an 
infectious disease process, 
excluding bronchoalveolar 
lavage fluid, a cranial sinus 
cavity specimen, and urine 
Recovery of a yeast by 
culture of a sample 
obtained by a sterile 
procedure (including a 
freshly placed [<24 h ago] 
drain) from a normally 
sterile site showing a 
clinical or radiographical 
abnormality consistent with 
an infectious disease 
process 
Blood 
Blood culture that yields a 
moldd (e.g. Fusarium 
species) in the context of a 
compatible infectious 
disease process 
Blood culture that yields 
yeast (e.g. Cryptococcus or 
Candida species) or yeast- 
like fungi (e.g. 
Trichosporon species) 
Serological analysis: CSF 
Not applicable 
Cryptococcal antigen in 
CSF indicates disseminated 
cyroptococcosis 
a If culture is available, append the identification at the genus or species level from the culture results. 
b Tissue and cells submitted for histopathologic or cytopathologic studies should be stained by 
Grocott‐Gomorri methenamine silver stain or by periodic acid Schiff stain, to facilitate inspection of fungal 
structures. Whenever possible, wet mounts of specimens from foci related to invasive fungal disease should 
be stained with a fluorescent dye (e.g., calcofluor or blankophor). 
c Candida, Trichosporon, and yeast‐like Geotrichum species and Blastoschizomyces capitatus may also 
form pseudohyphae or true hyphae. 
e Recovery of Aspergillus species from blood cultures invariably represents contamination 
2. 
Probable invasive fungal infection (not endemic mycosis) 
Host factorsa 
• Recent history of neutropenia (<0.5 x 109 neutropils/mm3) for > 10 days) temporally 
related to the onset of fungal disease 
• Receipt of an allogeneic stem cell transplant 
• Prolonged use of corticosteroids (excluding among patients with allergic 
bronchopulmonary aspergillosis) at a mean minimum dose of 0.3 mg/kg/day of 
prednisone equivalent for > 3 weeks. 
• Treatment with other recognized T cell immunusuppressants, such as cyclosporine, TNF-α 
blockers, specific monoclonal antibodies (such as alemtuzumab), or neucleoside analogues 
during the past 90 days. 
• Inherited severe immunodeficiency (such as chronic granulomatous disease or severe combined 
immunodeficiency) 


ALLR18 
Appendix VI 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
Clinical criteriab 
• Lower respiratory tract fungal diseasec 
o The presence of 1 of the following 3 signs on CT: 
▪ Dense, well-circumscribed lesion(s) with our without a halo sign 
▪ Air-crescent sign 
▪ Cavity 
• Tracheobronchitis 
o Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on 
bronchoscopic analysis 
• Sinonasal infection 
o Imaging showing sinusitis plus at least 1 of the following 3 signs: 
▪ Acute localized pain (including pain radiating to the eye) 
▪ Nasal ulcer with black eschar 
▪ Extension from the paranasal sinus across bony barriers, including into the 
orbit 
• CNS infection 
o 1 of the following 2 signs: 
▪ Focal lesions on imaging 
▪ Meningeal enhancement on MRI or CT 
• Disseminated candidiasisd 
o At least 2 of the following 2 entities after an episode of candidemia within the 
previous 2 weeks: 
▪ Small, target-like abscesses (bull’s eye lesions) in liver or spleen 
▪ Progressive retinal exudates on ophthalmologic examination 
Mycological criteria 
• Direct test (cytology, direct microscopy, or culture) 
o Mold in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate 
samples, indicated by 1 of the following 
▪ Presence of fungal elements indicating a mold 
▪ Recovery by culture of a mold (e.g. Aspergillus, Fusarium, Zygomycetes, or 
Scedosporium species) 
• Indirect tests (detection of antigen or cell-wall constituents)e 
o Aspergillosis 
▪ Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage, 
or CSF 
o Invasive fungal disease other than cryptococcosis and zygomycoses 
▪ β-D-glucan detected in serum 
 
NOTE: Probable IFD requires the presence of a host factor, a clinical criteriaon, and a mycological criterion. 
Cases that meet the criteria for a host factor and a clinical criterion but for which mycological criteria are 
absent are considered possible IFD. 
a Host factors are not synonymous with risk factors and are characteristics by which individuals predisposed to 
IFDs can be recognized. They are intended primarily to apply to patients given treatment for malignant disease 
and to recipients of allogeneic hematopoietic stemm cell and solid-organ transplants. These factors are also 
applicable to patients who receive corticosteroids and other T-cell suppressants as well as to patients with 
primary immunodeficiencies. 
b Must be consistent with the mycological findings, if any, and must be temporally related to current episode 
c Every reasonable attempt should be made to exclude an alternative etiology 


ALLR18 
Appendix VI 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
d The presence of signs and symptoms consistent with sepsis syndrome indicates acute disseminated disease, 
whereas their absence denotes chromic disseminated disease 
e These tests are primarily applicable to aspergillosis and candidiasis and are not useful in diagnosing 
infections due to Cryptococcus species or Zygomycetes (e.g. Rhizopus, Mucor, or Absidia species). Detection of 
nucleic acid is not included, because there are as yet no validated or standardized methods. 
 
3. 
Possible invasive fungal infection (not endemic mycosis) 
In the table above, cases that meet the criteria for a host factor and a clinical criterion but 
for which mycological criteria are absent are considered possible IFD. 
 
C. 
Histoplasmosis: a diagnosis of disseminated disease may be established by a 
positive Histoplasma antigen test on CSF, urine or serum by EIA, or the presence 
of characteristic intracellular yeast forms in a peripheral blood smear or in bone 
marrow. 
Criteria for the diagnosis of endemic mycoses 
Diagnosis and criteria 
Proven endemic mycosis 
In a host with an illness consistent with an endemic mycosis, 1 of the following 
• Recovery in culture from a specimen obtained from the affected site or from 
blood 
• Histopathologic or direct microscopic demonstration of appropriate morphologic 
forms with a truly distinctive appearance characteristic of dimporphic fungi, such 
as Coccidiodes species spherules, Blastomyces dermatitis thick-walled broad- 
based budding yeasts, Paraccidioides brasilensis multiple budding yeast cells, 
and, in the case of histoplasmosis, the presence of characteristic intracellular yeast 
forms in a phagocyte in a peripheral blood smear or in tissue macrophages 
• For coccidioidomycosis, demonstration of coccidioidal antibody in CSF, or a 2- 
dilution rise measured in 2 consecutive blood samples tested concurrently in the 
setting of an ongoing infectious disease process. 
• For paracoccidioidomycosis, demonstration in 2 consecutive serum samples of a 
precipitin band to paracoccidioidin concurrently in the setting of an ongoing 
infectious disease process 
Probable endemic mycosis 
• Presence of a host factor, including but not limited to those specified in #2 Table 
above, plus a clinical picture consistent with endemic mycosis and mycological 
evidence, such as positive Histoplasma antigen test result from urine, blood, or 
CSF 
Note: Endemic mycosies includes histoplasmosis, blastomycosis, coccidioidomycosis, 
paracoccidioidomycosis, sporotrichosis, and infection due to Penicillium marneffei. Onset within 
3 months after presentation defines a primary pulmonary infection. There is no category of 
possible endemic mycosis, as such, because neither host factors nor clinical features are 
sufficiently specific; such cases are considered to be of value too limited to include in clinical 
trials, epidemiological studies, or evaluations of diagnostic tests. 
 
D. 
Others: the investigator may include certain other infectious diseases of unique 
nature. Acceptance requires decision before decoding occurs and with the 
agreement of the principal investigator and an attending from the Infectious 
Disease Department. 


ALLR18 
Appendix VI 
St. Jude 
IRB NUMBER: Pro00002817 
IRB Approval date: 0IR6-B13A-P2P0R1O8 VAL DATE: 03/18/2019 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
 
 
 
IV. 
PROTOZOAN 
 
A. 
Pneumocystis carinii Pneumonia: discernible radiographic lesion plus 
identification of P. carinii in bronchoalveolar lavage fluid, biopsy or induced 
sputum. 
B. 
Cryptosporidiosis: C. parum identified in stool plus diarrhea. 
C. 
Toxoplasmosis: see ACTG protocol 254. 
 
V. 
TOPOGRAPHICAL 
 
A. 
The following diagnoses are acceptable for objectively identified infections 
without confirmation of etiology. 
1. 
Pneumonia: lesion on radiograph 
2. 
Osteomyelitis: radiological diagnosis 
3. 
Sinusitis: radiological diagnosis (x-ray, CT, MRI) 
4. 
Cellulitis: physician diagnosis 
 
VI. 
FEVER OF UNDETERMINED ETIOLOGY 
 
B. 
Fever without any focus or etiology identified by clinical history, physical 
examination, radiological or microbiologic finding. Identify as: 
1. 
neutropenic = ANC <500/mm3 
2. 
non-neutropenic = ANC >500/mm3 
 
VII. 
CULTURE NEGATIVE SEPSIS 
 
In the absence of a positive culture, a systemic response to a possible infection by 
hemodynamic instability, focal or multiple organ involvement such as poor skin 
perfusion, oliguria, hypoxemia, and/or altered mental status or lethargy 


ALLR18 
Appendix VII 
IRB Approval date: 0S6t-.1J3u-2d0e18 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
 
 
 
APPENDIX VII: COMMON SUBSTRATES, INHIBITORS AND INDUCERS OF 
CYP3A4/3A5 
 
The following lists describe medications which are common CYP3A4 substrates, inhibitors and 
inducers. This list should not be considered all inclusive. Consult Pharmaceutical Services for 
specific information on metabolism by CYP3A4/CYP3A5 and particularly for Ph+ participants 
receiving tyrosine kinase inhibitor. 
 
substrates 
Macrolide antibiotics 
clarithromycin 
erythromycin 
NOT azithromycin 
Anti-arrhythmics 
quinidine 
Benzodiazepines 
alprazolam 
diazepam 
midazolam 
triazolam 
Immune modulators 
cyclosporine 
tacrolimus (FK506) 
sirolimus 
HIV antivirals 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
Antihistamines 
astemizole 
chlorpheniramine 
terfenidine 
Calcium channel blockers 
amlodipine 
diltiazem 
felodipine 
lercanidipine 
nifedipine 
nisoldipine 
nitrendipine 
verapamil 
HMG CoA reductase inhibitors 
atorvastatin 
cerivastatin 
lovastatin 
NOT pravastatin 
simvastatin 
Steroid 6beta-OH 
estradiol 
hydrocortisone 
progesterone 
testosterone 


ALLR18 
Appendix VII 
IRB Approval date: 0S6t-.1J3u-2d0e18 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
 
 
 
Substrates - continued 
Other 
alfentanyl 
buspirone 
cafergot 
caffeine=>TMU 
cocaine 
dapsone 
codeine-N-demethyl 
dextromethorphan 
eplerenone 
fentanyl 
finasteride 
imatinib 
haloperidol (in part) 
irinotecan 
Lidocaine methadone 
ondansetron 
pimozide 
propranolol 
quinine 
salmetrerol 
sildenafil 
tamoxifen 
paclitaxel 
trazodone 
vincristine 
zaleplon 
zolpidem 
inhibitors 
HIV antivirals 
delaviridine 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
Other 
amiodarone NOT azithromycin 
cimetidine 
ciprofloxacin 
clarithromycin 
diethyl-dithiocarbamate 
diltiazem 
erythromycin 
fluconazole 
fluvoxamine 
gestodene 
grapefruit juice 
itraconazole 
ketoconazole 
mifepristone 
nefazodone 
norfloxacin 
norfluoxetine 
mibefradil 
verapamil 
voriconazole 
inducers 
HIV antivirals 
efavirenz 
nevirapine 
Other 
barbiturates 
carbamazepine 
glucocorticoids 
modafinil 
phenobarbital 
phenytoin 


ALLR18 
Appendix VII 
IRB Approval date: 0S6t-.1J3u-2d0e18 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
 
 
 
APPENDIX VIII: HDMTX ADMINISTRATION AND MONITORING GUIDELINES 
INDUCTION BLOCK II 
 
High-dose MTX (HDMTX) will be given at a dose of 5 g/m2 over 24 hours or targeted to a Cpss 
of 65 µM. 
 
The physician or pharmacist should review the past and current medication list for the patient 
prior to administration of HDMTX. Every effort should be made to avoid nephrotoxins 
(amphotericin, acyclovir) and drug that could compete with MTX (penicillins and proton pump 
inhibitors) on the day of and the day after HDMTX begins; use of NSAIDs and salicylates of any 
kind is contraindicated. HDMTX should not be given to patients with any residual mucositis 
without discussion with the PI of the protocol. 
 
Standing orders should be in place that includes twice daily BMP, magnesium, and phosphorus. 
In addition, orders should include specific instructions to notify the physician of record or their 
designee. These include: 
 
• Notification if HDMTX stopped for a cumulative time of 60 minutes or more 
• Any increase in serum creatinine by > 0.3 mg/dL or a doubling of creatinine from pre- 
HDMTX value 
• 2 or more consecutive urine pH < 6.5 or 2 consecutive urine pH > 9 
• No urine output for 4 hours 
• > 2 episodes of diarrhea in a 24 hour period within first 48 hours after start of HDMTX 
• > 2 episodes of emesis in a 4 hour period within first 48 hours after start of HDMTX 
• Any episode of hypotension or sepsis within first 48 hours after start of HDMTX 
 
MTX plasma concentrations will be obtained at least 4 times with the HDMTX: prior to starting 
the infusion and at hours 6, 23, and 42 from the start of the infusion. Patients with MTX 
concentrations at 42 hours above 0.5 µM will be assessed at least daily until the concentration is 
< 0.1 µM. After the patient has cleared MTX, please fax copies of the MTX concentrations (from 
your lab system) to the SJ Pharmacokinetics Lab at 
for inclusion into the SJ 
electronic medical record. 
 
Ideally, each patient will receive IV hydration with Bicarb beginning the evening prior to 
scheduled admission for HDMTX with a rate of at least 125 mL/m2/hr. Hydration should 
continue at this rate until the MTX concentration is < 0.5 µM or longer if the patient has a 
history of toxicity or delayed excretion. Patients with poor clearance are candidates for increased 
hydration and more aggressive alkalinization. Acetazolamide is an effective diuretic in patients 
with delayed MTX excretion. Patients with MTX concentrations > 1 µM benefit from increasing 
urine output. 
 
MTX dosing may be individualized to achieve a target Cpss of 65 µM. The physician or their 
designee at the collaborating site should contact a SJ clinical pharmacist to discuss targeting and 
leucovorin rescue. (Please use the group email 
).SJ will also 
provide contact information for help during the infusion at that time. 


ALLR18 
Appendix VII 
IRB Approval date: 0S6t-.1J3u-2d0e18 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
 
 
 
Leucovorin rescue should begin at 42 hour from the start of HDMTX. The dose is 15 
mg/m2/dose po or IV q6h x 3 doses. Patients with a history of delayed Grade 3 or 4 GI toxicity 
with prior HDMTX or a history of typhlitis with any chemotherapy should have leucovorin 
continue for 5 doses, rather than 3. Those with early toxicity should have leucovorin begin at 
hour 36. Patients with vomiting, poor oral intake, period (>4 hours) of no urine output should 
receive all leucovorin doses IV. All doses > 50 mg should be given IV. 
 
MTX 
Concentration 
Threshold for 
Action 
Recommended LV Rescue 
6 hr – 5 gm/m2 or 
targeted to 65 µM 
95 – 150 µM 
Check that hydration and alkalinization are adequate; 
check for nephrotoxic drugs; check creatinine; notify the 
house officer and floor nurse to be particularly vigilant 
with urine output 
> 150 µM 
All of above plus obtain another blood sample between 12 
and 24 hrs for assay 
Extra sample 
between 12 and 24 
hr because of 
suspected delayed 
excretion - 5 gm/m2 
or targeted to 65 µM 
95 - 150 µM 
Check that hydration and alkalinization are adequate; 
check for nephrotoxic drugs; check creatinine; notify the 
house officer and floor nurse to be particularly vigilant 
with urine output 
> 150 µM 
All of above plus stop MTX, continue monitoring MTX to 
estimate half-life. 
23 hr - 5 gm/m2 or 
targeted to 65 µM 
95 - 150 µM 
Check that hydration and alkalinization are adequate; 
check for nephrotoxic drugs; check creatinine; notify the 
house officer and floor nurse to be particularly vigilant 
with urine output 
> 150 µM 
All of above plus obtain another blood sample for assay; 
consider possible early LV rescue;* consider obtaining 
glucarpidase, etc. 
42 hr# 
< 0.5 µM 
Protocol rescue & no further concentrations indicated, 
unless clinically warranted 
0.5 – 1 µM 
Protocol rescue, cont IVF with bicarb & check 66 hr conc 
1 – 2 µM 
30 mg/m2/dose po/IV q6h 
2 – 5 µM 
50 mg/m2/dose IV q6h 
5 – 10 µM 
100 mg/m2/dose IV q6h 
10 – 20 µM* 
200 mg/m2/dose IV q6h or continuous infusion 
>20 µM* 
Individualized 
66 hr# 
< 0.1 µM 
Per protocol and stop checking unless clinically indicated 
0.1 – 0.2 µM 
5 mg/m2-/dose po/IV q12h & continue checking until < 0.1 
0.2 – 0.5 µM 
15 mg/m2/dose po /IV q12h & continue checking until < 
0.1 
0.5 – 1 µM 
15 mg/m2/dose po/IV q6h & continue checking until < 0.1 
1 – 2 µM 
30 mg/m2/dose po/IV q6h & continue checking until < 0.1 
2 – 5 µM 
50 mg/m2/dose IV q6h & continue checking until < 0.1 
>5 µM 
Individualized 


ALLR18 
Appendix VII 
IRB Approval date: 0S6t-.1J3u-2d0e18 
Amendment 3.0, dated: 03-19-2018 
Protocol document date: 06-12-2018 
IRB NUMBER: Pro00002817 
IRB APPROVAL DATE: 03/18/2019 
 
 
 
 
MTX 
Concentration 
Threshold for 
Action 
Recommended LV Rescue 
90 hr and later# 
< 0.1 µM 
Stop LV & stop checking, unless clinically indicated 
0.1 – 0.2 µM 
5 mg/m2/dose po/IV q12h & continue checking until < 0.1 
0.2 – 0.5 µM 
15 mg/m2/dose po/IV q12h & continue checking until < 0.1 
0.5 – 1 µM 
15 mg/m2/dose po/IV q6h & continue checking until < 0.1 
>1 µM 
As above under hr 66 
*Early rescue should be initiated and glucarpidase availability should be checked whenever it is 
a possibility that the patient will have plasma MTX concentrations > 10 µM at 42 hours. 
 
#Higher doses of leucovorin may be indicated based on the clinical condition of the patient. 
Patients with MTX concentrations > 1 µM benefit from increased urine output. Forced diuresis 
with acetazolamide, along with increased hydration may be necessary. 
 
NOTE: Glucarpidase would not need to start before hr. 42, but availability should be checked 1 
day prior. Nephrology should be consulted and hemoperfusion should be anticipated if 
glucarpidase will not be available by 42 hours. Ideally, leucovorin should NOT be given within 2 
hours BEFORE or AFTER glucarpidase dosing because leucovorin is also a substrate for 
glucarpidase and will interfere with methotrexate hydrolyzation. 
 
NOTE: Early leucovorin rescue should not need to start prior to 24 hours, regardless of the 
concentration. Although it is not likely to be very effective, early leucovorin should be instituted 
sometime between 24 and 42 hours at a dose of ~2000 – 2400 mg/m2/day if the 24 hour 
concentration is > 300 µM or it is above 200 µM and the half-life is > 8 hours. Continuous 
infusions of leucovorin are slightly preferred over bolus infusions, on the off chance that high 
leucovorin concentrations could either compete with MTX for excretion or contribute to 
neurotoxicity, but doses as high as 500 mg/m2 can be given safely if necessary.