RAVEN: A Phase I/II Trial Treating Relapsed Acute Lymphoblastic Leukemia With Venetoclax and Navitoclax
Phase: PHASE1
Conditions: Refractory Acute Lymphoblastic Leukemia, Relapsed Acute Lymphoblastic Leukemia
Sponsor: St. Jude Children's Research Hospital



RAVEN
Amendment 3.0, dated: 01-16-2024
Protocol document date: 01-16-2024
Protocol Summary
RAVEN: A PHASE I/II TRIAL TREATING RELAPSED ACUTE LYMPHOBLASTIC 
LEUKEMIA WITH VENETOCLAX AND NAVITOCLAX 
Principal Investigator: Seth E. Karol, MD 
Institution/Sponsor-IND holder: St. Jude Children’s Research Hospital. IND# 157865
Brief overview: This is a Phase I/II clinical trial. In Block I, all patients receiving common therapy 
evaluating the activity of combination chemotherapy with venetoclax and navitoclax in children with 
relapsed or refractory acute lymphoblastic leukemia or lymphoma (rALL). In Block 2, a phase 1 
rolling six design and phase 2 extension will be used to assess the combination dose of venetoclax 
combinations with either blinatumomab for CD19-postive patients or navitoclax and high-dose 
cytarabine for CD19-negative patients.
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RAVEN
Amendment 3.0, dated: 01-16-2024
Protocol document date: 01-16-2024
RAVEN: A PHASE I/II TRIAL TREATING RELAPSED ACUTE LYMPHOBLASTIC 
LEUKEMIA WITH VENETOCLAX AND NAVITOCLAX 
Intervention: 
Block 1:
Venetoclax 120mg/m2 (max 200mg) PO D1; 240mg/m2 (max 400mg) PO D2-22
Navitoclax 25mg (20-44.9kg) OR 50mg (>=45kg) D3-22
Dexamethasone 5mg/m2/dose PO BID D1-7, 15-22
Vincristine 1.5mg/m2/dose (max 2mg) IV D1, 8, 15, 22
Calaspargase pegol 2500units/m2 IV/ D2
Intrathecal chemotherapy: LPIT D -7 to 1, then weekly until clear if CNS+
Dasatinib 80mg/m2/day (max 140mg) QD/PO D1-28 for ABL-fusion-positive and T-cell
Block 2a (CD19 negative):
Venetoclax 240mg/m2 (max 400mg) PO D1-7
Navitoclax 25mg (20-44.9kg) OR 50mg (>=45kg) PO D1-7
Dexamethasone 3mg/m2/dose PO BID D1-5
Calaspargase pegol 1000units/m2 IV/ D3
Dasatinib 80mg/m2/day (max 140mg) QD/PO D1-28 for ABL-fusion-positive and T-cell
Cytarabine dosing during phase 1 portion for Block 2a
Dose level
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
1
3000mg/m2/dose q12h IV 
infusion over 3 hours 
4
Days 1-2
0
1500mg/m2/dose q12h IV 
infusion over 3 hours 
4
Days 1-2
-1
1000mg/m2/dose q12h IV 
infusion over 3 hours 
2
Day 1
Block 2b (CD19 positive):
Blinatumomab 5mcg/m2/day D1-7 (max 9mcg/day) IV (if Block 1 MRD>5%)
Blinatumomab 15mcg/m2/day (max 28mcg/day) IV D8-28 (if Block 1 MRD >5%)
Blinatumomab 15mcg/m2/day (max 28mcg/day) IV D1-28 (if Block 1 MRD ≤5%)
Dexamethasone 10mg/m2 (max 20mg) PO/IV 6-12 hrs. and 5mg/m2 30 min prior to blinatumomab 
Day 1
Dasatinib 80mg/m2/day (max 140mg) QD/PO D1-28 for ABL-fusion-positive
Venetoclax dosing during phase 1 portion for Block 2b
Dose 
level
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
1
240mg/m2 (max 400mg) PO 
21
Days 8-28
0
240mg/m2 (max 400mg) PO 
14
Days 8-21
-1
240mg/m2 (max 400mg) PO 
7
Days 8-14
Brief outline of treatment plan: Patients will receive therapy as described in the intervention. 
Response evaluation will be performed on Day 29 of Block 1. MRD-negative (<0.01%) patients will 
await ANC recovery to 500/µL or 14 days, whichever is shorter, before proceeding to Block 2 
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RAVEN
Amendment 3.0, dated: 01-16-2024
Protocol document date: 01-16-2024
RAVEN: A PHASE I/II TRIAL TREATING RELAPSED ACUTE LYMPHOBLASTIC 
LEUKEMIA WITH VENETOCLAX AND NAVITOCLAX 
therapy. Patients who are MRD positive proceed to Block 2 therapy without awaiting hematological 
recovery. 
Patients receiving Block 2b therapy will begin venetoclax according to the current dose level. 
Venetoclax may be held if the peripheral absolute lymphocyte count is <300/microL or the ANC is 
<500/microL. Response evaluation following Block 2 therapy will occur with count recovery.
Following Block 2 of therapy, late (≥36 months from diagnosis) first relapse B-ALL who are MRD 
negative after Block 1 will continue chemotherapy using adapted R3 intensification, interim, and 
continuation therapies. Other patients are off therapy for alternative therapy including cellular 
therapy/ transplant.
Study design: Multi-center non-randomized phase I/II trial with a common Block 1 therapy and 
biologically-determined Block 2 therapy utilizing a rolling six dose finding phase I followed by a 
phase II extension.
Sample size: We anticipate 78 enrollees to yield 70 research participants evaluable for Block 1 
response. We also anticipate that additional patients may enroll on exploratory cohorts to assess 
therapy in specific populations or with specific therapy modifications. This will not exceed 20 patients 
in total with no more than 8 patients >21.99 years old.
Data management: Data management and statistical analysis will be provided by the Comprehensive 
Cancer Center Hematological Malignancies Program and the Biostatistics Department at St. Jude 
Children’s Research Hospital.
Human subjects: The risks to subject will be related to the toxicity of therapy for relapsed ALL and 
the investigational agents venetoclax and navitoclax. The research participants will be informed of 
the toxicities that have been associated with the study drugs and potential side effects of procedures 
recommended in this study. Adverse events will be monitored, treated, and reported following 
institutional and federal guidelines and regulations.
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Protocol document date: 01-16-2024
TABLE OF CONTENTS
1.0
OBJECTIVES..........................................................................................................1
1.1
Primary Objective.........................................................................................................................1
1.2
Secondary Objectives...................................................................................................................1
1.3
Exploratory Objectives.................................................................................................................1
2.0
BACKGROUND AND RATIONALE .......................................................................1
2.1
Background....................................................................................................................................1
2.2
Study Plan Rationale ....................................................................................................................8
2.3
Background and Rationale for Ancillary and Exploratory Studies ......................................10
3.0
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT .......................................11
3.1
Inclusion Criteria ........................................................................................................................11
3.2
Exclusion Criteria .......................................................................................................................14
3.3
Definitions ...................................................................................................................................14
3.4
Research Participant Recruitment and Screening ...................................................................17
3.5
Enrollment on Study at St. Jude................................................................................................17
3.6
Enrollment on Study for Affiliate Sites Sharing St. Jude Participants.................................17
3.7
Enrollment on Study at Collaborating Sites ............................................................................17
4.0
TREATMENT PLAN.............................................................................................19
4.1
Design and Study Overview......................................................................................................19
4.2
Treatment Administration and Schedule..................................................................................20
5.0
Dose Modifications and Supportive Care..................................................................28
5.1
Dose Modifications during Continuation Treatment..............................................................28
5.2
Dose Modifications for Agent-Specific Toxicity....................................................................29
6.0
DRUG INFORMATION.........................................................................................38
6.1
Venetoclax (ABT-199)...............................................................................................................38
6.2
Navitoclax....................................................................................................................................39
6.3
Dexamethasone ...........................................................................................................................39
6.4
Vincristine....................................................................................................................................40
6.5
Pegaspargase................................................................................................................................41
6.6
Erwinia asparaginase..................................................................................................................42
6.7
Calaspargase Pegol .....................................................................................................................44
6.8
Methotrexate................................................................................................................................45
6.9
Dasatinib ......................................................................................................................................47
6.10
Blinatumomab .............................................................................................................................48
6.11
Cyclophosphamide .....................................................................................................................48
6.12
Etoposide......................................................................................................................................49
6.13
Leucovorin...................................................................................................................................50
6.14
Mercaptopurine ...........................................................................................................................51
6.15
Intrathecal Triples .......................................................................................................................52
6.16
Cytarabine………………………………………………………………………………..55
7.0
EVALUATIONS, TESTS, OBSERVATIONS.................................................................53
7.1
Pre-Treatment Clinical Evaluations..........................................................................................53
7.2
Evaluations during Therapy – all Participants ........................................................................55
7.3
Evaluations for Late Relapsing B-ALL Participants Receiving Therapy After Protocol 
Block 2 ......................................................................................................................................................56
7.4
Evaluations after Completion of Therapy................................................................................56
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8.0
EVALUATION CRITERIA....................................................................................57
8.1
Response Criteria........................................................................................................................57
8.2
Toxicity Evaluation Criteria ......................................................................................................57
8.3
Breakthrough Infections during Treatment..............................................................................57
8.4
Acceptable Percentage of Missed Doses for Drugs................................................................57
9.0
OFF-TREATMENT AND OFF-STUDY CRITERIA ................................................57
9.1
Off-Treatment Criteria ...............................................................................................................57
9.2
Off-Study Criteria.......................................................................................................................58
10.0
SAFETY AND ADVERSE EVENT REPORTING requirements................................58
10.1
Reporting Adverse Experiences and Deaths ...........................................................................58
10.2
Reporting to Regulatory Affairs Office and FDA ..................................................................61
10.3
Reporting to Drug Manufacturer (AbbVie, Inc.) ....................................................................62
10.4
Recording Adverse Events and Serious Adverse Events.......................................................62
10.5
Process for Reporting Adverse Events from and to Collaborating Sites .............................63
11.0
DATA COLLECTION, MONITORING AND CONFIDENTIALITY ........................64
11.1
Data Collection............................................................................................................................64
11.2
Study Monitoring........................................................................................................................64
11.3
Confidentiality.............................................................................................................................65
12.0
STATISTICAL CONSIDERATIONS......................................................................65
12.1
Total Sample Size and Accrual .................................................................................................65
12.2
Primary Objectives .....................................................................................................................66
12.3
Secondary Objectives.................................................................................................................72
12.4
Exploratory Objectives...............................................................................................................77
12.5
Anticipated Completion Dates ..................................................................................................79
13.0
OBTAINING INFORMED CONSENT....................................................................79
13.1
Consent Prior to Research Interventions..................................................................................79
13.2
Consent at Age of Majority .......................................................................................................79
13.3
Consent When English is Not the Primary Language............................................................79
14.0
REFERENCES ......................................................................................................80
APPENDICES
Appendix I: Performance Status Criteria
Appendix II: Sample Processing
Appendix III: CYP3A Inducers and Inhibitors
Appendix IV: Venetoclax Dose Adjustments with CYP3A Inhibitors
Appendix V: List of changes in amendments
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1.0
OBJECTIVES
1.1
Primary Objective
1.1.1
To compare MRD-negative CR/CRi rate in children with relapsed or refractory 
acute lymphoblastic leukemia or lymphoma (rALL) following Block 1 therapy with 
venetoclax and navitoclax based reinduction to historical controls.
1.1.2
To identify the recommended phase 2 combination dose (RP2D) of venetoclax 
based consolidation in novel combinations with a) high-dose cytarabine and 
navitoclax or b) blinatumomab.
1.2
Secondary Objectives
1.2.1
To estimate the tolerability and activity of venetoclax based consolidation in novel 
combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab.
1.2.2
To describe event-free and overall survival in patients treated with this regimen.
1.3
Exploratory Objectives
1.3.1
To evaluate MRD-negative CR/CRi rates in each prespecified groups: late first 
relapse B-ALL; early first relapse and second or greater relapse B-ALL; and 
relapsed T-ALL.
1.3.2
To identify drug sensitivity patterns in patient samples prior to and after receiving 
combination therapy and evaluate mechanisms of disease resistance/ escape.
1.3.3
To explore immune subsets during and after this regimen.
1.3.4
Evaluate response to therapy in rare relapse patient subsets.
1.3.5
Explore breakthrough infections in children and young adults with relapsed or 
refractory ALL
2.0
BACKGROUND AND RATIONALE
2.1
Background
2.1.1
Relapsed Acute Lymphoblastic Leukemia/Lymphoma
Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood.1 
While frontline therapy for children with newly diagnosed ALL will cure the majority of 
patients, 10-20% of children with ALL will relapse.2-6 The outcome for children with 
relapsed ALL (rALL) is generally poor and varies by site and timing of relapse as well as 
immunophenotype, with very early relapse (<18 months from diagnosis) and early (18-36 
months from diagnosis) relapses, medullary relapse (compared to isolated extramedullary 
relapse), and T-ALL relapse faring even more poorly.7,8 These poor outcomes are reflected 
in both early disease clearance as determined by end of induction minimal residual disease 
(MRD) as well as survival. Survival rates for 1) late (≥36 months from diagnosis) or 
isolated extramedullary, 2) early, and 3) very early or T-cell marrow relapse approximate 
60, 30, and 25%, respectively.9 Patients with relapsed ALL have chemotherapeutic 
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resistance which results in both initial and retrieval treatment failure and have outcomes 
inferior to those of patients with newly diagnosed ALL.10-12 
Intensification of chemotherapy accompanied by hematopoietic cell transplantation (for 
patients with either early relapse or residual disease after induction) is the current standard 
of care, with combination chemotherapy in first reinduction including a glucocorticoid 
(dexamethasone or prednisone), vincristine, asparaginase, and an anthracycline 
(doxorubicin or mitoxantrone).8,13-15 For patients with B-cell precursor ALL (B-ALL), 
early (or very early) marrow relapse, or detectable residual disease (positive-MRD) after 
induction, transplantation after achieving an MRD-negative remission is the standard of 
care. 
Two standard of care regimens are most frequently employed in the United States. The 
UKALL R3 regimen, which was also utilized in the recently completed AALL1331 trial,16 
utilizes 
high-dose 
dexamethasone 
(20mg/m2), 
vincristine, 
pegaspargase, 
and 
mitoxantrone.8 The Children’s Oncology Group (COG) AALL01P2 trial replaced 
dexamethasone with prednisone and mitoxantrone with doxorubicin in efforts to reduce 
toxicity.14 Typical therapy involves a 4-drug induction (as described above) followed by 2 
consolidation 
blocks 
including 
intermediate- 
or 
high-dose 
methotrexate, 
cyclophosphamide, etoposide (Block 2) and high-dose cytarabine and asparaginase (Block 
3). For patients with B-ALL who experience a late relapse and are MRD-negative after 
Block 1, continued chemotherapy with continuation and maintenance therapy after the 
completion of the induction and 2 consolidation blocks are standard. Total therapy for these 
patients lasts 2 years from the beginning of reinduction for relapsed disease.
Despite therapy intensifications, many patients still experience reinduction failure and few 
achieve MRD-negative remissions after induction Block 1 (Table 1). MRD-negative 
remission, in which fewer than 0.01% bone marrow mononuclear cells are leukemia blasts, 
is strongly associated with a favorable prognosis in relapsed ALL. Patients without MRD-
negative remissions are more likely to experience both therapy toxicity and refractory or 
recurrent disease, resulting in lower event-free and overall survival (EFS and OS). In the 
Children’s Oncology Group AALL01P2 trial, failure to achieve MRD-negative CR after 
Block 1 resulted in a 58% 1-year event-free survival compared to 80% in those who 
achieved MRD-negativity.14 On the AALL07P1 trial, patients with early relapse (18-36 
months from diagnosis) who were MRD-negative after Block 1 had a 3-year EFS of 58% 
vs. 10% in those MRD-positive, while those with very early relapse (<18 months from 
diagnosis) who were MRD-negative had 3-year EFS of 70% vs. 3% in those MRD-
positive.15 Overall survival was also lower in MRD-positive patients, with 3-year OS of 
0% and 19% for very early and early relapse vs. 70% and 65% in those same populations 
who were MRD-negative. 
Despite the need to achieve an MRD-negative remission, current therapy fails to do this 
for most patients. Patients treated with the R3 backbone who experienced a late relapse 
achieved MRD-negative remission after 1 block of therapy in 82/193 cases (42.5%).17 
AALL01P2 achieved an MRD-negative remission among patients in CR in 49% (21/43) 
of late relapse patients and 25% (9/36) of early relapse patients.14 However, data was 
incomplete among patients in CR and CR was not obtained in an additional 32% of early 
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and 4% of late relapse. For patients with T-ALL in first relapse, MRD-negative remission 
was achieved in 4/20 reported (of 22 evaluable) patients treated with bortezomib based 
therapy on AALL07P1.15 For early relapse B-ALL treated on the same trial, 29% of 
patients in CR were MRD-negative, and only 68% of patients (70/103) patients achieved a 
CR. Thus, only 19.7% of evaluable patients achieved a CR.15 In the AALL1331 trial, end 
of induction 1 bone marrow results for early relapse patients have been reported for 189 of 
206 patients who began induction, with other patients off therapy prior to assessment. Only 
52/206 (25%) achieved MRD-negative CR using the protocol defined recovery threshold 
of ANC ≥500/microL and platelets of ≥50,000/microL.(Brown et al)18
Table 1: Proportion of patients achieving MRD-negative remission according to 
timing of relapse and immunophenotype
Study
Early and Very Early
(< 36 months from diagnosis)
Late
(> 36 months from diagnosis)
B
T
B
T
R38,17#
Not reported
Not reported
42.5% [82/193]
Not reported
AALL1331^
25% [52/206]
Not included
Not reported
Not included
AALL07P115
27% [27/100]
18.2% [8/22]
No included
Not included
AALL01P214*
25% [9/36]
0%
47% [21/43]
0
#B/T not reported separately
*of available samples, with samples not available for the entire cohort
^Brown et al.18; early and very early relapse combined
For patients with multiply relapsed ALL, response rates are even lower. In a retrospective 
cohort from the Therapeutic Advances in Childhood Leukemia (TACL) consortium, less 
than half of patients in >1st relapse B-ALL achieved a complete response or complete 
response with incomplete hematological recovery (CR/CRi: <5% bone marrow disease 
without extramedullary disease but without peripheral blood count criteria).19 Specifically, 
51% of second salvage attempts (84/165), 37% of third salvage attempts (27/73), and 31% 
of subsequent relapses (16/52) achieved a CR/CRi. Combining these treatment attempts, 
patients in >1st relapse achieved a CR/CRi in 43.8% (127/290) of courses. Data are 
relatively similar from a historical Berlin-Frankfurt-Münster cohort of 74 second relapse 
patients.20 In this cohort, 30/74 were able to achieve a 3rd CR (40.5%), including 30/55 
(55.6%) for whom therapy details were available and who did not receive palliative care. 
For patients in 3rd relapse (18 of the 30 who achieved a CR after 2nd relapse), only 6 (33.3%) 
achieved a 4th CR. Combining 2nd and 3rd salvage attempts, CR/CRi was achieved in 39% 
of treated patients. MRD responses in these populations are not available. 
2.1.2
Venetoclax and Navitoclax Background
Venetoclax (ABT-199) is a first-in-class orally available selective inhibitor of B cell CLL/ 
lymphoma 2 (BCL-2).21 Overexpression of BCL-2 and BCL-2 family member proteins 
result in reduced sensitivity to therapy-induced apoptosis, resulting in treatment failure. 
These proteins sequester pro-apoptotic initiator and effector proteins needed for 
mitochondrial outer membrane permeabilization (MOMP). Venetoclax binds to BCL-2, 
displacing the pro-apoptotic proteins BIM and BAX and allowing initiation of MOMP. 
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This in turn results in outer membrane depolarization, cytochrome c release, and the 
activation in intracellular caspases resulting in apoptosis.22
Venetoclax has demonstrated in vitro cytotoxicity to ALL cell lines including RS4;11, a 
KMT2A-rearranged line.21 Early clinical data in adults suggested venetoclax had wide-
ranging activity against B-cell malignancies, including CLL, myeloma, and lymphoma 
(summarized by Roberts and Huang).23 Preclinical data suggested that sensitivity extended 
to ALL, with venetoclax sensitivity observed in B-ALL from multiple genetic 
backgrounds.24 In a separate analysis, 8/11 B-ALL primary patient samples tested and 1/6 
T-ALL samples were responsive to venetoclax.25 In vivo studies of xenografted patient 
samples demonstrated the efficacy of venetoclax in prolonging leukemia free survival in 
these animals and mirrored the responsiveness seen in vitro. Furthermore, synergy was 
noted between venetoclax and the classical chemotherapeutic agents dexamethasone, 
vincristine, and asparaginase). Data also suggests venetoclax sensitivity among other high 
risk genetic subgroups of ALL, including hypodiploid ALL,26 KMT2A rearranged 
ALL,24,27,28 Ph+ ALL,29,30 and the highly chemotherapy resistant (and rare) TCF3-HLF 
fusion ALL. In addition to specific genetic subtypes, venetoclax is also active against 
pediatric leukemias with diverse genetic lesions which dysregulate CELSR2, with 
venetoclax showing synergism with prednisone in this common mechanism of 
glucocorticoid resistance.31
Preclinical data suggests that common mechanisms of venetoclax resistance involve 
dependence on alternative BCL-2 family members for apoptosis inhibition. While many 
cell lines and primary samples are sensitive to venetoclax, some show resistance while 
remaining sensitive to navitoclax (ABT-263), a combined BCL-2/ BCL-XL/ BCL-W 
inhibitor.32 Notably, many T-ALL samples appear to be more dependent on BCL-XL with 
corresponding relative sensitivity to navitoclax compared to venetoclax.25,33 Additional 
work has shown that T-cell maturation stage may play a significant role in the susceptibility 
of T-ALL to venetoclax and navitoclax, with early T-cell precursor (ETP) ALL 
demonstrating venetoclax sensitivity and more mature T-ALL having navitoclax (BCL-
XL) or MCL-1 inhibitor sensitivity.34,35
2.1.3
Clinical Experience with Venetoclax and Navitoclax in Pediatric Leukemia
While data suggests that many high-risk B-cell precursor (BCP) ALL subtypes are 
susceptible to the BCL-2 inhibitor venetoclax, a common mechanism of resistance to 
venetoclax is dependence on alternative BCL family members including BCL–XL. 
Additionally, some BCP ALL and most T–ALL (with the notable exception of ETP) have 
primary dependence on BCL–XL, rendering venetoclax therapy less effective. This 
suggests that combination therapy with navitoclax, an inhibitor of BCL-2, BCL–XL, and 
BCL-W, is likely to have broader activity. Results from the M13–833 (Place et al., 2020, 
ASH annual meeting) and M16–10636 studies support these preclinical data. In the M13-
833 trial which combined venetoclax with one of two chemotherapy backbones, children 
treated with a vincristine/ asparaginase/ high-dose dexamethasone (VLD) backbone 
achieved a complete response/ complete response with incomplete hematological recovery/ 
complete response with incomplete platelet recovery (CR/CRi/CRp) in 9/16 cases, 
including 1/3 patients with T-ALL. Minimal residual disease (MRD) negativity <0.01% 
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was achieved in 6/16 cases. In the M16-106 trial which utilized venetoclax and navitoclax 
in combination with VLD, a CR/CRi/CRp was achieved in 9/12 pediatric patients including 
6/12 who were MRD negative. Both trials allowed the addition of a tyrosine kinase 
inhibitor (including dasatinib) in patients with ABL1 fusions. These patients did not 
experience excessive toxicity with the combination therapy.
Interestingly, the predicted BCL-2 dependency pattern was not observed, with 3/4 T-ALL 
showing primary BCL-2 dependence and 4/8 B-ALL showing primary BCL–XL 
dependence. However, despite these encouraging initial responses (60% CR/CRp/CRi in 
all patients including adults and children, 75% in children), 18-month overall survival was 
~20% in the combined adult and pediatric cohort. Responses in T-ALL were encouraging 
but limited, with 10/19 patients (including adults) achieving a CR/CRi of which 6 were 
MRD-negative and 3 of these patients proceeding to transplantation. Together, these data 
suggest that initial response rates are high (given the heavily pretreated nature of the 
population) but better consolidative strategies are needed for patients treated with these 
agents to provide long-term cure.
2.1.4
Rationale for Dasatinib in T-ALL
Primary treatment failure and relapse are more common in T-ALL than in B-ALL. In many 
studies, response to a 7-day prednisone window is used to identify poor response. In studies 
of T-ALL, hyperactivation of lymphocyte cell-specific protein-tyrosine kinase (LCK), a 
SRC family kinase potentially targetable by dasatinib, was associated with a poor 
prednisone response.37 Separately, in silico analysis also identified LCK overexpression in 
T-ALL.38 In vitro evaluation of 22 primary T-ALL samples demonstrated nanomolar 
sensitivity to dasatinib in 6/22 cases (27%). Separately, dasatinib sensitivity was identified 
in 12/40 (30%) of patients with T-ALL patients not harboring ABL-class fusions.24 
Notably, ETP ALL does not appear to be sensitive to dasatinib.
To further understand these findings, pharmacotyping to assess in vitro drug sensitivity 
was performed on 45 T-ALL samples including 18 adult and 27 pediatric cases.39 In this 
cohort, 12/27 (44%) of pediatric cases were exquisitely dasatinib sensitive. This sensitivity 
was confirmed in vivo using patient derived xenografts. Analysis of gene interactome 
networks confirmed LCK as a driver of this sensitivity. Using phosphoproteomics, 
introduction of a dasatinib resistance mutation in LCK, and specific inhibitors of LCK, this 
kinase was confirmed as being the target and driver of dasatinib sensitivity in T-ALL. 
Interestingly, there appeared to be a direct, correlative relationship between dasatinib and 
navitoclax sensitivity in available cases while there was an inverse correlation between 
dasatinib and venetoclax sensitivity [i.e. venetoclax resistant cases were sensitive to 
dasatinib (via LCK) and navitoclax (due to upregulation of BCL–XL), while venetoclax 
sensitive cases (primarily ETP ALL) were resistant to dasatinib]. These changes in 
sensitivity appear to be related to the maturational stage of the T-ALL; T-cell receptor 
signaling; and LCK, BCL-2, and BCL–XL activity. These patterns observed in bulk 
leukemia samples were also observed in clonal subpopulations evaluated with single-cell 
RNA sequencing. Preliminary studies have also evaluated synergy between dasatinib and 
navitoclax in T-ALL samples and have shown promising results, suggesting a novel 
mechanism for targeting this challenging population.
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While work is underway to identify optimal biomarkers to select T-ALL patients for 
dasatinib therapy, there is not currently a CLIA approved test to identify such patients. 
Given the extremely poor prognosis of patients with relapsed T-ALL (<50% 3-year OS for 
first-relapse receiving bortezomib based reinduction and <15% in non-bortezomib 
combinations),14,40 the fact that dasatinib was well tolerated when combined with M16-106 
therapy,36 and preclinical data demonstrating synergy between navitoclax and dasatinib in 
T-ALL, we will combine these agents for all patients with T-ALL.
2.1.5
Rationale for Combining Venetoclax and Blinatumomab
Blinatumomab, a bispecific T-cell engager targeting CD19, is rapidly becoming the 
standard of care for consolidation therapy for patients with relapsed CD19-positive B-ALL. 
It is FDA approved for adults and children with relapsed or refractory ALL. In adults with 
relapsed ALL, blinatumomab provided better CR and MRD-negative CR rates than 
chemotherapy and improved survival.41 Blinatumomab has also been shown to be active in 
children with bulk disease with ~20% of patients achieving an MRD-negative CR within 
2 cycles.42 The Children’s Oncology Group AALL1331 trial compared blinatumomab vs. 
standard of care consolidation chemotherapy based on the UKALL R3 backbone 
(intermediate-dose methotrexate combined with cyclophosphamide and etoposide in Block 
2 and high-dose cytarabine in Block 3) for children with CD19-positive B-ALL in first 
relapse. Results for patients at intermediate and high risk have now been published.16,43 In 
these patients, blinatumomab was superior to conventional therapy in achieving CR and 
MRD-negative CR and was associated with lower toxicity, resulting in more patients 
reaching transplant. This translated into an improvement in 2-year overall survival (71.3% 
for blinatumomab vs. 58.4% for chemotherapy, p=0.02). Separately, a single cycle of 
blinatumomab consolidation improved EFS compared to a third chemotherapy based 
consolidation block in children with high-risk B-cell relapsed ALL.44 Blinatumomab has 
also been shown to be effective when used as a bridge to transplantation in children who 
achieved a CR with conventional therapy.45 Blinatumomab has been successfully 
combined with dasatinib in large clinical trials of adults with BCR-ABL1 ALL with 
excellent results.46 
There have been case reports of combining blinatumomab with venetoclax in relapsed B-
ALL.47 In that report, 2 adult patients received venetoclax 400mg/day after a ramp-up 
phase and blinatumomab 9mcg/day on days 1-7 and 28mcg/day on Days 8-28. This therapy 
was well tolerated without significant cytopenias. Both patients tolerated the therapy well 
and achieved an MRD-negative remission after 1 cycle before proceeding to 
transplantation. Another case report by a different group describes a patient who received 
blinatumomab after a reinduction failure (33% disease) and had persistent disease (45%) 
after 1 week of therapy with blinatumomab alone. Venetoclax was added at that time and 
disease responded with undetectable disease by MRD on Day 21, following 14 days of 
venetoclax and blinatumomab combination (Herrera Rojas et al., 2017. Rev Hematol Mex). 
This strategy has also been employed in several adult patients at MD Anderson with 
relapsed ALL with similar efficacy and tolerability observed (Elias Jabbour, personal 
communication).
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These clinical responses are supported by preclinical data on the potential combinatorial 
efficacy of blinatumomab and venetoclax. Venetoclax enhanced the cellular cytotoxicity 
of antigen specific T-cells directed against CMV in both an antigen specific and an antigen 
non-specific manner.48 Separately, chimeric antigen receptor T-cells (CAR T-cells) had 
enhanced cytotoxicity in the presence of ABT-737, a preclinical compound with similar 
activity to navitoclax (BCL-2 and BCL-XL inhibition).49 This synergy appeared to be 
mediated by increased sensitivity of blasts to CAR T-cells and could be achieved either by 
pre-sensitizing with ABT-737 or by co-exposure of blasts to CAR T-cells and ABT-737. 
Venetoclax has also be successfully combined with PD-1 blockade in pre-clinical models 
of breast cancer with demonstration of improved intra-tumoral cellular cytotoxicity from 
tumor infiltrating T-cells.50 This study demonstrated the preservation of effector memory 
and activated T-cells with a loss of naïve T-cells during venetoclax therapy. Regulatory T-
cells were also affected by the addition of venetoclax, with sensitivity intermediate to CD-4 
and CD-8 positive T-cells. Surviving T-cells had unimpaired function in the presence of 
venetoclax. The preservation of these effector populations is relevant to combinations with 
blinatumomab. Effector memory T-cells appear to be the cells most responsible for 
blinatumomab activity in preclinical models of blinatumomab.51 Indeed, loss of regulatory 
T-cells from venetoclax may actually be beneficial, as non-responders to blinatumomab 
had higher levels of peripheral blood T-regs than responders.52 Thus, combining venetoclax 
may selectively eliminate immune cell subsets which reduce blinatumomab efficacy while 
retaining effector cells. Published reports describe the use of venetoclax with 
blinatumomab for all 28 days of the blinatumomab cycle. Because patients on RAVEN 
will have just completed Block 1 when proceeding to Block 2b, we will hold venetoclax 
for the first 7 days of the blinatumomab infusion to support further hematological recovery.
2.1.6
Rationale for Combining Venetoclax with Navitoclax and High-Dose Cytarabine
Venetoclax has previously been successfully combined with high-dose cytarabine and 
idarubicin in children with relapsed and refractory acute myeloid leukemia (AML). In the 
St. Jude VENAML trial,53 all evaluated dose levels of venetoclax with high-dose 
cytarabine were well tolerated. The recommended phase 2 dose combination was 
venetoclax 360mg/m2 (equivalent to an adult dose of 600mg) combined with cytarabine 
1000mg/m2 x 8 doses and idarubicin 12mg/m2 x1 dose. Hematological and infectious 
toxicities were consistent with the backbone chemotherapy without excess toxicity 
attributable to venetoclax. These results have since been extended in adults with both newly 
diagnosed and relapsed/ refractory AML at MD Anderson, where FLAG-Ida has shown 
both tolerability and impressive activity.54
Acute lymphoblastic leukemia resistant to chemotherapy is frequently characterized by 
immature/ stem cell characteristics.35,55 Moreover, within the bulk leukemic population, 
leukemic stem cells act as a reservoir which are more resistant to chemotherapy and drive 
the development of relapse.55 Cytarabine has been demonstrated to target leukemic stem 
cells in AML56, and the addition of cytarabine to condition regimens prior to transplant 
improve outcomes in ALL.57 One proposed mechanism of this interaction is a 
downregulation of MCL1 through cellular stress from cytarabine administration.56 
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Based on these data, we will combine high-dose cytarabine (which may downregulate 
MCL1) with the BCL2 inhibitor venetoclax and the BCL-XL inhibitor navitoclax to try to 
eliminate leukemic stem cells which persist following Block 1 therapy.
For combination therapy as described in Block 2a, we believe the experience of the 
VENAML trial (NCT0319493253) provides an appropriate signal to indicate the planned 
therapy is likely to be safe. In that trial for children with relapsed AML, all dose levels 
were deemed to be tolerable with excellent activity. To increase the safety of the planned 
therapy in RAVEN, we have pre-emptively modified the planned treatment to attempt to 
reduce toxicity. Specifically, we have reduced the starting dose of venetoclax (400mg vs. 
600mg), utilize fewer doses of cytarabine (4 doses vs. 8 doses), and are not using an 
anthracycline (omitting 12mg/m2 of idarubicin). We have further reduced therapy intensity 
to minimize myelotoxicity compared to the historical R3 Block 3 treatment by stopping 
chemotherapy after day 7 rather than repeating high-dose cytarabine on days 8 and 9.
2.2
Study Plan Rationale
As described in the background, outcomes for children with relapsed acute lymphoblastic 
leukemia and lymphoma who fail to achieve MRD-negative remissions are extremely poor, 
with most MRD-positive patients progressing to frank relapse. Current standard of care 
options (AALL01P2 and AALL1331/ R3) fail to achieve an MRD-negative remission in 
most patients resulting in adverse outcomes. Thus, achieving this level of remission is a 
meaningful therapeutic outcome for children with relapsed ALL.
While data from the phase I and expansion cohorts of M16-106 suggest that the 
combination therapy of Block 1 is active and able to achieve MRD-negative responses, the 
pediatric experience with this combination is limited to 12 patients. Additional assessment 
of this combination in children is needed to refine estimates of response and further 
characterize toxicities. Additionally, overall survival rates following this combination 
remain lower than response rates, suggesting that persistent residual disease below the level 
of MRD detection may persist in heavily pretreated populations such as those who received 
therapy on M16-106. Thus, additional consolidative strategies prior to cellular therapy or 
transplantation are needed to deepen remissions and allow for long-term survival. As 
described above, combining venetoclax with blinatumomab (for CD19-positive ALL) or 
navitoclax and high-dose cytarabine (for other patients) provide rational approaches to such 
consolidation therapies which build on existing standards of care while providing needed 
assessments of these combinations. As these combinations have not previously been 
explored in pediatrics, assessments of both tolerability and response to these combinations 
are needed.
Dosing for this study is based on the M16-106 study.36 Here, dosing of venetoclax was 
capped at 400mg daily and was combined with navitoclax (25mg for those 20-44.9kg and 
50mg for those 45kg and heavier). With this dosing, the selective BCL-2 inhibition of 
venetoclax combines with the combination BCL-2, BCL-XL, and BCL-w inhibition of 
navitoclax to achieve higher levels of combined BCL-2 family inhibition. Dasatinib dosing 
is identical to that used in two recent trials of children with newly diagnosed ALL.2,58
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2.2.1
Rationale for intensification of CNS directed therapy compared to R3 backbone for 
late first relapse who continue therapy past Block 2
As described in the study plan, patients with B-cell precursor ALL who experience a late 
relapse (≥ 36 months from diagnosis) and achieve an MRD-negative remission after Block 
1 of therapy will continue protocol therapy after Block 2. Therapy after Block 2 has been 
modeled after the UKALL R3 backbone.8,17 Post-induction therapy using this backbone 
includes intermediate dose methotrexate, an intensification block utilizing high-dose 
cytarabine (similar to RAVEN Block 2A), and continuation therapy including daily 6-
mercaptopurine, weekly oral methotrexate, and every 4 week dexamethasone and 
vincristine “pulses”. This backbone was utilized as the standard of care/ control arm of the 
recently completed Children’s Oncology Group relapse trial AALL1331, which compared 
this control arm to an arm including blinatumomab. However, unpublished data suggests 
that the isolated extramedullary relapse rate in both the control and experimental arms of 
AALL1331 for patients treated with this therapy was unexpectedly high (Mignon Loh and 
Patrick Brown, personal communication; AALL1821 investigator memo dated March 23, 
2021). As a result of these findings, intensification of post-induction CNS directed therapy 
is being planned for the current COG B-ALL relapse trial AALL1821.
The implications of the findings from AALL1331 for the RAVEN trial are unknown. 
Venetoclax does penetrate the cerebrospinal fluid, albeit at low levels, and thus may 
contribute to the antileukemic activity of chemotherapy in the CNS. However, to ensure 
effective extramedullary control for patients treated on RAVEN, additional modifications 
to the R3 backbone were felt to be needed. These include: the addition of an additional 
dose of intrathecal chemotherapy for CNS1 patients during Block 1, the exclusion of all 
patients with isolated extramedullary relapse from Block 2B (to enable them to receive a 
block of high-dose cytarabine for extramedullary disease), the addition of an intensification 
block utilizing two cycles of high-dose methotrexate (HD-MTX) immediately after Block 
2, changing intermediate dose methotrexate to high-dose methotrexate during interim 
continuation therapy, and adding additional intrathecal therapy to high-risk populations 
during the first year of continuation.
In addition to HD-MTX being the standard of care for patients with NCI-high risk B-ALL 
during initial therapy,2,3 both St. Jude and the COG have utilized HD-MTX in patients with 
relapsed ALL. The recently completed ALLR18 protocol (NCT01700946) used 2 cycles 
of HD-MTX spaced 1 week apart without exclusion for patients with prior CNS irradiation 
and did not note unexpected neurological toxicity. The ALLR15 trial also used HD-MTX 
and none of the 4 patients who had received 18 Gy cranial irradiation in frontline therapy 
experienced grade 3 or higher neurotoxicity during this therapy.59 A retrospective 
evaluation of 11 patients treated on relapse ALL trials at St. Jude who had received 
radiation therapy during frontline treatment identified 1 patient who experienced a seizure 
and no cases of leukoencephalopathy or necrosis (Matthew Krasin, personal 
communication). The COG AALL0433 trial used 9 cycles of HD-MTX in patients with 
intermediate risk relapse and observed a rate of leukoencephalopathy of <1%.60 Notably, 
no patients died during either induction 2 or intensification 1, both blocks which contained 
HD-MTX.60 Data from newly diagnosed patients treated on St. Jude Total V-X protocols 
compared the frequency of seizures in patients receiving ongoing methotrexate therapy 
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after CNS directed radiation. These data demonstrated that the rate of seizure was higher 
in patients receiving intrathecal or intravenous methotrexate earlier than 12 months after 
CNS directed radiation therapy but not after 12 months. Together, these data suggest that 
HD-MTX will be tolerable in relapse patients on this trial including those who received 
CNS directed radiation therapy during initial treatment, as all of these patients will be >18 
months from initial radiation at the time of study entry.
2.3
Background and Rationale for Ancillary and Exploratory Studies
In vitro drug sensitivity is associated with clinical response in children with newly 
diagnosed ALL.12,31,61 The drug responsiveness of large cohorts of relapsed or refractory 
ALL patients has not been systematically characterized, making it more challenging to 
identify appropriate combination therapies in this population. Similarly, the BH3 (BCL-2 
Homology 3) dependence of relapsed ALL has not been previously systematically 
characterized.
As described in the background, immunotherapy is rapidly emerging as a standard part of 
therapy for relapsed ALL. Challenges with immunotherapy include understanding reasons 
for treatment failure and the optimal timing of immunotherapy within combination therapy 
platforms. Mechanisms of leukemic escape from immunotherapy include loss of the target 
antigen (CD19 loss or CD22 downregulation)41,42,62-67 as well as failure to respond to 
therapy despite antigen preservation.41,42,62,63,65,67 Treatment failure without antigen loss is 
frequently mediated by T-cell exhaustion. This exhaustion may be mediated by cytokine 
secretion within the leukemic microenvironment as well as immune checkpoint signaling 
mediated by PD-1/ PD-L1.68,69 These mechanisms also impair the function of tumor 
neoantigen-specific T-cells which may be generated during both immunotherapy and 
conventional chemotherapy and can be present in significant numbers of patients with 
ALL.70 These signals impair T-cell function and can impair the activity of blinatumomab 
and CAR-T therapy. This signature can be detected using single-cell genomics.71 
Evaluation of changes in T-cell potential across therapy is needed to optimize use of these 
therapeutics. 
Mixed phenotype acute leukemia (MPAL), also sometimes termed acute leukemia of 
ambiguous lineage (ALAL), is a heterogenous disease with characteristics of multiple 
lineages, including, variably, B-ALL, T-ALL, and acute myeloid leukemia (AML).72,73 
Data on newly diagnosed patients suggests that ALL-based therapy is more likely to be 
beneficial in these patients than AML therapy.72 These patients are now being included on 
frontline ALL trials. However, the optimal treatment strategy for these patients in relapse 
remains unknown. Venetoclax and cytarabine have activity in relapsed AML.53 Thus, the 
proposed therapy offers therapy likely to be beneficial in this population which has 
characteristics of both ALL and AML.
Similarly, there are limited data available on therapies for patients who are intolerant to 
asparaginase due to toxicity. Data from frontline trials clearly demonstrate a decrement in 
therapeutic efficacy when asparaginase is inactivated (as in immune mediated inactivation 
or accelerated drug clearance) or omitted due to shortage or toxicity.74-76 There are, 
however, limited trial data suggesting optimal therapy for these patients without 
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asparaginase. Venetoclax and navitoclax have synergy with multiple chemotherapeutic 
agents including asparaginase.77,78 Thus, although patients may benefit more from therapy 
including both asparaginase and these agents, synergy between non-asparaginase 
chemotherapy and these agents may still provide therapeutic benefit to such patients who 
have limited other therapeutic options.
Young adults also comprise a group who may experience differential toxicity to 
combination therapy compared to the general pediatric population.6,79,80 Although data are 
limited, experts in the treatment of young adults with ALL have suggested prolonging time 
between asparaginase exposure as a mechanism of reducing asparaginase-induced 
hepatotoxicity.81 Small case-series data also suggest the use of a reduced dose of 
asparaginase (i.e. 1000u/m2 compared to 2500u/m2) to reduce toxicity without an obvious 
decrement in overall efficacy.82 To evaluate such therapy modifications for this population, 
they will be considered separately from pediatric patients in this cohort.
Patients with isolated extramedullary relapse are frequently excluded from clinical trials 
due to their different therapeutic needs. The planned therapy includes multiple agents 
which are active against central nervous system (CNS) leukemia including dexamethasone, 
asparaginase, vincristine, and, for patients who will receive it, dasatinib. Venetoclax also 
enters the cerebrospinal fluid at levels ~1000-fold lower than in the plasma83 and thus may 
also contribute to extramedullary disease clearance.
Infectious toxicities in children receiving reinduction therapy for relapsed ALL are 
extremely common. In AALL1331 therapy for 206 patients with relapse before 36 months 
from diagnosis (early relapses), grade 4 or 5 toxicity occurred in 33% of patients, including 
a 5% toxic death rate.18,43 In a retrospective review of real-world data evaluating 59 patients 
including 16 in >1st relapse, the TACL consortium indicated 97% of patients experienced 
a grade 3 or higher non-hematological toxicity and 90% experienced a grade 3 or higher 
infection.84 Additionally, 15.5% of patients required intensive care unit admission for 
toxicities (primarily infectious). Further characterization of infections experienced by these 
patients is needed to identify strategies which mitigate such toxicities
3.0
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT
3.1
Inclusion Criteria
According to institutional and NIH policy, the study will enroll research participants 
regardless of gender and ethnic background. Institutional experience confirms broad 
representation in this regard.
3.1.1
Diagnosis
3.1.1.1 Relapsed or refractory acute lymphoblastic leukemia or lymphoma with ≥1% bone 
marrow disease as measured by flow cytometry, PCR, or next generation 
sequencing. However, if an adequate bone marrow sample cannot be obtained, 
patients may be enrolled if there is unequivocal evidence of leukemia with ≥ 5% 
blasts in the peripheral blood.
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
Patients with 1-4.99% bone marrow involvement must have disease confirmed 
in one of the following ways: an alternative minimal residual disease assay (e.g. 
flow cytometry and PCR or NGS), cytogenetic abnormality consistent with 
patient’s leukemia, FISH abnormality, or a second bone marrow with MRD 
≥1% separated by 1-4 weeks.

Patients with ≥5% bone marrow disease by a single measurement as measured 
by flow cytometry, PCR, or next generation sequencing do not require a second 
confirmatory test.

Refractory disease is defined as residual leukemia ≥1% after at least 2 prior 
lines of frontline therapy with curative intent.

Patients in exploratory cohort I must have measurable extramedullary disease 
but may have <1% bone marrow disease.

Patients in exploratory cohort M must have ≥1% bone marrow disease as 
measured by flow cytometry of mixed phenotype acute leukemia (MPAL)/ 
acute leukemia of ambiguous lineage (ALAL).
3.1.2
Age > 4 to < 30 years. Patients ≥ 22 years old are only eligible for exploratory 
cohort O. Sites may have different (lower) maximum ages based on institutional 
guidelines but may not exceed 30 years.
3.1.3
Patient weighs > 20 kg.
3.1.4
Patient is able to swallow pills.
3.1.5
Lansky/Karnofsky score is > 60%. The Lansky performance score should be used 
for participants < 16 years and the Karnofsky performance score for participants > 
16 years (See Appendix I).
3.1.6
Participant has adequate organ function as defined by the following:

Direct bilirubin ≤ 1.5x the institutional upper limit of normal (ULN) unless 
attributable to leukemic involvement. At institutions which do not obtain a 
direct bilirubin in patients with a normal total bilirubin, a normal total bilirubin 
may be used as evidence that the direct bilirubin is not > 1.5 x the ULN. Patients 
with a direct bilirubin ≥ 2 mg/dl may not enroll regardless of attribution.

Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x the ULN 
unless increase is attributable to leukemic involvement.

Normal creatinine for age or a calculated creatinine clearance ≥ 60 mL/min/1.73 
m2. 

Left ventricular ejection fraction (LVEF) ≥ 40% or shortening fraction ≥ 25%.
o
Patients with a history of reduced LVEF which subsequently improved 
with medical management are eligible if they meet the criteria above. 
3.1.7
Patients must have fully recovered from the acute effects of all prior therapy 
(defined as resolution of all such toxicities to ≤ Grade 2).
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3.1.8
For patients with prior hematopoietic stem cell transplant (HSCT), at least 90 days 
must have elapsed since transplant, the patient cannot have evidence of active graft-
versus-host disease (GVHD), and they must be off calcineurin inhibitors for ≥4 
weeks, and off other immunosuppression for ≥2 weeks.
3.1.9
Patients with Down Syndrome/ germline Trisomy 21 are eligible for Block 1 and 
Block 2b therapies but are ineligible for Block 2a therapy. Patients with Down 
Syndrome and CD19-negative disease are off therapy after the response evaluation 
to Block 1.
3.1.10 Prior therapy

≥14 days must have elapsed since the completion of cytotoxic therapy, with the 
exception of standard maintenance therapy (glucocorticoids, vincristine, 
methotrexate, 6-mercaptopurine), tyrosine kinase inhibitors, and steroids.

Cytoreduction with prednisone, methylprednisolone, or hydroxyurea for ≤ 120 
hours (5 days) in patients with hyperleukocytosis or extramedullary disease 
compromising organ function can be initiated and continued until up to 24 hours 
prior to the start of protocol therapy.

At least 21 days must have elapsed since completion of therapy with a biologic 
agent excluding blinatumomab. For agents that have known adverse events 
occurring beyond 21 days after administration, this period prior to enrollment 
must be extended beyond the time during which adverse events are known to 
occur. At least 7 days must have elapsed since blinatumomab infusion and 
patients must have recovered from all toxicities as described above.

Intrathecal cytotoxic therapy: No waiting period is required for patients having 
received intrathecal cytarabine, methotrexate, and/or hydrocortisone. 
Intrathecal chemotherapy given at the time of diagnostic LP to evaluate for 
relapse prior to study enrollment is allowed.

Patient has not had prior exposure to navitoclax
3.1.11 Male or female participant of reproductive potential must agree to use appropriate 
methods of contraception for the duration of study treatment and for at least 30 days 
after last dose of protocol treatment.
3.1.12 Additional criteria for exploratory cohorts

Cohort I: Diagnosis of isolated extramedullary relapse as defined by bone 
marrow blasts of <1% AND 1) central nervous system white blood cell count 
(WBC) of ≥ 5WBC/mL with blasts or 2) biopsy confirmed extramedullary 
leukemia.

Cohort M: Diagnosis of relapsed or refractory mixed phenotype acute 
leukemia (MPAL)/ acute leukemia of ambiguous lineage (ALAL).
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
Cohort N: Patients with relapsed or refractory ALL who, in the view of the 
provider, are unable to tolerate further asparaginase therapy due to prior 
toxicities.

Cohort O: Patients with relapsed or refractory ALL who are ages 22-29.9 
years. This cohort may not enroll patients at all sites based on institutional 
guidelines or capacity.
3.2
Exclusion Criteria
3.2.1
Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen–
positive) or C (defined as hepatitis C antibody–positive).
3.2.2
Pregnant or lactating (female participant of childbearing potential must have 
negative serum or urine pregnancy test required within 7 days prior to start of 
treatment). 
3.2.4
Concomitant medications and food

Treatment with moderate or strong cytochrome P450 3A (CYP3A) inhibitors 
within 3 days of starting protocol therapy (see Appendix III for examples).

Treatment with moderate or strong CYP3A inducers within 7 days of starting 
protocol therapy (see Appendix III for examples).

Administration or consumption within 3 days prior to the first dose of study 
drug or grapefruit or grapefruit products, Seville oranges (including marmalade 
containing Seville oranges), or star fruit.
3.2.5
Inability or unwillingness of research participant or legal guardian/representative 
to give written informed consent.
3.3
Definitions
3.3.1
Bone marrow status

M1: <5% leukemic blasts

M2: 5-25% leukemic blasts

M3: >25% leukemic blasts
3.3.2
Minimal residual disease status (MRD)

Positive: ≥ 0.01% detectable leukemia cells

Negative: < 0.01% detectable leukemia cells within a marrow with adequate 
cellular composition to enable evaluation of at least 100,0000 viable 
mononuclear cells.

Equivocal: no detectable leukemia but with inadequate cellular composition to 
enable evaluation of at least 100,000 viable mononuclear cells.
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3.3.3
CNS Status 

CNS1: Absence of blasts in the cerebral spinal fluid (CSF), regardless of the 
number of white blood (WBC) cells present 

CNS2: <5 WBC/ microL CSF and cytospin positive for blasts 

Traumatic LP with blasts: ≥ 10 red blood cells (RBC)/ microL CSF with 
morphologically identifiable blasts on cytospin 

CNS3: ≥5 WBC/ microL CSF and cytospin positive for blasts OR cranial nerve 
palsy
3.3.4
Definitions of Relapse
Relapse: Re-emergence of measurable leukemic burden after obtaining a CR.
Marrow Relapse:
o
Rel-M3: A single bone marrow sample with M3 morphology
o
Rel-M2: A single bone marrow sample with M2 morphology and 
confirmatory testing showing ≥ 5% leukemic blasts by flow cytometry, 
FISH testing or other molecular method
o
Rel-M1: A single bone marrow sample with M1/M2 morphology and at 
least two tests showing ≥1% leukemic blasts (Rel-M1); examples of tests 
include:

flow cytometry showing leukemia ≥1% of all cells

karyotypic abnormality (must display at least 1 metaphase 
similar/identical to diagnosis)

FISH abnormality identical to one present at diagnosis/ prior relapse

PCR or NGS-based demonstration of Ig or TCR rearrangement that 
matches diagnosis and is quantifiable as ≥1% in a CLIA approved 
laboratory.

PCR or NGS-based demonstration of validated leukemogenic lesion 
(e.g., fusion, mutation) that matches diagnosis and is quantifiable as 
≥ 1% in a CLIA approved laboratory.
Equivocal Marrow (Equiv-M): A single bone marrow sample with M1 
morphology, but also with at least one evaluation that suggests recurrence of 
leukemia (e.g., flow cytometry, karyotype, FISH, PCR, NGS) but does not meet 
the definition of a definitive relapse. 
In the case of Equiv-M, bone marrow evaluation should be repeated at least 1 week 
and at most, 4 weeks later.
o
To convert to definitive relapse, the repeat marrow must either: 
a.
meet criteria for definitive relapse (Rel-M3, Rel-M2 or Rel-M1), or
b. demonstrate ≥1% MRD 
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CNS Relapse: Occurrence, after remission, of either a single LP with CNS3 or two-
consecutive LP with CNS2 status and supportive testing demonstrating 
lymphoblasts. Supportive testing can include positive TdT staining, flow 
cytometry, FISH, or PCR positivity.
Extramedullary Relapse: Biopsy proven recurrence of disease after first remission.
Timing of relapse:

Early: less than 36 months from initial diagnosis

Late: ≥ 36 months from initial diagnosis
Response criteria: Disease burden within the bone marrow will be determined by 
flow cytometry when available for the patient. Peripheral blood count criteria will 
utilize a CBC obtained within one day before and 2 weeks after the corresponding 
bone marrow evaluation.
Complete remission (CR)

Bone marrow with < 5% blasts, no evidence of circulating blasts or 
extramedullary disease and with peripheral count recovery.

Peripheral count recovery defined as absolute neutrophil count higher than 
or equal to 500/μL and platelet count higher than or equal to 50,000/μL.

Patients who begin therapy with <5% blasts must achieve an MRD-negative 
(<0.01%) to be deemed a CR or CRi. 
Complete remission with incomplete blood count recovery (CRi)

Bone marrow with < 5% blasts, no evidence of circulating blasts or 
extramedullary 
disease 
but 
without 
peripheral 
count 
recovery 
(ANC<500/μL or platelets <50,000/μL).

Peripheral count recovery defined as absolute neutrophil count higher than 
or equal to 500/μL and platelet count higher than or equal to 50,000/μL.

Patients who begin therapy with <5% blasts must achieve an MRD-negative 
(<0.01%) response to be deemed a CR or CRi.
Partial response (PR)

A decrease of at least 50% in the percentage of blasts and 5% to 25% blasts 
by flow cytometry. 

Patients who began therapy with <5% blasts, have at least a 50% decrease 
in the percentage of blasts, and do not achieve and MRD-negative CR/CRi 
will be deemed PR.

At least a 50% reduction in the sum of the product of the diameters of up to 
the six largest nodes or nodal masses without new lesions.
No response (NR)

Leukemia/ lymphoma reduction less than required to meet the definition 
of PR or CR/CRi, or increase in leukemia/ lymphoma after treatment.
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
If a patient also meets the definition of treatment failure (TF), the patient 
will be recorded as a TF in the research database.
Treatment Failure (TF)

Failure to achieve CR/CRi/PR criteria after cycle 2.
3.4
Research Participant Recruitment and Screening
RAVEN is be conducted on two continents. Fourteen (14) institutions in North America 
will collaborate in the proposed project: St. Jude Children's Research Hospital; University 
of North Carolina School of Medicine; Nationwide Children’s Hospital Columbus; 
Children’s Hospital of Philadelphia; Vanderbilt University Medical Center; Memorial 
Sloan Kettering Cancer Center; Rady Children’s Hospital-San Diego; Cook Children’s 
Medical Center; Children’s Hospital of Michigan; Children’s Healthcare of Atlanta; Texas 
Children’s Hospital/ Baylor; University of California San Francisco; Sanford Children’s 
Hospital Sioux Falls; Sanford Roger Maris Cancer Center.
Ten (10) institutions in Australia and New Zealand as part of the ANZCHOG group: John 
Hunter Children’s Hospital, Queensland Children’s Hospital, Monash Children’s Hospital, 
Perth Children’s Hospital, Royal Children’s Hospital, Sydney Children’s Hospital, 
Women’s and Children’s Hospital Adelaide, the Children’s Hospital at Westmead, Starship 
Children’s Hospital, and Christ Church Hospital.
3.5
Enrollment on Study at St. Jude
A member of the study team will confirm potential participant eligibility as defined in 
Sections 3.1-3.2, and complete the ‘Participant Eligibility Checklist’ in OnCore. A research 
participant-specific consent form and assent document (where applicable) will be 
generated. The entire signed consent/assent form(s) must be scanned into the Electronic 
Health Record (EHR) by the study team designee.
3.6
Enrollment on Study for Affiliate Sites Sharing St. Jude Participants
For Affiliate sites sharing patients, eligibility will already have been determined at St. Jude 
and the participant will already have been enrolled via the St. Jude participant enrollment 
process. The CTO Clinical Research Monitor (CRM) will monitor the completed consent 
forms of the shared participants during scheduled monitoring vests with the affiliate sites.
3.7
Enrollment on Study at Collaborating Sites
Collaborating sites and enrolling affiliate sites will screen potential study participants. 
Determine eligibility status through the OnCore system. Enroll participants meeting 
eligibility criteria into the OnCore system. 
OnCore will generate a unique patient ID number. The OnCore system will also generate 
a patient research record in the TrialMaster database.
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4.0
TREATMENT PLAN
4.1
Design and Study Overview
Figure 1: Graphical study schema
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Amendment 3.0, dated: 01-16-2024
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Enrolled patients will receive protocol therapy as described. A graphical schema is shown 
in Figure 1. The primary outcome assessment will be a bone marrow with MRD testing on 
Day 29 of Block 1 therapy. Following that assessment, patients should continue with 
protocol therapy including either Block 2A (which includes high-dose cytarabine with 
venetoclax and navitoclax) for patients with CD19 negative leukemia, those with isolated 
extramedullary relapse, or whose treating physician determines that blinatumomab therapy 
is not in the patient’s best interest; or Block 2B for patients with leukemia which is CD19 
positive. Following recovery from Block 2 therapy, all patients except those with late first 
relapse of B-ALL (≥ 36 months from diagnosis) who are MRD-negative at <0.01% after 
Block 1 therapy are off therapy. Further therapy for these patients is at the treating 
physician’s discretion. Patients with late first relapse B-ALL relapse and who are MRD 
negative will proceed with intensification, interim continuation, and continuation therapy 
as described. Patients with Down’s Syndrome with CD19 negative leukemia will be off 
therapy after Block 1 as they are ineligible for Block 2A. Patients in exploratory cohorts I 
and N who are late first relapse B-ALL and who are MRD-negative after Block 1 therapy 
may continue on protocol therapy after Block 2 or receive alternative therapy at their 
treating physician’s discretion. Patients in exploratory cohort M and O are off therapy after 
Block 2.
4.2
Treatment Administration and Schedule
4.2.1
Block 1 Therapy
Agent
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
Dexamethasone
5mg/m2/dose BID PO/IV
30
Days 1-7, 15-22
Vincristine
1.5mg/m2/dose IV (Max 2mg)
4
Days 1, 8, 15, 22
Calaspargase*
2500units/m2/dose IV
1
Day 2
Dasatinib#
80mg/m2/day QD/PO (Max 
140mg)
28
Days 1-28
Venetoclax
120mg/m2 (max 200mg) QD/PO
1
Day 1
Venetoclax
240mg/m2/dose (max 400mg) 
QD/PO 
21
Days 2-22
Navitoclax
50mg QD/PO (for patients 
≥45kg) 
25mg (for patients 20 - <45kg)
20
3-22
IT MHA
Methotrexate 12mg IT
Hydrocortisone 24mg IT
Cytarabine 36mg IT
1-4
See table below
Leucovorin
5mg/m2 (max 5mg) PO or IV
2+
24 and 30 hours after 
each lumbar puncture
*Calaspargase may be replaced by alternative forms of asparaginase due to local practice or prior allergy. 
If pegaspargase is used, two doses (on days 2 and 15) of 2500units/m2 replace the single day 2 dose of 
calaspargase doses. Asparaginase formulation must be documented in the research database. Other 
substitutions should be discussed with PI and documented in the research database. For patients in 
exploratory cohort N, asparaginase will be omitted. For patients in exploratory cohort O, the Day 15 dose 
of pegaspargase may be omitted and the Day 2 dose may be capped at 2000units/m2 with a maximum dose 
of 3750 units. These modifications should be documented in the research database.
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# Dasatinib will be given to patients with ABL-class fusions (in-frame fusions of ABL1, ABL2, CSF1R, 
PDGFRB, PDGFRA, or LYN that include the tyrosine kinase domain) and those with non-ETP T-
ALL/ALLy. For patients who are discovered to have ABL-class fusions while on therapy, dasatinib will be 
begun upon identification of that fusion.
Intrathecal schedule
CNS status
Relapse
# Doses
Days
1 (no blasts)
Untreated first relapse
3
-7 to 1, 8, 22
1 (no blasts)
>1st including 
refractory after relapse
1
-7 to 1
2, 3, traumatic with 
blasts (blasts 
present)
Any
3-4
-7 to 1, 8, 15, *22
*Give Day 22 intrathecal therapy to patients with persistent CSF blasts on Day 8 of Induction.
Day 1 LPIT can be delayed if clinical condition requires.
Continue intrathecal chemotherapy weekly until negative x 2. Patients with persistent CSF 
blasts on day 15 should have a diagnostic LP performed with end of Block 1 therapy 
evaluations (days 29-32). Patients with persistent CSF blasts at the end of Block 1 are 
treatment failures and off therapy.
4.2.2
Block 2a and 2b Therapy
Criteria to begin Block 2 therapy: Patients who achieve an MRD-negative (MRD<0.01%) 
CR/CRi after Block 1 are recommended to wait up to 2 weeks for count recovery, defined 
as a WBC ≥1500/microL, ANC ≥500/microL and platelets ≥50,000/microL. Patients 
without count recovery at 2 weeks should have a repeat bone marrow assessment at 2 weeks 
to confirm continued MRD-negative remission but should then proceed with Block 2 
therapy. Patients who are MRD-positive after Block 1 should begin Block 2 when the MRD 
result is known and they have recovered from toxicities to ≤ grade 2. Variations needed for 
patient care are allowable but should be discussed with the PI.
4.2.2.1 Block 2a Therapy
For patients with ≥ 5% of leukemic blasts which do not have detectable CD19 on their 
surface (i.e., at least 5 of every 100 blasts do not express CD19), those with isolated 
extramedullary relapse, or whose physician determines this therapy arm is in their patient’s 
best interest. Patients with Down Syndrome are not eligible for Block 2a therapy. 
Patients in exploratory cohort O are not eligible for the phase I/ dose de-escalation phase 
of the study but may enroll on block 2 therapy after the dose has been established.
Agent
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
Dexamethasone
3mg/m2/dose BID PO/IV
10
Days 1-5
Calaspargase*
1000units/m2/dose IV
1
Day 3
Cytarabine
According to current dose level: see table below
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Agent
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
Dasatinib#
80mg/m2/day QD/PO (Max 
140mg)
28
Days 1-28
Venetoclax&
240mg/m2 (max 400mg) QD/PO
7
Days 1-7
Navitoclax&
50mg QD/PO (for patients 
≥45kg)
25mg (for patients 20 - <45kg)
7
Days 1-7
IT MHA
Methotrexate 12mg IT
Hydrocortisone 24mg IT
Cytarabine 36mg IT
1
With end of cycle 
bone marrow 
assessment
*Calaspargase may be replaced by alternative forms of asparaginase due to local practice or prior allergy. 
Asparaginase formulation must be documented in the research database. For patients in exploratory cohort 
N, asparaginase will be omitted. This omission should be documented in the research database.
# Dasatinib will be given to patients with ABL-class fusions (in-frame fusions of ABL1, ABL2, CSF1R, 
PDGFRB, PDGFRA, or LYN that include the tyrosine kinase domain) and those with non-ETP T-ALL/LLy.
&Patients with late relapse and MRD-negative response to Block 1 who are receiving a repeat of Block 2 
following interim continuation therapy will not receive venetoclax or navitoclax during the repeated Block 2 
therapy.
Cytarabine dosing during phase 1 portion for Block 2a
Dose level
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
1
3000mg/m2/dose q12h IV 
infusion over 3 hours 
4
Days 1-2
0
1500mg/m2/dose q12h IV 
infusion over 3 hours 
4
Days 1-2
-1
1000mg/m2/dose q12h IV 
infusion over 3 hours 
2
Day 1
Rules for dose selection are described in section 12.2.
All of the first 5 patients enrolled at dose level 1 tolerated therapy without a dose limiting toxicity 
as defined in section 12.2.2.2. With 5/5 patients tolerating this dose, dose level 1 was declared the 
recommended phase two dose and future patients will be enrolled at this RP2D.
4.2.2.2 Block 2b Therapy
For patients with >95% of leukemic blasts with detectable CD19 on their surface. Patients with 
isolated extramedullary relapse are ineligible for Block 2b therapy. Patients in exploratory 
cohort O are not eligible for the phase I/ dose de-escalation phase of the study but may enroll on 
block 2 therapy after the dose has been established.
Agent
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
Blinatumomab; 
for patients with 
end of Block 1 
MRD >5%
5mcg/m2/day (max 9mcg/day; 
patients weighing ≥45kg receive 
9mcg/day fixed dose) IV
7
Days 1-7
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Agent
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
Blinatumomab; 
for patients with 
end of Block 1 
MRD >5%
15mcg/m2/day (max 28mcg/day; 
patients weighing ≥45kg receive 
28mcg/day fixed dose) IV
21
Days 8-28
Blinatumomab; 
for patients with 
end of Block 1 
MRD ≤5%
15mcg/m2/day (max 28mcg/day; 
patients weighing ≥45kg receive 
28mcg/day fixed dose) IV
28
Days 1-28
Dexamethasone
10mg/m2 (max 20mg) 6-12 
hours and 5mg/m2 (max 20mg) 
30-60 minutes prior to day 1 
blinatumomab* PO/IV
2*
Day 1, 8*
Dasatinib#
80mg/m2/day QD/PO (Max 
140mg)
28
Days 1-28
Venetoclax&
 According to current dose level: see table below^
IT MHA
Methotrexate 12mg IT
Hydrocortisone 24mg IT
Cytarabine 36mg IT
1
Day 29 With end of 
cycle bone marrow
# Dasatinib will be given to patients with ABL-class fusions (in-frame fusions of ABL1, ABL2, 
CSF1R, PDGFRB, PDGFRA, or LYN that include the tyrosine kinase domain).
^ Venetoclax will be held for patient with a peripheral lymphocyte count (WBC x percent 
lymphocytes) <300/mm3 or if ANC <500/microL, or in the presence of grade 3 or higher cytokine 
release syndrome.
* For patients who start blinatumomab at 5mcg/m2/day, an additional dose of dexamethasone will 
be given on day 8 30-60 minutes prior to dose increase. For patients whose blinatumomab is 
interrupted for more than 4 hours for any reason, an additional dose of dexamethasone will be 
given prior to restarting blinatumomab.
&Patients with late relapse and MRD-negative response to Block 1 who are receiving a repeat of 
Block 2 following interim continuation therapy will not receive venetoclax during the repeated 
Block 2 therapy.
Patients with Down syndrome should receive leucovorin rescue after every IT (5 mg/m2 [max 
5mg] PO q6h x 2 doses starting 24 hours after IT).
Venetoclax dosing during phase 1 portion for Block 2b
Dose level
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
1
240mg/m2 (max 400mg) QD/PO 
21
Days 8-28
0
240mg/m2 (max 400mg) QD/PO 
14
Days 8-21
-1
240mg/m2 (max 400mg) QD/PO 
7
Days 8-14
Rules for dose selection are described in section 12.2.
All of the first 5 patients enrolled at dose level 1 tolerated therapy without a dose limiting toxicity 
as defined in section 12.2.2.2. With 5/5 patients tolerating this dose, dose level 1 was declared the 
recommended phase two dose and future patients will be enrolled at this RP2D.
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4.2.2.3
End of Block 2 Evaluations
Patients on Block 2A will undergo a bone marrow with count recovery ANC ≥ 300/microL and 
platelets ≥50,000/microL or on Day 35, whichever is sooner. 
Patients on Block 2b will undergo a bone marrow on Day 28-30. 
Patients who are MRD-negative without count recovery by Day 42 should undergo repeat bone 
marrow evaluation weekly until count recovery or Day 70. Patients without count recovery by 
Day 70 will be removed from protocol therapy. 
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4.2.3
Intensification Therapy
For late first relapse B-ALL and MRD<0.01% after Block 1 only. Patients in exploratory cohort 
O are excluded.
Patients should begin therapy when ANC ≥ 300/microL and platelets ≥50,000/microL.
Agent
Dose (with maximum daily dose if 
applicable) and Route
Number 
of 
doses
Schedule
HD-Methotrexate
5000mg/m2/dose IV: 500mg/m2 
over 60 minutes then 4500mg/m2 
over 23 hours; or targeted 65 
microM
2
Day 1, 15#
Mercaptopurine
50mg/m2/dose PO daily*
28
Days 1-28
IT MHA
Methotrexate 12mg IT
Hydrocortisone 24mg IT
Cytarabine 36mg IT
1
Day 15
Leucovorin
15mg/m2/dose 
PO/IV 
every 
6 
hours: Start 42 hours after HD-
MTX begins ^
At least 3
Days 2, 16
#The subsequent dose of high dose methotrexate and mercaptopurine will be delayed if ANC <300/mm3, 
WBC < 1500/mm3, platelet count < 50 x 109/L, SGPT >500 U/L, total bilirubin >2 mg/dl and direct bilirubin 
>1.4 mg/dl, or mucositis is present.
* Mercaptopurine may be held in the presence of ANC < 300/microL, WBC < 1,500/microL, platelet count < 
50x 109/L or grade 3 or 4 mucositis. Dosage of mercaptopurine may be reduced to 25 mg/m2/day in 
participants who have developed neutropenia after the first high dose methotrexate and mercaptopurine 
treatment. See section 5.2.7 for modifications of mercaptopurine based on TPMT status.
^ Patients with a history of Grade 3 or 4 gastrointestinal toxicities with prior methotrexate or a history of 
typhlitis with any chemotherapy should have leucovorin continue for 5, rather than 3 doses; those with early 
toxicity should have leucovorin begin at 36 hours with subsequent methotrexate. Leucovorin may be extended 
in the presence of evidence of mucositis or other methotrexate toxicity. Leucovorin dose should be increased 
if 42 hour MTX level is >1 microM and continued until the methotrexate concentration is less than the 
threshold level for toxicity (historically 0.1 microM by TDx assay; ~0.15 microM by ARK assay). See section 
5.2.2 for additional information
4.2.4
Interim Continuation Therapy 1 and 2 (8 weeks each)
For late first relapse B-ALL (see Section 3.3 for definitions) and MRD<0.01% after Block 1 only. 
Patients should begin therapy when ANC ≥ 500/microL and platelets ≥50,000/microL.
Agent
Dose (with maximum daily dose if 
applicable) and Route
Number 
of 
doses
Schedule
Dexamethasone
3mg/m2/dose BID PO/IV
10
Days 1-5
Vincristine
1.5mg/m2 (max 2mg) IV
1
Day 1
Mercaptopurine
75mg/m2/dose PO daily*
49
Days 1-49
Methotrexate
20mg/m2/dose PO/IV@
4
Days 
8, 
15, 29, 36
HD-Methotrexate
5000mg/m2/dose IV: 500mg/m2 
over 60 minutes then 4500mg/m2 
1
Day 22$
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Agent
Dose (with maximum daily dose if 
applicable) and Route
Number 
of 
doses
Schedule
over 23 hours; or targeted 65 
microM
Leucovorin
15mg/m2/dose PO/IV every 6 
hours: Start 42 hours after HD-
MTX^
At least 3
Days 24, 
25^
Cyclophosphamide
300mg/m2/dose IV over 15-30 
minutes
2
Days 43$, 
50
Etoposide
150mg/m2/dose IV over 1-2 hours
2
Days 43, 
50$
Cytarabine
50mg/m2/dose 
IV 
over 
1-30 
minutes
8
Days 44-
47, 51-54
Dasatinib#
80mg/m2/day QD/PO (Max 140mg)
56
Days 1-56
IT MHA
Methotrexate 12mg IT
Hydrocortisone 24mg IT
Cytarabine 36mg IT
2
Day 22, 43
*For patients with known heterozygous inactivating mutations of TPMT or NUDT15, reduce dose 
to 60mg/m2/day. For patients with known homozygous/ biallelic inactivating mutations, consult 
PI. Mercaptopurine dose may be decreased in the presence of neutropenia <500/microL or 
platelets <50,000/microL.
@IV delivery is preferred. PO is acceptable for logistical reasons, intolerance of IV delivery, and 
is preferred in patients who have previously received cranial radiation. Day 29 low-dose 
methotrexate may be delayed or omitted if a patient is still receiving leucovorin following HD-
MTX administration.
^Patients with a history of Grade 3 or 4 gastrointestinal toxicities with prior methotrexate or a 
history of typhlitis with any chemotherapy should have leucovorin continue for 5, rather than 3 
doses; those with early toxicity should have leucovorin begin at 36 hours with subsequent 
methotrexate. Leucovorin may be extended in the presence of evidence of mucositis or other 
methotrexate toxicity. Leucovorin dose should be increased if 42 hour MTX level is >1 microM 
and continued until the methotrexate concentration is less than the threshold level for toxicity 
(historically 0.1 microM by TDx assay; ~0.15 microM by ARK assay). See section 5.2.2 for 
additional information.
$ANC must be ≥500/microL and platelets must be ≥50,000/microL prior to Day 22 and 43/44 
therapies. Day 22 therapy may be delayed up to 1 week due to cytopenias. If counts have not 
recovered by day 29, omit HD-methotrexate and proceed with Day 29 low-dose methotrexate. 
Consider mercaptopurine dose modification if cytopenias precluded HD-methotrexate 
administration. Once Day 43 therapy begins, Day 44 therapy begins 1 day later and Day 50 
therapy proceeds 1 week from Day 43 therapy unless non-hematological toxicity precludes 
administration.
#Dasatinib will be given to patients with ABL-class fusions (in-frame fusions of ABL1, ABL2, 
CSF1R, PDGFRB, PDGFRA, or LYN that include the tyrosine kinase domain). Dasatinib should 
be held beginning 48 hours prior to HD-methotrexate administration and until methotrexate levels 
are <0.5microM without evidence of residual methotrexate toxicity (e.g. mucositis). Day 22 
intrathecal treatment should be given on the same day as HD-MTX administration. Consult the 
PI or clinical pharmacist if the IT and HD-MTX are separated by more than 12 hours.
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Following recovery from Interim Continuation therapy 1 (ANC must be ≥500/microL and 
platelets must be ≥50,000/microL), patients will repeat Block 2 therapy according to their initial 
Block assignment (2A for CD19-negative, 2B for CD19-positive) and receive a second cycle of 
interim continuation. Patients will not receive venetoclax or navitoclax during this repeated Block 
2 cycle. Following recovery from Interim Continuation 2, patients will proceed to Continuation 
therapy.
4.2.5 Continuation Therapy
For late first relapse B-ALL and MRD <0.01% after Block 1 only.
Continuation cycles last 8 weeks (56 days) each. Continuation therapy continues until 2 years 
from the start of protocol therapy.
Agent
Dose (with maximum daily dose if 
applicable) and Route
Number 
of doses
Schedule
Dexamethasone
6mg/m2/dose BID PO/IV
20
Days 1-5, 29-33
Vincristine
1.5mg/m2 (max 2mg) IV
2
Day 1, 29
Mercaptopurine
75mg/m2/dose PO daily*
56
Days 1-56
Methotrexate
20mg/m2/dose PO/IV@
6
Days 8, 15, 22, 36, 
43, 50
Dasatinib#
80mg/m2/day QD/PO (Max 140mg)
56
Days 1-56
IT MHA^
Methotrexate 12mg IT
Hydrocortisone 24mg IT
Cytarabine 36mg IT
1
Day 1, 29%
#Dasatinib will be given to patients with ABL-class fusions (in-frame fusions of ABL1, ABL2, 
CSF1R, PDGFRB, PDGFRA, or LYN that include the tyrosine kinase domain).
*For patients with known heterozygous inactivating mutations of TPMT or NUDT15, reduce dose 
to 60mg/m2/day. For patients with known homozygous/ biallelic inactivating mutations, consult 
PI.
@ IV delivery is preferred. PO is acceptable for logistical reasons, intolerance of IV delivery, and 
is preferred in patients who have previously received cranial radiation.
^For patients who are CNS3 at the time of relapse and receive radiation therapy after cycle 2 of 
continuation, IT MHA will be replaced by oral methotrexate 20mg/m2 on Day 1 of subsequent 
cycles. Lumbar puncture for monitoring of CNS remission is indicated every 2 cycles.
%Patients with CNS2 or traumatic lumbar puncture with blasts present at the time of relapse will 
receive day 1 and 29 IT MHA for the first year of continuation therapy. Following this, patients 
will receive IT MHA on day 1 of each cycle until the completion of therapy. Patients with CNS3 
disease at relapse will receive day 1 and 29 IT MHA during cycles 1 and 2 of continuation and 
then proceed to chemoradiation as described.
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4.2.6 Chemoradiation for those with CNS3 disease at relapse (late first relapse [≥36 months from 
diagnosis] B-ALL and MRD<0.01% after Block 1 only)
Patients with CNS3 disease at relapse will receive 18Gy cranial irradiation after Cycle 2 of 
Continuation Therapy. Patients will not receive additional intrathecal chemotherapy following 
irradiation. Chemoradiation lasts 21 days.
Agent
Dose (with maximum daily dose if 
applicable) and Route
Number 
of doses
Schedule
Dexamethasone
6mg/m2/dose BID PO/IV
20
Days 1-5, 15-19
Vincristine
1.5mg/m2 (max 2mg) IV
3
Day 1, 8, 15
Calaspargase*
2500units/m2/dose IV
1
Day 2
Dasatinib#
80mg/m2/day QD/PO (Max 140mg)
21
Days 1-21
*Calaspargase may be replaced by alternative forms of asparaginase due to local practice or prior 
allergy. Asparaginase formulation must be documented in the research database. If pegaspargase 
is used, two doses of 2500units/m2 may be given on Day 2 and 15 to replace the single Day 2 
dose of calaspargase. For patients in exploratory cohort N, asparaginase will be omitted. This 
omission should be documented in the research database.
#Dasatinib will be given to patients with ABL-class fusions (in-frame fusions of ABL1, ABL2, 
CSF1R, PDGFRB, PDGFRA, or LYN that include the tyrosine kinase domain).
4.2.7 Testicular Radiation
Patients with persistent testicular involvement by leukemia at the end of Block 1 may continue 
on study and may receive testicular radiation during Block 2 therapy. Suggested radiation for 
patients with persistent testicular involvement is 24Gy, although this can be adjusted due to prior 
therapy, plans for transplant, or other patient specific factors. Testicular radiation should be 
documented in the research database. Radiation should not be given concurrently with venetoclax 
or navitoclax.
Radiation for scenarios not described in sections 4.2.6 and 4.2.7 should be discussed with the PI. 
Radiation therapy techniques are at the treating physician’s discretion. 
5.0
DOSE MODIFICATIONS AND SUPPORTIVE CARE
5.1
Dose Modifications during Continuation Treatment
Dexamethasone and vincristine can be given regardless of counts. For all other drugs, doses 
are recommended to be reduced as follows:

WBC >1,500/mm3 and ANC >300 /mm3; give full dose 

WBC > 1,000/mm3 but <1,500/mm3 and ANC > 300 /mm3; reduce the dose by 50%.

WBC < 1,000/mm3 or ANC <300/mm3; hold chemotherapy.

Participants with an inactivating TPMT allele should receive no more than 60 
mg/m2 of 6MP.
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
Patients with recurrent myelosuppression should have doses of methotrexate and 
mercaptopurine reduced 50% with slow increases back to protocol dose as 
tolerated.

Patients receiving dasatinib who experience recurrent myelosuppression may 
decrease dasatinib to 60mg/m2/day or 100mg/day.
5.2
Dose Modifications for Agent-Specific Toxicity
5.2.1
Asparaginase Toxicity
Asparaginase may be dosed based on ideal body weight or the dose may be capped at 
3,750u/ dose based on local practice.
Allergic reactions
Patients with allergic reactions to Pegaspargase or calaspargase pegol may receive 
desensitization (prolonged administration with anti-allergic premedication), Erwinia 
asparaginase at 25,000 units/m2/dose IM thrice weekly (2 to 3 days apart, e.g., Monday, 
Wednesday and Friday), or (if FDA approved for use in pediatric patients with ALL), 
Recombinant Crisantaspase Pseudomonas fluorescens (RC-P) at the FDA approved dose. 
Patients who undergo desensitization for allergic reactions should be monitored for rapid 
drug clearance resulting in asparaginase activity < 0.1 IU/mL on Day 15. Patients receiving 
Erwinia or RC-P during Block 2A either due to allergy or local practice will receive only 
a single dose (25,000 units/m2 Erwinia) on day 3, while dosing during Block 1 will be 
thrice weekly as described. Premedication prior to asparaginase of all forms may be given 
at the investigator’s discretion.
Pancreatitis
Acute hemorrhagic pancreatitis is a contraindication to continue calaspargase pegol and 
PEG-asparaginase treatment. In the case of mild to moderate pancreatitis, calaspargase or 
PEG-asparaginase should be held until symptoms and signs subside, and amylase and 
lipase levels return to normal and then resumed. Any participants with abdominal pain 
suspected of pancreatitis should have serum amylase and lipase measured as well as an 
abdominal sonogram or CT scan done. In the case of severe pancreatitis (i.e. abdominal 
pain of 72 hours or more, amylase and lipase level three times or more of the upper limit 
of normal, and sonographic or CT scan evidence of pancreatitis), calaspargase or PEG-
asparaginase may be discontinued permanently when the possibility of glucocorticoid- or 
mercaptopurine induced pancreatitis is excluded. In cases with mild to moderate 
pancreatitis (abdominal pain less than 72 hours and amylase and lipase level less than three 
times the upper limit of normal), calaspargase or PEG-asparaginase should be held and 
resumed once symptoms and signs subsided. Call the PI to discuss the management if the 
patient is asymptomatic (without abdominal pain) and has only elevated amylase or lipase 
levels.
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5.2.2
High Dose Methotrexate 
Participants with Down Syndrome
Dosage of high dose methotrexate in patients with Down Syndrome receiving interim 
continuation therapy will be modified because participants with Down syndrome have 
altered MTX pharmacokinetics and enhanced tissue sensitivity to the effects of MTX. The 
hydration and alkalinization regimen should be the same as outlined in Section 5.2.13. 
However, the dose of HD-MTX should be 500 mg/m2 (50 mg/m2 over 1 h and 450 mg/m2 
given over 23 h). Baseline leucovorin rescue will begin early (at hour 30 at 30 mg/m2 IV 
q6h × 2 doses, followed by 10 mg/m2 IV q6h × 6 doses). If MTX plasma levels are elevated, 
increased leucovorin rescue is recommended. Vigorous hydration should be ensured until 
the 42-hr MTX level is known.
Hepatic dysfunction
High-dose methotrexate should be withheld if there is evidence of existing mucositis or if 
total bilirubin >2 mg/dl and direct bilirubin >1.4 mg/dl. Subclinical hypertransaminasemia 
(SGPT >500 IU/L) is an indication to delay only high dose methotrexate but no other 
chemotherapy.
Renal dysfunction
Subclinical renal impairment (normal serum creatinine but decreased GFR) may be present 
in patients receiving concurrent nephrotoxic drugs (e.g. IV acyclovir) which, if possible, 
should be held during and for 20 hours after HD-MTX infusions or until adequate MTX 
clearance has been documented. Consideration to delaying MTX administration should be 
given if a patient's serum creatinine indicates renal impairment, and/or GFR/CrCl is < 50 
ml/min/1.73m2.
SLCO1B1 inhibitors
Coadministration of high dose methotrexate with SLCO1B1 inhibitors such as proton 
pump inhibitors, aminopenicillins, or dasatinib may result in delayed methotrexate 
clearance and increased toxicity. These agents should be held for at least 48 hours prior to 
high-dose methotrexate and until methotrexate clearance is complete.
5.2.3
Etoposide Toxicity
Hepatic dysfunction
Etoposide should be modified in participants with elevated direct bilirubin concentrations 
or other evidence of biliary obstruction:

Direct bilirubin 2-4 mg/dl: 50% dosage decrease

Direct bilirubin 4-6 mg/dl: 75% dosage decrease

Direct bilirubin >6 mg/dl: withhold dose
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Renal dysfunction
Both renal and liver functions affect drug clearance. Each route of clearance takes on added 
significance with higher vs lower doses and short vs long IV infusions. The following dose 
adjustment should be performed.

GFR/CrCl 10-50 mL/minute/1.73m2: Administer 75% of dose.

GFR/CrCl <10 mL/minute/1.73m2: Administer 50% of dose.

Hemodialysis/peritoneal dialysis (PD) (after dialysis on dialysis days): administer 
50% of dose.

Continuous renal replacement therapy (CRRT): Administer 75% of dose and 
reduce for hyperbilirubinemia.
Hypotension
Transient hypotension has occurred in about 1 to 2 % of participants following rapid IV 
administration of etoposide during clinical trials. However, hypotension has not been 
associated with cardiac toxicity or electrocardiogram changes. Blood pressure usually 
normalizes within a few hours after discontinuation of the infusion. To avoid this 
complication, etoposide should be infused over 30 – 60 minutes. If hypotension should 
occur, stop the infusion, and if necessary, give 10 mL/kg NS bolus over 15 minutes. Repeat 
as necessary. Once symptoms resolve, resume infusion at ½ the previous infusion rate until 
the full dose administered. If hypotension recurs, stop infusion and administer 10 mL/kg 
NS bolus as indicated. Once hypotension resolves, resume infusion at ½ previous infusion 
rate until complete. Consider infusing NS at 1 – 1.5 x maintenance during remainder of 
infusion. For all subsequent doses, further dilute and infuse over 2 hours.
Sensitivity reactions
Anaphylactoid reactions consisting principally of chills, rigors, diaphoresis, pruritis, loss 
of consciousness, nausea, vomiting, fever, bronchospasm, dyspnea, tachycardia, 
hypertension, and/or hypotension have occurred in 0.7 – 3% of patients receiving 
etoposide. Other manifestations include flushing, rash, substernal chest pain, lacrimation, 
sneezing, coryza, throat pain, back pain, abdominal cramps, and auditory impairment. 
Facial/lingual swelling, coughing, diaphoresis, cyanosis, tightness in the throat, and 
laryngospasm have also occurred. If an anaphylactoid reaction should occur:
1. Stop the infusion immediately
2. Administer the following as indicated:
a.
diphenhydramine 1mg/kg IV (max dose 50 mg) or similar anti-histamine 
according to institutional practice.
b. hydrocortisone 50 – 100 mg/m2 IV
c.
epinephrine 0.01 mg/kg of a 1:1000 concentration for SQ administration (max. 
0.5 mg)
d. fluid bolus 10 mL/kg NS infused over 15 minutes
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3. Once symptoms have resolved, resume infusion at ½ previous rate until infusion 
complete. Consider infusing NS at 1 – 1.5 x maintenance during remainder of 
infusion.
4. If anaphylaxis recurs, stop the infusion and re-treat as above. Do not administer 
remainder of dose. Consider substituting etoposide with etoposide phosphate 
(Etopophos®) for all subsequent doses.
5. If anaphylaxis does not recur, pre-medicate all subsequent doses with 
diphenhydramine 1mg/kg (max 50 mg) and hydrocortisone 50 – 100 mg/m2. 
Consider slowing the loading dose to be administered over 1 hour.
6. Have at bedside all of the following for all subsequent infusions:
a.
Diphenhydramine 1mg/kg IV (max 50 mg)
b. Hydrocortisone 50 – 100 mg/m2 IV
c.
Epinephrine 0.01 mg/kg of a 1:1000 concentration for SQ administration (max 
0.5 mg)
5.2.4
Venetoclax Toxicity
Venetoclax should be reduced 50% in patients with a direct bilirubin of 4-6 mg/dl and held 
in patients with a direct bilirubin >6 mg/dl.85 
Venetoclax must be dose adjusted if given with moderate-strong CYP3A inhibitors. See 
Appendix III for a list of prohibited CYP3A inducers and a list of CYP3A inhibitors 
requiring dose adjustment. See appendix IV for appropriate dose adjustments in the 
presence of strong-moderate CYP3A inhibitors. These dose adjustments and the reason for 
adjustment should be included in the research database.
5.2.5
Vincristine Toxicity
Neurotoxicity
Mild vinca alkaloid toxicities are anticipated. These include jaw pain, constipation, 
decreased deep tendon reflexes. If there are persistent severe abdominal cramps, gait 
impairment, severe pain that requires narcotics or SIADH develops, the dose may be 
reduced to 50%. Motor paralysis or typhlitis will warrant temporary discontinuation of 
vincristine.
Hepatic dysfunction
Vincristine should be modified in participants with elevated direct bilirubin concentrations 
or other evidence of biliary obstruction.

Direct bilirubin 2-4 mg/dl: 50% dosage decrease

Direct bilirubin 4-6 mg/dl: 75% dosage decrease

Direct bilirubin >6 mg/dl: withhold dose
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5.2.6
Blinatumomab Toxicity
Adverse 
Reaction
Grade
Patients Weighing 45 kg or More
Patients Weighing Less than 45 kg
Grade 3
Interrupt Blinatumomab
Administer dexamethasone 8 mg 
every 8 hours IV or orally for up 
to 3 days and taper thereafter 
over 4 days
When CRS is resolved, restart 
blinatumomab at 9 mcg/day, and 
escalate to 28 mcg/day after 7 
days if the adverse reaction does 
not recur.

Interrupt blinatumomab

Administer dexamethasone 5 
mg/m2 (max 8 mg) every 8 hours 
intravenously or orally for up to 3 
days and taper thereafter over 4 
days.

When CRS is resolved, restart 
blinatumomab at 5 mcg/m2/day, 
and escalate to 15 mcg/m2/day 
after 7 days if the adverse 
reaction does not recur.
Cytokine Release 
Syndrome (CRS)
Grade 4
Discontinue blinatumomab permanently. Administer dexamethasone as 
instructed for Grade 3 CRS
Seizure
Discontinue blinatumomab permanently if more than one seizure occurs
Grade 3
Withhold blinatumomab until no 
more than Grade 1 (mild) and for at 
least 3 days, then restart 
blinatumomab at 9 mcg/day. 
Escalate to 28 mcg/day after 7 days 
if the adverse reaction does not 
recur. If the adverse reaction 
occurred at 9 mcg/day, or if the 
adverse reaction takes more than 7 
days to resolve, discontinue 
blinatumomab permanently
Withhold blinatumomab until no 
more than Grade 1 (mild) and for at 
least 3 days, then restart 
blinatumomab at 5 mcg/m2/day. 
Escalate to 15 mcg/m2/day after 7 
days if the adverse reaction does not 
recur. If the adverse reaction 
occurred at 5 mcg/m2/day, or if the 
adverse reaction takes more than 7 
days to resolve, discontinue 
blinatumomab permanently.
Neurological 
Toxicity
Grade 4
Discontinue blinatumomab permanently
Other Clinically 
Relevant Adverse 
Reactions
Grade 3
Withhold blinatumomab until no 
more than Grade 1 (mild), then 
restart blinatumomab at 9 mcg/day. 
Escalate to 28 mcg/day after 7 days 
if the adverse reaction does not 
recur. If the adverse reaction takes 
more than 14 days to resolve, 
discontinue blinatumomab 
permanently
Withhold blinatumomab until no 
more than Grade 1 (mild), then 
restart blinatumomab at 5 
mcg/m2/day. Escalate to 15 
mcg/m2/day after 7 days if the 
adverse reaction does not recur. If 
the adverse reaction takes more than 
14 days to resolve, discontinue 
blinatumomab permanently.
Grade 4
Consider discontinuing blinatumomab permanently.
These are strong recommendations. Variations from these recommendations should be discussed with the PI and documented
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5.2.7
TPMT and NUDT15 Status and Thiopurine Dosage 
Participants who have at least one mutant TPMT allele often require dosage decreases of 
6MP to avoid severe myelosuppression.86,87 Thus, we recommend that participants with 
phenotype or genotype consistent with at least one variant allele start mercaptopurine at 60 
mg/m2 and adjust the subsequent doses according to blood count and red blood cell 6 
thioguanine nucleotide level. Patients with two copies of non-functional TPMT alleles 
should have mercaptopurine dose adjusted in discussion with the PI. For the participants 
who did not have TPMT/NUDT15 testing in the frontline protocol and will receive 
mercaptopurine, a blood sample (5-10 ml) will be drawn along with routine lab work at the 
start of Block 2 to allow for timely TPMT genotyping and/or phenotyping. In participants 
in whom TPMT genotype and phenotype are discordant, or in whom suspected 
noncompliance, problems with toxicities or high blood counts are present, samples for red 
blood 6TGN and/or repeat TPMT activity may be measured. The dose of 6MP may be 
adjusted based on participants’ TPMT status, 6TGN levels and WBC.
Similarly, patients with inherited non-functional alleles in NUDT15 also experience 
excessive myelosuppression and can tolerate significantly lower mercaptopurine dosages 
during maintenance therapy.86,88-90 NUDT15 encodes nucleotide diphosphatase which 
directly inactive thiopurine metabolites. In vitro and in vivo data indicate that loss of 
NUDT15 (e.g., patients inheriting no functional alleles) leads to increased levels of 
thiopurine active metabolite (TGTP) and higher incorporation of thioguanine into DNA 
(DNA-TG) and thus toxicity. Because ALL blasts with non-functional NUDT15 alleles are 
also more sensitive to thiopurine,91 reduction of mercaptopurine dose in at-risk patients is 
likely to mitigate toxicity without compromising anti-leukemic efficacy. Following the 
same principle of TPMT-driven thiopurine dosing, the starting dose of mercaptopurine 
should be adjusted to 60 mg/m2/day for patients with only one copy of non-functional 
NUDT15 alleles. Patients with two copies of non-functional NUDT15 alleles should have 
mercaptopurine dose adjusted in discussion with the PI.
5.2.8
Obesity
Actual body weight will be used to calculate body surface area in all participants and used 
for dosage calculations.
5.2.9
Minor Modifications
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on 
established standards of care. Minor unavoidable departures (up to 72 hours) from protocol 
directed therapy and/or disease evaluations for valid clinical, patient and family logistical, 
or facility, procedure and/or anesthesia scheduling issues are acceptable. 
The term “every” is an approximate term meaning that these medications noted will be 
administered approximately “every” 12 hours. The drug administration timing in the case 
of “every 12 hours” may be modified by approximately +/- 4 hours or as clinically indicated 
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such as in the case of surgical procedures or to accommodate other necessary medication, 
blood product delivery or procedures (such as a needed CT scan). 
The term “day” does not refer to an absolute calendar day. It refers to a general 24-hour 
period. 
Medication doses may be rounded to the nearest integer or to the nearest appropriate 
quantity when clinically or pharmaceutically indicated as per the MD and PharmD.
5.2.10 Dose Modifications for Collaborating Sites 
Doses of intrathecal therapy may be modified to match institutional standard practice. 
Single agent intrathecal cytarabine or methotrexate may be administered if standard 
practice at collaborating institutions. Mercaptopurine doses may be modified such that the 
weekly total dose is equal with differing doses given on differing days of the week to 
support the use of pills/ tablets. There are no other dose modifications anticipated for 
collaborating sites.
5.2.11 Participation of St. Jude Affiliates in the Treatment Plan 
Patients with late 1st relapse B-ALL who are MRD-negative at the end of Block 1 may 
receive treatment after Block 2a or 2b (including the repeat of block 2a or 2b without 
venetoclax or navitoclax) at St. Jude affiliates.
5.2.12 Concomitant Therapy
Additional, non-protocol specified, leukemia directed therapy while receiving protocol 
therapy is prohibited. Use of steroids for other reasons (e.g. as premedication) is allowed.
5.2.13 Supportive Care
Prophylaxis and Treatment of Tumor Lysis Syndrome
Although not reported among patients with ALL, significant tumor lysis syndrome (TLS) 
has been observed in patients with CLL who were treated with venetoclax. Therefore, 
during Block 1, all patients should receive IV hydration at 1500-3000 mL/m2/day, starting 
prior to the first dose of venetoclax and continuing until 24 hours after the administration 
of the first dose of navitoclax. Patients will receive allopurinol unless there is a specific 
contraindication and should also receive oral phosphate binders or recombinant urate 
oxidase as needed. Tumor lysis labs, including potassium, calcium, phosphate, uric acid, 
and creatinine, will be monitored prior to the first dose and every 6-8 hours until 24 hours 
after the first dose of navitoclax is given. A physician or designee should review TLS labs 
prior to each ramp-up dose.
Venetoclax and navitoclax should be held in patients who develop significant TLS, 
including, but not limited to grade 3 or greater hyperkalemia, grade 3 or greater acute 
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kidney injury, and grade 3 TLS. Venetoclax and navitoclax should be resumed at the 
planned dose when electrolyte abnormalities related to TLS resolve or return to baseline.
Hydration for High Dose Methotrexate
The following guidelines for hydration during and around high dose methotrexate are 
strongly recommended. Minor deviations to match institutional practice are allowed. 
At least two hours before high dose methotrexate, pre-hydration IV fluid (D5W + 40 mEq 
NaHCO3/L + 20 mEq KCl/L) will be administered at the rate of 200 ml/m2/hr. At start of 
pre-hydration, one IV dose of NaHCO3 (25 mEq/m2) diluted in 50 ml D5W will be given 
over 15 minutes. Pre-hydration fluid may also be given overnight at a rate of at least 125 
ml/m2/hr. High-dose methotrexate treatment will follow, provided that urinary pH is ≥ 6.5.
During the methotrexate infusion, participants should receive hydration fluid with D5W + 
40 mEq/L NaHCO3 + 20 mEq KCl/L at 125-150 ml/m2/hr. Urine pH will be monitored 
with each void during infusion. An IV bolus of 12 mEq/m2 NaHCO3 will be given if urine 
pH is 6.0 and 25 mEq/m2 will be given if urine pH is <6.0. Acetazolamide 500 mg/m2 
orally every 6 to 8 hours may be used if systemic alkalosis limits the administration of 
bicarbonate for urinary alkalinization. Participants with evidence of renal dysfunction or 
delayed clearance during the methotrexate infusion may receive less than a 24 hour 
methotrexate infusion. Hydration fluids should continue until the last dose of leucovorin 
rescue is given.
Leucovorin Rescue for High Dose Methotrexate
Leucovorin, 15 mg/m2 (IV or PO) will be started at 42 hours after the start of methotrexate 
and repeated every 6 hours for a total of three to five doses, as determined by primary 
physician and Pharm D based on patient’s prior treatment history or present condition. The 
dosage of leucovorin will be increased in participants with high plasma methotrexate 
concentrations (>1.0 microM at 42 hours) and continued until the methotrexate 
concentration is less than the threshold level for toxicity (historically 0.1 microM by TDx 
assay; ~0.15 microM by ARK assay). Additional measures, such as hydration, 
hemoperfusion, or carboxypeptidase will be considered in participants with 42-hour 
methotrexate levels > 10 microM. Participants with a history of delayed Grade 3 or 4 
gastrointestinal toxicity with prior methotrexate or a history of typhlitis with any 
chemotherapy should have leucovorin continue for 5 doses; those with early toxicity should 
have leucovorin begin at 36 hours with subsequent methotrexate; if toxicity recurs, the 
baseline leucovorin dosage should also be increased.
Prophylactic Antibiotics during Periods of Immunosuppression
All patients should receive prophylactic antibiotics (levofloxacin preferred) and 
antifungals (micafungin or caspofungin preferred during concomitant venetoclax therapy, 
voriconazole or posaconazole during periods without venetoclax) from the start of therapy 
(if neutropenic at therapy start) or onset of neutropenia (ANC <500/microL) until 
neutrophil recovery. Azoles, if used, should be held for 24 hours before and after 
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vincristine. Use of an azole with venetoclax requires venetoclax dose adjustment as 
described in Appendix IV . If azoles are used in a patient receiving dasatinib, the dasatinib 
dose should be reduced by 75% (i.e. to 20mg/m2/day or a max of 40mg/day).
Prophylaxis for Pneumocystis jiroveci Pneumonia
All participants should receive TMP/SMZ (trimethoprim 150 mg/m2/day in 2 divided doses 
on Monday, Tuesday, and Wednesday of each week) or according to institutional 
guidelines. For those who cannot tolerate TMP/SMZ, monthly pentamidine may be 
substituted. Other options include atovaquone or dapsone.
Immunoglobulin prophylaxis
Low levels of gamma globulin are common in children with relapsed ALL. Monitoring of 
IgG levels should be considered throughout treatment. If the IgG level falls below age-
determined normal levels (recommended threshold 400mg/dl), administration of IVIG at 
400 mg/kg is recommended.
Vomited Doses
If doses of venetoclax or navitoclax are vomited within one hour of ingestion, it will be 
replaced. If vomiting occurs more than 1 hour after dosing, it will be considered a complete 
dose.
Delayed or Missed Doses
Both venetoclax and navitoclax will be administered as an oral tablet. The tablets are 
intended to be swallowed intact and are not to be crushed or otherwise altered for 
administration.
If a dose of venetoclax and/or navitoclax is missed by less than 8 hours, the dose should be 
taken right away. The next dose should be taken at the usual time the next day. If a dose of 
venetoclax and/or navitoclax is missed by more than 8 hours, the dose should not be taken 
that day. The next dose should be taken at the usual time the next day.
Growth Factors
Prophylactic use of hematopoietic growth factors (GM-CSF or G-CSF) is not 
recommended. However, GM-CSF (250 mcg/m2/day) or G-CSF (5-10 mcg/kg/day) may 
be considered for participants who have life threatening fungal infections or bacterial sepsis 
after discussion with PI. Use of growth factors must be documented in the research 
database. Biosimilar versions of G-CSF are allowed. Long acting G-CSF such as 
Pegfilgrastim is not allowed.
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Management of Febrile Neutropenia
All patients with fever ≥ 38.3° C on a single occasion or ≥ 38.0°C that persists for one hour 
should be hospitalized and treated immediately with broad spectrum antibiotics according 
to institutional guidelines.
6.0
DRUG INFORMATION
Dose rounding at St. Jude will be allowed according to institutional policy (See St. Jude 
Policy # 20.109, Institutional Policy and Procedure Manual). 
Dose rounding for standard of care medications may follow each institution’s policy.
6.1
Venetoclax (ABT-199)
Source and pharmacology: Venetoclax is a selective and orally bioavailable small-
molecule inhibitor of BCL2, an antiapoptotic protein. Overexpression of BCL2 has been 
demonstrated in CLL cells where it mediates tumor cell survival and has been associated 
with resistance to chemotherapeutics. Venetoclax helps restore the process of apoptosis by 
binding directly to the BCL2 protein, displacing pro-apoptotic proteins like BIM, 
triggering mitochondrial outer membrane permeabilization and the activation of caspases. 
In nonclinical studies, venetoclax has demonstrated cytotoxic activity in tumor cells that 
overexpress BCL2.
Formulation and stability: Venetoclax tablets for oral administration are supplied in bottles 
or blister cards that contain 10, 50, or 100 mg venetoclax as the active ingredient. 
Venetoclax dispersible tablets for oral suspension are supplied in blister cards that contain 
25 mg tablets. Venetoclax powder sachets contain 3, 10, 25, or 100 mg of venetoclax and 
are packaged in bottles or cartons or in blisters in cartons. See clinical label for appropriate 
storage condition requirements.
 
Supplier: AbbVie, Inc.
Toxicity: The safety of single agent venetoclax at the 400 mg recommended daily dose 
following a dose ramp-up schedule is based on pooled data of 240 patients with previously 
treated CLL from two phase 2 trials and one phase 1 trial. In the pooled dataset, the median 
age was 66 years (range: 29 to 85 years), 95% were white, and 69% were male. The median 
number of prior therapies was 3 (range: 1 to 12). The median duration of treatment with 
venetoclax at the time of data analysis was approximately 10.3 months (range: 0 to 34.1 
months). Approximately 46% of patients received venetoclax for more than 48 weeks. The 
most common adverse reactions (≥20%) of any grade were neutropenia, diarrhea, nausea, 
anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Serious adverse 
reactions were reported in 43.8% of patients. The most frequent serious adverse reactions 
(≥2%) were pneumonia, febrile neutropenia, pyrexia, autoimmune hemolytic anemia 
(AIHA), anemia, and TLS. Discontinuations due to adverse reactions occurred in 8.3% of 
patients. The most frequent adverse reactions leading to drug discontinuation were 
thrombocytopenia and AIHA. Dosage adjustments due to adverse reactions occurred in 
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9.6% of patients. The most frequent adverse reactions leading to dose adjustments were 
neutropenia, febrile neutropenia, and thrombocytopenia. See Investigational Brochure for 
additional information.
Dosage and route of administration: Oral. See Treatment and Dose Modifications sections 
of the protocol.
Accountability: Because this study is being conducted under an IND, participating 
pharmacies will be required to submit Drug Accountability Logs at the time of monitoring 
documenting receipt and shipment of drug supply, dispensing/ordering of supply, and 
destruction of unused study medication and/or damaged or expired drug.
6.2
Navitoclax
Source and pharmacology: Navitoclax is an oncolytic agent designed to bind and inhibit 
antiapoptotic Bcl-2 family proteins with high affinity. Thus, it selectively induces program 
death in cells that have a Bcl-2 protein ratio shifted towards survival as observed in human 
cell lines derived from small cell lung carcinomas and lymphoid malignancies 
(concentration required for 50% effect [EC50] ≤ 1 μM). Additionally, navitoclax potently 
enhances the cytotoxicity of both chemotherapy and radiation in cells derived from 
multiple, major tumor types, regardless of whether single-agent efficacy is achieved.
Formulation and stability: Navitoclax is available in 25 mg tablets in 30 count HDPE 
bottles, which should be stored at 15º to 25ºC (59º to 77ºF).
Supplier: AbbVie, Inc.
Toxicity: The most common toxicities include thrombocytopenia, lymphopenia and 
neutropenia. See Investigator’s brochure for additional information.
Dosage and route of administration: Oral, see Treatment and Dose Modifications sections 
of the protocol.
Accountability: Because this study is being conducted under an IND, participating 
pharmacies will be required to submit Drug Accountability Logs at the time of monitoring 
documenting receipt and shipment of drug supply, dispensing/ordering of supply, and 
destruction of unused study medication and/or damaged or expired drug.
6.3
Dexamethasone
Source and pharmacology: Dexamethasone is a synthetic fluorinated glucocorticoid devoid 
of mineralocorticoid effects. Dexamethasone, 0.75 mg, has potent anti-inflammatory 
activity equivalent to approximately 5 mg of prednisone. Glucocorticoids produce 
widespread and diverse physiologic effects on carbohydrate, protein, and lipid metabolism, 
electrolyte and water balance, functions of the cardiovascular system, kidney, skeletal 
muscle, and the nervous systems. Glucocorticoids reduce the concentration of thymus-
dependent lymphocytes (T-lymphocytes), monocytes, and eosinophils. Glucocorticoids 
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selectively bind to the cortisol receptors on human lymphoid cells which are found in larger 
numbers on leukemic lymphoblasts. They also decrease binding of immunoglobulin to cell 
surface receptors and inhibit the synthesis and/or release of interleukins, thereby decreasing 
T-lymphocyte blastogenesis and reducing expansion of the primary immune response. The 
specific cellular mechanisms that act to halt DNA synthesis are thought to be related to 
inhibition of glucose transport or phosphorylation, retardation of mitosis, and inhibition of 
protein synthesis. Elimination half-lives for the following age groups have been reported 
to be: infants and children under 2 years of age: 2.3 to 9.5 hours, 8 to 16 years: 2.82 to 7.5 
hours, and adults (age not specified): 3 to 6 hours. The biologic half-life is 36-72 hours. It 
is primarily metabolized in the liver and excreted by the kidneys.
Toxicities (>20%): Insomnia, hyperphagia, immunosuppression, personality changes 
(mood swings, euphoria, anxiety, and depression), pituitary-adrenal axis suppression, acne 
(L) Cushing’s syndrome (moon facies, truncal obesity).
Formulation and stability: Oral: Available in 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, 
and 6 mg tablets; liquid formulations are available in 0.5 mg/5 mL and 1 mg/1 mL 
concentrations. Liquid formulations may include: 5%-30% alcohol, benzoic acid, sorbitol, 
sodium saccharin, glycerin, purified water, and various dyes. Injection: Dexamethasone 
Sodium Phosphate Solution for Injection is available as 4 mg/mL (1 mL, 5 mL, and 30 mL 
vials) and 10 mg/mL (1 mL and 10 mL vial sizes). Vials are available in multi-dose vials 
as well as unit of use vials and syringes.
Guidelines for administration: See Treatment and Dose Modifications sections of the 
protocol. Tablets and oral solution are preferred; intravenous preparations may be used if 
needed.
Supplier: Commercially available. See package insert for further information.
6.4
Vincristine
Source and pharmacology: Vincristine is an alkaloid isolated from Vinca rosea Linn 
(periwinkle). It binds to tubulin, disrupting microtubules and inducing metaphase arrest. 
Its serum decay pattern is triphasic. The initial, middle, and terminal half-lives are 5 
minutes, 2.3 hours, and 85 hours respectively; however, the range of the terminal half-life 
in humans is from 19 to 155 hours. The liver is the major excretory organ in humans and 
animals; about 80% of an injected dose of vincristine sulfate appears in the feces and 10% 
to 20% can be found in the urine. The p450 cytochrome involved with vincristine 
metabolism is CYP3A4. Within 15 to 30 minutes after injection, over 90% of the drug is 
distributed from the blood into tissue, where it remains tightly, but not irreversibly bound. 
It is excreted in the bile and feces. There is poor CSF penetration.
Toxicities (>20%): Alopecia, constipation, loss of deep tendon reflexes.
Formulation and stability: vincristine is supplied in 1 mL and 2 mL vials in which each mL 
contains vincristine sulfate 1 mg (1.08 μmol), mannitol 100 mg, SWFI; acetic acid and 
sodium acetate are added for pH control. The pH of vincristine sulfate injection, USP 
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ranges from 3.5 to 5.5. This product is a sterile, preservative free solution. Store 
refrigerated at 2˚-8˚C or 36˚-46˚F. Protect from light and retain in carton until time of use. 
Do not mix with any IV solutions other than those containing dextrose or saline.
Guidelines for administration: See Treatment and Dose Modifications sections of protocol. 
The World Health Organization, the Institute of Safe Medicine Practices (United States) 
and the Safety and Quality Council (Australia) all support the use of minibag rather than 
syringe for the infusion of vincristine. Vincristine should NOT be delivered to the patient 
at the same time with any medications intended for central nervous system administration. 
Vincristine is fatal if given intrathecally.
Injection of vincristine sulfate will be as per institutional policy. Vincristine sulfate must 
be administered via an intact, free-flowing intravenous needle or catheter. Care should be 
taken to ensure that the needle or catheter is securely within the vein to avoid extravasation 
during administration. The solution may be injected either directly into a vein or into the 
tubing of a running intravenous infusion.
Special precautions: FOR INTRAVENOUS USE ONLY. The container or the syringe 
containing vincristine must be enclosed in an overwrap bearing the statement: “Do not 
remove covering until moment of injection. For intravenous use only - fatal if given by 
other routes.
Supplier: Commercially available. See package insert for further information.
Guidelines for administration: See Treatment and Dose Modifications sections of the 
protocol.
6.5
Pegaspargase
Source and pharmacology: Pegaspargase is a modified version of the enzyme L-
asparaginase. L-asparaginase is modified by covalently conjugating units of 
monomethoxypolyethylene glycol (PEG), molecular weight of 5000, to the enzyme, 
forming the active ingredient PEG-L-asparaginase. The L-asparaginase (L-asparagine 
amidohydrolase, type EC-2, EC 3.5.1.1) used in the manufacture of Pegaspargase is derived 
from Escherichia coli which is purchased in bulk from Merck, Sharp and Dohme. L-
asparagine is a nonessential amino acid synthesized by the transamination of L-aspartic acid 
by a reaction catalyzed by the enzyme L-asparagine synthetase. The ability to synthesize 
asparagine is notably lacking in malignancies of lymphoid origin. Asparaginase depletes L-
asparagine from leukemic cells (especially lymphoblasts) by catalyzing the conversion of 
L-asparagine to aspartic acid and ammonia. In predominately L-asparaginase naive adult 
patients with leukemia and lymphoma, initial plasma levels of L-asparaginase following 
intravenous administration of pegaspargase were determined. Apparent volume of 
distribution was equal to estimated plasma volume. L-asparaginase was measurable for at 
least 15 days following the initial treatment with Pegaspargase. The approximate t½ in adult 
patients is 5.73 days. The enzyme could not be detected in the urine. The half-life is 
independent of the dose administered, disease status, renal or hepatic function, age, or 
gender. In a study of newly diagnosed pediatric patients with ALL who received either a 
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single intramuscular injection of pegaspargase (2500 units/m2), E. coli L-asparaginase 
(25000 units/m2), or Erwinia (25000 units/m2), the plasma half-lives for the three forms of 
L-asparaginase were: 5.73 ± 3.24 days, 1.24 ± 0.17 days, and 0.65 ± 0.13 days respectively. 
The plasma half-life of pegaspargase is shortened in patients who are previously 
hypersensitive to native L-asparaginase as compared to non-hypersensitive patients. L-
asparaginase is cleared by the reticuloendothelial system and very little is excreted in the 
urine or bile. Cerebrospinal fluid levels are <1% of plasma levels.
Toxicities (>20%): Allergic reactions (total likelihood of local, and or systemic reaction 
especially if previous hypersensitivity reaction to native asparaginase), pain at injection 
site, weakness, fatigue, diarrhea, hyperammonemia (late), coagulation abnormalities with 
prolonged PTT, PT and bleeding times (secondary to decreased synthesis of fibrinogen, 
AT-III & other clotting factors) (late).
Formulation and stability: Each milliliter of pegaspargase contains: PEG-L-asparaginase 
750 IU ± 20%, monobasic sodium phosphate, USP 1.20 mg ± 5% dibasic sodium 
phosphate, USP 5.58 mg ± 5%, sodium chloride, USP 8.50 mg ± 5% , Water for Injection, 
USP qs to 1 mL. The specific activity of pegaspargase is at least 85 IU per milligram 
protein. Available in 5 mL vials as Sterile Solution for Injection in ready to use single-use 
vials, preservative free. Keep refrigerated at 2°-8°C (36°-46°F). Do not use if stored at 
room temperature for more than 48 hours. DO NOT FREEZE. Do not use product if it is 
known to have been frozen. Freezing destroys activity, which cannot be detected visually. 
Guidelines for administration: Intravenous (preferred) or intramuscular. See Treatment and 
Dose Modifications sections of the protocol. 
For IV administration: dilute pegaspargase in 100 mL of NS or D5W and infuse over 1 to 
2 hours through a NS or D5W running infusion line. Pegaspargase admixed in 100 mL of 
NS or D5W is stable for 48 hours at room temperature. Pegaspargase diluted in 100 mL of 
NS is stable for up to 72 hours refrigerated (4ºC [39°F]) (refrigerated stability data on file 
with Sigma-Tau). Avoid excessive agitation. DO NOT SHAKE. Do not use if cloudy or if 
precipitate is present. If necessary (e.g., shortage of intravenous fluid), pegaspargase can 
be given intramuscularly in this protocol.
Supplier: Commercially available. See package insert for further information
6.6
Erwinia asparaginase
To be used in case of hypersensitivity or intolerance to Pegaspargase or calaspargase 
pegol.
Source and pharmacology: L-asparagine is a nonessential amino acid synthesized by the 
transamination of L-aspartic acid by a reaction catalyzed by the enzyme L-asparagine 
synthetase. Neoplastic cells associated with acute lymphoblastic leukemia, acute myeloid 
leukemia and lymphoblastic lymphosarcoma are asparagine-dependent but lack asparagine 
synthetase activity. The administration of L-asparaginase produces an anti-neoplastic 
effect by catalyzing asparagine into aspartic acid and ammonia. As a result, these cells lack 
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the ability to produce the asparagine necessary for protein metabolism and survival. 
Deamination of glutamine may also play a role in the antineoplastic activity of 
asparaginase. 
Asparaginase Erwinia chrysanthemi (ErwinazeTM) is asparaginase derived from cultures of 
Erwinia chrysanthemi. L-asparaginase is a tetrameric enzyme; each of the four identical 
subunits has a molecular weight of approximately 35 kDa. Asparaginase Erwinia 
chrysanthemi is immunologically distinct from E. coli L-asparaginase and may allow 
continued asparaginase therapy when a hypersensitivity reaction occurs to Escherichia 
coli-derived asparaginase. The package labeling states that there is insufficient information 
to characterize the incidence of antibodies to asparaginase Erwinia chrysanthemi. Several 
factors are involved in immunogenicity assay results and the assessment of antibodies, 
including assay methodology, assay sensitivity and specificity, sample handling, timing of 
sample collection, concomitant medications, and the underlying disease state.
The following data have been reported on each of the three preparations of asparaginase:
Asparaginase Preparations
Clinical Pharmacology of 
Asparaginase Formulation
Elimination half-life (IM
% Anti-Asparaginase 
Antibody positive 
patients
Native Escherichia Coli
26-30 hours
45-75
Pegylated-asparaginase
5.5-7 days
5-18
Erwinia asparaginase
16 hours (7-13 hrs. package 
insert)
30-50
From: Avramis, V; Panosyan, E; Pharmacokinetic/Pharmacodynamic Relationships of Asparaginase 
Formulations: The Past, the Present and Recommendations for the Future. Clin Pharmacokinet 2005; 44 
(4): 367-393.
Effective asparaginase levels have been defined as activity of ≥0.1 International Units per 
mL. No formal drug interaction studies have been performed with asparaginase Erwinia 
chrysanthemi.
Toxicities (5-20%): Allergic reactions, anaphylaxis, urticaria.
Formulation and stability: Asparaginase Erwinia chrysanthemi is supplied as a sterile, 
white lyophilized powder for reconstitution in a clear glass vial with a 3 mL capacity. Each 
vial contains 10,000 International Units of asparaginase Erwinia chrysanthemi and the 
following inactive ingredients: glucose monohydrate (5.0 mg), sodium chloride (0.5 mg). 
Store intact vials between 2°C and 8°C (36° to 46ºF). Protect from light. 
Guidelines for administration: Intravenous (preferred) or intramuscular. See Treatment and 
Dose Modification sections of the protocol. 
Use appropriate precautions for preparation of a hazardous agent. Visually inspect the 
powder in vial for foreign particles or discoloration prior to reconstitution. The contents of 
each vial should be reconstituted by slowly adding 1 mL or 2 mL of sterile, preservative-
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free NS to the inner vial wall. The final concentration is 10,000 International Units per mL 
when using 1 mL for reconstitution or 5,000 International Units per mL when using 2 mL 
for reconstitution. Gently mix or swirl the contents to dissolve the contents of the vial. Do 
not shake or invert the vial. The resulting solution should be clear and colorless. Discard if 
any particulate matter or protein aggregates are visible. Withdraw the appropriate dosing 
volume into a polypropylene syringe within 15 minutes of reconstitution. 
Polycarbonate luer-lok syringes from B-D (1 mL) are also acceptable (personal 
communication, EUSA Pharma). Discard any unused drug; do not save or use any unused 
drug remaining in the vial.
Administer the dose within a 4-hour time period from reconstitution. If the dose is not 
used within this time period, discard the dose. Do not freeze or refrigerate the reconstituted 
solution. If administering the dose IM, no more than 2 mL should be given at any one 
injection site. Doses larger than 2 mL should be divided and given in separate 
administration sites.
Supplier: Commercially available. See package insert for further information.
6.7
Calaspargase Pegol
Source and pharmacology: L-asparaginase is an enzyme which catalyzes the deamidation 
of asparagine to aspartic acid and ammonia, reducing circulating levels of asparagine. 
Leukemic cells with low asparagine synthetase expression have a reduced ability to 
synthesize L-asparagine. L-asparaginase reduces the exogenous asparagine source for the 
leukemic cells, resulting in cytotoxicity specific to leukemic cells. Calaspargase pegol 
contains an E. coli-derived asparagine-specific enzyme, as a conjugate of L-asparaginase 
and monomethoxypolyethylene glycol (mPEG) with a succinimidyl carbonate (SC) linker, 
which produces a chemically stable carbamate bond between the mPEG component and 
the L-asparaginase lysine groups. L-asparaginase is a tetrameric enzyme that is produced 
endogenously by E. coli and consists of identical 34.5 kDa subunits. Approximately 31 to 
39 molecules of SC-PEG are linked to L-asparaginase; the molecular weight of each SC-
PEG molecule is about 5 kDa. The activity of calaspargase pegol is expressed in units (U). 
Calaspargase pegol is FDA-approved as a component of a multi-agent chemotherapeutic 
regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult 
patients age 1 month to 21 years.
Asparagine concentrations in plasma were maintained below the assay limit of 
quantification for more than 18 days following a single dose of calaspargase pegol 2,500 
U/m2 during the induction phase. Mean CSF asparagine concentrations decreased from a 
pretreatment concentration of 0.8 μg/mL to 0.2 μg/mL on Day 4 and remained decreased 
at 0.2 μg/mL 25 days after the administration of a single dose of calaspargase pegol 2,500 
U/m2 in the induction phase. Plasma asparaginase activity pharmacokinetics are nonlinear 
following calaspargase pegol administration. The time to peak concentration (Tmax) = 
1.17 hours and Cmax = 1.62 U/mL. Area under the curve (AUC0-∞) is 25.5 day x U/mL. 
Calaspargase pegol has a long elimination half-life (T1/2) of 16.1 days, volume of 
distribution (Vss) of 2.96 L, and clearance of 0.147 L/day.
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Toxicities: Grade 3 and 4 hypersensitivity reactions including anaphylaxis have been 
reported in clinical trials with calaspargase pegol and include angioedema, lip swelling, 
eye swelling, erythema, blood pressure decreased, bronchospasm, dyspnea, pruritis, and 
rash. Other toxicities include pancreatitis, thrombosis, hemorrhage, transaminitis, and 
increased bilirubin. 
Formulation and stability: Calaspargase pegol is supplied as a clear, colorless, preservative-
free, isotonic sterile solution in phosphaste-buffered saline, pH 7.3 that requires dilution 
prior to intravenous infusion. Each vial of calaspargase pegol-mknl contains 3,750 units in 
5 mL of solution. Each milliliter contains 750 units of calaspargase pegol-mknl; dibasic 
sodium phosphate, USP (5.58 mg); monobasic sodium phosphate, USP (1.20 mg); and 
sodium chloride, USP (8.5 mg) in water for injection, USP. Store calaspargase pegol 
refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do 
not shake or freeze product. Unopened vials may be stored at room temperature (15°C to 
25°C [59°F to 77°F]) for no more than 48 hours. 
Guidelines for administration: See Treatment and Dose Modifications sections of the 
protocol. 
For IV administration: dilute in 100 mL of 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP using sterile/aseptic technique. After dilution, administer 
immediately into a running infusion of either 0.9% sodium chloride or 5% dextrose, 
respectively. Administer over one hour. The diluted solution may be stored for up to 4 
hours at room temperature (15°C to 25°C [59°F to 77°F]) for up to 24 hours. Protect from 
light. Do not shake or freeze. 
Supplier: Commercially available. See package insert for further information. 
6.8
Methotrexate
Source and pharmacology: A folate analogue which reversibly inhibits dihydrofolate 
reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of 
tetrahydrofolate formation limits the availability of one carbon fragments necessary for the 
synthesis of purines and the conversion of deoxyuridylate to thymidylate in the synthesis 
of DNA and cell reproduction. The polyglutamated metabolites of MTX also contribute to 
the cytotoxic effect of MTX on DNA repair and/or strand breaks. MTX cytotoxicity is 
highly dependent on the absolute drug concentration and the duration of drug exposure. 
MTX is actively transported across cell membranes. At serum methotrexate concentrations 
exceeding 0.1 μmol/mL, passive diffusion becomes a major means of intracellular transport 
of MTX. The drug is widely distributed throughout the body with the highest concentration 
in the kidney, liver, spleen, gallbladder and skin. Plasma concentrations following high 
dose IV MTX decline in a biphasic manner with an initial half-life of 1.5-3.5 hours, and a 
terminal half-life of 8-15 hours. About 50% is bound to protein. After oral administration, 
approximately 60% of a 30 mg/m2 dose is rapidly absorbed from the GI tract, with peak 
blood levels at 1 hour. At doses >30 mg/m² absorption decreases significantly. Even at low 
doses absorption may be very erratic, varying between 23% and 95%. The elimination of 
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MTX from the CSF after an intrathecal dose is characterized by a biphasic curve with half-
lives of 4.5 and 14 hours. After intrathecal administration of 12 mg/m², the lumbar 
concentration of MTX is ~100 times higher than in plasma (ventricular concentration is ~ 
10% of lumbar concentration). MTX is excreted primarily by the kidneys via glomerular 
filtration and active secretion into the proximal tubules. Renal clearance usually equals or 
exceeds creatinine clearance. Small amounts are excreted in the feces. There is significant 
entero-hepatic circulation of MTX. The distribution of MTX into third-space fluid 
collections, such as pleural effusions and ascitic fluid, can substantially alter MTX 
pharmacokinetics. The slow release of accumulated MTX from these third spaces over time 
prolongs the terminal half-life of the drug, leading to potentially increased clinical toxicity.
Toxicities (>20%): Transaminase elevations. Intrathecal administration: nausea, headache.
Formulation and stability: Methotrexate for Injection is available as a lyophilized powder 
for injection in 1000 mg vials. The powder for injection contains approximately 7 mEq 
sodium in the 1000 mg vial. Methotrexate for Injection is also available as a 25 mg/mL 
solution in 2, 4, 8, 10, and 40 mL preservative free vials and 2 and 10 mL vials with 
preservative. The 2, 4, 8, 10, and 40 mL solutions contain approximately 0.43, 0.86, 1.72, 
2.15, and 8.6 mEq sodium per vial, respectively. The preserved vials contain 0.9% benzyl 
alcohol as a preservative. Sterile methotrexate powder or solution is stable at 20º-25ºC 
(68º-77ºF); excursions permitted to 15º-30ºC (59º- 86 Fº). Protect from light.
Methotrexate tablets are available as 2.5 mg, 5 mg, 7.5 mg, 10 mg and 15 mg. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include: 
anhydrous lactose, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, 
microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, 
sodium carbonate monohydrate, talc and titanium dioxide and various dyes. Store at 
controlled room temperature 15°-30°C (59°-86°F) and protect from light. 
Australia/New Zealand – only 2.5 mg and 10 mg tablets available. 
Methotrexate is also available as a clear yellow to orange oral solution (Xatmep®) that 
contains 2.5 mg of methotrexate per milliliter (equivalent to 2.74 mg of methotrexate 
sodium/mL) in a 120 mL bottle. Inactive ingredients include purified water, sodium citrate, 
citric acid, methylparaben sodium, propylparaben sodium, and sucralose. It may also 
contain sodium hydroxide or hydrochloric acid for pH adjustment. It is packaged in a high-
density polyethylene (HDPE) bottle with a child-resistant cap and tamper-evident seal. 
Store oral solution under refrigeration (2°C to 8°C/36°F to 46°F) prior to dispensing. Avoid 
freezing and excessive heat. After dispensing, patients may store methotrexate oral solution 
at room temperature (20°C to 25°C/68°F to 77°F) for up to 60 days; excursions permitted 
to 15°C to 30°C (59°F to 86°F).
Guidelines for administration: IV, IM, PO, and Intrathecal. See Treatment and Dose 
Modifications sections of protocol. 
Supplier: Commercially available. See package insert for further information.
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6.9
Dasatinib
Source and pharmacology: Dasatinib (BMS-354825) (an aminothiazole analogue) is 
indicated for treatment of chronic, accelerated, myeloid or lymphoid blast phase chronic 
myeloid leukemia in adults who are resistant or intolerant to prior therapy including 
imatinib. It is also indicated for the treatment of Philadelphia chromosome- positive acute 
lymphoblastic leukemia in adults who are resistant or intolerant to prior therapy. Dasatinib 
is a potent, broad-spectrum ATP-competitive inhibitor of 5 critical oncogenic tyrosine 
kinase families: BCR-ABL, SRC family kinases, c-KIT, ephrin (EP) receptor kinases, and 
PDGFβ receptor. Each of these protein kinases has been strongly linked to multiple forms 
of human malignancies. Dasatinib is rapidly absorbed following oral administration. At the 
adult therapeutic dose of 70 mg BID, neither disease status nor study day had a marked 
influence on the Tmax of dasatinib in subjects with leukemia. The overall mean half-life 
was 4 to 6 hours. Dasatinib is likely to reach steady state conditions by the second day of 
treatment at 70 mg BID. Dasatinib is highly bound to serum proteins, has extensive 
extravascular distribution and has a moderate rate of blood clearance. Elimination is 
predominantly in the feces, mostly as metabolites. Following a single oral dose of [14C]-
labeled dasatinib, approximately 85% of the dose was recovered in the feces within 10 
days, and approximately 4% of the administered radioactivity was recovered in the urine. 
Unchanged dasatinib accounted for 19% and 0.1% of the administered dose in feces and 
urine, respectively, with the remainder of the dose being metabolites. Dasatinib is primarily 
metabolized in the liver by the human CYP3A4 enzyme and is a significant inhibitor of 
CYP3A4. It may decrease the metabolic clearance of drugs that are significantly 
metabolized by the CYP3A4 enzyme. CYP3A4 substrates known to have a narrow 
therapeutic index should be administered with caution in patients receiving dasatinib. 
Concomitant use of dasatinib and drugs that inhibit CYP3A4 may increase exposure to 
dasatinib and should be avoided. Drugs that induce CYP3A4 activity may reduce exposure 
to dasatinib and concomitant use of potent CYP3A4 inducers with dasatinib should be 
avoided.
Due to the potential of dasatinib to prolong the QT/QTc, use caution when administering 
dasatinib with other potential QTc-prolonging medications. Due to the possibility of 
gastrointestinal, cardiac, and cutaneous hemorrhage, avoid using medications that inhibit 
platelet function or anticoagulants with dasatinib. Dasatinib is not a p-glycoprotein 
inhibitor.
Toxicity (>20%): anemia, diarrhea, nausea, fatigue, neutrophil count decreased, platelet 
count decreased, myalgia, headache, dyspnea, pleural effusion, and maculo-papular rash.
Formulation and stability: Dasatinib is commercially available as a 20 mg, 50 mg, 70 mg, 
80 mg, 100 mg, or 140 mg oral tablet. The intact bottles should be stored at controlled 
room temperature 15°-25°C (59°-77°F) and protected from light. Excursions are permitted 
up to 30 °C. Stability studies are ongoing. Additional formulations may be provided as 
available from the manufacturer.
Guidelines for administration: See the Treatment and Dose Modifications sections of the 
protocol. Administer orally with or without food, per institutional guidelines.
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Supplier: Commercially available. See package insert for further information.
6.10
Blinatumomab
Source and pharmacology: Blinatumomab is a fusion protein composed of two single-chain 
antibodies (scFv), murine anti-CD19 scFv and murine anti-CD3 scFv. Through CD3 
binding, blinatumomab recruits and engages T cells for redirected lysis of CD19-positive 
B cells, including those expressed with B-cell malignancies. T cells are bound by its anti-
CD3 moiety, whereas B cells are bound by the anti-CD19 moiety. The subsequent serial 
lysis of multiple malignant cells by a single blinatumomab-activated T cell closely 
resembles a natural cytotoxic T cell reaction. Treatment with blinatumomab is associated 
with a rapid depletion of peripheral B cells, accompanied by T cell activation and a 
transient increase in cytokines.
Blinatumomab consists of a single chain of 504 amino acids with a molecular weight of 
approximately 54 kDa. The pharmacokinetics of blinatumomab was assessed over a dose 
range from 5 to 90 mcg/m2/day (approximately equivalent to 9-162 mcg/day). Following 
continuous intravenous infusion, the steady state serum concentration (Css) was achieved 
within a day and remained stable over time. The estimated mean (SD) volume of 
distribution based on terminal phase (Vz) was 4.52 (2.89) L. The estimated mean (SD) 
systemic clearance was 2.92 (2.83) L/hour and the estimated mean (SD) half-life was 
2.11(1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the 
tested clinical doses. Like other protein therapeutics, blinatumomab is expected to be 
degraded into small peptides and amino acids via catabolic pathways. At the clinical doses 
of 9 mcg/day and 28 mcg/day for the treatment of adult relapsed/refractory ALL, the mean 
(SD) Css was 211 (258) pg/mL and 621 (502) pg/mL, respectively.
Formulation and stability: Intravenous powder for solution 35 mcg/vial mcg single-use 
vial. See package insert for more information.
Toxicities (>20%): Diarrhea, nausea, fatigue, fever, lymphocyte count decreased, white 
blood cell decreased, hypokalemia, headache, tremor.
Guidelines for administration: See Treatment and Dose Modifications sections of protocol. 
Preparation and administration of blinatumomab may follow institutional guidelines.
Supplier: Commercially available. See package insert for further information.
6.11
Cyclophosphamide
Source and pharmacology: Cyclophosphamide is an alkylating agent related to nitrogen 
mustard. Cyclophosphamide is inactive until it is metabolized by P450 isoenzymes 
(CYP2B6, CYP2C9, and CYP3A4) in the liver to active compounds. The initial product is 
4-hydroxycyclophosphamide (4-HC) which is in equilibrium with aldophosphamide which 
spontaneously releases acrolein to produce phosphoramide mustard. Phosphoramide 
mustard, which is an active bifunctional alkylating species, is 10 times more potent in vitro 
than is 4-HC and has been shown to produce interstrand DNA cross-link analogous to those 
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produced by mechlorethamine. Approximately 70% of a dose of cyclophosphamide is 
excreted in the urine as the inactive carboxyphosphamide and 5-25% as unchanged drug. 
The plasma half-life ranges from 4.1 to 16 hours after IV administration.
Toxicities (>20%): Anorexia, nausea and vomiting (acute and delayed), leukopenia, 
alopecia, immune suppression, gonadal dysfunction: azoospermia or oligospermia 
(prolonged or permanent) (late).
Formulation and stability: Cyclophosphamide for injection is available as powder for 
injection or lyophilized powder for injection in 500 mg, 1 g, and 2 g vials. The powder for 
injection contains 82 mg sodium bicarbonate/100 mg cyclophosphamide and the 
lyophilized powder for injection contains 75 mg mannitol/100 mg cyclophosphamide. 
Storage at or below 25ºC (77ºF) is recommended. The product will withstand brief 
exposures to temperatures up to 30ºC (86ºF). 
Guidelines for administration: See Treatment and Dose Modifications sections of the 
protocol.
Supplier: Commercially available. See package insert for further information.
6.12
Etoposide
Source and pharmacology: A semisynthetic derivative of podophyllotoxin that forms a 
complex with topoisomerase II and DNA, which results in single and double strand DNA 
breaks. Its main effect appears to be in the S and G2 phase of the cell cycle. The initial t½ 
is 1.5 hours and the mean terminal half-life is 4 to 11 hours. It is primarily excreted in the 
urine. In children, approximately 55% of the dose is excreted in the urine as etoposide in 
24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² or about 35% of the 
total body clearance over a dose range of 80 to 600 mg/m². Etoposide, therefore, is cleared 
by both renal and non-renal processes (i.e., metabolism and biliary excretion). The effect 
of renal disease on plasma etoposide clearance is not known. Biliary excretion appears to 
be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is 
recovered in the bile as etoposide. Metabolism accounts for most of the non-renal clearance 
of etoposide.
The maximum plasma concentration and area under the concentration time curve (AUC) 
exhibit a high degree of patient variability. Etoposide is highly bound to plasma proteins 
(~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide 
systemic exposure is related to toxicity. Preliminary data suggests that systemic exposure 
for unbound etoposide correlates better than total (bound and unbound) etoposide. There 
is poor diffusion into the CSF < 5%.
Etoposide phosphate is a water-soluble ester of etoposide which is rapidly and completely 
converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate 
that etoposide phosphate is bioequivalent to etoposide when it is administered in molar 
equivalent doses.
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Toxicities (>20%): Nausea, vomiting Myelosuppression (anemia, leukopenia), alopecia.
Formulation and stability: Etoposide for Injection is available as a 20 mg/mL solution in 
sterile multiple dose vials (5 mL, 25 mL, or 50 mL each). The pH of the clear, nearly 
colorless to yellow liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 
mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg polyethylene glycol 
300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. Unopened vials of 
etoposide are stable until expiration date on package at controlled room temperature (20˚-
25˚C or 68˚-77˚F). 
Etoposide phosphate for injection is available for intravenous infusion as a sterile 
lyophilized powder in single-dose vials containing etoposide phosphate equivalent to 100 
mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate 
must be stored under refrigeration (2°-8°C or 36°-46°F). Unopened vials of etoposide 
phosphate are stable until the expiration date on the package
Supplier: Commercially available. See package insert for further information.
Guidelines for administration: See Treatment and Dose Modifications sections of the 
protocol.
6.13
Leucovorin
Source and pharmacology: Leucovorin is a mixture of the diastereoisomers of the 5-formyl 
derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture 
is the (-)- l-isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin does not 
require reduction by the enzyme dihydrofolate reductase in order to participate in reactions 
utilizing folates as a source of “one-carbon” moieties. Administration of leucovorin can 
counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, 
which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the 
therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-
fluorouracil. Leucovorin is readily converted to another reduced folate, 5,10-
methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid 
(an active metabolite of 5-FU) to thymidylate synthase and thereby enhances the inhibition 
of this enzyme. Peak serum levels of 5-methyl THF (an active metabolite) were reached at 
approximately 1.3-1.5 hours (IV/IM) and 2.3 hours for the oral form. The terminal half-
life of total reduced folates was approximately 6.2 hours. Following oral administration, 
leucovorin is rapidly absorbed and expands the serum pool of reduced folates. At a dose of 
25 mg, almost 100% of the l-isomer (the biologically active form) but only 20% of the d-
isomer is absorbed. Oral absorption of leucovorin is saturable at doses above 25 mg. The 
apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg, and 37% for 
100 mg doses. Both oral and parenteral leucovorin raise the CSF folate levels.
Toxicities (rare): anaphylaxis, urticaria, seizure.
Formulation and stability: Leucovorin calcium for injection is supplied as a sterile ready to 
use liquid and a sterile powder for injection. The 10 mg/mL preservative free liquid is 
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available in 50 mL vials containing sodium chloride 400 mg/vial. Store preservative free 
liquid in the refrigerator at 2°-8°C (36°-46°F) protected from light. The powder for 
injection is available in 50 mg, 100 mg, 200 mg, and 350 mg vials. Store at room 
temperature 15°-25°C (59°-77°F) protected from light. Reconstitute the sterile powder with 
sterile water for injection or bacteriostatic water for injection to a concentration of 10 
mg/mL leucovorin calcium. Do not use diluents containing benzyl alcohol for doses > 
10 mg/m² or in infants < 2 years of age or patients with allergy to benzyl alcohol. When 
Bacteriostatic Water is used, the reconstituted solution is good for 7 days. If reconstituted 
with SWFI, use solution immediately as it contains no preservative. One milligram of 
leucovorin calcium contains 0.004 mEq of leucovorin and 0.004 mEq of calcium.
The oral form of leucovorin is available as 5 mg, 10 mg, 15 mg, and 25 mg tablets. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include corn 
starch, dibasic calcium phosphate, magnesium stearate, pregelatinized starch, lactose, 
microcrystalline cellulose, and sodium starch glycolate.
Supplier: Commercially available. See package insert for further information.
Guidelines for administration: See Treatment and Dose Modifications sections of the 
protocol.
6.14
Mercaptopurine
Source and pharmacology: Mercaptopurine is an analogue of the purine bases adenine and 
hypoxanthine. The main intracellular pathway for MP activation is catalyzed by the 
enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) which catalyzes the 
conversion of MP to several active nucleotide metabolites including thioinosinic acid, a 
ribonucleotide which can interfere with various metabolic reactions necessary for nucleic 
acid (RNA and DNA) biosynthesis. It can also cause pseudofeedback inhibition of the first 
step in de novo purine biosynthesis or convert to another ribonucleotide which can cause 
feedback inhibition. Mercaptopurine can be incorporated into DNA in the form of TG 
nucleotides as well and thus produce toxicity. The absorption of an oral dose of MP is 
incomplete and variable, with only about 16%-50% of an administered dose reaching the 
systemic circulation secondary to a first pass metabolism in the liver. Co-administration 
with cotrimoxazole (TMP/SMX) significantly reduces absorption of MP. After IV 
administration, MP has a plasma half-life of 21 minutes in children and 47 minutes in 
adults. Approximately 19% is bound to protein. Mercaptopurine is well distributed into 
most body compartments except the CSF. (With high dose IV MP the CSF to plasma ratio 
is 0.15.) MP is metabolized by xanthine oxidase in the liver to 6-Thiouric acid an inactive 
metabolite. In patients receiving both MP and allopurinol (a xanthine oxidase inhibitor) the 
dose of MP must be reduced by 50-75%. Since TPMT, thiopurine methyltransferase, is 
also one of the enzymes involved in the metabolism of MP, those individuals who have an 
inherited deficiency of the enzyme may be unusually sensitive to the myelosuppressive 
effects of MP and prone to develop rapid bone marrow suppression following the initiation 
of treatment. Mercaptopurine is excreted in urine as metabolites and some unchanged drug; 
about half an oral dose has been recovered in 24 hours. A small proportion is excreted over 
several weeks.
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Toxicities (>20%): Anemia, neutrophil count decreased, white blood cell decreased, 
platelet count decreased.
Formulation and stability: Mercaptopurine is available as a 50 mg tablet containing 
mercaptopurine and the inactive ingredients corn and potato starch, lactose, magnesium 
stearate, and stearic acid. Store at 15°-25°C (59°-77°F) in a dry place. Mercaptopurine is 
also available as an oral suspension in a concentration of 20 mg/mL (2000 mg/100 mL per 
bottle). The oral suspension is a pink to brown viscous liquid supplied in amber glass 
multiple-dose bottles with a child resistant closure. It should be stored at 15°-25°C (59°-
77°F) in a dry place.
NOTE: the concentration of the commercially available suspension (20 mg/mL) and 
the compounded suspension (50 mg/mL) are NOT the same; doses should be 
prescribed in the milligrams required, not mL. Please contact PI for compounding 
instructions if needed.
Supplier: Commercially available. See package insert for further information.
Guidelines for administration: See Treatment and Dose Modifications sections of the 
protocol.
6.15
Intrathecal Triples 
(ITMHA, methotrexate/hydrocortisone/cytarabine)
Source and pharmacology: The intrathecal route of administration of a drug produces more 
consistent CSF drug concentrations at relatively smaller doses because of the volume 
difference between the CSF and blood compartments (140 mL vs. 3500 mL in an adult). 
(The CSF volume of children after the first 3 years is equivalent to that of an adult). Drug 
half-lives are longer as well because clearance is related to flow rather than metabolism or 
protein binding. Intrathecal methotrexate has a biphasic elimination curve from the CSF 
with a t½ of 4.5 and 14 hours respectively. Following IT injection of cytarabine the 
elimination of the drug from the CSF is biphasic with a t½ of 1 and 3.4 hours respectively 
which is 8-fold longer than the clearance from plasma. The elimination of hydrocortisone 
is similarly prolonged.
Formulation and stability: Methotrexate 25 mg/mL preservative free 2 mL vial or 
methotrexate 20 mg preservative free sterile powder for injection vial. Cytarabine 100 mg 
preservative free sterile powder for injection. Hydrocortisone sodium succinate100 mg vial 
sterile powder for injection.
Toxicity: Nausea, vomiting, fever, headache.
Guidelines for administration: See treatment plan.
Supplier: Commercially available. Refer to the package insert for complete information.
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6.16
Cytarabine (Cytosine arabinoside, Ara-C, Cytosar®)
Source and pharmacology: Cytarabine appears to act through the inhibition of DNA 
polymerase. A limited, but significant, incorporation of cytarabine into both DNA and 
RNA has also been reported. It exhibits cell phase specificity, primarily killing cells 
undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression 
of cells from the G1 phase to the S-phase. Cytarabine is metabolized by deoxycytidine 
kinase and other nucleotide kinases to the nucleotide triphosphate (Ara-CTP), an effective 
inhibitor of DNA polymerase. Ara-CTP is inactivated by a pyrimidine nucleoside 
deaminase, which converts it to the nontoxic uracil derivative (Ara-U). It appears that the 
balance of kinase and deaminase levels may be an important factor in determining 
sensitivity or resistance of the cell to cytarabine. It has an initial distributive phase t½ of 
about 10 minutes, with a secondary elimination phase t½ of about 1 to 3 hours. Peak levels 
after intramuscular or subcutaneous administration of cytarabine occur about 20 to 60 
minutes after injection and are lower than IV administration. Intrathecally administered 
doses are metabolized and eliminated more slowly with a t½ of about 2 hours.
Toxicities: Most common (>20%) nausea, vomiting, anorexia, conjunctivitis (with high 
dose), myelosuppression, stomatitis, alopecia.
Formulation and stability: Cytarabine for Injection is available in vials of 100 mg, 500 
mg, 1 g, and 2 g containing a sterile powder for reconstitution. It is also available at a 20 
mg/mL concentration with benzyl alcohol (25 mL per vial) or as a preservative free 
solution (5 mL, 50 mL per vial), and at a 100 mg/mL concentration with benzyl alcohol 
(20 mL vial) or as preservative free solution (20 mL vial). Hydrochloric acid and/or 
sodium hydroxide may be added to adjust the pH. Store at 25°C (77°F); excursions 
permitted to 15°-30°C (59°-86°F). Cytarabine solutions should be protected from light.  
When reconstituted with Bacteriostatic Water for Injection, cytarabine is stable for 48 
hours at room temperature. Solutions reconstituted without a preservative should be used 
immediately. Discard if solution appears hazy. Diluted solutions in D5W or NS are stable 
for 8 days at room temperature; however, the diluted cytarabine should be used within 24 
hours for sterility concerns.
Guidelines for administration: See Treatment Plan.
Supplier: Commercially available. Refer to the package insert for complete information.
7.0
EVALUATIONS, TESTS, OBSERVATIONS
7.1
Pre-Treatment Clinical Evaluations

History and physical exam with height (cm), weight (kg), and BSA

Performance status

Diagnosis of relapsed/ refractory ALL/ALLy/ALAL confirmed by bone 
marrow or peripheral blood as described in inclusion criteria
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
Imaging of extramedullary disease (excluding CNS disease identified by 
cerebrospinal fluid analysis)

Laboratory studies as needed to confirm eligibility (direct bilirubin [may be 
omitted if total bilirubin is within normal limits], AST, ALT, creatinine)

Echocardiogram
Obtain other studies as needed for good patient care.
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7.2
Evaluations during Therapy – all Participants
STUDIES TO BE 
OBTAINED
Day 
-7 to 1
Block 1
Block 2
End of 
Treatment@
History and Physical
X
Weekly
Start of Block
X
CBC, differential, platelets
X
Weekly®
Weekly
X
Creatinine, ALT, Bilirubin
X
Weekly
Weekly
X
Tumor lysis monitoring: 
potassium, creatinine, calcium, 
phosphorus, uric acid
Prior to Day 1 dose 
of venetoclax and 
every 6-8 hours until 
24 hours after the 
first dose of 
navitoclax. See 
section 5.2.13.
*Pregnancy Test
X
CSF cell count and cytospin
X
With each IT
With each IT
X
Bone marrow (BM) with 
minimal residual disease 
evaluation
X
Day 29-32
With count 
recovery (Block 
2A); Day 28-30 
(Block 2B)
X
Bone marrow for 
pharmacotyping
X
Bone marrow for 
comprehensive leukemia 
genomics#
X
Skin biopsy for germline 
comparator sample#
X
Bone marrow for BH3 
profiling
X
Bone marrow immune 
profiling
X
End of Block
End of Block
X
Peripheral blood immune 
profiling%
X
Day 15, end of 
Block
Day 1 (if >7 days 
from end of Block 
1), Days 8, 15, end 
of block
X
TPMT/NUDT15 genotyping^
Once during block
® Platelet count required on Day 4
@ End of treatment studies should be obtained at the end of Block 2 for all patients except late (≥36 months from 
diagnosis) first relapse B-cell ALL who are MRD-negative at <0.01% after Block 1. For these patients, they will be 
obtained at the end of continuation.
* Required as a condition of enrollment for all females of childbearing potential.
# To be obtained only in patients consenting to comprehensive leukemia sequencing without prior germline 
sequencing at SJCRH and collaborating sites. For patients who wish to consent to these studies at sites with 
pending agreements, consider collection of appropriate samples and banking as feasible.
^ For patients with late first relapse of B-ALL who are MRD-negative at <0.01% after Block 1 (and thus will 
continue chemotherapy after Block 2) and who do not have prior TPMT/NUDT15 genotyping.
%Sample collection may be +/- 2 days if needed to accommodate patient scheduling.
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Patients with peripheral blasts and resulting inability to obtain bone marrow at diagnosis may submit peripheral 
blood for pharmacotyping, leukemia genomics, and BH3 profiling. Patients with isolated extramedullary leukemia/ 
lymphoma may submit relevant samples as available for these studies.
Patients will be offered enrollment in TBANK so that samples and data may be used for future research to better 
understand the biology of relapsed ALL and to identify potential treatments for this population.
7.3
Evaluations for Late Relapsing B-ALL Participants Receiving Therapy After 
Protocol Block 2
STUDIES TO BE 
OBTAINED
Intensification, 
Interim 
continuation 1 
& 2
Block 2 cycle 2
Continuation
End of 
Treatment
History and physical
Weekly
Start of Block
Every 2 weeks
X
CBC, differential, platelets
Weekly
Weekly
Every 2 weeks
X
Creatinine, ALT, bilirubin
Weekly
Weekly
Every 2 weeks
X
*Pregnancy test
CSF cell count and 
cytospin
With each IT
With each IT
With each IT
X
Bone marrow (BM) with 
minimal residual disease 
evaluation
Start of cycle 1
X
Obtain other studies as needed for good patient care.
* Pregnancy tests in females of childbearing potential should be repeated during treatment according to 
institutional guidelines.
7.4
Evaluations after Completion of Therapy
A peripheral blood or bone marrow sample should be submitted for pharmacotyping, 
genomics, and BH3 profiling at the time of relapse if possible. If this cannot be done, it 
will not be a deviation.
It is recommended that participants completing continuation therapy be followed at least 
every 4 months for 1 year and then every 6 months for 1 additional year after completion 
of therapy. 
Participants will be followed for 30 days after last treatment taken. Adverse events will not 
be recorded off-therapy unless they are unanticipated and deemed related to study 
treatment.
All patients will be followed for relapse and survival for 5 years from enrollment.
Evaluations will be performed as described for consenting patients. Minor modifications 
for good patient care or to align with institutional practice are allowed.
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8.0
EVALUATION CRITERIA
8.1
Response Criteria
See section 3.3 for definitions of response. Response will be assessed after Blocks 1 and 2 
and at the completion of therapy.
8.2
Toxicity Evaluation Criteria
Common Terminology Criteria for Adverse Events v5 (CTCAE): This study will utilize 
the CTCAE of the National Cancer Institute (NCI) for toxicity and performance reporting. 
A copy of the current version of the CTCAE can be downloaded from the Cancer Therapy 
Evaluation Program home page (http://ctep.info.nih.gov). Additionally, toxicities will be 
reported on the appropriate data collection screens.
8.3
Breakthrough Infections during Treatment
All infection adverse events will be prospectively assessed, categorized, and recorded. 
Identified organisms and their sensitivities will be obtained.
8.4
Acceptable Percentage of Missed Doses for Drugs
It is understood that deviations from the protocol should be avoided, except when necessary 
to eliminate an immediate hazard to a research participant. In such case, the deviation must 
be reported to the IRB. However, it is expected that participants will occasionally miss 
some doses or receive the wrong dose of oral chemotherapy. Appropriately documented 
doses of missed or wrong doses of chemotherapy will not constitute a deviation unless the 
amount in question is over 10% of the expected total dose due in the respective protocol 
cycles. Missed doses do not include doses held or reduced for medical reasons (toxicity, 
illness) and will not be considered protocol deviations or violations.
9.0
OFF-TREATMENT AND OFF-STUDY CRITERIA
9.1
Off-Treatment Criteria

Research participants who fail to achieve MRD-negative complete remission 
after Block 2 of therapy

30 days after completion of protocol directed therapy, or if a participant 
proceeds to alternative therapy (including cellular therapy/ transplant), off 
therapy day is defined as the first date of receipt of non-protocol therapy 
(including conditioning therapy)

Any relapse

Second malignancy

Development of unacceptable toxicity during treatment which precludes 
continuing therapy

Refusal of therapy
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
Physician determination that protocol therapy is no longer appropriate
9.2
Off-Study Criteria

Death

Lost to follow up

Withdrawal of consent

5 years from enrollment
10.0
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS
10.1
Reporting Adverse Experiences and Deaths 
Only “unanticipated problems involving risks to participants or others” referred to hereafter 
as “unanticipated problems” are required to be reported to the St. Jude IRB promptly, but 
in no event later than 10 working days after the investigator first learns of the unanticipated 
problem. Regardless of whether the event is internal or external (for example, an IND 
safety report by the sponsor pursuant to 21 CFR 312.32), only adverse events that constitute 
unanticipated problems are reportable to the St. Jude IRB. 
As further described in the definition of unanticipated problem, this includes any event that 
in the PI’s opinion was:

Unexpected (in terms of nature, severity, or frequency) given (1) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document, as well as other 
relevant information available about the research; (2) the observed rate of 
occurrence (compared to a credible baseline for comparison); and (3) the 
characteristics of the subject population being studied; and

Related or possibly related to participation in the research; and

Serious; or if not serious suggests that the research places subjects or others at a 
greater risk of harm (including physical, psychological, economic, or social harm) 
than was previously known or recognized.
Unrelated, expected deaths do not require reporting to the IRB. Though death is “serious”, 
the event must meet the other two requirements of “related or possibly related” and 
“unexpected/unanticipated” to be considered reportable.
Deaths meeting reporting requirements are to be reported immediately to the St. Jude IRB, 
but in no event later than 48 hours after the investigator first learns of the death. 
The following definitions apply with respect to reporting adverse experiences: 
Serious Adverse Event: Any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria:
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
results in death;

is life-threatening (places the subject at immediate risk of death from the event as 
it occurred);

requires inpatient hospitalization or prolongation of existing hospitalization;

results in a persistent or significant disability/incapacity;

results in a congenital anomaly/birth defect; or

any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the other outcomes listed in this definition (examples of such events 
include: any substantial disruption of the ability to conduct normal life functions, 
allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse), a congenital anomaly/birth 
defect, secondary or concurrent cancer, medication overdose, or is any medical 
event which requires treatment to prevent any of the medical outcomes previously 
listed.  
Unexpected Adverse Event: Any adverse event for which the specificity or severity is not 
consistent with the protocol-related documents, including the applicable investigator 
brochure, IRB approved consent form, Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) application, or other relevant sources of information, such as 
product labeling and package inserts; or if it does appear in such documents, an event in 
which the specificity, severity or duration is not consistent with the risk information 
included therein; or the observed rate of occurrence is a clinically significant increase in 
the expected rate (based on a credible baseline rate for comparison); or
The occurrence is not consistent with the expected natural progression of any underlying 
disease, disorder, or condition of the subject(s) experiencing the adverse event and the 
subject’s predisposing risk factor profile for the adverse event. 
Internal Events: Events experienced by a research participant enrolled at a site under the 
jurisdiction of St. Jude IRB for either multicenter or single-center research projects.
External Events: Events experienced by participants enrolled at a site external to the 
jurisdiction of the St. Jude Institutional Review Board (IRB) or in a study for which St. 
Jude is not the coordinating center or the IRB of record.
Unanticipated Problem Involving Risks to Subjects or Others: An unanticipated 
problem involving risks to subjects or others is an event which was not expected to occur, 
and which increases the degree of risk posed to research participants.  
Such events, in general, meet all of the following criteria:

unexpected; 

related or possibly related to participation in the research; and 

suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
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known or recognized. An unanticipated problem involving risk to subjects or others 
may exist even when actual harm does not occur to any participant. 
Consistent with FDA and OHRP guidance on reporting unanticipated problems and 
adverse events to IRBs, the St. Jude IRB does not require the submission of external events, 
for example IND safety reports, nor is a summary of such events/reports required; however, 
if an event giving rise to an IND safety or other external event report constitutes an 
“unanticipated problem involving risks to subjects or others” it must be reported in 
accordance with this policy. In general, to be reportable external events need to have 
implications for the conduct of the study (for example, requiring a significant and usually 
safety-related change in the protocol and/or informed consent form).
Although some adverse events will qualify as unanticipated problems involving risks to 
subjects or others, some will not; and there may be other unanticipated problems that go 
beyond the definitions of serious and/or unexpected adverse events. Examples of 
unanticipated problems involving risks to subjects or others include:

The theft of a research computer containing confidential subject information 
(breach of confidentiality); and 

The contamination of a study drug. Unanticipated problems generally will warrant 
consideration of substantive changes in the research protocol or informed consent 
process/document or other corrective actions in order to protect the safety, welfare, 
or rights of subjects or others. 
The principal investigator has the obligation to report all serious adverse events to the FDA 
and IRB.
The following adverse events that are commonly observed in this patient population will 
not be reported as individual expedited reports, but with annual continuing review and 
progress reports:

Grade 3 or 4 infection or fever

Grade 3 or 4 fever and neutropenia with or without infection

Grade 3 or 4 elevation in hepatic transaminases, alkaline phosphatase, GGT, 
bilirubin, and triglycerides that resolve to less than grade 3 within 5 days

Grade 3 or 4 elevation of amylase or lipase

Grade 3 electrolyte disturbances and Grade 4 electrolyte disturbances that resolve 
to < grade 3 within 24 hours allowing for replacement as needed

Grade 3 and 4 electrolyte disturbances due to tumor lysis

Grade 3 hyperglycemia or hypoglycemia and Grade 4 hyperglycemia or 
hypoglycemia that resolve to < grade 3 within 24 hours, allowing for replacement 
or insulin as needed

Grade 3 fatigue and nausea

Grade 3 vomiting or diarrhea that resolves to ≤ Grade 2 within 7 days with 
supportive care as needed (antiemetics, antidiarrheal medications)

Grade 3 or 4 hypotension explained by sepsis, pancreatitis, or infusion reaction
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study team will meet regularly to discuss AEs. The PI will review AE reports generated 
from the research database, and corrections will be made if applicable. Once the 
information is final the PI will sign and date reports, to acknowledge his review and 
approval of the AE as entered in the research database.
All adverse events reported from the time of study drug administration until 30 days
following discontinuation of study drug administration have elapsed will be collected,
whether solicited or spontaneously reported by the subject. In addition, protocol-related
serious adverse events and protocol-related nonserious adverse events will be collected
from the time the subject signed the study-specific informed consent/assent.
10.5
Process for Reporting Adverse Events from and to Collaborating Sites
Adverse events from collaborating sites will also be reviewed by the PI and discussed in 
study team meetings as described above. SAE reports from collaborating sites for AEs that 
are serious, unexpected, and at least possibly related to protocol treatment or interventions 
will be reported to site IRB and the St. Jude IRB within the reporting requirements 
described above.  
The PI will determine if this is an event that will need to be reported expeditiously to all 
participating sites, considering the following criteria:

Is the AE serious, unexpected, and related or possibly related to participation in the 
research?

Is the AE expected, but occurring at a significantly higher frequency or severity 
than expected?

Is this an AE that is unexpected (regardless of severity that may alter the IRB’s 
analysis of the risk versus potential benefit of the research and, as a result, warrant 
consideration of substantive changes in the research protocol or informed consent 
process/document?
With the submission of the “Reportable Event” in St. Jude iRIS application, the PI will 
indicate if all sites should be notified to report to their IRBs, and if the protocol and/or 
consent should be amended (consent will be amended if event is information that should 
be communicated to currently enrolled subjects). Generally, only events that warrant an 
amendment to the protocol and/or consent will be reported expeditiously to all sites. 
However, any event may be reported expeditiously to all sites at the discretion of the PI. A 
cumulative summary of all clinically significant non-hematologic grade 2adverse events, 
and all non-hematological grade 3 or higher AEs and expected/unrelated deaths that occur 
more than 30 days after protocol treatment will be reported to all sites with study progress 
report at the time of continuing review. 
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11.0
DATA COLLECTION, MONITORING AND CONFIDENTIALITY
11.1
Data Collection 
Data will be entered directly into a secure database, developed and maintained by St. Jude 
Clinical Research Informatics. Data Management will be supervised by the Director of 
Clinical Trials Management, and Manager of Clinical Research Operations for the 
Hematological Malignancies Program, working with Dr. Karol or his designee. All 
protocol-specific data and all clinically significant non-hematologic grade 2 adverse 
events, and all non-hematological grade 3 or higher adverse events will be recorded by the 
clinical research associates into a protocol-specific database, ideally within 2-4 weeks of 
completion of study phase. All questions will be directed to the attending physician and/or 
PI and reviewed at regularly-scheduled working meetings. The attending physicians (or 
their designees) are responsible for keeping up-to-date roadmaps in the patient’s primary 
St. Jude medical chart. 
Regular summaries of toxicity and protocol events will be generated for the PI and the 
Department of Biostatistics to review.
11.2
Study Monitoring
This study is considered high risk (HR-3) for monitoring purposes. Protocol and regulatory 
compliance, including essential regulatory documentation, will be assessed as well as the 
accuracy and completeness of all data points relating to the primary and secondary 
objectives semi-annually. If the study design has strata, accrual will be tracked 
continuously. The first two enrollees will be monitored and 15 % of the study enrollees 
thereafter, semi-annually. 
The PI and study team are responsible for protocol and regulatory compliance, and for data 
accuracy and completeness. The study team will meet frequently to review active case 
histories or quality summaries on all participants and retain copies of the minutes which 
are signed by the PI.
Clinical Trials Operations (CTO) will verify informed consent documentation and 
eligibility status on 100% of St. Jude participants within 5 working days of enrollment 
completion.
The Clinical Research Monitor (CRM) will verify the informed consent and eligibility 
processes of all non-St. Jude participants and perform a quality verification of all St. Jude 
enrollments during routine monitoring intervals (every 6 months). Overall study conduct, 
compliance with primary and secondary objectives, age of majority consenting, safety 
assessments and reporting, and the timeliness and accuracy of database entries are 
monitored routinely.
Study documents routinely monitored on selected participants include medical records, 
database entries, study worksheets, and case report forms. Study documents are monitored 
for participant status, demographics, staging, subgroup assignment, treatments, 
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investigational drug accountability, evaluations, responses, participant protocol status, off-
study and off-therapy criteria, and for other specifics as detailed in a separate study-specific 
monitoring plan. The study-specific monitoring plan may be revised over time, to adapt 
monitoring frequency and/ or intensity to a changing environment when appropriate (for 
example: new safety signals; positive history of compliance; all participants are in long 
term follow-up; or the enrollment period has ended).
The recording and reporting of Adverse Events, Serious Adverse Events (SAEs), and 
Unanticipated Problems (UPs) to include type, grade, attribution, duration, timeliness and 
appropriateness will be reviewed by the Monitor/ CRM. The CRM will generate a formal 
report which is shared with the Principal Investigator (PI), study team and the Internal 
Monitoring Committee (IMC).
Continuing reviews by the Institutional Review Board (IRB) and Clinical Trials- Scientific 
Review Committee (CT-SRC) will occur at least annually. In addition, unanticipated 
problems are reviewed in a timely manner by the IRB.
11.3
Confidentiality
Study numbers will be used in place of an identifier such as a medical record number. No research 
participant names will be recorded on the data collection forms. The medical records of study 
participants may be reviewed by the St. Jude IRB, FDA, AbbVie, and clinical research monitors.
12.0
STATISTICAL CONSIDERATIONS
12.1
Total Sample Size and Accrual
We anticipate it is logistically possible to enroll 78 patients, yielding 70 evaluable patients 
for the primary objective. The most recent SJCRH relapsed ALL trial ALL-R18 accrued 
42 patients in 6 years. Notably, this study was primarily performed at a single center and 
limited to 1st relapse of B-ALL only. With expanded eligibility and multicenter 
participation, we expect to obtain 70 evaluable patients in 2.5 years. Anticipated numbers 
in distinct strata are shown in Table 2 below. Estimates are based on the proportion of early 
and late first relapse B-ALL on recent trials. We anticipate a relatively higher proportion 
B-ALL beyond first relapse and T-ALL relapse due to the potential presence of competing 
trials at collaborating institutions. As described in the summary, we also anticipate 
enrolling up to 20 patients total into the exploratory cohorts (including no more than 8 age 
22 years or older) in addition to the 70 patients in the primary cohort (i.e. up to 90 patients 
total on trial).
By enrolling 70 patients we project that at least 56 will enroll in a combined cohort 
comprised of early first relapse B-ALL, relapsed T-ALL, and ALL beyond first relapse 
(Table 2). These groups comprise the highest risk relapse groups with a historical MRD-
negativity rate of ≤25%. A sample size of 56 in this cohort assures sound statistical 
behavior for the group-sequential design for futility monitoring and declaration of efficacy 
as shown below in Table 3.
Table 2: Anticipated accrual by stratum with 70 total patients
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Stratum
Number and percentage 
of enrolled patients for 
70 patients total
Historical response 
(MRD-neg CR after 
Block 1)
Source of 
historical/literature
B-ALL, 1st relapse, 
late (≥36 months 
from diagnosis)
14, 21%
42.5% [82/193]
UKALL R317
B-ALL, 1st relapse, 
early (<36 months 
from diagnosis)
12, 17%
25% [52/206]
 AALL1331
>1st relapse or 
primary refractory
32, 45%
20% 
BFM20 and 
AALL01P214
T-ALL, 1st relapse
12, 17%
18.2% [4/22]
AALL07P115
12.2
Primary Objectives
To compare MRD-negative CR/CRi rate in children following Block 1 therapy with 
venetoclax and navitoclax based reinduction to historical controls.
Responsible investigators: Seth Karol, MD
Responsible statistician: Cheng Cheng, PhD
Historical MRD negativity rates according to stratum are shown above in Table 2. For 
patients in first relapse, these patients include patients who achieved a CR following 1 
block of therapy. For patients treated on the UKALL R3 protocol, no specified count 
recovery was required, with patients having to achieve a “less than 5% blasts in the marrow 
or no blasts in the CSF.”8,17 Patients treated on AALL1331 needed to achieve a CR with 
count recovery as defined in section 3.3.4, while patients treated on AALL07P1 required 
count recovery with ANC ≥750/microL and platelets of ≥75,000/microL.15 To enable an 
effective comparison to historical data while simultaneously ensuring results of the present 
study inform future use, we will use the current definitions of CR utilized in ongoing 
Children’s Oncology Group protocols (ANC ≥500/microL and platelets of 
≥50,000/microL) for all patients in first relapse. We regard this comparison as reasonable 
despite the difference in bone marrow recovery parameters as the MRD-negative response 
to induction for patients with early relapse B-ALL is highly similar in AALL01P2 (25%), 
AALL07P1 (27%), and AALL1331 (25%) despite the differing count threshold used in 
AALL1331. This suggests that the difference in count recovery parameters between prior 
generation and current generation trials do not significantly alter the observed MRD-
negativity rate.
For patients beyond first relapse, there are not MRD response data available for patients 
with either B- or T-ALL, and the published data indicates that hematological recovery was 
not required to determine remission in these patients. “Complete remission (CR) was 
characterized by a non-aplastic BM with <5% blasts, absence of blasts in peripheral blood 
and no evidence of any extra-medullary leukemic disease spread.”20 Both historically and 
in current practice, hematological recovery is not required as these patients frequently 
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proceed to transplant prior to full hematological recovery. Thus, we will evaluate these 
patients in CR or CRi as long as bone marrow cellularity is sufficient to assess MRD. In 
the absence of historical MRD data for this population, we have conservatively estimated 
that 50% of patients in CR/CRi will be MRD positive, a rate consistent with the best-
responding group in our historical control (i.e. the late first relapse of B-ALL). Given the 
high rate of MRD detected in patients with marrows without morphologic 
leukemia,14,15,17,18 we believe that the estimated rate of MRD-negativity in the historical 
population is conservative (i.e. the true rate is likely higher than the estimate provided).
The primary endpoint is a binary (success/failure) MRD response at the end of remission 
Reinduction Block 1. Patients in first relapse must achieve a CR according to definitions 
in section 3.3.4, while patients beyond first relapse must achieve a CR or CRi. A patient 
achieving an MRD level <0.01% at the end of Block 1 is a success; MRD level 0.01% or 
higher, treatment related death during Block 1, as well as severe toxicity resulting in 
incomplete Block 1 treatment (i.e. unable to continue therapy or undergo disease 
assessments) are failures; other scenarios rendering a patient not being able to finish Block 
1 are considered unevaluable. Patients in the exploratory cohorts will not be counted 
toward the primary objective, and their responses will be provided descriptively.
The MRD-negative CR/CRi rate will be estimated separately for patients in late first 
relapse and other patients by the sample proportion (projected denominators n=14 and 56, 
respectively) and the 95% Binomial exact confidence interval and compared to the 
historical/literature controls. Patients with late first relapse in the historical control (Table 
2) have an MRD-negative CR rate of 42.5%. With a 14-patient sample, there is an 80% 
power to detect an increase to 71% with a one-sided alpha of 0.1. Given the small size of 
this cohort, we regard this elevated alpha as reasonable for this phase 2 study and note that 
identification of a greater MRD-negativity rate without anthracycline therapy would be 
clinically meaningful. 
From Table 2 above, the overall MRD-negative rate in historical/literature control for other 
patients (early first B-ALL, first T-ALL, beyond first relapse) is approximately 20.7% = 
[(12/56)*0.25+(32/56)*0.20+(12/56)*0.182]. To plan the sample size, we have 
conservatively estimated that all patients in this cohort would have a historical response as 
good as those observed in early first relapse (i.e. 25%). The projected cohort of 56 patients 
assures sound statistical behavior for group-sequential analysis with futility monitoring 
shown in Table 3 below.
The group-sequential design tables below are produced by an in-house R program using an 
algorithm based on exact binomial probabilities. It assumes that individual patients develop 
AEs (or respond to treatment) independently to each other. With a projected total number 
of patients, the stopping boundaries and postulated true success rates specified to the 
program, it compute the probabilities of stopping at each stage for each postulated true 
success rate.
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12.2.1. Efficacy monitoring using group sequential analysis for Block 1
In light of the historical differences in MRD-negative rate between late first relapse B-
ALL (42.5%) and all other patients (25% for early first relapse B-ALL, 18.2% for first 
relapse T-ALL, 20% for patients beyond first relapse), we will monitor futility in these 2 
groups separately. 
For patients in late first relapse B-ALL, we will consider the treatment sufficiently active 
if the response rate is at least 50% (null 49.9%). We will monitor for futility in an ad hoc 
fashion. If at any time the number of failures reaches 7, we will suspend enrollment in the 
trial for late first relapse B-ALL and investigate. 
For other patients in the primary analysis cohort (early first relapse B-ALL, first relapse 
T-ALL, and patients beyond first relapse), the therapy will be considered sufficiently 
effective if the overall response rate is 25% (null 24.9%). We will monitor for futility 
against this rate. The decision boundary and operating characteristics outlined in Table 3 
below are derived from a group sequential design. By this rule, we will watch the number 
of failures sequentially in the first 28 patients, if at any point this number reaches 21, the 
trial will be suspended. The probability of suspension in the first 28 patients is 0.82, 0.37, 
and 0.18 if the true success probability is 0.2, 0.3, and 0.35 respectively. Likewise, we 
will watch the cumulative number of failures in the second stage and suspend the trial if 
this number reaches 41. The cumulative probability to suspend the trial in any stage is 
0.94, 0.48, and 0.23 if the true success probability is 0.2, 0.3, and 0.35 respectively. We 
regard these operating characteristics reasonable. Conversely, if the true response rate is 
0.35 or 0.4, we have a 0.77 or 0.92 probability to declare efficacy.
Table 3: Stopping boundary and probabilities for several scenarios of true MRD-
negative CR/CRi rate (Monitor against <25% MRD-negative responses)
True MRD-negative rate (probability)
0.20
0.25
0.30
0.35
0.40
Stop if ≤7/28 successes
0.82
0.60
0.37
0.18
0.07
Stop if ≤ 15/56 successes
0.12
0.16
0.11
0.05
0.01
Obtain ≥ 16/56 successes
Declare sufficient efficacy
0.06
0.24
0.52
0.77
0.92
12.2.2 Safety Monitoring
Patients in exploratory cohort I (extramedullary disease only), M (MPAL/ALAL), and N 
(without asparaginase) will be included in the safety (not efficacy) stopping rules with 
patients from the primary cohort. Efficacy/ futility will be monitored separately for these 
patients either because MRD is unlikely to be informative (cohort I), there is no historical 
control available to determine response (cohort M), or therapy modifications make 
comparison to historical controls and other patients treated on the study uninformative 
(cohort N). Patients is cohort O will be monitored separately based on published data that 
young adult patients experience greater toxicity with identical therapy compared to 
pediatric patients. Specifically, induction death and high-grade toxicity requiring therapy 
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discontinuation was more common on CALGB10403 when compared to AALL0232.3,79 
There was also a higher incidence of heart failure and thrombosis in young adults treated 
on NOPHO ALL2008. Thus, we will monitor patients in cohort O separately.
12.2.2.1 Safety monitoring in Block 1
Patients in the primary analysis cohort as well as exploratory cohorts I (extramedullary 
disease), M (MPAL/ALAL), and N (without asparaginase) will be included in the safety 
cohort. Thus, we project the sample size for toxicity monitoring to be 82 patients (70 from 
the primary analysis and 12 from the 3 exploratory cohorts).

Death: By literature (Raetz et al., 200814; von Stackelberg et al., 201642) we believe 
a toxic death rate (i.e. not related to disease progression) of ≤5% is consistent with 
background toxicity for this population. We will use a group sequential design with 
3 stages to monitor against a >5% toxic death rate. The decision boundary and 
operating characteristics are outlined in Table 4. 
Table 4: Stopping boundary and probabilities for several scenarios of true rate 
of toxic death (monitor against death rate of >5%)
True death rate (probability)
0.08
0.05
0.02
Suspend if 1/8 deaths
0.49
0.34
0.15
Suspend if 2/16 deaths
0.07
0.04
0.01
Suspend if 3/24 deaths
0.03
0.01
0.00
Suspend if 3/32 deaths
0.07
0.04
0.01
Suspend if 4/40 deaths
0.02
0.01
0.00
Suspend if 4/48 deaths
0.05
0.03
0.00
Suspend if 4/56 deaths
0.06
0.04
0.01
Suspend if 5/64 deaths
0.01
0.01
0.00
Suspend if 5/72 deaths
0.03
0.02
0.00
Suspend if 5/82 deaths
0.05
0.04
0.00
Obtain ≤ 4/82 deaths
0.12
0.42
0.82

Grade 4 or higher non-hematologic, non-infection AEs not attributable to 
underlying disease excluding asymptomatic laboratory abnormalities which resolve 
to grade 1 or less within 72 hours with or without supplementation, AST/ ALT 
elevations which resolve to grade 1 or less within 7 days, fever, or nausea/ 
vomiting/ or diarrhea adequately managed with supportive care. We will use a 
group sequential design to monitor against a >20% rate of these toxicities. The 
decision boundary and operating characteristics are outlined in Table 5. 
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Table 5: Stopping boundary and probabilities for several scenarios of true rate 
of monitored toxicities (monitor against rate >20%)
True monitored toxicity rate 
(probability)
0.25
0.20
0.15
Suspend if 3/8 AEs
0.32
0.20
0.11
Suspend if 5/16 AEs
0.13
0.08
0.03
Suspend if 7/24 AEs
0.08
0.04
0.02
Suspend if 9/32 AEs
0.05
0.03
0.01
Suspend if 10/40 AEs
0.09
0.06
0.02
Suspend if 12/48 AEs
0.04
0.02
0.01
Suspend if 14/56 AEs
0.03
0.02
0.00
Suspend if 16/64 AEs
0.02
0.01
0.00
Suspend if 17/72 AEs
0.04
0.03
0.01
Suspend if 18/82 AEs
0.06
0.05
0.01
Obtain if ≤ 17/82 AEs
0.15
0.45
0.79

Uncontrolled Grade 4 or Grade 5 infections: Grade 4 infections which are 
uncontrolled after 7 days, or any Grade 5 infection, will be included as a targeted 
toxicity. Uncontrolled infections are defined as exhibiting ongoing signs/ 
symptoms related to the infection and without improvement, despite appropriate 
antibiotics or other treatment. We will use a group sequential design monitor 
against a >20% rate of such infections. The decision boundary and operating 
characteristics are outlined in Table 5. 

Hematological toxicity: Patients will be termed prolonged aplasia if they have not 
recovered to an ANC ≥500/microL after day 42 in the absence of evidence of 
leukemia. We will use a group sequential design to monitor against a >20% rate of 
these toxicities. The decision boundary and operating characteristics are outlined in 
Table 5. 
Monitoring of patients who receive dasatinib: These patients are included in the above 
monitoring. Additionally, patients receiving dasatinib will be monitored for toxicities as 
described above to ensure a rate of monitored toxicity of no more than 20% using the 
characteristics in Table 6 below, with hematological toxicity, uncontrolled infectious 
toxicities, and high-grade non-hematological/ non-infectious toxicities monitored 
separately.
Table 6: Stopping boundary and probabilities for several scenarios of true rate of 
monitored toxicities in patients receiving dasatinib (monitor against rate >20%)
True grade 4+ toxicity rate (probability)
0.25
0.20
0.15
Suspend if 3/8 AEs
0.32
0.20
0.11
Suspend if 4/16 AEs
0.29
0.22
0.13
Suspend if 7/24 AEs
0.03
0.02
0.00
Obtain if ≤ 6/24 AEs
0.44
0.56
0.76
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Monitoring of patients in cohort O: Patients is cohort O will be monitored separately 
based on published data that young adult patients experience greater toxicity with identical 
therapy compared to pediatric patients. Specifically, induction death and high-grade 
toxicity requiring therapy discontinuation was more common on CALGB10403 when 
compared to AALL0232.3,79 There was also a higher incidence of heart failure and 
thrombosis in young adults treated on NOPHO ALL2008. Due to the small size of this 
cohort, patients in this cohort will be monitored ad hoc. We will pause enrollment in this 
cohort and investigate if we observe either 1 death or 3 other monitored toxicities (see 
definitions above for grade 4 or higher infections, non-hematological toxicities, and 
hematological toxicity).
To identify the recommended phase 2 combination of venetoclax based consolidation in 
novel combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab.
Responsible investigators: Seth Karol, MD
Responsible statistician: Cheng Cheng, PhD
12.2.2.2 Dose finding stage: For Blocks 2a and 2b we will first run a dose de-escalation study 
(for cytarabine and venetoclax, respectively) to identify the safe dose level for the subsequent 
phase-II component. In each block we will start at the highest dose and de-escalate (or stay) 
according to the rolling-6 design. Patients in exploratory cohort O are not eligible for the phase I 
dose de-escalation part of the study.
Cytarabine dosing during phase 1 portion for Block 2a
Dose level
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
1
3000mg/m2/dose q12h IV 
infusion over 3 hours 
4
Days 1-2
0
1500mg/m2/dose q12h IV 
infusion over 3 hours 
4
Days 1-2
-1
1000mg/m2/dose q12h IV 
infusion over 3 hours 
2
Day 1
Venetoclax dosing during phase 1 portion for Block 2b
Dose level
Dose (with maximum daily 
dose if applicable) and Route
Number 
of doses
Schedule
1
240mg/m2 (max 400mg) PO 
21
Days 8-28
0
240mg/m2 (max 400mg) PO 
14
Days 8-21
-1
240mg/m2 (max 400mg) PO 
7
Days 8-14
The rolling-6 design will be used for the conduct of this portion of the study. Dose/ 
combination limiting toxicities (DLTs) are defined separately for Blocks 2a and 2b.

For block 2a, dose limiting toxicities are defined as:
o
Toxic death due to any cause.
o
Grade 4 or higher non-hematologic, non-infection AEs not attributable to 
underlying disease excluding asymptomatic laboratory abnormalities which 
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resolve to grade 1 or less within 72 hours with or without supplementation, 
AST/ ALT elevations which resolve to grade 1 or less within 7 days, fever, 
or nausea/ vomiting/ or diarrhea adequately managed with supportive care.
o
Grade 4 infections which are uncontrolled after 7 days. 
o
Prolonged aplasia, defined as failure to recover to an ANC ≥500/microL by 
day 42 in the absence of leukemia.

For block 2b, dose limiting toxicities are defined as: 
o
Toxic death due to any cause.
o
Grade 3 or higher non-hematologic, non-infection AEs not attributable to 
underlying disease excluding asymptomatic laboratory abnormalities which 
resolve to grade 1 or less within 72 hours with or without supplementation, 
AST/ ALT elevations which resolve to grade 1 or less within 7 days, fever, 
nausea/ vomiting/ or diarrhea adequately managed with supportive care, or 
grade 3 cytokine release syndrome which does not resolve to grade 2 or less 
within 48 hours with supportive care.
o
Grade 3 or 4 infections which are uncontrolled after 7 days. 
o
Prolonged aplasia, defined as failure to recover to an ANC ≥500/microL 
past day 28 in the absence of evidence of leukemia.
Following completion of Block 1 therapy, patients will enroll on the appropriate arm (2a 
or 2b, based on the criteria in 4.2.2). One to six participants can be concurrently enrolled 
onto a dose level, depending on the number of participants enrolled at the current dose 
level, the number of participants who have experienced a dose/ combination limiting 
toxicity (DLT) at the current dose level, and the number of participants entered but with 
tolerability data pending. Dose de-escalation will occur if 2 patients at a dose level 
experience a targeted toxicity. If 6 patients complete a therapy block and experience 0-1 
DLT, that dose will be considered the recommended phase 2 dose (RP2D). New enrollment 
on an arm (2a/2b) will be paused if further enrollment would result in more than 6 patients 
being treated on that arm before the RP2D is identified.   
If dose level 1 is not tolerable, patients will be enrolled on level 0.
If dose level 0 is not tolerable, patients will be enrolled on level -1.
If dose level -1 is not tolerable, the block will be suspended for evaluation.
12.3
Secondary Objectives
12.3.1 To estimate the tolerability and activity of venetoclax based consolidation in novel 
combinations with a) high-dose cytarabine and navitoclax or b) blinatumomab.
Responsible investigators: Seth Karol, MD
Responsible statistician: Cheng Cheng, PhD
The (secondary) endpoint for tolerability of Block 2a / 2b (consolidation) is the 
development of grade 3 or higher non-hematologic adverse effects (AE) according to 
CTCAE criteria and death due to any cause other than disease progression. Tolerability 
must be assessed separately in Block 2a and 2b. The rate of AEs will be estimated by 
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sample proportions along with the 95% exact Binomial confidence interval in Block 2a and 
2b respectively. 
Safety in Block 2a and 2b will be monitored separately as well. We anticipate that the 
cytarabine-containing treatment (Block 2a) is more toxic than the blinatumomab (Block 
2b) regimen. Monitoring will be carried out in a group-sequential fashion.
12.3.1.1 Safety monitoring in Block 2a:
Phase 1/ dose finding monitoring and de-escalation schema are shown above. The below 
monitoring describes safety monitoring rules for patients being treated on the 
recommended phase 2 dose (RP2D). The projected estimates below assume that 6 patients 
will be treated during the phase 1 portion of the study (all at the RP2D). In the event that 
additional patients are treated during the phase 1 portion of the study, the tables below will 
be used. For the rules below, patients treated at the RP2D during the phase 1 portion will 
be counted toward the rules for study suspension.

Death: By literature (Raetz et al., 200814; von Stackelberg et al., 201642) we believe 
a toxic death rate (i.e. not related to disease progression) of ≤5% is consistent with 
background toxicity for this population. We will use a group sequential design for 
patients treated at the recommended phase 2 dose (RP2D), including those treated 
during the dose finding phase. The design will monitor against a >5% toxic death 
rate. The decision boundary and operating characteristics are outlined in Table 7. 
Table 7: Stopping boundary and probabilities for several scenarios of true rate 
of toxic death (monitor against death rate of >5%)
True death rate (probability)
0.08
0.05
0.02
Suspend if 1/8 deaths
0.49
0.34
0.15
Suspend if 2/16 deaths
0.07
0.04
0.01
Suspend if 3/24 deaths
0.03
0.01
0.00
Suspend if 3/32 deaths
0.07
0.04
0.00
Suspend if 4/40 deaths
0.02
0.01
0.00
Suspend if 4/48 deaths
0.05
0.03
0.00
Suspend if 4/52 deaths
0.03
0.02
0.00
Obtain if ≤ 3/52 deaths
0.24
0.51
0.83

Grade 4 or higher non-hematologic, non-infection AEs not attributable to 
underlying disease excluding asymptomatic laboratory abnormalities which resolve 
to grade 1 or less within 72 hours with or without supplementation, AST/ ALT 
elevations which resolve to grade 1 or less within 7 days, fever, or nausea/ 
vomiting/ or diarrhea adequately managed with supportive care. We will use a 
group sequential to monitor against a >20% rate of these toxicities. The decision 
boundary and operating characteristics are outlined in Table 8. 
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Table 8: Stopping boundary and probabilities for several scenarios of true rate 
of monitored toxicities (monitor against rate >20%)
True monitored toxicity rate 
(probability)
0.25
0.20
0.15
Suspend if 3/8 AEs
0.32
0.20
0.10
Suspend if 5/16 AEs
0.13
0.09
0.03
Suspend if 7/24 AEs
0.08
0.04
0.01
Suspend if 9/32 AEs
0.05
0.03
0.01
Suspend if 10/40 AEs
0.09
0.06
0.02
Suspend if 12/48 AEs
0.04
0.02
0.01
Suspend if 12/52AEs
0.06
0.05
0.02
Obtain if ≤ 11/52 AEs
0.23
0.51
0.80

Uncontrolled Grade 4 or Grade 5 infections: Grade 4 infections which are 
uncontrolled after 7 days, or any Grade 5 infection, will be included as a targeted 
toxicity. Uncontrolled infections are defined as exhibiting ongoing signs/symptoms 
related to the infection and without improvement, despite appropriate antibiotics or 
other treatment. We will use a group sequential design to monitor against a >20% 
rate of such infections. The decision boundary and operating characteristics are 
outlined in Table 8. 
Hematological toxicity: Patients will be termed prolonged aplasia if they have not 
recovered to an ANC ≥500/microL after day 42 in the absence of evidence of leukemia. 
We will use a group sequential design to monitor against a >20% rate of such aplasia. The 
decision boundary and operating characteristics are outlined in Table 8.
12.3.1.2
Safety monitoring in Block 2b:
Phase 1/ dose finding monitoring and de-escalation schema are shown above. The below 
describes safety monitoring rules for patients being treated on the recommended phase 2 
dose (RP2D). The projected estimates below assume that 6 patients will be treated during 
the phase 1 portion of the study (all at the RP2D). In the event that additional patients are 
treated during the phase 1 portion of the study, the tables below will be used. For the rules 
below, patients treated at the RP2D during the phase 1 portion will be counted toward the 
block suspension rules.
 

Death: By literature (Raetz et al., 200814; von Stackelberg et al., 201642) we believe 
a toxic death rate (i.e. not related to disease progression) of ≤5% is consistent with 
background toxicity for this population. We will use a group sequential design for 
patients treated at the recommended phase 2 dose (RP2D), including those treated 
during the dose finding phase. The design will monitor against a >5% toxic death 
rate. The decision boundary and operating characteristics are outlined in Table 9. 
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Table 9: Stopping boundary and probabilities for several scenarios of true rate 
of toxic death (monitor against death rate of >5%)
True death rate (probability)
0.08
0.05
0.02
Suspend if 1/8 deaths
0.49
0.34
0.15
Suspend if 1/16 deaths
0.25
0.22
0.13
Suspend if 2/24 deaths
0.03
0.03
0.01
Suspend if 3/30 deaths
0.01
0.00
0.00
Obtain ≤ 2/30 deaths
0.22
0.41
0.71

Grade 3 or higher non-hematologic AEs excluding infection, asymptomatic 
laboratory abnormalities which resolve to grade 1 or less within 72 hours with or 
without supplementation, AST/ ALT elevations which resolve to grade 1 or less 
within 7 days, fever, or nausea/ vomiting/ or diarrhea adequately managed with 
supportive care. Grade 3 cytokine release syndrome which resolves to grade 2 or 
less within 2 days with supportive care is also excluded. During the phase 2 portion, 
we will use a group sequential design to monitor against a >20% rate of these 
toxicities. The decision boundary and operating characteristics are outlined in Table 
10.
Table 10: Stopping boundary and probabilities for several scenarios of true 
rate of monitored toxicities (monitor against toxicity rate of >20%)
True monitored toxicity rate 
(probability)
0.25
0.20
0.15
Suspend if 3/8 AEs
0.32
0.20
0.11
Suspend if 4/16 AEs
0.29
0.22
0.13
Suspend if 7/24 AEs
0.03
0.02
0.00
Suspend if 7/30 AEs
0.11
0.08
0.04
Obtain ≤ 6/30 AEs
0.25
0.47
0.72

Grade 3-4 infections which are uncontrolled after 7 days, or any grade 5 infection, 
will be included as a targeted toxicity. Uncontrolled infections are defined as 
exhibiting ongoing signs/symptoms related to the infection and without 
improvement, despite appropriate antibiotics or other treatment. During the phase 
2 portion, we will use a group sequential design to monitor against a >20% rate of 
these toxicities. The decision boundary and operating characteristics are outlined in 
Table 10 (above). 

Hematological toxicity: Patients will be termed prolonged aplasia if they have not 
recovered to an ANC ≥500/microL after day 28 in the absence of evidence of 
leukemia. During the phase 2 portion, we will use a group sequential design with 2 
stages to monitor against a >20% rate of these toxicities. The decision boundary 
and operating characteristics are outlined in Table 10 (above). 
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Activity of the consolidation blocks (2a, 2b) will be analyzed descriptively. We will 
estimate among the patients who are MRD-positive after Block 1 the proportion of patients 
who attain negative MRD after Block 2a/ 2b, along with an exact 95% confidence interval. 
We will also estimate the overall proportion of MRD-negative patients after Block 2a/ 2b 
using the sample proportion and the denominator of all evaluable patients after Block 2a/ 
2b.
12.3.1.3
Safety monitoring for cohort O during Block 2
Patients is cohort O will be monitored separately based on published data that young adult 
patients experience greater toxicity with identical therapy compared to pediatric patients. 
Specifically, induction death and high-grade toxicity requiring therapy discontinuation was 
more common on CALGB10403 when compared to AALL0232.3,79 There was also a 
higher incidence of heart failure and thrombosis in young adults treated on NOPHO 
ALL2008.80 Due to the small size of this cohort, patients in this cohort will be monitored 
ad hoc. We will pause enrollment in block 2 for this cohort and investigate if we observe 
either 1 death or 3 other monitored toxicities (as defined above for blocks 2a and 2b in 
sections 12.3.1.1 and 12.3.1.2, respectively). As indicated above, patients in cohort O are 
not eligible for the phase I/ dose de-escalation phase.
12.3.1.4
Safety monitoring beyond Block 2
Because only last first relapse B-ALL who are MRD-negative after Block 1 are eligible to 
continue therapy after Block 2, we anticipate no more than 14 patients will receive this 
therapy. Due to the small number of patients, we will monitor safety in this cohort ad hoc 
to ensure a rate of death of <5% and <20% of other monitored AEs (grade 4 or higher non-
hematologic, non-infectious AEs excluding asymptomatic laboratory abnormalities which 
resolve to grade 1 or less within 72 hours with or without supplementation, AST/ ALT 
elevations which resolve to grade 1 or less within 7 days, fever, or nausea/ vomiting/ or 
diarrhea adequately managed with supportive care; grade 4 or higher infections not 
controlled within 7 days). We will suspend post-Block 2 therapy for the trial and investigate 
if 1 death or 3 other monitored AEs occur.
12.3.2 To describe event-free and overall survival in patients treated with this regimen.
Responsible investigators: Seth Karol, MD
Responsible statistician: Cheng Cheng, PhD
Patients will be followed for 5 years from enrollment. Failure in overall survival (OS) is death of 
any cause. Patients staying alive at the last follow up are censored. Failures in event-free survival 
(EFS) is death of any cause, relapse, or refractory disease (≥5% MRD at the end of Block 2). 
Patients remaining failure-free are censored at the last follow up date. The time to event is the 
time between on-treatment date and the date of failure or last follow up. Kaplan-Meier estimates 
of the OS and EFS functions will be calculated, along with the standard error at any given time 
point (1 year, 3 year, etc.) computed by Peto’s method. 
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12.4
Exploratory Objectives
12.4.1 To evaluate MRD-negative CR/CRi rates in each prespecified groups: late first 
relapse B-ALL; early first relapse and second or greater relapse B-ALL; and 
relapsed T-ALL.
Responsible investigators: Seth Karol, MD
Responsible statistician: Cheng Cheng, PhD
Sample proportions of MRD-negative CR/CRi rate will be computed in each stratum along 
with standard error. 
12.4.2 To identify drug sensitivity patterns in patient samples prior to and after receiving 
combination therapy and evaluate mechanisms of disease resistance/ escape.
Responsible investigators: Charles Mullighan, MBBS, Jun Yang, PhD, Joseph Opferman, 
PhD
Responsible statistician: Cheng Cheng, PhD
Statistical approaches as described previously will be applied.31,92 Specifically, for each 
anti-leukemic agent, we will treat the in vitro drug sensitivities and BH3 protein 
sensitivities as continuous phenotypes in data analyses. Associations between various 
genomic features/ factors and the drug sensitivity phenotypes will be analyzed/ tested by 
regression modeling or rank correlations. For each type of genomic feature, to assess the 
top hits’ (genomic features’) ability to different sensitive and resistant leukemic cells, we 
will separate patients into top 25%, middle 50%, and bottom 25% groups based on their 
drug sensitivities, ranging from the most resistant to the most sensitive, perform a model 
based clustering (MCLUST) using the top k genomic features, and pick the value for k as 
the number of features for which the generated clusters agree the most with the quartile 
grouping by the Chi-square/ Fisher’s test (minimum P value). Approaches based on false 
discovery rate will also be applied to determine a threshold to define the set of top genomic 
features highly associated with drug sensitivity. Given anticipated limited sample 
availability, exploratory analyses will be performed on residual leukemia samples after 
treatment to identify mechanisms of resistance. Xenografting to further evaluate these 
findings may be utilized for samples from consenting patients.
12.4.3 To explore immune subsets during and after this regimen.
Responsible investigators: Paul Thomas, PhD, Benjamin Youngblood, PhD, Caitlyn 
Zebley, MD, PhD
In the Thomas lab, high resolution flow cytometry will be used to identify infiltrating 
immune cell subsets and their phenotypes, including, but not limited to CD4+ T cells, 
CD4+ Treg cells, CD8+ cells, γδ T cells, NK cells, neutrophils, macrophages, monocytes, 
eosinophils, and B cells. T cell populations will be analyzed for activation status, 
transcriptional profile, and T cell receptor sequence using a single cell sequencing platform 
such as the 10X Genomics 5’ Kit or smartSeq3. Responses to tumor-specific and associated 
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antigens will be probed with functional assays such as intracellular cytokine staining. T 
cell receptors of interest will be cloned and characterized for specificity. Patient HLA 
information will be acquired from the clinical chart or from dedicated RNA-sequencing to 
construct immune multimers where possible. We will explore associations between 
changes in immune cell phenotypes, transcriptional profiles, activation states, frequencies, 
with objective responses as well as with PFS/OS using logistic regression models and Cox 
proportional hazards models, respectively. 
For T cell repertoire studies, we will analyze the clonal distribution and composition of 
tumor-associated T cells at different time points relative to therapy. Specific receptor 
profiles will be characterized using clustering methods developed by the Thomas lab 
(TCRdist and related algorithms)93 and by using approaches that relate TCR specificity to 
gene expression profiles (clonotype neighbor graph analysis, CoNGA). These will be 
associated with objective responses and PFS/OS. TCR specificity will also be inferred, 
where possible, by matching to known receptor specificities in public and private 
databases.
In parallel, DNA will be extracted from T cells and bisulfite treated to convert all 
unmethylated cytosines to uracils. Bisulfite-modified DNA will be submitted for whole 
genome sequencing to quantify the methylation status of CpG sites. The T cell 
Multipotency Index71,94 will be determined to score of patients’ T cells and correlate this 
multipotency score to clinical response in patients. A multivariate linear regression model 
will be used to model the relationship between clinical response in patients and the 
multipotency score with clinical response as the dependent variable as methods previously 
described.71,94-101 
12.4.4 Evaluate response to therapy in rare relapsed acute leukemias to this regimen. 
Responsible investigators: Seth Karol, MD
Responsible statistician: Cheng Cheng, PhD
MRD levels at the end of Block 1 and Block 2 will be summarized with mean, standard 
deviation, and the 5-number summary. Proportion of MRD-negative response will be 
estimated by sample proportion. 
12.4.5 Explore breakthrough infections in children and young adults with relapsed or 
refractory ALL.
Responsible investigators: Joshua Wolf, MBBS, PhD
Responsible statistician: Li Tang, PhD
All enrolled participants will be eligible for this component. Descriptive statistics, such as 
frequency and proportion, will be summarized for breakthrough infections, antibiotic-
resistant infections, febrile neutropenia episodes and adverse events. Cumulative incidence 
of breakthrough infection, febrile neutropenia and adverse events will also be explored, 
with competing risks and/or recurrent event appropriately adjusted. Death not due to the 
toxicity of interest, relapse, and other reasons unrelated to the toxicity of interest rendering 
off treatment are considered as competing events. For cumulative incidence, time to the 
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first episode will be considered as the time to failure. Recurrence rate will be estimated by 
Poisson process modeling.
12.5
Anticipated Completion Dates
Anticipated primary completion date: 2.5 years from study opening.
Anticipated study completion date: 4.5 years from study opening.
13.0
OBTAINING INFORMED CONSENT
13.1
Consent Prior to Research Interventions 
Initially, informed consent will be sought for the institutional banking protocol (TBANK 
or local banking protocol as applicable) and for other procedures as necessary. During the 
screening process for eligibility, informed consent is required before any research tests are 
performed.  
The process of informed consent and assent for RAVEN will follow institutional policy. 
The informed consent process is an ongoing one that begins at the time of diagnosis and 
ends after the completion of therapy. Informed consent should be obtained by the attending 
physician or his/her designee, in the presence of at least one non-physician witness. 
Throughout the entire treatment period, participants and their parents receive constant 
education from health professionals at St. Jude and collaborating sites and are encouraged 
to ask questions regarding alternatives and therapy. All families have ready access to 
chaplains, psychologists, social workers, and child life specialists, in addition to that 
provided by the primary clinicians involved in their care.
13.2
Consent at Age of Majority
The age of majority in the state of Tennessee is 18 years old. Research participants must 
be consented at the next clinic visit after their 18th birthday. If an affiliate or collaborating 
site is located in a country or state where a different age of majority applies, that location 
must consent the participants according to their local laws.
13.3
Consent When English is Not the Primary Language
When English is not the patient, parent, or legally authorized representative’s primary 
language, the Social Work department will determine the need for an interpreter. This 
information documented in the participant’s medical record. Either a certified interpreter 
or the telephone interpreter’s service will be used to translate the consent information. The 
process for obtaining an interpreter and for the appropriate use of an interpreter is outlined 
on the Interpreter Services, OHSP, and CTO websites. Collaborating sites will follow 
institutional policy.
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14.0
REFERENCES
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Clin Oncol 26:3971-8, 2008
15. Horton TM, Whitlock JA, Lu X, et al: Bortezomib reinduction chemotherapy in high-risk ALL 
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16. Brown P, Ji L, Xu X, et al: A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy 
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Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report from Children’s 
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Orlando, FL, 2019
17. Parker C, Krishnan S, Hamadeh L, et al: Outcomes of patients with childhood B-cell precursor 
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ALLR3 open-label randomised trial. Lancet Haematol 6:e204-e216, 2019
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lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study. 
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52. Duell J, Dittrich M, Bedke T, et al: Frequency of regulatory T cells determines the outcome of 
the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL. Leukemia 
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53. Karol SE, Alexander TB, Budhraja A, et al: Venetoclax in combination with cytarabine with 
or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 
1, dose-escalation study. Lancet Oncology 21:551-560, 2020
54. DiNardo CD, Lachowiez CA, Takahashi K, et al: Venetoclax Combined With FLAG-IDA 
Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid 
Leukemia. J Clin Oncol 39:2768-2778, 2021
55. Senft D, Jeremias I: A rare subgroup of leukemia stem cells harbors relapse-inducing potential 
in acute lymphoblastic leukemia. Exp Hematol 69:1-10, 2019
56. Teh TC, Nguyen NY, Moujalled DM, et al: Enhancing venetoclax activity in acute myeloid 
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57. Arai Y, Kondo T, Shigematsu A, et al: High-dose cytarabine added to CY/TBI improves the 
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with B-Cell Lymphoblastic Leukemia. N Engl J Med 378:439-448, 2018
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Lymphoblastic Leukemia. N Engl J Med 378:449-459, 2018
64. Gardner R, Wu D, Cherian S, et al: Acquisition of a CD19-negative myeloid phenotype allows 
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65. Bhojwani D, Sposto R, Shah NN, et al: Inotuzumab ozogamicin in pediatric patients with 
relapsed/refractory acute lymphoblastic leukemia. Leukemia 33:884-892, 2019
66. Fry TJ, Shah NN, Orentas RJ, et al: CD22-targeted CAR T cells induce remission in B-ALL 
that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 24:20-28, 2018
67. Zhao Y, Aldoss I, Qu C, et al: Tumor-intrinsic and -extrinsic determinants of response to 
blinatumomab in adults with B-ALL. Blood 137:471-484, 2021
68. Deng Q, Han G, Puebla-Osorio N, et al: Characteristics of anti-CD19 CAR T cell infusion 
products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat 
Med 26:1878-1887, 2020
69. Finney OC, Brakke HM, Rawlings-Rhea S, et al: CD19 CAR T cell product and disease 
attributes predict leukemia remission durability. J Clin Invest 129:2123-2132, 2019
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70. Zamora AE, Crawford JC, Allen EK, et al: Pediatric patients with acute lymphoblastic 
leukemia generate abundant and functional neoantigen-specific CD8(+) T cell responses. Sci 
Transl Med 11, 2019
71. Abdelsamed HA, Zebley CC, Nguyen H, et al: Beta cell-specific CD8(+) T cells maintain stem 
cell memory-associated epigenetic programs during type 1 diabetes. Nat Immunol 21:578-587, 
2020
72. Orgel E, Alexander TB, Wood BL, et al: Mixed-phenotype acute leukemia: A cohort and 
consensus research strategy from the Children's Oncology Group Acute Leukemia of 
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73. Alexander TB, Gu Z, Iacobucci I, et al: The genetic basis and cell of origin of mixed phenotype 
acute leukaemia. Nature 562:373-379, 2018
74. Kawedia JD, Liu C, Pei D, et al: Dexamethasone exposure and asparaginase antibodies affect 
relapse risk in acute lymphoblastic leukemia. Blood 119:1658-64, 2012
75. Gupta S, Wang C, Raetz EA, et al: Impact of Asparaginase Discontinuation on Outcome in 
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Clin Oncol 38:1897-1905, 2020
76. Vrooman LM, Stevenson KE, Supko JG, et al: Postinduction dexamethasone and 
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77. Richard-Carpentier G, Jabbour E, Short NJ, et al: Clinical Experience With Venetoclax 
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78. El-Cheikh J, Moukalled NM, El Darsa H, et al: Feasibility of the Combination of Venetoclax 
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W, 
Douer 
D, 
DeAngelo 
DJ, 
et 
al: 
Prevention 
and 
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of 
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be effective in chronic lymphocytic leukemia with central nervous system involvement. 
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Amendment 3.0, dated: 01-16-2024
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metabolism and hematopoietic toxicity. Nat Genet 48:367-73, 2016
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94. Abdelsamed HA, Moustaki A, Fan YP, et al: Human memory CD8 T cell effector potential is 
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95. Ghoneim HE, Fan Y, Moustaki A, et al: De Novo Epigenetic Programs Inhibit PD-1 Blockade-
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96. Hale JS, Youngblood B, Latner DR, et al: Distinct memory CD4+ T cells with commitment to 
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APPENDIX I: Performance Status Criteria
PERFORMANCE STATUS CRITERIA
Karnofsky and Lansky performance scores are intended to be multiples of 10
ECOG (Zubrod)
Karnofsky (Participants >16 years)
Lansky (Participants <16 years)
Score
Description
Score
Description
Score
Description
100
Normal, no complaints, no 
evidence of disease
100
Fully active, normal
0
Fully active, able to carry 
on all pre-disease 
performance without 
restriction
90
Able to carry on normal 
activity, minor signs or 
symptoms of disease
90
Minor restrictions in 
physically strenuous 
activity
80
Normal activity with effort; 
some signs or symptoms of 
disease
80
Active, but tires more 
quickly
1
Restricted in physically 
strenuous activity by 
ambulatory and able to 
carry out work of a light 
or sedentary nature, e.g., 
light housework, office 
work
70
Cares for self; unable to carry 
on normal activity or do 
active work
70
Both greater restriction of 
and less time spent in 
play activity
60
Requires occasional 
assistance, but is able to care 
for most of his/her needs
60
Up and around, but 
minimal active play; 
keeps busy with quieter 
activities
2
Ambulatory and capable 
of self-care but unable to 
carry out any work 
activities; up and about 
more than 50% of 
waking hours
50
Requires considerable 
assistance and frequent 
medical care
50
Gets dressed, but lies 
around much of the day; 
no active play, able to 
participate in all quiet 
play and activities
40
Disabled, requires special 
care and assistance
40
Mostly in bed; 
participates in quiet 
activities
3
Capable of only limited 
self-care, confined to bed 
or chair more than 50% 
of waking hours
30
Severely disabled, 
hospitalization indicated; 
death not imminent
30
In bed; needs assistance 
even for quiet play
20
Very sick, hospitalization 
indicated.  Death not 
imminent
20
Often sleeping; play 
entirely limited to very 
passive activities
4
Completely disabled; 
cannot carry on any self-
care; totally confined to 
bed or chair
10
Moribund, fatal processes 
progressing rapidly
10
No play; does not get out 
of bed
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APPENDIX II: SAMPLE PROCESSING
Refer to the RAVEN Procedures Manual for specimen submission guidelines and shipping 
information.
Specimen descriptions
Immune profiling: 3mL of blood or bone marrow as appropriate in ACD.
Pharmacotyping/ genomics/ BH3 profiling: 10mL of bone marrow in preservative free sodium 
heparin tube (dark green top tube). 
Clinical genomics specimens must be labeled with name and date of birth.
Skin biopsy (for patients consenting to comprehensive genomic sequencing) should be done at the 
site of port/line placement or BMA. A minimum of 3mm punch biopsy is needed, preferably 4mm. 
The biopsy should be placed in a sterile container with RPMI with the lid wrapped with parafilm. 
Seal in a bag and ship ambient overnight. This specimen must be labeled with name and date of 
birth.
MRD (if St. Jude will serve as reference lab): Specimens should be collected in a preservative free 
sodium heparin tube (dark green top tube) and shipped ambient. 5mL of sample is required. The 
MRD assay is performed in a CLIA lab, and specimens for MRD must be labelled with patient 
name and date of birth.
Note that biomarker studies are not performed on weekends. Hence, samples should be drawn 
Monday through Thursday and sent by overnight delivery.
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APPENDIX III: CYP3A INDUCERS AND INHIBITORS
Excluded during protocol therapy: 
Strong CYP3A inducers - avasimibe, carbamazepine, enzalutamine, mitotane, phenytoin, 
rifampin, St. John's wort
Moderate CYP3A inducers - bosentan, efavirenz, etravirine, modafinil, nafcillin
Excluded during Block 1; caution during Block 2; if used during Block 2, dose 
adjustments of venetoclax may be needed: contact PI
Strong CYP3A inhibitors - boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, elvitegravir/ritonavir, idelalisib,* indinavir, itraconazole, ketoconazole, 
mibefradil, lopinavir/ritonavir, nefazodone, nelfinavir, ritonavir, paritaprevir/ritonavir 
combinations, posaconazole, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, 
voriconazole
Moderate CYP3A inhibitors - amprenavir, aprepitant, atazanavir, cimetidine, ciprofloxacin, 
clotrimazole, crizotinib*, cyclosporine*, darunavir/ritonavir, diltiazem1, erythromycin, 
fluconazole, fosamprenavir, imatinib*, isavuconazole, tofisopam, verapamil
Cautionary
Warfarin**
P-gp substrates
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus*, fexofenadine, 
lapatinib*, loperamide, maraviroc, nilotinib*, ranolazine, saxagliptin, sirolimus*, sitagliptin, 
talinolol, tolvaptan, topotecan*
BCRP substrates
Methotrexate*, mitoxantrone*, irinotecan*, lapatinib*, rosuvastatin, sulfasalazine, topotecan*
OATP1B1/1B3 substrates
Atrasentan, atorvastatin, ezetimibe, fluvastatin, glyburide, rosuvastatin, simvastatin acid, 
pitavastatin, pravastatin, repaglinide, telmisartan, valsartan, olmesartan
P-gp inhibitors
Amiodarone, azithromycin, captopril, carvedilol, dronedarone, felodipine, quercetin, 
quinidine, ronalzine, ticagrelor
BCRP inhibitors
Geftinib*
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Amendment 3.0, dated: 01-16-2024
Protocol document date: 01-16-2024
APPENDIX IV: DOSE ADJUSTMENTS WITH CYP3A INHIBITORS
Patient size
Standard 
venetoclax (Ven) 
dosing
Ven dose when 
also using 
moderate 
CYP3A4 
inhibitors
Ven dose 
when also 
using strong 
CYP3A4 
inhibitors
Ven dose when 
also using 
Posaconazole
BSA adjusted
240mg/m2
120mg/m2
60mg/m2
45mg/m2
Maximum
400mg
200mg
100mg
70mg
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Amendment 3.0, dated: 01-16-2024
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APPENDIX V: LIST OF PROTOCOL CHANGES IN AMENDMENTS
AMENDMENT 1:

Expanded screening window from 4 to 7 days.
o
Reduce need for repeat assessments to avoid out of window screening data.

Increased eligibility for Block 2b to patients with >95% blasts expressing CD19.
o
The threshold for CD19+ needed to respond to blinatumomab has not been 
previously well defined.

Clarified that blinatumomab dosing for patients ≥45kg is a fixed dose rather than BSA 
based to align with FDA label.
o
To align with FDA label.

Removed requirement that PI be notified for coadministration of venetoclax and azole 
antifungals provided appropriate dose adjustment is made.
o
Improve ease of therapy delivery. The dose adjustments are explicit within the 
protocol so PI input for these adjustments are not needed.

Added information on the venetoclax powder sachet formulation.
o
Change in available venetoclax formulation.

Indicated that patients with non-ETP T-cell acute lymphoblastic lymphoma (ALLy) can 
receive dasatinib.
o
Similar genomics present in ALL and ALLy suggest agent may be active. These 
patients do poorly with existing therapy. 

Added the option of asparaginase dose capping or dosing based on ideal body weight.
o
Alignment with other ALL trials and practice across sites.

Changed listed asparaginase from pegaspargase to calaspargase and removed requirement 
to notify PI of alternative asparaginase formulations.
o
Address change in available formulation in the US but variable availability of 
asparaginase across sites. Research database continues to document formulation.

Clarified that prophylactic antibiotics did not need to be started at protocol entry if the 
patient was not neutropenic.
o
Reduce unneeded antibiotic exposure for patients without neutropenia.

Removed leukemia sample collection at end of therapy and added sample submission at 
time of relapse.
o
Align sample collection timepoints with periods most likely to be informative for 
mechanisms of resistance.

Added option for peripheral blood or extramedullary leukemia/ lymphoma sample 
submission for correlative biology sample at diagnosis in patients with leukocytosis 
precluding initial bone marrow sampling.
o
Align with standard practice and with ability of patients with high peripheral blast 
burden to go on protocol therapy without a bone marrow, and allow analysis of 
samples without isolated extramedullary disease.

Indicated that the day 1 LPIT could be delayed if required by the patient’s clinical 
condition.

Indicated that samples and data may be used for future research to better understand the 
biology of relapsed ALL and to identify potential treatments for this population.
o
To increase generalizable knowledge gained for future patients in this population 
with a high unmet need.
St. Jude Children's Research Hospital
IRB NUMBER: 21-0719
IRB APPROVAL DATE: 02/19/2024

Amendment 3.0, dated: 01-16-2024
Protocol document date: 01-16-2024

Increased flexibility of peripheral blood immune profile sample collection.
o
To minimize the need for visits just for blood sample collection and align with 
blinatumomab bag changes or clinical visits.

Increased availability for post-block 2 therapy to be given at affiliates.
o
To improve access to local therapy for these patients.

Minor clarifications and corrections of typographical errors.
AMENDMENT 2:

Updated consents to further clarify infectious risks.
AMENDMENT 3:

Consents and protocol updated to include RP2D defined during phase I of blocks 2A and 
2B.

Added definition of No Response (NR) to describe patients not achieving CR or PR after 
block 1. The definition of treatment failure continues to describe these patients after block 
2.

Minor clarifications and corrections of typographical errors.
St. Jude Children's Research Hospital
IRB NUMBER: 21-0719
IRB APPROVAL DATE: 02/19/2024