Conditions: Recurrent B Acute Lymphoblastic Leukemia Recurrent Ph-Like Acute Lymphoblastic Leukemia Refractory B Acute Lymphoblastic Leukemia Refractory Ph-Like Acute Lymphoblastic Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 11
Healthy volunteers: no

Brief summary:
This phase II trial studies the side effects and best dose of ruxolitinib phosphate and how well it works compared to dasatinib when given with chemotherapy in treating patients with Philadelphia chromosome-like acute lymphoblastic leukemia that has come back (relapsed) or has not responded to treatment (refractory). Ruxolitinib phosphate and dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving ruxolitinib phosphate or dasatinib with chemotherapy works better in treating patients with previously treated acute lymphoblastic leukemia.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and maximal tolerated dose (MTD) of ruxolitinib phosphate (ruxolitinib) in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL). (Phase I, ruxolitinib cohort only) II. To determine the response rate (complete response \[CR\]/CR with incomplete marrow recovery \[CRi\]) of ruxolitinib or dasatinib in combination with chemotherapy in patients with Ph-like ALL. (Phase II)

SECONDARY OBJECTIVES:

I. To determine the response rate (CR/CRi) of ruxolitinib in combination with chemotherapy in patients with Ph-like ALL. (Phase I, ruxolitinib cohort only) II. To determine the duration of response, disease-free survival and overall survival of ruxolitinib in combination with chemotherapy in patients with Ph-like ALL. (Phase I, ruxolitinib cohort only) III. To determine the safety and toxicity profile of ruxolitinib or dasatinib in combination with chemotherapy in patients with Ph-like ALL. (Phase II) IV. To determine the duration of response, disease-free survival and overall survival of ruxolitinib or dasatinib in combination with chemotherapy in patients with Ph-like ALL. (Phase II)

OUTLINE: This is a phase I, dose escalation study of ruxolitinib followed by a phase II study. Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive dasatinib PO once daily (QD). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

INTENSIVE CHEMOTHERAPY: After cycle 1, patients not achieving a response also receive cyclophosphamide intravenously (IV) over 3 hours BID on days 1-3, doxorubicin IV over 24-48 hours on day 4, vincristine IV over 30 minutes on days 4 and 11, and dexamethasone PO QD or IV over 30 minutes on days 1-4 and 11-14 of cycles 1, 3, 5, and 7. Patients receive methotrexate IV over 24 hours on day 1, leucovorin IV over 1 hour or PO every 6 hours on days 2-5, cytarabine IV over 2 hours BID on days on days 2 and 3 of cycles 2, 4, 6, and 8. At the discretion of the treating physician, patients may also receive rituximab IV over several hours on days 1 and 11 of cycles 1 and 3 and on days 1 and 8 of cycles 2 and 4 only. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive mercaptopurine PO thrice daily (TID), methotrexate PO once a week, vincristine IV over 30 minutes on day 1, and prednisone PO on days 1-5. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Arms:
arm 1: Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cyclophosphamide intervention 2: Cytarabine intervention 3: Dasatinib intervention 4: Dexamethasone intervention 5: Doxorubicin intervention 6: Laboratory Biomarker Analysis intervention 7: Leucovorin intervention 8: Mercaptopurine intervention 9: Methotrexate intervention 10: Prednisone intervention 11: Rituximab intervention 12: Ruxolitinib Phosphate intervention 13: Vincristine
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO intervention 4: Given PO or IV intervention 5: Given IV intervention 6: Correlative studies intervention 7: Given IV or PO intervention 8: Given PO intervention 9: Given IV and PO intervention 10: Given PO intervention 11: Given IV intervention 12: Given PO intervention 13: Given IV

Protocol document:
Prot_SAP_000.pdf: 
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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2014‐0521 
Protocol Title 
A Phase I‐II Study of the Combination of Ruxolitinib or Dasatinib with 
Chemotherapy in Patients with Philadelphia Chromosome (Ph)‐Like Acute 
Lymphoblastic Leukemia (ALL) 
Protocol Phase 
I/II 
Protocol Version 
4 
Version Date 
07/09/2020 
 
Protocol PI 
Nitin Jain 
Department 
Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
101814 


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A Phase I-II Study of the Combination of Ruxolitinib or Dasatinib with Chemotherapy in 
Patients with Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL) 
 
Coordinating Center: 
 
MD Anderson Cancer Center, Houston, TX, USA 
Principal Investigator: 
Name:  
 
Nitin Jain, MD 
 
 
 
 
Address: 
 
Department of Leukemia 
MD Anderson Cancer Center  
 
 
 
 
 
 
 
1515 Holcombe Blvd, Unit 428 
 
 
 
 
 
 
 
Houston, TX, 77030 
 
 
 
 
Telephone: 
 
713-745-6080 
 
 
 
 
Fax: 
 
 
713-794-4297 
 
 
 
 
e-mail address: 
njain@mdanderson.org 
 
Co-Principal Investigator: Name:   
 
Marina Konopleva, MD, PhD 
 
 
 
 
Address: 
 
Department of Leukemia 
MD Anderson Cancer Center  
 
 
 
 
 
 
 
1515 Holcombe Blvd, Unit 428 
 
 
 
 
 
 
 
Houston, TX, 77030 
 
 
 
 
Telephone: 
 
713-794-1628 
 
 
 
 
Fax: 
 
 
713-794-4297 
 
 
 
 
e-mail address: 
mkonople@mdanderson.org 
 
Collaborator:  
 
Name:   
 
Keyur Patel, MD, PhD 
 
 
 
 
Address: 
 
Department of Pathology 
MD Anderson Cancer Center  
 
 
 
 
 
 
 
1515 Holcombe Blvd, Unit 149 
 
 
 
 
 
 
 
Houston, TX, 77030 
 
 
 
 
Telephone: 
 
713-563-6780 
 
 
 
 
Fax: 
 
 
713-794-4297 
 
 
 
 
e-mail address: 
kppatel@mdanderson.org 
 
 
Collaborator:  
 
Name:  
 
Sarah Tasian, MD 
 
 
 
 
Address: 
 
Children’s Hospital of Philadelphia 
 
 
 
 
 
 
 
3501 Civic Center Boulevard, CTRB 3100 
 
 
 
 
 
 
 
Philadephia, PA  19104 
 
 
 
 
Telephone: 
 
267-426-0118 
 
 
 
 
Fax: 
 
 
215-590-6334 
 
 
 
 
email address:  
tasians@email.chop.edu 


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Statistician:  
 
 
 
 
Study Coordinator: 
Jing Ning, PhD 
 
 
 
 
Hayley Balkin, RN 
MD Anderson Cancer Center  
 
 
MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit 1411  
 
 
1515 Holcombe Blvd, Unit 428 
Houston, TX 77030                                               
Houston, TX 77030 
Telephone: 713-792-5310 
 
 
 
Telephone: 713-745-4642 
Fax: 713-563-4243 
 
 
 
 
Fax: 713-745-2232 
e-mail address: jning@mdanderson.org           
e-mail address adeshmukh@mdanderson.org 
 
Table of Contents 
1.0   INTRODUCTION .............................................................................................................. 4 
1.1  
Acute lymphoblastic leukemia (ALL) .......................................................................... 4 
1.2  
Ph-Like ALL ................................................................................................................... 5 
1.3  
CRLF2 rearrangements and JAK mutations in B-cell ALL ...................................... 6 
1.4  
IL7R mutations in B-cell ALL ...................................................................................... 9 
1.5  
JAK inhibition in B-cell ALL ........................................................................................ 9 
1.6  
Activating cytokine receptor and tyrosine kinase signaling in B-cell ALL .............. 9 
1.7  
Ruxolitinib in myeloproliferative neoplasms and other hematologic malignancies
 
10 
1.8  
Dasatinib in Ph+ ALL .................................................................................................. 10 
1.9  
Chemotherapy regimen (Hyper-CVAD) in B-cell ALL ............................................ 10 
1.10 Molecular Diagnostic Plan ........................................................................................... 11 
2.0  
OBJECTIVES ................................................................................................................... 13 
2.1 
Primary Objective ........................................................................................................ 13 
2.2 
Secondary Objectives ................................................................................................... 13 
3.0  
ELIGIBILITY CRITERIA ............................................................................................. 13 
3.1  
Inclusion Criteria ......................................................................................................... 13 
3.2  
Exclusion Criteria ........................................................................................................ 14 
4.0  
TREATMENT PLAN ...................................................................................................... 15 
5.0  
TREATMENTS ADMINISTERED ............................................................................... 17 
5.1 
Ruxolitinib..................................................................................................................... 17 


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5.2 
Dasatinib ....................................................................................................................... 19 
5.3  
Hyper-CVAD plus Rituximab regimen ...................................................................... 20 
5.4  
Hyper-CVAD (Courses 1, 3, 5, 7) ................................................................................ 21 
5.5  
Hyper-CVAD (Courses 2, 4, 6, 8) ................................................................................ 22 
5.6  
Maintenance phase chemotherapy (POMP maintenance) ....................................... 23 
5.7  
Suggested dose modifications ...................................................................................... 24 
7.0  
CONCOMITANT THERAPY ........................................................................................ 27 
7.1  
Allowed Concomitant Therapy ................................................................................... 28 
7.2  
Prohibited Concomitant Therapy ............................................................................... 28 
8.0  
PRETREATMENT EVALUATIONS ............................................................................ 28 
9.0  
EVALUATIONS DURING THE STUDY ..................................................................... 29 
10.0  STUDY CALENDAR ....................................................................................................... 30 
11.0  CRITERIA FOR RESPONSE ........................................................................................ 31 
12.0  ADVERSE EVENT REPORTING ................................................................................. 32 
13.0  DISCONTINUATION OF STUDY TREATMENT ....................................................... 34 
14.0  BIOMARKER STUDIES ................................................................................................ 35 
15.0  STATISTICAL CONSIDERATIONS ............................................................................ 35 
16.0  REFERENCES ................................................................................................................. 38 
 
1.0   INTRODUCTION 
 
1.1  
Acute lymphoblastic leukemia (ALL) 
Acute lymphoblastic leukemia (ALL) is a malignant proliferation of lymphoid cells blocked at an 
early stage of differentiation. Combination chemotherapy has been the cornerstone of treatment of 
ALL. While currently employed induction regimens in adults with ALL now routinely result in 
these very high CR rates of 80-90%, none of them have yet translated into the 80-85% disease-
free survival rates that are routinely achieved in pediatric ALL. In adult ALL, DFS generally has 
been reported to be at 40-45% at 3 years and 30-35% at 5-years.1 Thus, the major problem with 
the current treatment programs in adult ALL is disease relapse due to the emergence of resistant 
disease. Further intensification of chemotherapy has not proved to be effective.2 The prognosis of 
patients with relapsed or refractory ALL or LL is extremely poor.3,4  
ALL in first relapse: In the largest report of relapsed adult ALL patients to date, Fielding and 
colleagues analyzed the outcomes of adult ALL patients in first relapse who were treated on the 
MRC UKALLXII/ECOG E2993 trial.5 Of the 1508 evaluable patients, 1372 (91%) achieved CR1 


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of whom 609 (44% of the CR1 patients) relapsed at a median of 11 months. The median OS after 
relapse was only 5.5 months with a 5-year OS of 7%. The rate of achievement of CR2 was not 
reported. Tavernier and colleagues reported outcomes of 421 ALL patients who experienced first 
relapse treated on the French LALA-94 trial.6 A CR2 was achieved in 44% patients with a median 
OS of 6.3 months. Oriol and colleagues reported the outcomes of 263 ALL patients in first relapse 
treated on 4 consecutive PETHEMA trials.7 CR2 was achieved in 45% of patients with the median 
OS after relapse of 4.5 months and 5-year OS of 10%.     
ALL in second relapse or greater: O’Brien and colleagues reported 18% CR rate after second 
salvage chemotherapy in 288 patients with ALL. The median survival of the entire cohort was 
only 3 months. Kantarjian and colleagues reported outcomes of patients with ALL who achieve 
CR2/CR3.8 The median OS post achievement of the response was 10 months.  
Overall CR rate in patients with relapsed/refractory ALL is <20% with a median survival of <6 
months. In a recently reported study of clofarabine and cyclophosphamide in patients with 
relapsed/refractory ALL (majority were salvage 2 or greater), CR/CRp rate was 12% with a median 
survival of 3 months.9  In another recently reported study in patients with relapsed/refractory ALL 
(salvage 2 or greater), single-agent liposomal vincristine led to CR/CRi rate of 20% with an OS of 
only 4.6 months.10 Novel therapeutic strategies are clearly needed. 
 
1.2  
Ph-Like ALL 
There has been significant advancement in our understanding of the biology of ALL in the last few 
years which provides an opportunity for ‘targeted therapy’.11,12 In 2009, a subgroup of childhood 
B-cell ALL patients was identified that had a gene expression signature similar to that of BCR-
ABL1 (Philadelphia chromosome) positive ALL, but these patients had no Philadelphia 
chromosome.13,14 These patients had frequent deletion of transcription factor IKZF1 (also common 
in BCR-ABL1 positive ALL), and poor outcome.13-15 These cases categorized as “Ph-like ALL” 
comprise up to 15% of childhood B-ALL16, 20-25% in adolescents and young adults, and a higher 
frequency of ALL in adults (up to 30%).17 Patients with Ph-like ALL have a very high rate of 
disease relapse and poor overall survival.17-20 
 
In a study by the German and Dutch groups, 190 children with newly-diagnosed ALL (154 B-cell 
ALL, 36 T-cell ALL) were evaluated for gene expression using Affymetrix chip assay. Hierarchal 
clustering with 110 gene probe set clustered major subtype of B-cell pediatric ALL separated into 
distinct groups (ETV6-RUNX1 (TEL-AML1, t(12;21) (p13.1;q22)); hyperdiploid (>50 
chromosomes); TCF3 (E2A)-rearranged such as TCF3–PBX1 (t(1;19)(q23;p13)); MLL-
rearranged; BCR-ABL1). There were 44 patients which did not fit into anyone of the known genetic 
subgroups and were classified as B-other. Of these 44 patients, 30 patients (19% of the entire B-
cell ALL cohort (30/154); 68% of B-other (30/44)) had gene expression profile similar to BCR-
ABL1 positive ALL. These patients are referred to as Ph-like ALL and their outcome is very poor 
(5-year DFS 59% vs. 84% for B-cell ALL (excluding Ph-Like ALL), p=0.01). Patients with Ph-
like ALL were noted to have significantly higher WBC count than the other B-cell ALL. 


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Up to half of Ph-like ALL cases harbor rearrangement of CRLF2 located at the pseudoautosomal 
region of Xp22.3/Yp11.3, either as a translocation to the immunoglobulin heavy chain enhancer 
region at 14q32.33 (IGH-CRLF2), or a focal deletion proximal to CRLF2 resulting in the 
expression of a P2RY8-CRLF2 fusion transcript.18,21-25 
 
1.3  
CRLF2 rearrangements and JAK mutations in B-cell ALL        
CRLF2 encodes cytokine receptor–like factor 2 (also known as thymic stromal lymphopoietin 
(TSLP) receptor), a lymphoid signaling receptor molecule that forms a heterodimeric complex 
with interleukin-7 receptor alpha (IL7R) and binds TSLP. IL7-TSLP receptor signaling pathway 
is important in lymphoid development. These 2 cytokine receptors are dimeric, share IL7R, and 
use IL2RG (interleukin-2 receptor gamma, which is a common gamma chain shared by the 
receptors of various cytokines, including interleukin 2, 4, 7, 9, and 15) and CRLF2, respectively, 
to form heterodimers. TSLP-CRLF2 signaling has important roles in T-cell and dendritic cell 
development, inflammation and allergic disease and promotes B-lymphoid proliferation.26 TSLP 
is produced by epithelial cells at sites of inflammation, where it activates myeloid dendritic cells 
and Th2 immune responses. Signaling from the TSLP receptor activates signal transducer and 
activator of transcription (STAT5) by phosphorylation of JAK1 and JAK2 through association 
with IL-7R and CRLF2, respectively.22,27,28 
 
Mulligan and colleagues had identified deletion involving the pseudoautosomal region 1 
(PAR1) of Xp22.3/Yp11.3 in B-cell ALL, including in several children with Down syndrome–
associated ALL (DS-ALL).15,21,29 Further analysis showed that PAR1 deletion extended from 
immediately upstream of CRLF2 exon 1 to P2RY8 intron 1 creating a fusion transcript P2RY8-
CRLF2.21 The breakpoints were identical in all patients and detectable by RT-PCR. These patients 
also had increased cell surface expression of CRLF2, detectable by flow-cytometry. Overall 53% 
(40/75) of patients with DS-ALL had P2RY8-CRLF2 fusion. IGH@-CRLF2 translocations, that 
also lead to increased CRLF2 expression, are rare in DS-ALL (only 1/75 patients in this study).21 
Importantly, P2RY8-CRLF2 fusion was associated with JAK2 mutations (32% vs. 4% without the 
fusion), most commonly at JAK2 pseudokinase domain, JAK2R683. In contrast to 
myeloproliferative diseases, in which homozygous alteration of JAK2V617F is common, the JAK 
alterations in B-cell ALL are usually heterozygous and do not occur at JAK2V617.30-34 
Coexpression of P2RY8-CRLF2 and JAK mutation led to constitutive JAK-STAT activation and 
cytokine-independent growth in Ba/F3-IL7R cells. Moreover, this transformation was attenuated 
by pharmacological JAK inhibition and knockdown of CRLF2 by shRNA.21 
 
Russell and colleagues evaluated 97 patients, mostly children (median age 5.5 years; range, 1-76) 
with CRLF2 deregulation (deletion or translocations), including 41 patients with DS-ALL. 22 
Overall the incidence of CRLF2 deregulation in childhood ALL was reported as 5% (4.2% 
deletion, 0.8% translocations). Apart from intrachromosomal amplification of chromosome 21 


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(iAMP21) seen in the non-DS ALL patients with CRLF2 deletion, none of the patients in this study 
showed established chromosomal abnormalities of prognostic significance (such as high 
hyperdiploidy, rearrangements of MLL, BCR-ABL1, and ETV6-RUNX1 fusions). Quantitative real-
time PCR showed an increase in CRLF2 mRNA expression in samples from patients with the 
CRLF2 translocations and deletion. mRNA levels were increased from 80- to >1500-fold in the 
translocation patients and from 5- to 100-fold in the deletion patients. Notably, mRNA levels of 
IL7RA and IL2RG (IL7RA and IL2RG form the heterodimeric receptor for IL-7) were normally 
expressed. CRLF2 mutation screening revealed single nucleotide polymorphisms (SNPs) but no 
somatic mutations.22  
 
Harvey and colleagues evaluated 207 children with ‘high-risk’ B-cell ALL enrolled on COG 
P9906 study with augmented BFM regimen.18 Twenty-nine patients (14%) had CRLF2 
overexpression (2/3 were IGH@-CRLF2 translocations; 1/3 were P2RY8-CRLF2). Notably, there 
is higher rate (14%) of CRLF2 overexpression in this cohort of high-risk ALL patients, compared 
to 5% in unselected childhood B-cell ALL cases.22 Also, in this ‘high-risk’ cohort, the IGH@-
CRLF2 translocations were more common than P2RY8-CRLF2 fusion (2:1 incidence ratio). This 
is in contrast to other reports P2RY8-CRLF2 fusion is more common than IGH@-CRLF2 
translocations (~2:1 in unselected childhood B-cell ALL and >9:1 in DS-ALL cases with CRLF2 
rearrangement).21,22 In the report by Harvey and colleagues, patients with Hispanic ethnicity were 
more like to have CRLF2 overexpression (35% vs. 7% in others, p <0.001).18 IKZF1 alternations 
were more common in patients with CRLF2 overexpression (81% vs. 22% in non-CRLF2 
overexpressed cases, p <0.001). JAK mutations were more common in patients with CRLF2 
overexpression (69% vs. 1% in non-CRLF2 overexpressed cases, p <0.001).  Conversely, 90% of 
JAK mutated cases had CRLF2 rearrangements. Patients with CRLF2 deregulation had a 
significantly inferior 4-year RFS (35.3% vs. 71.3% for those with intact CRLF2, p=0.001). There 
was no difference in the outcome according to the type of CRLF2 rearrangement (translocation vs 
deletion). Approximately 62% of patients with CRLF2 deregulation had the Ph-Like GEP. 
Notably, 4/8 patients that were CRLF2-rearranged but lacked JAK mutations had a Ph–like 
signature suggesting the presence of additional unidentified mutations resulting in activated kinase 
signaling (all 4 had IKZF1 alteration). Conversely, 3/18 CRLF2-rearranged cases with JAK 
mutations lacked a Ph–Like GEP (all 3 had less common JAK2 or JAK1 mutations). 
 
Yoda and colleagues reported CRLF2 overexpression in 5.9% (15/254) of adults with B-cell 
ALL.25 As reported in the pediatric series, CRLF2 expression is restricted to B-cell ALL patients 
without known recurrent chromosomal aberrations (12.5% (15/120) in those with lacking recurring 
chromosomal aberrations; none in 134 patients with recurrent chromosomal aberrations). They 
also reported a point mutation in the CRLF2 (CRLF2 F232C, CRLF2 711 T>G) in 3 of the 14 
(21%) patients with CRLF2 overexpression. CRLF2 F232C, a gain of function mutation, leads to 
constitutive dimerization through the cysteine residues and thereby, signal transduction. They also 
report that CRLF2 F232C mutation was mutually exclusive with JAK mutations, suggesting that 


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these mutations function within the same pathway. In this series, all patients with JAK mutations 
overexpressed CRLF2. They also screened patients with CLL and T-cell ALL, none of whom had 
CRLF2 overexpression. 
 
Chen and colleagues evaluated a large cohort of pediatric ALL (n=1061), enrolled on the COG 
trials (P9905 and P9906).35 This cohort included 562 ALL patients classified as NCI SR (with ages 
ranging from 1 to 9.99 years and initial WBC <50K/uL) and 499 patients classified as NCI HR 
(age ≥ 10 years or initial WBC ≥50K/uL). A total of 186 of the 1061 patients (17.5%) were noted 
to have CRLF2 overexpression (CRLF2 mRNA was assessed by quantitative RT-PCR). CRLF2 
overexpression was noted in 19% of the HR cohort and 16.2% of the SR cohort. The 186 ALL 
patients with high CRLF2 mRNA expression had higher rates of end induction MRD (30% vs 
21.3%, P = .016) and higher rates of relapse (38.2% vs 22.1%, P <.001). Patients with high CRLF2 
mRNA expression also contained all of the CRLF2 genomic lesions (IGH@-CRLF2, P2RY8-
CRLF2, and CRLF2 F232C), virtually all of the JAK mutations (37 of 39), and a higher frequency 
of IKZF1 deletions and mutations (43.3% vs 18.9%, P <.001). In addition, consistent with reports 
by other groups, high CRLF2-expressing ALL cases lacked common ALL-associated sentinel 
cytogenetic lesions. One surprising finding in this study was that only 53% of the cases with 
CRLF2 overexpression (9% of the entire ALL cohort) had genomic rearrangements of CRLF2 
(ratio of P2RY8-CRLF2:IGH@-CRLF2 = 2.1:1). Notably, the ratio of P2RY8-CRLF2 to IGH@-
CRLF2 was 1.1:1 for HR and 4.5:1 for SR cohorts. Three patients with CRLF2 overexpression 
(2.2% of the CRLF2 overexpressors) had CRLF2 F232C mutation. Notably, all 3 had concomitant 
CRLF2 aberrations (either IGH@-CRLF2 or P2RY8-CRLF2) and consistent with the report by 
Yoda and colleagues,25 CRLF2 F232C mutations were mutually exclusive with JAK mutations, 
indicating that these mutations function within the same pathway. In this report, JAK mutations 
were seen in almost exclusively in patients with CRLF2 rearrangements (38% of patients with 
CRLF2 rearrangements had JAK mutations; 4.4% of the entire B-cell ALL cohort had JAK 
mutations). Of the 39 mutations in JAK, 33 were in JAK2, 6 JAK1 and 1 in JAK3. In a multivariate 
model for RFS in the entire cohort, only 4 variables (NCI risk status, MRD, high CRLF2 
expression, and IKZF1 deletions/mutations) retained independent prognostic significance. In a 
multivariate model for RFS for the HR cohort, only 2 variables (MRD and high CRLF2 expression 
(irrespective of presence or absence of a known genomic lesion)) retained independent prognostic 
significance.      
 
In the UKALLXII/ECOG2993 trial, 454 patients (15-60 year old) with available samples were 
evaluated for CRLF2 deregulation by FISH.36 Incidence of CRLF2 deregulation was 5% (2/3 were 
IGH@-CRLF2 translocations; 1/3 were P2RY8-CRLF2). In most cases, CRLF2 deregulation was 
not associated with other primary chromosomal abnormalities. Patients with CRLF2 deregulation 
had a higher WBC count, worse 5-year relapse-free survival (RFS) (30% vs. 55% for all patients, 
p=0.02) and worse 5-year OS (21% vs. 43% for all patients, p=0.03). 
 


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1.4  
IL7R mutations in B-cell ALL        
IL7R is required for normal lymphoid development. Loss-of-function mutations in IL7R cause 
autosomal recessive severe combined immune deficiency by the complete absence of T 
lymphocytes and the presence of B and NK cells.37 IL-7R heterodimerizes either with IL2RG to 
form a receptor to IL-7, or with CRLF2 to form a receptor for TSLP. Shochat and colleagues 
reported gain-of-function mutations in IL7R in 6% (8/133) of childhood B-ALL patients 
overexpressing CRLF2 compared to 0.6% (1/153) in the rest of B-cell ALL group.38 Two types of 
mutations in IL7R were identified. Replacement of serine with cysteine at position 185 at the 
extracellular domain in four patients and complex in-frame insertions and deletions resulted in the 
addition of 3–7 amino acids at the transmembrane domain in 5 patients. Whereas the inserted 
amino acids varied from patient to patient, cysteine was always included. They also showed that 
the presence of cysteine was critical for the gain-of-function phenotype. Biochemical and 
functional assays revealed that these IL7R mutations were activating mutations conferring 
cytokine-independent growth of progenitor lymphoid cells. All mutations were heterozygous and 
somatic. A concomitant JAK2 mutation was present in 3/8 samples.  
In contrast, Chen and colleagues reported IL7R mutations in 1.5% (5/335) patients with childhood 
B-ALL.35 Surprisingly, only 1 of the 5 mutations was in the CRLF2 overexpression cohort giving 
a low frequency of 0.7% (1/141) for IL7R mutations in the CRLF2 overexpression cohort. 
Interestingly, IL7R mutations have also been reported in approximately 10% (30/295) of childhood 
T-ALL.38 
  
1.5  
JAK inhibition in B-cell ALL        
CRLF2 rearrangements and JAK mutations result in activation of JAK-STAT signaling that may 
be amenable to therapy with JAK inhibitors such as ruxolitinib.39 Maude and colleagues 
investigated the efficacy of the JAK inhibitor ruxolitinib in xenograft models of 8 pediatric B-ALL 
cases with and without CRLF2 and JAK mutations.39 Ruxolitinib treatment yielded significantly 
lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts 
and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were 
observed in samples harboring JAK-activating lesions and higher levels of STAT5 
phosphorylation.  
 
1.6  
Activating cytokine receptor and tyrosine kinase signaling in B-cell ALL        
Transcriptome and whole genome sequencing of 15 Ph-like ALL cases, 12 of which lacked CRLF2 
rearrangement, identified a set of genetic alterations activating cytokine receptor and tyrosine 
signaling.23  These were most commonly rearrangements resulting in chimeric fusion genes 
deregulating tyrosine kinases (NUP214-ABL1, ETV6-ABL1, RANBP2-ABL1, RCSD1-ABL1, BCR-
JAK2, PAX5-JAK2, STRN3-JAK2 and EBF1-PDGFRB) and cytokine receptors (IGH-EPOR). Up 
to 20% of Ph-like cases lack a chimeric fusion on mRNA-seq analysis, and sequence mutations 
(e.g. activating mutations of FLT3 and IL7R) and structural alterations (e.g. focal deletions of 


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SH2B3, also known as LNK, which suppresses JAK signaling)40 activating signaling have been 
identified in fusion-negative cases.38,41 These diverse genetic alterations activate specific signaling 
pathways, notably ABL1 and PDGFRB (both of which may be inhibited with the tyrosine kinase 
inhibitors (TKI) such as dasatinib) and JAK-STAT signaling (via JAK mutations and JAK fusions 
such as BCR-JAK2, PAX5-JAK2, STRN3-JAK which may be inhibited by JAK inhibitor such as 
ruxolitinib).23,39 These rearrangements have been shown to activate signaling pathways in 
preclinical cell lines and xenograft models, and xenografts of Ph-like ALL are highly sensitive to 
TKIs in vivo.23,39 Recent reports of patients with refractory EBF1-PDGFRB positive ALL that was 
exquisitely sensitive to imatinib, and RCSD1-ABL1 positive ALL that was sensitive to dasatinib 
emphasizes the potential clinical utility of TKI therapy in Ph-like ALL.42-46 
 
1.7  
Ruxolitinib in myeloproliferative neoplasms and other hematologic malignancies 
Ruxolitinib is approved by for the treatment of intermediate and high risk myelofibrosis, including 
primary 
myelofibrosis, 
post-polycythemia 
vera 
myelofibrosis, 
and 
post-essential 
thrombocythemia myelofibrosis. Verstovsek and colleagues reported phase 1-2 study of 
ruxolitinib in patients with primary myelofibrosis, post−essential thrombocythemia myelofibrosis, 
or post−polycythemia vera myelofibrosis.47 A dose of 25mg orally twice daily was recommended 
for further study. Subsequent phase III studies have used ruxolitinib dose based on baseline platelet 
count. In COMFORT-I trial (a phase III placebo-controlled trial) and COMFORT-II trial (a phase 
III trial of ruxolitinib vs. best available therapy), ruxolitinib was given at a starting dose of 20mg 
orally BID (if platelet count >200K/uL) or 15mg orally BID (if platelet count 100-200 K/uL).48,49 
In patients with myelofibrosis, ruxolitinib significantly improves constitutional symptoms and 
decreases spleen size. Ruxolitinib is myelosuppressive. In phase III studies (COMFORT 1 and 2), 
the rates of grade 3-4 thrombocytopenia, neutropenia, and anemia ranged from 8-13%, 7%, 42-
45%, respectively.48,49  
 
1.8  
Dasatinib in Ph+ ALL 
Dasatinib, a second tyrosine kinase inhibitor, is approved for use in patients with Ph+ ALL with 
resistance or intolerance to prior therapy. MD Anderson group was the first report on the 
combination of dasatinib with chemotherapy (Hyper-CVAD) in patients with Ph+ ALL.50 In the 
front line setting, 94% patients achieved CR. Estimated 2-year survival was 64%. Grade 3-4 
pleural effusion was seen in 3% of the patients. The combination of chemotherapy and dasatinib 
did not result in unacceptable myelosuppression, with the median time to platelet and neutrophil 
recovery for the induction course being 23 and 18 days, respectively. In the relapsed setting, 
Hyper-CVAD + dasatinib led to 89% CR/CRp rate; however, the 3-year OS was only 26%.51  
 
1.9  
Chemotherapy regimen (Hyper-CVAD) in B-cell ALL 
We plan to use combination chemotherapy with Hyper-CVAD plus rituximab (rituximab for 
patients with ALL blasts expressing CD20).52-55 We choose this regimen for the following reasons: 
1) Patients with relapsed/refractory ALL can be very proliferative and therefore a 


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myelosuppressive chemotherapy regimen in indicated; 2) We believe that the proposed regimen 
can be safely combined with ruxolitinib without excess myelosuppression; 3) Leukemic cells from 
patients with Ph-like ALL have been shown to retain in vitro sensitivity to vincristine and steroids 
(these cells are more resistant to other standard ALL chemotherapy agents such as L-asparaginase 
and daunorubicin).13 In addition, there is extensive clinical experience with the use of tyrosine 
kinase inhibitors such as dasatinib with chemotherapy in Ph(+) ALL, and we have used ruxolitinib 
in AML patients with no excess toxicities.50,56  
 
1.10 
Molecular Diagnostic Plan 
Patients will undergo flow-cytometry for CRLF2 at the CLIA-Certified flow-cytometry laboratory 
at MDACC. The patients will undergo molecular testing at the CLIA-Certified Clinical Molecular 
Diagnostic Laboratory (MDL) at the MD Anderson Cancer Center. The multiplex diagnostic assay 
involves mutations, translocations and copy number (amplification/ deletion) analysis of multiple 
genes using a next generation sequencing (NGS) platform. Briefly, total nucleic acid (DNA+RNA) 
will be extracted from bone marrow aspirates and analyzed using an ALL-specific NGS panel for 
mutations (JAK1/2/3, FLT3, NRAS, TP53, BRAF, IL7R, NOTCH1), translocations (ABL1/2, 
PDGFRB, EPOR, JAK2, CSF1R, CRLF2, MLL, RUNX1, PBX1) and gene deletions (LNK, 
IKZF1/2/3, TP53). The testing will be performed as a part of diagnostic clinical workup and, will 
be reviewed and reported by the pathologist in the patient’s electronic medical record.  
Alternatively, the molecular testing can be performed as a send-out test to the Nationwide 
Children’s Hospital (CHILDLAB®, 700 Children’s Drive, Columbus, OH 43205). This will 
involve targeted JAK1/JAK2 mutation analysis (exons 13, 14, 15, 18, and 19 of JAK1; exons 16, 
20 and 21 of JAK2) and a multiplex RT-PCR fusion detection (ABL1 fusions, ABL2 fusions, 
PDGFRB fusions, CSF1R fusions, JAK2 fusions, NTRK3 fusions, TYK2 fusions).   
 
Patients will be divided into 2 cohorts based on sensitivity of the molecular aberrations – A) 
Ruxolitinib arm (patients with JAK mutations/fusions; B) Dasatinib arm (rearrangements of 
PDGFRB and ABL1/2). Table 1 provides a partial list of known molecular abnormalities reported 
in patients with Ph-like ALL and their sensitivity to ruxolitinib or dasatinib. Figure 1 shows the 
various lesions in patients with Ph-like ALL and sensitivity to TKIs.   
 
 
 
 
 
 
 
 
 
 


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Table 1. Partial list of known molecular abnormalities reported in patients with Ph-like ALL and 
their sensitivity to ruxolitinib or dasatinib. 
Drug Cohort 
Molecular Aberrations  
Ruxolitinib 
CRLF2 overexpression 
JAK (JAK1, JAK2, JAK3) mutations 
BCR-JAK2 fusion 
PAX5-JAK2 fusion 
STRN3-JAK2 fusion 
IGH-EPOR fusion 
IL7R mutation 
SH2B3 deletion 
Dasatinib 
 
EBF1-PDGFRB fusion (Interstitial deletion at 5q33) 
NUP214-ABL1 fusion 
ETV6-ABL1 fusion (t(9;12)(q34;p13)) 
RANBP2-ABL1 fusion 
RCSD1-ABL1 fusion (t(1;9)(q24;q34)) 
Figure 1. Various lesions in patients with Ph-like ALL and sensitivity to TKIs (D. Fruman, 
unpublished).   
 
 
 
 
 
 
 


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2.0  OBJECTIVES 
 
2.1 
Primary Objectives 
 
Phase I (Ruxolitinib Cohort only) 
1. To determine the safety and maximal tolerated dose (MTD) of ruxolitinib in combination with 
chemotherapy in patients with Ph-like ALL 
 
Phase II 
1.  To determine the response rate (CR/CRi) of ruxolitinib or dasatinib in combination with 
chemotherapy in patients with Ph-like ALL  
 
2.2 
Secondary Objectives 
 
Phase I (Ruxolitinib Cohort only) 
1. To determine the response rate (CR/CRi) of ruxolitinib in combination with chemotherapy in 
patients with Ph-like ALL  
2. To determine the duration of response, disease-free survival and overall survival of ruxolitinib 
in combination with chemotherapy in patients with Ph-like ALL 
 
Phase II 
1.  To determine the safety and toxicity profile of ruxolitinib or dasatinib in combination with 
chemotherapy in patients with Ph-like ALL  
2.  To determine the duration of response, disease-free survival and overall survival of ruxolitinib 
or dasatinib in combination with chemotherapy in patients with Ph-like ALL  
 
3.0  ELIGIBILITY CRITERIA 
 
3.1  
Inclusion Criteria 
1.  Patients with previously treated B-cell ALL (relapsed and/or refractory after prior therapy)  
2.  Bone marrow involvement with ≥5% lymphoblasts 
3.  Age ≥10 years 
4.  Documented genetic lesion(s) known to confer susceptibility to inhibition by either ruxolitinib 
or dasatinib (See Table 1); or CRLF2 positivity by flow cytometry (for the Ruxolitinib cohort) 
5.  ECOG performance status ≤2 
6.  Adequate organ function (total bilirubin < 2.0 mg/dL, SGPT or SGOT < 3 x upper limit of 
normal [ULN], creatinine < 2 mg/dL) 
7.  Females of childbearing potential must have a negative serum or urine beta human chorionic 
gonadotropin (β-hCG) pregnancy test result within 14 days prior to the first dose of study drugs 
and must agree to use an effective contraception method during the study and for 30 days 
following the last dose of study drug. Females of non- childbearing potential are those who are 


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postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy. 
Appropriate methods of birth control include the following: 
 
1.  Any 2 of the following methods used together: 
-  Birth control implants, injections, or pills (except for progesterone only pills) 
-  Intrauterine device (IUD) 
-  Vasectomy 
-  Tubal Ligation 
-  Barrier method (female or male condom with spermicide, cervical cap with spermicide, 
diaphragm with spermicide) 
2.  Male condom with spermicide and diaphragm 
3.  Male condom with spermicide and cervical cap 
 
Unacceptable methods of birth control include using no birth control, withdrawal, rhythm 
method, vaginal sponge, any barrier method that does not use spermicide, progesterone only 
pills, and using male and female condoms at the same time. 
8.  Males who have partners of childbearing potential must agree to use an effective contraceptive 
method during the study and for 30 days following the last dose of study drug 
9.  Patients or their legally authorized representative must provide written informed consent 
 
3.2  
Exclusion Criteria 
1.  Burkitt’s Leukemia or Lymphoma, T-cell ALL or lymphoblastic lymphoma  
2.  Patients having undergone prior allogeneic stem cell transplant within 3 months or having 
active graft versus host disease 
3.  Patient is pregnant or breastfeeding 
4.  Patients with uncontrolled active infections (Fever ≥38°C, Septic shock)  
5.  Isolated extramedullary relapse (i.e. testicular, central nervous system) 
6.  Current or chronic hepatitis B or C infection, or known seropositivity for HIV 
7.  Concurrent chemotherapy (except intrathecal chemotherapy) 
8.  Major surgery within 4 weeks prior to first study dose 
9.  Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the 
exception of hydroxyurea and steroids) prior to starting therapy. For patients receiving ALL 
maintenance with 6-mercaptopurine, methotrexate, vincristine, and steroids - these agents 
should be discontinued at least 48 hours prior to start of study drugs. For patients on oral 
targeted therapies (such as imatinib, dasatinib, ponatinib), - these agents should be 
discontinued at least 48 hours prior to start of study drugs. 
10. Patients must have recovered from acute non hematologic toxicity (to ≤ grade 1) of all previous 
therapy prior to enrollment 
11. Known active central nervous system (CNS) leukemia, as defined by unequivocal morphologic 
evidence of lymphoblasts in the cerebrospinal fluid (CSF), use of CNS-directed local treatment 
for active disease within the prior 28 days, symptomatic CNS leukemia (i.e., cranial nerve 
palsies or other significant neurologic dysfunction) within 28 days. Patients may have history 
of CNS leukemic involvement if definitively treated with prior therapy and no evidence of 


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active disease (defined as ≥2 consecutive spinal fluid assessments with no evidence of disease) 
at the time of registration. Prophylactic intrathecal chemotherapy is not a criterion for 
exclusion.  
12. Patients with active heart disease (NYHA class 3-4 as assessed by history and physical 
examination, unstable angina/stroke/myocardial infarction within the last 6 months )  
13. Patients with a cardiac ejection fraction (as measured by either MUGA or echocardiogram) 
<40% (Note: Patients who have had prior anthracycline exposure of >250 mg/m2 may be 
eligible after discussion with the PI) 
14. Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ 
carcinoma of the cervix or the breast, unless they are successfully treated with curative intent 
for more than 2 years before entering the study 
15. Malabsorption syndrome or other conditions that preclude enteral route of administration 
16. Patients requiring strong CYP3A4 inhibitors (See Appendix 1) 
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
in the opinion of the investigator may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study results 
and/or would make the patient inappropriate for enrollment into this study. 
 
4.0  TREATMENT PLAN 
This is an open label phase I-II study of single-agent ruxolitinib or dasatinib in patients with Ph-
like ALL. All patients will undergo molecular testing per Section 1.10. This will be done as part 
of the screening bone marrow testing (peripheral blood could be considered for this testing in place 
of bone marrow aspirate, if there are sufficient blasts in the peripheral blood). Based on the 
molecular profile, patients will be stratified into 2 cohorts- Cohort A (ruxolitinib arm); Cohort B 
(dasatinib arm).  
 
For patients who fail to respond to a single agent ruxolitinib or dasatinib by 3 weeks (earlier if 
evidence of progressive disease), Hyper-CVAD chemotherapy will be added. Single-agent 
ruxolitinib or dasatinib cycle will be cycle 0. Hyper-CVAD intensive cycles will be labelled cycles 
1-8. The hyper-CVAD regimen consists of an intensive phase comprised of 8 cycles of 
chemotherapy alternating courses of hyper-CVAD (fractionated cyclophosphamide, vincristine, 
doxorubicin, dexamethasone) with courses of high-dose methotrexate and cytarabine  every 21 
days (or later depending on blood count recovery from myelosuppression). Maintenance phase 
chemotherapy with POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) will 
commence after the completion of the intensive phase of chemotherapy. Ruxolitinib or dasatinib 
will be given continuously concurrently with the intensive and maintenance phases. 
 Note: Patients with CD20 expression (≥1% expression in leukemic blasts by flow-
cytometry) will receive 8 doses of rituximab (Rituximab 375 mg/m2 on days 1 and 11 (± 2 
days) for cycles 1 and 3, and days 1 and 8 (± 2) days for cycles 2 and 4).    
 


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Cohort A (Ruxolitinib) 
In the Phase I part, the eligible patients will receive ruxolitinib at the starting dose of 15 mg orally 
twice daily as per the dose schedule below.   
Dose level 
Ruxolitinib dose (Adults, 
Age ≥18 years) 
Ruxolitinib dose 
(Pediatric Patients, Age 
≥10 and <18 years) 
-2 
5 mg twice daily 
2.9 mg/m2 twice daily 
(Max. 5 mg twice daily) 
-1 
10 mg twice daily 
5.9 mg/m2 twice daily 
(Max. 10 mg twice daily) 
1 (starting dose) 
15 mg twice daily 
8.8 mg/m2 twice daily 
(Max. 15 mg twice daily) 
2 
20 mg twice daily 
11.8 mg/m2 twice daily 
(Max. 20 mg twice daily) 
3 
25 mg twice daily 
14.7 mg/m2 twice daily 
(Max. 25 mg twice daily) 
 
Disease assessment with a bone marrow aspirate will be performed after cycle 0 (each cycle = 21 
days). Patients having a response (CR, CRi, PR) can continue with ruxolitinib monotherapy. For 
patients that continue with monotherapy, the cycle will remain labelled as Cycle 0. For patients 
without a response, Hyper-CVAD chemotherapy will be added to ruxolitinib. DLT assessment 
will be the duration of the ruxolitinib monotherapy and the first cycle of the combination of 
ruxolitinib and chemotherapy. Each cycle of Hyper-CVAD chemotherapy is 21 days. Note: 
patients with clinically progressive disease earlier than day 21 assessment can start the Hyper-
CVAD chemotherapy at an earlier time point. Steroids (up to 40mg/day of dexamethasone or 
equivalent for 4 days) and/or hydroxyurea are allowed for the first 2 weeks of the study period to 
control rapidly proliferating disease. Patients will undergo disease assessments with a bone 
marrow aspirate at the end of every cycle (disease assessment interval can be increased to every 
2-3 cycles once the patient has achieved CR/CRi).      
For pediatric patients (<18 years of age) – the starting ruxolitinib dose will be 8.8 mg/m2 twice 
daily (Max. 15 mg twice daily). Please see Appendix 2 for the pediatric dosing table. 
 
DLT is defined as clinically significant non-hematologic adverse event or abnormal laboratory 
value assessed as unrelated to disease progression, intercurrent illness, or concomitant 
medications that meets any of the following criteria:  
 
 Non-hematological Grade 3 laboratory abnormalities lasting > 7 days OR non-
hematological Grade 4 laboratory abnormalities of any duration 
 


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Note: (1) Grade 3 or 4 nausea, vomiting and diarrhea will be considered DLT only if not 
controlled by optimal therapy 
         (2) Grade 3 biochemical abnormalities (e.g., lipase or bilirubin elevation) will only 
be considered DLT if accompanied by clinical consequences. 
         (3) Grade 3 or 4 electrolyte abnormalities will only be considered DLT if possibly 
related to study drug and not corrected by optimal replacement therapy. 
 
 Any other non-hematological AE of Grade ≥3 
 
 Hematologic DLT is defined as absolute neutrophil count (ANC) <0.5 x109/L or platelet 
count <25 x109/L with a hypocellular bone marrow lasting for 6 weeks or more after the 
start of a course in the absence of residual leukemia (i.e., with less than 5% blasts). (In 
case of a normocellular bone marrow with <5% blasts, 8 weeks with pancytopenia will be 
considered DLT). Anemia will not be considered for the definition of DLT. 
 
                                                                                
Cohort B (Dasatinib) 
Eligible patients will receive dasatinib monotherapy at 100 mg orally once daily. This dose is lower 
than the FDA approved dose of 140 mg once daily for patients with Ph+ ALL. Several studies 
have reported safety of dasatinib 100 mg once daily dosing with chemotherapy for patients with 
Ph+ ALL and therefore there is no need for a Phase I part.50 Disease assessment with a bone 
marrow aspirate will be performed after cycle 0 (each cycle = 21 days). Patients having a response 
(CR, CRi, PR) can continue with dasatinib monotherapy. For patients that continue with 
monotherapy, the cycle will remain labelled as Cycle 0. For patients without a response, Hyper-
CVAD chemotherapy will be added to the dasatinib. Note: patients with clinically progressive 
disease earlier than day 21 assessment can start the Hyper-CVAD chemotherapy at an earlier time 
point. Steroids (up to 40mg/day of dexamethasone or equivalent for 4 days) and/or hydroxyurea 
are allowed for the first 2 weeks of the study period to control rapidly proliferating disease. Patients 
will undergo disease assessments with a bone marrow aspirate at the end of every cycle (disease 
assessment interval can be increased to every 2-3 cycles once the patient has achieved CR/CRi).  
For pediatric patients (<18 years of age) – the dasatinib dose will be 60 mg/m2 orally once daily 
(Maximum dose 100 mg daily). Please see Appendix 2 for the pediatric dosing table. 
 
 
 
 
5.0  
TREATMENTS ADMINISTERED 
 
5.1 
Ruxolitinib 


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 Ruxolitinib, previously referred as INCB018424 phosphate, is a substituted 
pyrrolopyrimidine compound that acts as a potent and selective inhibitor of the Janus kinase 
family of enzymes. Ruxolitinib is a novel, potent, and selective inhibitor of the JAKs with 
modest selectivity for JAK2. Ruxolitinib potently (IC50 values < 5 nM) inhibits JAKs, yet 
it does not significantly inhibit (<30% inhibition) a broad panel of 26 other kinases when 
tested at 200 nM (approximately 100 times the average IC50 value for JAK enzyme 
inhibition). Moreover, in cell-based assays relevant to the pathogenesis of MPDs, such as 
JAK-STAT signaling and the growth of cytokine-dependent lines, ruxolitinib demonstrated 
excellent potency (IC50 values of 80-141 nM). This effect was not due to general 
cytotoxicity, because ruxolitinib (up to 25 μM) had no significant effect on the growth of 
cytokine-independent cell lines transformed by the Bcr-Abl oncogene. In addition, 
ruxolitinib inhibited JAK/STAT signaling and growth of a cell line expressing the JAK2 
mutant variant (JAK2V617F) that has been implicated in the pathogenesis of the majority 
of Philadelphia chromosome negative MPD. Additional details as to the in vitro 
pharmacology of ruxolitinib may be found in the Investigator’s Brochure (IB) (Edition 12, 
Dated 11th September 2013 with safety cut-off date of 22nd July, 2013). 
 The chemical name of ruxolitinib is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
1Hpyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate. Ruxolitinib has a molecular 
formula of C17H21N6O4P and a molecular weight of 404.36.  
 Ruxolitinib drug product will be provided as 5mg or 25mg strength tablets. The tablet 
formulation contains the active ingredient along with commonly used excipients. All 
excipients are of compendia grade.  
 The medication will be provided for free to participants in this study by the manufacturer, 
Incyte Inc.  
 The 5 mg tablets are stable for six months at 40C/75% RH and at least 24 months at 
25C/60% RH. The 25 mg tablets are stable for six months at 40C/75% RH and at least 36 
months at 25C/60% RH. Additional details may be found in the Investigator’s Brochure 
(IB) (Edition 12, Dated 11th September 2013 with safety cut-off date of 22nd July, 2013). 
 Ruxolitinib will be administered twice daily orally, without regard to food.  
 Returned or expired study drugs will be destroyed per MDACC policy. 
 Prior to advancing/changing dose levels a cohort summary will be completed and submitted 
to the IND Medical Monitor for review and approval. 
 Dose modifications – For ruxolitinib related toxicities, the following dose modifications 
are proposed  
 
 
Dose level 
Ruxolitinib dose (Adults, 
Age ≥18 years) 
Ruxolitinib dose 
(Pediatric Patients, Age 
≥10 and <18 years) 


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-2 
5 mg twice daily 
2.9 mg/m2 twice daily 
(Max. 5 mg twice daily) 
-1 
10 mg twice daily 
5.9 mg/m2 twice daily 
(Max. 10 mg twice daily) 
1 (starting dose) 
15 mg twice daily 
8.8 mg/m2 twice daily 
(Max. 15 mg twice daily) 
2 
20 mg twice daily 
11.8 mg/m2 twice daily 
(Max. 20 mg twice daily) 
3 
25 mg twice daily 
14.7 mg/m2 twice daily 
(Max. 25 mg twice daily) 
     Please see Appendix 2 for the pediatric dosing table. 
5.2 
Dasatinib 
 Dasatinib is a multityrosine kinase inhibitor with activity against BCR-ABL, the SRC 
family of kinases (SFKs), c-KIT, EPHA2, and platelet derived growth factor (PDGFR-β) 
at nanomolar concentrations. 
 The 
chemical 
name 
for 
dasatinib 
is 
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-
hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, 
monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a 
formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight 
of 488.01. 
 Dasatinib is manufactured and distributed by Bristol-Myers Squibb.  
 It is approved for use in newly diagnosed patients with Philadelphia chromosome-positive 
(Ph+) chronic myeloid leukemia (CML) in chronic phase, patients with chronic, 
accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance 
to prior therapy including imatinib, and patients with Philadelphia chromosome-positive 
ALL.  
 Commercial supply of dasatinib will be used for this study. 
 Dasatinib will be administered once daily orally, without regard to food.  
 Returned or expired study drugs will be destroyed per MDACC policy. 
 Dose modifications – For dasatinib related toxicities, the following dose modifications are 
proposed  
 
 
 
 
Dose level 
Dasatinib dose (Adults, 
Age ≥18 years) 
Dasatinib dose (Pediatric 
Patients, Age ≥10 and <18 years) 
-3 
20 mg once daily 
11.8 mg/m2 orally once daily  


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(Max. 20 mg daily) 
-2 
50 mg once daily 
30 mg/m2 orally once daily  
(Max. 50 mg daily) 
-1 
70 mg once daily 
41.2 mg/m2 orally once daily  
(Max. 70 mg daily) 
1 (starting dose level)  
100 mg once daily 
60 mg/m2 orally once daily  
(Max. 100 mg daily) 
           Please see Appendix 2 for the pediatric dosing table. 
5.3  
Hyper-CVAD plus Rituximab regimen 
 Hyper-CVAD consists of 8 cycles of dose intensive therapy with hyper-CVAD (odd 
courses) alternating with high-dose methotrexate and cytarabine (even courses) 
administered approximately every 21 days (or later to allow for recovery from 
myelosuppression or infection).  
 Rituximab (anti-CD20 monoclonal antibody) will be administered to patients with 
leukemic blasts expressing CD20. Rituximab 375 mg/m2 days 1 and 11 (± 2) days for 
cycles 1 and 3, and days 1 and 8 (± 2) days for cycles 2 and 4.   
 Anti-emetic therapy with each course of intensive chemotherapy as indicated. 
 G-CSF 5 mcg/kg/day (rounded) within 72 ± 48 hours after completion of chemotherapy 
until neutrophil recovery 1 x 109/L or higher. G-CSF may be stopped earlier for bone pain 
or other related toxicity. Pegfilgrastim (given 6 mg subcutaneously for one dose 
approximately 24 hours after completion of the chemotherapy) may be substituted for G-
CSF at the discretion of the treating physician.  
 Prophylactic antibacterial antibiotics, antifungal agents, and antiviral agents are 
recommended for anti-infective prophylaxis during periods of neutropenia as per standard 
practice. Use of specific agents will be left to the treating physician’s discretion.  
 Next course may be started when granulocyte count > 1 x 109/L and platelet count > 50 x 
109/L, following discontinuation of G-CSF for at least 24 hours. Courses may be started 
with dose reductions of the chemotherapy prior to full count recovery if the treatment is 
delayed (e.g., 28 days or later from the start of last course) and the start of next course is 
deemed in the best interest of the patient by the treating physician. 
 Patients will be required to receive all chemotherapy treatments at MDACC. For the first 
two treatment courses, patients will be monitored at MDACC. Subsequently, the patients 
may obtain labs and be monitored by the local oncologist under directions by the treating 
physician at MDACC and/or study chair. To assure adequate monitoring of the study, the 
letter will be provided to the treating physicians. The participants must return to MDACC 
at least every 30 days for clinic visits and to obtain a new supply of ruxolitinib/dasatinib. 
PI/MDACC treating physician must review the lab results, determine clinical significance 
and sign and date the lab report. 


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 Central nervous system (CNS) management: Intrathecal and/or intra-Ommaya 
chemotherapy for CNS prophylaxis is permitted concurrently with the systemic 
chemotherapy.  Suggested regimen: intrathecal methotrexate 12 mg (6 mg via Ommaya 
reservoir) day 2 (± 2 days) and cytarabine 100 mg day 7 (± 2 days) of each of the first 4 
cycles of Hyper-CVAD chemotherapy. Total number of treatments for CNS prophylaxis 
should not exceed 8 (in the absence of CNS disease). Alternative regimens are permitted if 
deemed in the best interest of the patient according to discretion of the treating physician. 
 
If the patient develops active CNS disease while on study, the suggested CNS management 
is as follows: intrathecal and/or intra-Ommaya methotrexate alternating with cytarabine 
twice weekly until CSF clear; then once weekly for 4 weeks, then back to prophylaxis 
schedule. Radiotherapy for symptomatic CNS disease is allowed. 
5.4  
Hyper-CVAD (Courses 1, 3, 5, 7) 
 Cyclophosphamide (CTX) 300 mg/m2 IV over 3 hours every 12 hours x 6 doses days 1, 2, 
3 (total dose 1800 mg/m2). 
 MESNA 600 mg/m2/d IV continuous infusion daily for 24 hours days 1-3. 
 Doxorubicin 50 mg/m2 IV over 24 hours via central venous catheter on day 4, after last 
dose of CTX given (infuse over 48 hours in patients with reduced ejection fractions).  May 
be given by shorter infusion if difficulty with central venous access. 
 Vincristine 2 mg IV on day 4 (± 2) and day 11 (± 2 days). Vincristine is not 
myelosuppressive and will be given on day 11 while patients are receiving G-CSF; no 
known adverse effects have been observed with the two agents given together. For patients 
<18 years old, the vincristine dose will be 1.5mg/m2 with a maximum dose of 2mg. 
 Dexamethasone 40 mg IV or orally daily days 1-4 (± 2 days) and days 11-14 (± 2 days). 
For patients <18 years old, the dexamethasone dose will be 20mg/m2 with a maximum of 
40mg. 
 Rituximab 375 mg/m2 days 1 and 11 (± 2) days for cycles 1 and 3.   
 G-CSF 5 mcg/kg/day (rounded) within 72 ± 48 hours after completion of chemotherapy 
until neutrophil recovery 1 x 109/L or higher. G-CSF may be stopped earlier for bone pain 
or other related toxicity. Pegfilgrastim (given 6 mg subcutaneously for one dose 
approximately 24 hours after completion of the chemotherapy) may be substituted for G-
CSF at the discretion of the treating physician.  
 Next course may be started when granulocyte count > 1 x 109/L and platelet count > 50 x 
109/L, following discontinuation of G-CSF for at least 24 hours. Courses may be started 
with dose reductions of the chemotherapy prior to full count recovery if the treatment is 
delayed (e.g., 28 days or later from the start of last course) and the start of next course is 
deemed in the best interest of the patient by the treating physician. 
 CNS prophylaxis at the discretion of the treating physician. Suggested regimen:   
Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir) day 2 (± 2 days) and 
cytarabine 100 mg intrathecally or intra-Ommaya day 7 (± 2 days) during cycles 1 and 3. 


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Tumor lysis prophylaxis with allopurinol, intravenous alkalization, oral bicarbonate for 
course 1 as per standard practice.  Urate oxidase may be substituted for allopurinol.  
5.5  
Hyper-CVAD (Courses 2, 4, 6, 8) 
 Methotrexate (MTX) 200 mg/m2 IV over 2 hours followed by 800 mg/m2 IV over 22 hours 
day 1. 
 Solumedrol 50 mg IV over 2 hours approximately every 12 hours for 6 doses days 1-3. For 
patients <18 years old, the solumedrol dose will be 25mg/m2 with a maximum of 50mg. 
 Cytarabine 3 gm/m2 IV over 2 hours every 12 hours for 4 doses on days 2, 3.  
 Reduce the cytarabine to 1 gm/m2 IV over 2 hours every 12 hours for 4 doses days 2, 3 
for: 
o Age > 60 years 
o Creatinine > 1.5 mg/dL 
o Serum MTX level > 20 μM at time “0" (see below), confirmed on repeat sample 
o Neurotoxicity (grade 2 reversible cerebellar toxicity or other cytarabine- related 
CNS toxicity) with prior course.  
 Reduce the cytarabine to 1 gm/m2 IV continuous infusion days 2, 3 for: 
o Grade 2 reversible cerebellar toxicity related to ara-C 1 g/m2 or grade 3 
reversible cerebellar toxicity related to any dose of ara-C. 
 Leucovorin rescue 50 mg IV followed by 15 mg IV every 6 hours for 8 doses (or until MTX 
cleared) beginning 12 hours (± 2 hours) post MTX completion, e.g., approximately 36 
hours from start of MTX. Additional rescue allowed as indicated for elevated levels or 
delayed MTX clearance. For patients <18 years old, leucovorin will be given at 100mg/m2 
IV followed by 15mg/m2 IV every 6 hours for 8 doses (or until MTX cleared) beginning 
12 hours (± 2 hours) post MTX completion.  
 Check serum MTX levels around time 0 hour, 24 hours and 48 hours post completion of 
MTX unless cleared (e.g. 0.15 μM or less). 
o if > 20 μM at time “0", hold cytarabine and repeat level; if continues to be > 20 μM 
reduce cytarabine to 1 gm/m2 IV over 2 hours every 12 hours for 4 doses on days 
2, 3.  
o if > 1 μM at 24 hours or > 0.1 μM at 48 hours, increase leucovorin rescue until 
serum MTX level < 0.1 μM.  Clearance to levels 0.15 μM or less is acceptable in 
patients with normal renal function.  
o Consider oral acetazolamide 250 mg orally BID to promote MTX excretion if urine 
pH <7.0. 
 Rituximab 375 mg/m2 days 1 and 8 (± 2) days for cycles 2 and 4.   
 G-CSF 5 mcg/kg/day (rounded) within 72 ± 48 hours after completion of chemotherapy 
until neutrophil recovery 1 x 109/L or higher.  G-CSF may be stopped earlier for bone pain 
or other related toxicity. Pegfilgrastim (given 6 mg subcutaneously for one dose 


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approximately 24 hours after completion of the chemotherapy) may be substituted for G-
CSF at the discretion of the treating physician.  
 Next course may be started when granulocyte count > 1 x 109/L and platelet count > 50 x 
109/L, following discontinuation of G-CSF for at least 24 hours. Courses may be started 
with dose reductions of the chemotherapy prior to full count recovery if the treatment is 
delayed (e.g., 28 days or later from the start of last course) and the start of next course is 
deemed in the best interest of the patient by the treating physician. 
 CNS prophylaxis at the discretion of the treating physician. Suggested regimen:  
Methotrexate 12 mg intrathecally (6 mg via Ommaya reservoir) day 2 (± 2 days) and 
cytarabine 100 mg intrathecally or intra-Ommaya day 7 (± 2 days) during cycles 2 and 4. 
5.6  
Maintenance phase chemotherapy (POMP maintenance) 
 Patients may be moved from the intensive chemotherapy phase to the maintenance phase 
prior to completion of 8 cycles of chemotherapy if significantly intolerant or at the 
discretion of the treating physician after discussion with the Principal Investigator.   
 Maintenance chemotherapy with 6-mercaptopurine (6-MP), methotrexate (MTX), 
vincristine, and prednisone (POMP) for approximately 24 months beginning at level 0 (or 
lower dose level if previous toxicity warrants).  
 A maintenance cycle will be defined as 28 days.  
 6-mercaptopurine 50 mg tablets orally 3 times daily. For patients <18 years old, the 6-
mercaptopurine dose will be 75mg/m2 divided TID with a maximum dose of 150mg 
divided TID. 
 Methotrexate 20 mg/m2 (rounded) orally weekly  
 Vincristine 2 mg IV approximately every 28 days. For patients <18 years old, the 
vincristine dose will be 1.5mg/m2 with a maximum dose of 2mg. 
 Prednisone 200 mg P.O. daily days 1 to 5 approximately every 28 days, starting with 
vincristine (if given). For patients <18 years old, the prednisone dose will be 100mg/m2 
with a maximum dose of 200mg.  
 Note that dose adjustments of POMP (see section 5.7) are guidelines. Dose adjustments 
should be individualized to the patient, as differential toxicities between 6-mercaptopurine 
and methotrexate may be difficult to discern.  
 Dose adjustments for myelosuppression include MTX and 6-MP, but not vincristine or 
prednisone (the latter should remain 200 mg unless steroid myopathy or other uncontrolled 
significant toxicity occurs). Titrate to keep granulocytes >= 1 x 109/L and platelet count >= 
50 x 109/L. 
 Antiviral prophylaxis for herpes zoster is strongly encouraged.  
 Consider antifungal prophylaxis during days of prednisone.   
 Consider PCP prophylaxis. 


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 After completion of POMP maintenance, patients may continue ruxolitinib or dasatinib 
indefinitely, as long as they are responding to the treatment and without intolerable side-
effects.  
5.7  
Suggested dose modifications 
 Dose reductions for components beyond those specified in the protocol are permitted at the 
discretion of the treating physician.  Dose escalation beyond doses specified in the protocol 
is not permitted. 
 Cytarabine (ara-C) 
o Reduce to 1 gm/m2 IV over 2 hours every 12 hours for 4 doses on days 2, 3: 
 Age > 60 years. 
 Creatinine > 1.5 mg/dL.  
 Serum MTX level > 20 μM at time “0" (see below), confirmed on repeat sample.  
 Neurotoxicity (grade 2 reversible cerebellar toxicity or other cytarabine- related 
CNS toxicity) with prior course.  
o Reduce the cytarabine to 1 gm/m2 IV continuous infusion days 2, 3 for: 
 Grade 2 reversible cerebellar toxicity related to ara-C 1 g/m2 or grade 3 
reversible cerebellar toxicity related to any dose of ara-C. 
 Vincristine  
o Reduce to 1 mg IV (50% reduction). For patients <18 years old, reduce vincristine dose 
to 0.75mg/m2 with a maximum of 1 mg. 
 Total bilirubin > 2 mg/dL and < 3 mg/dL. 
 Grade 2 persistent peripheral neuropathy. 
 Eliminate for total bilirubin ≥ 3 mg/dL and/or grade 3-4 neurotoxicity 
(including ileus and/or peripheral neuropathy). 
 Doxorubicin  
o Reduce by 50% for total bilirubin 2 to ≤3 mg/dL 
o Reduce by 75% for total bilirubin 3.1 to ≤5 mg/dL.  
o Eliminate for total bilirubin level > 5 mg/dL. 
o Administer over 48 hours in patients with reduced (< 50%) ejection fractions. 
 Methotrexate (intravenous) 
o Reduce by 25%-50% for grade 3 or worse mucositis with prior MTX course. 
o Reduce by 50% for calculated creatinine clearance (GFR) 10 - 50 mL/min.   
o Hold MTX if GFR < 10 mL/min. 
o Reduce by 25% to 75% for delayed excretion and/or nephrotoxicity with prior 
methotrexate course. 
o Reduce by 50% for pleural effusion or ascites (drain effusion if possible). 
 Methotrexate (oral) 
o Decrease by one dose level for mucositis > grade 2 


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o Decrease by one dose level for total bilirubin > 2.5 mg/dL or elevation transaminases 
> 5 x upper limit normal 
o Hold if granulocyte count nadir < 0.5 x 109/L or platelet count < 10 x 109/L, resume 
with decrease in one dose level or lower depending on duration of cytopenias. 
 6-mercaptopurine 
o Decrease by one dose level for total bilirubin > 2.5 mg/dL or elevation transaminases 
> 5 x upper limit normal 
o Hold if granulocyte count nadir < 0.5 x 109/L or platelet count < 10 x 109/L, resume 
with decrease in one dose level or lower depending on duration of cytopenias. 
 For POMP maintenance - Dose adjustments for myelosuppression include MTX and 6-MP, 
but not vincristine or prednisone (the latter should remain 200 mg unless steroid myopathy 
or other uncontrolled significant toxicity occurs). Titrate to keep granulocytes >= 1 x 109/L 
and platelet count >= 50 x 109/L. 
 Suggested POMP maintenance dose levels: 
 
Dose  
Level 
 
MTX (mg/m2) 
(Rounded) 
 
6-MP 
(mg/d) 
 
VCR 
(mg) 
 
Prednisone 
(mg) 
0 
20 
150 
2 
200 
-1 
15 
100 
1 
100 
-2 
10 
50 
0 
50 
-3 
5 
50 
0 
0 
 
 Dosing modifications based on age and performance status will be permitted on cycles 1-8 
and maintenance intensifications. Suggested dose adjustments as below:  
 
 
 
<60 years 
60-74 years and 
PS 0-2 
>74 years; ≥60 
years and PS 3-4 
Cyclophosphamide (mg/m2) 
300 
250 
200 
Doxorubicin (mg/m2) 
50 
37.5 
25 
Vincristine (mg) 
2 
2 
1 
Dexamethasone (mg) 
40 
20 
20 
Methotrexate (mg/m2) 
200/800 
100/400 
50/100 
Cytarabine (g/m2) 
3 
1 
0.5 
NOTE: Age 60 – 64 with PS 0-1 may be treated with full doses (except for reduction of 
cytarabine to 1 g/m2) at the discretion of the treating physician 
 
 
6.0  
DOSE MODIFICATIONS FOR TOXICITIES 
 If drug-related grade 3 or 4 non-hematologic toxicity is attributable to ruxolitinib or 
dasatinib, dose interruption of that particular drug is required.  


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 Patients who experience grade 3 drug related non-hematological toxicity may be given a 
subsequent course one dose level below the previous course, but the patient must have 
recovered to grade </=1 before institution of the next course.  
 If a patient has drug-related grade 4 non-hematological toxicity, he/she may receive a 
subsequent courses at one reduced dose level after resolution of toxicity to grade </=1, only 
if approved by the Principal Investigator based on the clinical significance of the toxicity 
and only if patient has had derived a benefit from the therapy.  
 The dose of therapeutic agents can be decreased during a cycle, at the discretion of treating 
physician, for chronic grade 2 non-hematological toxicity.  
 Documentation of the reason(s) study drug is discontinued is required.  
 Other dose modifications may be considered as clinically indicated with documentation 
and approval of the PI.  
 Hematological toxicity - Cytopenias are common in the patient population studied in this 
trial. Dose interruptions or modifications will be made for Grade 4 hematological toxicities, 
only if the Investigator and the PI strongly feel that the cytopenias are related to ruxolitinib 
or dasatinib and not related to underlying disease or the use of Hyper-CVAD 
chemotherapy.     
 For patients experiencing toxicities thought to be related to ruxolitinib or dasatinib, the 
following dose adjustments schema will be used – 
 
Dose level 
Ruxolitinib dose (Adults, 
Age ≥18 years) 
Ruxolitinib dose 
(Pediatric Patients, Age 
≥10 and <18 years) 
-2 
5 mg twice daily 
2.9 mg/m2 twice daily 
(Max. 5 mg twice daily) 
-1 
10 mg twice daily 
5.9 mg/m2 twice daily 
(Max. 10 mg twice daily) 
1 (starting dose) 
15 mg twice daily 
8.8 mg/m2 twice daily 
(Max. 15 mg twice daily) 
2 
20 mg twice daily 
11.8 mg/m2 twice daily 
(Max. 20 mg twice daily) 
3 
25 mg twice daily 
14.7 mg/m2 twice daily 
(Max. 25 mg twice daily) 
 
 
 
 
Dose level 
Dasatinib dose (Adults, 
Age ≥18 years) 
Dasatinib dose (Pediatric 
Patients, Age ≥10 and <18 years) 


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-3 
20 mg once daily 
11.8 mg/m2 orally once daily  
(Max. 20 mg daily) 
-2 
50 mg once daily 
30 mg/m2 orally once daily  
(Max. 50 mg daily) 
-1 
70 mg once daily 
41.2 mg/m2 orally once daily  
(Max. 70 mg daily) 
1 (starting dose level)  
100 mg once daily 
60 mg/m2 orally once daily  
(Max. 100 mg daily) 
 
Please see Appendix 2 for the pediatric dosing table. 
 
7.0  
CONCOMITANT THERAPY 
All concomitant medications will be collected from day 1 through the safety reporting period. All 
supportive measures consistent with optimal patient care should be provided throughout the study 
according to the institutional standards.  
 Patients should be instructed not to take any additional medications (including over-the-
counter products) during the course of the study without prior consultation with the 
investigator and/or treating physician. At each visit, the patient should be asked about any 
new medications he/she is or has taken after the start of the study drug. All concomitant 
medications/significant non-drug therapies taken ≤ 30 days prior to start and after start of 
study drug should be recorded. 
 
 Ruxolitinib and dasatinib are predominantly metabolized by CYP3A4. Concurrent 
administration of ruxolitinib or dasatinib and strong CYP3A4 inhibitors (such as 
ketoconazole, fluconazole, itraconazole, ritonavir) and inducers (such as rifampin, 
rifabutin) should be avoided.  
 If there is no good alternative available for a strong CYP3A4 inhibitor, ruxolitinib and 
dasatinib dose should be reduced as described in the Prescribing Information for each drug 
and patients should be closely monitored for potential toxicities.  
 Grapefruit and grapefruit juice affect cytochrome P450 and P-glycoprotein activity and 
should therefore be avoided.  In addition, patients should avoid Seville oranges and star 
fruit, as well as the juice of these fruits, which are potent CYP3A4-inhibitors.  
 Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. Long-term 
suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (e.g., 
famotidine and omeprazole) is likely to reduce dasatinib exposure. The concomitant use of 
H2 antagonists or proton pump inhibitors with dasatinib is not recommended. The use of 
antacids (at least 2 hours prior to or 2 hours after the dose of dasatinib) should be considered 
in place of H2 antagonists or proton pump inhibitors. 


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7.1  
Allowed Concomitant Therapy 
Intrathecal chemotherapy for CNS prophylaxis/treatment is allowed. Radiotherapy for 
symptomatic CNS disease is allowed. The use of hematopoietic growth factors or 
transfusions is allowed. Steroids (up to 40mg/day for 4 days dexamethasone or equivalent) 
and hydroxyurea is allowed for the first 2 weeks of the study period to control rapidly 
proliferating disease.  
7.2  
Prohibited Concomitant Therapy  
Patients may not receive other investigational drugs, immunosuppressive medications 
(except as described in Section 7.1), radiotherapy (except as described in Section 7.1), or 
systemic anti-neoplastic therapy during the study. 
 
8.0  
PRETREATMENT EVALUATIONS 
Procedure 
Comments 
Schedule 
Informed Consent 
Obtain standard informed consent 
approved by the IRB 
Within 14 days of study start 
Background information 
History of present illness, prior cancer 
history as far as traceable, and relevant 
past medical/ surgical history 
Within 14 days of study start 
Physical examination 
Vital signs (temperature, heart rate, 
respiratory rate, blood pressure) and 
performance status (Zubrod) 
Within 14 days of study start 
Concomitant medications 
Document concomitant medications 
Within 14 days of study start 
Hematology  
WBC with differential, unless WBC <0.5 
x109/L in which case differential not 
needed, Hemoglobin, Platelet count 
Within 14 days of study start 
Biochemistry 
Sodium, chloride, potassium, bicarbonate, 
alanine aminotransferase (ALT), bilirubin 
total, creatinine, uric acid, LDH 
Within 14 days of study start 
Chest X-ray 
Evaluation of lung fields and pleural 
effusion 
Within 14 days of study start 
Pregnancy test 
Perform only in women of child-bearing 
potential. Pregnancy test can be done in 
either serum or urine. 
Within 14 days of study start 
Screening for Hepatitis B, 
Hepatitis C and HIV 
 
Within 30 days of study start 
Bone marrow 
Aspirate and/or bone marrow biopsy 
Within 30 days of study start  
Electrocardiogram 
12 lead ECG 
Within 30 days of study start 
MUGA scan or 
echocardiogram  
Evaluation of ejection fraction 
Within 30 days of study start 
Optional Correlative 
studies 
Refer to Section 14.0 for details 
  
 
 
 


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9.0  
EVALUATIONS DURING THE STUDY 
Procedure 
Comments 
Schedule 
Physical exam 
including toxicity 
assessment 
 
Weekly for cycle 0, then prior to each 
cycle 
Hematology  
CBC with differential (except 
when WBC less than 0.5), platelet 
count, hemoglobin 
Hematology will be performed 1 to 3 
times weekly during the cycle 0 and at 
least weekly thereafter during the 
intensive chemotherapy cycles. During 
the maintenance cycles, Hematology 
should be performed at least monthly 
(prior to the start of each cycle)       
Clinical Chemistry 
Sodium, chloride, potassium, 
bicarbonate, alanine 
aminotransferase (ALT), bilirubin 
total, creatinine, uric acid, LDH 
Clinical Chemistry will be performed 1 to 
3 times weekly during the cycle 0 and at 
least weekly thereafter during the 
intensive chemotherapy cycles. During 
the maintenance cycles, Clinical 
Chemistry should be performed at least 
monthly (prior to the start of each cycle)     
Bone Marrow 
Aspirate and/or bone marrow 
biopsy 
At the end of cycle 0 (before start of 
cycle 1), and then before each 
subsequent cycle. Note: once CR/CRi is 
achieved, bone marrow will repeated 
every 2-3 cycle, or as clinically indicated. 
 
For patients starting chemotherapy 
before the end of cycle 0, a marrow will 
be repeated prior to starting 
chemotherapy, unless there is a clear 
evidence of disease progression 
 
Consider repeating cytogenetic studies 
only if abnormal at start.  
 
No marrow aspiration is necessary to 
document response if clearly failing to 
respond or progressive disease is noted 
(e.g., circulating blasts).   
 
Chest X-ray 
Evaluation of lung fields and 
pleural effusion 
Prior to even number courses (2, 4, 6, 8) 
of chemotherapy regimen (i.e. courses 
with high-dose MTX and cytarabine)    
Optional Correlative 
studies 
Refer to Protocol Section 14.0 for 
details 
  
 
 
 
 
 
 


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10.0  STUDY CALENDAR 
 
 
Cycle 0 
C0D22 (C1D1) and at the start of 
each subsequent cycle 
HyperCVAD cycles 1-8 (3 days) 
Study 
Assessments1 
Screen2 
Day 
12 
Day 8  
(3 days) 
 
Day 
15 
(3 days) 
 
Continuation3 
 
Informed Consent 
X 
 
 
 
 
Baseline 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Concomitant 
Medications 
X 
Continuous 
Physical Exam 
X 
X 
X 
X 
 
X 
 
ECOG 
Performance 
Status 
X 
X 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
 
X 
 
 
X 
 
Weight 
X 
X 
 
 
X 
Height 
X 
 
 
 
 
Hematology, 
Clinical 
Chemistry4,5 
X 
X 
X 
 
X 
 
 
X 
 
Screening for 
Hepatitis B, 
Hepatitis C and 
HIV 
X7 
 
 
 
 
Pregnancy Test6 
X 
 
 
 
 
 
Chest x-ray  
X 
 
 
 
X8 
12-Lead ECG 
X7 
 
 
 
 
 
ECHO or MUGA 
X7 
 
 
 
 
Disease 
Assessment9 
X7 
 
 
 
X10 
Adverse Events 
 
Continuous 
Optional 
Correlative 
studies  
(PB and BM) 
X11 
 
 
 
X11 
1. 
Assessments scheduled on days of dosing should be done prior to administration of study drug(s), unless 
otherwise specified. 


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Cycle 0 
C0D22 (C1D1) and at the start of 
each subsequent cycle 
HyperCVAD cycles 1-8 (3 days) 
Study 
Assessments1 
Screen2 
Day 
12 
Day 8  
(3 days) 
 
Day 
15 
(3 days) 
 
Continuation3 
 
2. 
Within 14 days before first dose. Screening assessments can be used as day 1 assessments if done within 
72 hours. 
3. 
If clinically indicated, assessments during continuation period can occur more frequently. 
4. 
Hematology (WBC with differential, unless WBC <0.5 x109/L in which case differential not needed), 
Hemoglobin, Platelet count); Clinical Chemistry (sodium, chloride, potassium, bicarbonate, alanine 
aminotransferase (ALT), bilirubin total, creatinine, uric acid, LDH). 
5. 
Hematology and Clinical Chemistry will be performed 1 to 3 times weekly during the cycle 0 and at least 
weekly thereafter during the intensive chemotherapy cycles. During the maintenance cycles, Hematology and 
Clinical Chemistry should be performed at least monthly (prior to the start of each cycle) 
6. 
Perform only in women of child-bearing potential. Pregnancy test can be done in either serum or urine. 
7. 
Within 30 days of start of treatment 
8. 
Prior to even number courses (2, 4, 6, 8) of chemotherapy regimen (i.e. courses with high-dose MTX and 
cytarabine) 
9. 
Disease assessment by bone marrow samples (aspirate and/or biopsy) should be done at screening, end of 
cycle 0 (before start of cycle 1), and then before each subsequent cycle. Note: Once CR/CRi is achieved, 
bone marrow will repeated every 2-3 cycle, or as clinically indicated. 
10. Note: For patients starting chemotherapy before the end of cycle 0, a marrow will be repeated prior to starting 
chemotherapy, unless there is a clear evidence of disease progression 
11. Peripheral blood and bone marrow will be collected at baseline, at the end of cycle 0 before start of 
chemotherapy (or earlier if chemotherapy is added before the completion of cycle 0, i.e. before day 21), at 
the time of CR/CRi, and at the time of relapse.  
 
11.0  CRITERIA FOR RESPONSE 
 
Complete Response (CR)  
Disappearance of all clinical and/or radiologic evidence of disease  
Neutrophil count ≥ 1.0 x 109/L 
Platelet count ≥ 100 x 109/L 
Normal bone marrow differential (≤ 5% blasts) 
No extra-medullary leukemia 
 
Complete Remission with Incomplete Blood Count Recovery (CRi) 
CR except for ANC < 1.0 x 109/L and/or platelets < 100 x 109/L 
 
Partial Remission (PR) 
Blood count recovery as for CR, but with a ≥50% decrease in the percentage of marrow blasts to 
>5% to 25% in the bone marrow.  


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12.0  ADVERSE EVENT REPORTING 
Annual reports to the FDA will include a summary tabulation of adverse events by treatment 
cohort. 
12.1 
Leukemia-specific Adverse Event Recording and Reporting Guidelines 
These guidelines will be followed for the recording and reporting of adverse and serious 
adverse events. 
1. Baseline events will be recorded in the medical history section of the case report 
form and will include the terminology event name, grade, and start date of the 
event. 
a. Baseline events are any medical condition, symptom, or clinically 
significant lab abnormality present before the informed consent is signed 
i. Hematologic laboratory abnormalities will not be recorded as 
baseline events for patients with acute leukemia,  myelodysplastic 
syndrome, chronic lymphocytic leukemia, or chronic myeloid 
leukemia in blast phase. 
ii. If exact start date is unknown, month and year or year may be used 
as the start date of the baseline event. 
2. The maximum grade of the adverse event will be captured per course or protocol 
defined visit date. 
3. These adverse events will be recorded in the case report form: 
a. Any grade adverse event that is possibly, probably, or definitely related to 
the study drug(s). 
b. All serious adverse events regardless of attribution to the study drug(s). 
c. Any grade adverse event regardless of attribution to the study drug(s) that 
results in any dose modification. 
4. Hematologic adverse events will not be recorded or reported for studies in patients 
with acute leukemia,  myelodysplastic syndrome, chronic lymphocytic leukemia, 
or chronic myeloid leukemia in blast phase except for: 
a. Prolonged myelosuppression as defined by the NCI-CTCAE criteria 
specific for leukemia, e.g. marrow hypocellularity on day 42 or later (6 
weeks) from start of therapy without evidence of leukemia (< 5% blasts), or 
that results in dose modifications, interruptions or meets the protocol 
definition of DLT or SAE. 
5. Serious adverse events will be reported according to institutional policy. 
6. Protocol specific language regarding the recording and reporting of adverse and 
serious adverse events will be followed in the event of discordance between the 
protocol and Leukemia-specific adverse event recording and reporting guidelines. 
 


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12.1.4 Serious Adverse Event Reporting (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience 
as it occurred. It does not include an adverse experience that, had it occurred in a more 
severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization. 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 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 (21 CFR 312.32). 
Important medical events as defined above may also be considered serious adverse events.  
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND Office. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The University 
of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on 
Reporting Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in the 
protocol, all SAEs, expected or unexpected, must be reported to the IND Office, regardless of 
attribution (within 5 working days of knowledge of the event). 
 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event to 
the Safety Project Manager in the IND Office.   
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws consent. 
Serious adverse events must be followed until clinical recovery is complete and laboratory tests 


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have returned to baseline, progression of the event has stabilized, or there has been acceptable 
resolution of the event. 
 
Additionally, any serious adverse events that occur after the 30 day time period that are related 
to the study treatment must be reported to the IND Office. This may include the development of a 
secondary malignancy. 
 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, 
the sponsor’s guidelines, and Institutional Review Board policy. 
Investigator Communication with Supporting Companies: 
All events reported to FDA will also be reported to Incyte Pharmacovigilance representative at 
email address IncytePhvOpsIST@Incyte.com or fax to Telerx at 866-726-9234 as provided in the 
Research Agreement within 24 hours of reporting. A copy of the FDA report will also be sent to 
the Incyte Pharmacovigilance representative as is in other MD Anderson Incyte funded protocols.   
13.0  DISCONTINUATION OF STUDY TREATMENT 
A patient’s treatment with study drugs may be discontinued for any of the following reasons: 
 Clinically significant progressive disease 
 Failure to achieve CR, CRi or PR after a maximum of 2 induction courses. Patients may 
continue therapy if deriving clinical benefit after discussion with the Principal Investigator  
 Adverse events that are not manageable with dose adjustments and/or optimal medical 
management, or that, in the opinion of the investigator, pose an unacceptable risk for the 
patient  
 Non-compliance with protocol requirements 
 Patient’s death 
 Investigator decision 
 Patient decision (e.g., withdrawal of consent) 
Patients who discontinue the study treatments will have a follow-up visit 30 days (± 10 days) after 
the last dose of the study drugs. For patients who cannot come for the clinic visit, a phone call to 
assess for any side-effects will be done. 


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14.0  BIOMARKER STUDIES 
Collection of research samples will be optional for all patients. Peripheral blood (30 cc) and bone 
marrow (5 cc) samples will be collected at baseline, at the end of cycle 0 before start of 
chemotherapy (or earlier if chemotherapy is added before the completion of cycle 0, i.e. before 
day 21), at the time of CR/CRi, and at the time of relapse. All samples are placed on ice 
immediately after sample collection. These samples will be stored and processed as following: (1) 
phospho-signaling studies to assess for modulation of JAK-STAT and cytokine receptor signaling, 
using multiparametric flow cytometry (to be performed in Dr. Marina Konopleva’s lab); (2) RNA 
sequencing analysis; (3) proteomics profiling; (4) sample storage for xenografting into 
immunodeficient mice. For xenografting analysis, in Konopleva lab or in the lab of our 
collaborator Sarah Tasian. For Dr. Tasian, de-identified samples will be shipped to Tasian 
Laboratory, Attn: JP Loftus, Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, 
CTRB 3100, Philadelphia 19104; (5) testing of novel agents or combinations in the in vivo 
generated PDX models.  We will also collect remission peripheral blood samples and store these 
as non-tumor DNA, for possible validation of novel mutations by targeted DNA sequencing.  
Additional Optional Pharmacodynamic Assessments. Any leftover sample will be stored for 
possible additional exploratory pharmacogenetic evaluations. Samples will be stored in Dr. 
Konopleva’s lab.   
 
15.0  STATISTICAL CONSIDERATIONS 
It is expected that a maximum total of 92 Ph-like ALL patients will be enrolled in this phase I-II 
study. 18 patients in the phase I study for ruxolitinib cohort (Cohort A), and 40 patients will be 
enrolled in each of the cohorts in phase II portion (for cohort A, 6 patients treated in the MTD 
level in phase I will be included in the phase II). 
 
Phase I 
The primary objective of the phase I portion of the study is to determine the MTD for ruxolitinib 
in combination with chemotherapy in patients with Ph-like ALL. The 3+3 algorithm in the 
following table will be used to guide dose escalation/de-escalation. Dose limited toxicities (DLTs) 
in ruxolitinib monotherapy and in the first cycle of the combination treatment will be used for dose 
escalation. The MTD is defined as the highest dose level at which no more than 1 out of 6 patients 
experience a DLT.  Once the MTD is determined, phase II portion for the ruxolitinib cohort will 
start. For this phase I study, a maximum of 18 patients will be enrolled. The 6 patients treated at 
the MTD dose level will be included in the phase II portion of this cohort.  
 
 
 
 
 
 


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Table: 3+3 algorithm for guidance of dose escalation 
Number of patients with DLT 
at a given dose 
Escalation Decision Rule 
0 out of 3 
Enter 3  patients at the next higher dose level 
 
 
 
 
 
1 out of 3 
Enter 3 additional patients at this dose level 
 
 
If 0 of these 3 patients experience DLT, proceed 
to the next higher dose level. 
 
 
 If 1 or more of this group suffer DLT, this dose 
exceeds the MTD and dose escalation is stopped. 
Three (3) additional patients will be entered at the 
next lower dose level if only 3 patients were 
treated previously at that dose level. 
 
≥2  
Three (3) additional patients will be entered at the next 
lower dose level if only 3 patients were treated previously 
at that dose. 
MTD: The highest dose at which no more that 1 of 6 patients has had a DLT. Six patients 
should be treated before the dose is declared MTD 
  
Phase II 
It is expected that a maximum total of 80 Ph-like ALL patients will be enrolled in this phase II 
portion of the study with 40 patients being in each of the cohorts, cohort A (up to 34 additional 
patients in cohort A by including 6 patients treated at the MTD in the phase I portion of the study) 
and cohort B (Table 1), with the expectation of 34 patients having assessments of the response. 
Patients who drop out of study early without completing cycle 2 due to excessive toxicity or 
progressed disease/death will be counted as treatment failure for the primary efficacy analysis. 
Otherwise patients who drop out of study early without completing cycle 2 and without the 
response evaluated due to other reasons will be replaced. All patients will be registered through 
the Clinical Oncology Research System (CORe) at MDACC, and the estimated accrual rate is 
approximately 2 patients per month. A patient will be considered as having cycle 2 completed if 
the patient is available for the assessment of response (section 11) at the end of cycle 2. 
The primary objective of this study is to assess efficacy in terms of complete response (CR/CRi) 
during the first 2 cycles. The Optimum two-stage design proposed by Simon57 will be implemented 
in each of the cohorts separately. For each cohort, a target CR/CRi of 25% will be assumed and a 
CR/CRi of 10% or lower will be considered as not desirable. The type I error and power will be 
set to 0.10 and 0.80 respectively. Under these specifications, we will enroll 13 patients, and will 
not enroll new patients until enough responders are observed to warrant further enrollment within 


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each cohort. If some patients among these 13 patients do not have assessments of the response, we 
will continue the accrual to replace such patients. The evaluation of the efficacy in the first stage 
will be performed when the first 13 patients have assessments of the response within each cohort. 
If no more than 1 patient out of these 13 patients achieves CR/CRi within a cohort, then the 
enrollment of patients into that cohort will be halted. If 2 or more out of these 13 patients achieve 
CR/CRi, then the accrual will continue until a total of 34 patients have been enrolled within each 
cohort. If some patients among these 34 patients do not have assessments of the response, we will 
continue the accrual to replace such patients. The evaluation in the second stage will be performed 
when the first 34 patients within each cohort have assessments of the response. For each cohort, if 
6 or more out of these 34 patients achieve CR/CRi, the treatment of that cohort will be considered 
efficacious and is worth further investigation. Under this criteria based on the Simon’s Optimum 
two-stage design, the per-cohort probability of early termination is 62% if the true ORR is 10% 
and the expected sample size is 21 patients for each cohort. Considering potential loss to follow-
up, a maximum total of 40 patients will be enrolled in each cohort.   
The method of Thall, Simon and Estey58 will be used for toxicity monitoring for this study. 
Toxicity will be monitored among the 40 patients for each cohort. Denote the probability of 
toxicity by p(T), where toxicity is defined as any ruxolitinib- related or dasatinib-related grade 4-
5 anemia, neutropenia or thrombocytopenia lasting more than 14 days or grade 3-5 organ toxicity 
(neurologic, pulmonary, cardiac, gastrointestinal, genitourinary, renal, hepatic, cutaneous) and 
occurs anytime during the treatment. We assume as a priori, p(T) ~ beta (0.6, 1.4).  We will stop 
the trial if Pr(p(T)> 0.30 | data)  >0.8. That is, we will stop the trial for new patient enrollment if 
at any time during the study that there is more than 80% chance that the toxicity rate is more than 
30%. This toxicity stopping monitoring rule will be applied by cohort size of 5, starting from the 
5th patient. Stopping boundaries corresponding to this stopping monitoring rule are listed in Table 
2. The operating characteristics are summarized in Table 3. Multc Lean Desktop (version 2.1) was 
used to generate the toxicity stopping boundaries and the OC table.  
Table 2.  Early stopping boundaries for toxicity monitoring 
# of patients ( in cohort size of 
5, starting from the 5th  patient) 
Stop the trial if there are this many 
patients with toxicities:  
5 
3-5 
10 
5-10 
15 
7-15 
20 
8-20 
25 
10-25 
30 
12-30 
35 
13-35 
 
Table 3. Operating characteristics for toxicity monitoring  


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True toxicity rate 
Prob(stop the trial early) 
Average sample size 
0.20 
0.10 
37.09 
0.25 
0.22 
33.98 
0.30 
0.40 
29.50 
0.35 
0.62 
24.18 
0.40 
0.80 
18.96 
 
Since there is little evidence to suggest that single-agent dasatinib or single-agent ruxolitinib would 
be expected to be of benefit in the treatment of patients with relapsed or refractory ALL, a futility 
monitoring for the monotherapy part in each cohort will be performed. Specifically, we will take 
three looks when every 10 patients are enrolled and evaluated for the single agent cycle within 
each cohort. For each look, if more than 20% of cumulative subjects’ progress during cycle 0, the 
single-agent cycle will be deleted from the cohort. 
 
15.1  Analysis Plan 
Summary statistics will be provided for continuous variables. Frequency tables will be used to 
summarize categorical variables.  The response rate (CR/CRi) will be estimated along with the 
confidence interval in each cohort. The estimation will be performed in 34 patients who are 
included for the two stage design, and also in all patients who received any treatment by counting 
patients who drop out the study early without evaluation of the primary outcome as treatment 
failures. Data from all subjects who receive any study drug will be included in the safety analyses. 
Subjects who enter the study and do not take any of the study drugs and have this confirmed will 
not be evaluated for safety. The severity of the toxicities will be graded according to the NCI 
CTCAE v4.0 whenever possible. We will follow standard reporting guidelines for adverse events. 
Safety data will be summarized by category, severity and frequency. Time to event outcomes 
including duration of response and progression-free survival will be estimated using the Kaplan-
Meier method, and the association of the time to event outcomes with patient characteristics will 
be evaluated using the log rank test and Cox proportional hazards regression analysis. 
 
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Appendix 1: Inhibitors and Inducers of CYP3A4/5 
Inhibitors of CYP3A4/5 are defined as follows. A comprehensive list of inhibitors can be found 
at the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx.  The general 
categorization into strong, moderate, and weak inhibitors according to the website is displayed 
below.  
Inhibitors of CYP3A4/5 
Inducers of CYP3A4/5 
Strong inhibitors: 
INDINAVIR 
NELFINAVIR 
RITONAVIR 
CLARITHROMYCIN 
ITRACONAZOLE 
KETOCONAZOLE 
NEFAZODONE 
SAQUINAVIR 
SUBOXONE 
TELITHROMYCIN 
Moderate inhibitors: 
aprepitant 
erythromycin 
diltiazem   
fluconazole  
grapefruit juice 
Seville orange juice 
verapamil 
Weak inhibitors: 
cimetidine 
All other inhibitors: 
amiodarone    
NOT azithromycin 
chloramphenicol 
boceprevir 
ciprofloxacin 
delaviridine 
diethyl-dithiocarbamate 
Carbamazepine 
Efavirenz 
Nevirapine 
Barbiturates 
Glucocorticoids 
Modafinil 
Oxcarbarzepine 
Phenobarbital 
Phenytoin 
Pioglitazone 
Rifabutin 
Rifampin 
St. John’s Wort 
Troglitazone 
fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin 
norfluoxetine 
star fruit 
telaprevir 
voriconazole 
 
Source:  http://medicine.iupui.edu/clinpharm/ddis/table.aspx 


 
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Appendix 2: Dosing Chart for Pediatric Patients 
DOSING CHART FOR PEDIATRIC PATIENTS 
 
Ruxolitinib (5mg tablets) 
BSA 
Dose level 3 
Dose level 2 
Dose level 1 
Dose level -1 
Dose level -2 
  
  
 14.7 mg/m2 
twice daily 
 11.8 mg/m2 twice 
daily 
 8.8 mg/m2 twice 
daily 
 5.9 mg/m2 twice daily 
 2.9 mg/m2 twice 
daily (5.8 
mg/m2/day) 
low 
BSA 
high 
BSA 
Dose  
Dose 
Dose  
Dose  
Dose 
0.8 
0.92 
10mg AM / 15mg 
PM 
10mg twice daily 
5mg AM / 10mg PM 
5mg twice daily 
5mg daily 
0.93 
1.05 
15mg twice daily 
10mg AM / 15mg PM 
5mg AM/ 10mg PM 
5mg twice daily 
5mg daily 
1.06 
1.18 
15mg AM / 20mg 
PM 
10mg AM / 15mg PM 
10mg twice daily 
5mg AM / 10mg PM 
10mg daily MWF / 
5mg daily TThSaSu 
1.19 
1.31 
15mg AM/ 20mg 
PM 
15mg twice daily 
10mg twice daily 
5mg AM / 10mg PM 
10mg daily MWF / 
5mg daily TThSaSu 
1.32 
1.44 
20mg twice daily 
15mg AM / 20mg PM 
10mg AM/ 15mg PM 
5mg AM / 10mg PM 
5mg daily MWF / 
10mg daily TThSaSu 
1.45 
1.57 
20mg AM / 25mg 
PM 
15mg AM / 20mg PM 
10mg AM / 15mg PM 
10mg twice daily 
5mg twice daily or 
10mg daily 
1.58 
1.73 
25mg twice daily 
20mg twice daily 
15mg twice daily 
10mg twice daily 
5mg twice daily or 
10mg daily 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Dasatinib (20mg, 50mg, 70mg, 100mg tablets) 
 
BSA 
Dose level 1 
Dose level -1 
Dose level -2 
Dose level -3 
 
  
  
 60 mg/m2 daily 
41.2 mg/m2 daily 
(288.4mg/m2/week) 
30 mg/m2 daily 
(210mg/m2/week) 
11.8 mg/m2 daily 
(82.6mg/m2/week) 
 
low 
BSA 
high 
BSA 
Dose  
Dose  
Dose  
Dose 
 
0.8 
0.92 
50mg daily 
20mg MWF / 40mg TThSaSu 
20mg M-F / 40mg SaSu 
20mg TThSaSu only 
 
0.93 
1.05 
60mg daily 
40mg daily 
20mg MWF / 40mg TThSaSu 
20mg TThSaSu only 
 
1.06 
1.18 
70mg daily 
40mg MWF / 50mg TThSaSu 
40mg M-F / 20mg SaSu 
20mg M-F only 
 
1.19 
1.31 
80mg daily 
50mg daily 
40mg daily 
20mg M-F only 
 
1.32 
1.44 
80mg daily 
50mg MWF / 60mg TThSaSu 
40mg daily 
20mg M-Sa only 
 
1.45 
1.57 
90mg daily 
60mg daily 
40mg MWF / 50mg TThSaSu 
20mg daily 
 
1.58 
1.73 
100mg daily 
70mg daily 
50mg daily 
20mg daily 
 
MWF: Monday, Wednesday, Friday;  SaSu: Saturday, Sunday;  M‐F: Monday through Friday;  TThSaSu: Tuesday, Thursday, Saturday, Sunday;  M‐Sa: Monday 
through Saturday