Updated Chemotherapy Regimen for the Treatment of Adolescents and Young Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVE:

I. To assess the ability of adolescent and young adult (AYA) participants to complete treatment through time point 3 (TP3) on the Dana-Farber Cancer Institute (DFCI) AYA protocol.

SECONDARY OBJECTIVES:

I. To prospectively determine safety and tolerability of the updated DFCI AYA ALL protocol among AYAs with newly diagnosed ALL.

II. To prospectively determine efficacy of the updated DFCI AYA ALL protocol among AYAs with newly diagnosed ALL.

III. To prospectively determine the rate of allogeneic transplantation among AYAs treated on the updated DFCI AYA ALL protocol, and reasons for transplantation.

EXPLORATORY OBJECTIVES:

I. To prospectively determine the following among AYAs with newly diagnosed ALL treated on the updated DFCI AYA ALL protocol:

Ia. Impact of obesity (as measured by body mass index [BMI]), and changes in weight/BMI on measures of efficacy, toxicity, and treatment completion;

Ib. Impact of disease response at early time points (time point [TP] 1, TP2, and TP3) as assessed by measures of measurable residual disease (MRD) (multi-parameter flow cytometry [MPFC], next generation sequencing [NGS], and reverse transcriptase-polymerase chain reaction [RT-PCR] for KMT2A::AFF4) on survival (disease-free survival [DFS], event-free survival [EFS], and overall survival [OS]);

Ic. Impact of disease immunophenotype (CD20 positivity, early T-cell precursor [ETP] immunophenotype) and genetics (including IKZF1 alteration, Philadelphia chromosome-like status, hypodiploid/near triploid and/or TP53 mutated, KMT2A-rearrangement) on measures of efficacy (complete remission [CR], MRD, and EFS, DFS, and OS).

II. To prospectively determine late effects after treatment including infertility, late orthopedic complications (osteonecrosis and fracture), and second malignancies.

III. To compare the sensitivity and specificity of novel genome-informed MRD monitoring of plasma cell-free deoxyribonucleic acid (DNA) versus existing established approaches for measuring MRD targeting immunoglobulin or T-cell receptor loci or disease-specific oncogene breakpoints within bone marrow genomic DNA.

IV. To define molecular programs enriched within residual leukemia to reveal novel therapeutic targets.

V. To generate preclinical model systems to support ongoing translational investigation of AYA leukemia biology and targeted therapy.

OUTLINE:

STEROID PROPHASE: Patients receive dexamethasone intravenously (IV) or orally (PO) twice daily (BID) on days 1-3 and cytarabine intrathecally (IT) on day 1 in the absence of disease progression or unacceptable toxicity.

INDUCTION IA: Patients receive dexamethasone IV or PO BID on days 1-22 followed by a taper on days 23-29 per discretion of treating clinician in the absence of disease progression or unacceptable toxicity. Patients also receive vincristine IV on days 1, 8, 15 and 22, doxorubicin IV on days 1 and 2, pegaspargase or calaspargase IV on day 3, and IT MAH (methotrexate IT, cytarabine IT, hydrocortisone IT) on day 15 in the absence of disease progression or unacceptable toxicity. Patients may receive methotrexate IT again on day 29 if peripheral blood criteria for complete remission are met and direct bilirubin < 1.4mg/dL. Patients with central nervous system (CNS) disease at diagnosis also receive cytarabine IT twice weekly between days 1 and 12 until they have 3 consecutive clear cerebrospinal fluid (CSF) specimen and may receive IT MAH on days 18, 22, and 25. Patients then undergo disease assessment. Patients with CR, patients not in CR and < 25% blasts on bone marrow, or who do not meet definition of either CR or induction failure proceed to induction IB. Patients with induction failure, with CNS disease at the end of induction IA or with extramedullary disease < 70% reduction in size of largest nodes or masses or with new masses are removed from the study.

INDUCTION IB: Patients receive cyclophosphamide IV and methotrexate IT on days 1 and 22, cytarabine IV or subcutaneously (SC) on days 1-4, 8-11, 22-25, and 29-32, 6-mercaptopurine PO once daily (QD) on days 1-14 and 22-35 in the absence of disease progression or unacceptable toxicity. Patents then undergo disease assessment. Patients in CR with B-cell ALL proceed to blinatumomab cycle 1 and patients with T-cell ALL proceed to consolidation IA. Patients with induction failure or with evidence of CNS leukemia are removed from the study.

BLINATUMOMAB CYCLES 1 AND 2: Patients receive dexamethasone IV or PO on day 1, blinatumomab IV continuously on days 1-28 and IT MAH on day 28 of each cycle. Cycles repeat every 42 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then proceed to consolidation IA.

CONSOLIDATION IA: Patients receive vincristine IV on days 1 and 15, 6-mercaptopurine PO QD on days 1-7 and 15-21, methotrexate IT on day 1, and methotrexate IV on days 1 and 15, over 24 hours, in the absence of disease progression or unacceptable toxicity. Patients then proceed to consolidation IC.

CONSOLIDATION IC: Patients receive dexamethasone IV or PO BID on days 1-5, cytarabine IV, every 12 hours on days 1-2, etoposide IV on days 3-5, methotrexate IT on day 1 and pegaspargase or calaspargase IV on day 8, except for patients proceeding to blinatumomab cycle 3. Patients with B-cell ALL proceed to blinatumomab cycle 3, patients with T-cell ALL proceed to CNS phase.

BLINATUMOMAB CYCLE 3: Patients receive dexamethasone IV or PO on day 1, blinatumomab IV continuously on days 1-28 and IT MAH on day 28 in the absence of disease progression or unacceptable toxicity. Patients then proceed to the CNS phase if they have CNS-3 disease or are unable to receive blinatumomab.

CNS PHASE: Patients receive vincristine IV on day 1, dexamethasone IV or PO BID on days 1-5, 6-mercaptopurine PO QD on days 1-14, pegaspargase or calaspargase IV 21 days from Consolidation IC dose (expected day 8), and IT MAH twice weekly for 4 doses beginning on day 1 in the absence of disease progression or unacceptable toxicity. Patients with CNS-3 disease at diagnosis also undergo cranial radiation for 10 treatments in the absence of disease progression or unacceptable toxicity. Patients then proceed to consolidation II.

CONSOLIDATION II CYCLE 1-8: Patients receive vincristine IV on day 1, dexamethasone IV or PO BID on days 1-5, 6-mercaptopurine PO QD on days 1-14, doxorubicin IV on day 1, pegaspargase or calaspargase IV on day 1 or 3-weeks after previous dose given during CNS phase and given every 3 weeks until 9 total post-induction doses of calaspargase or 10 total doses of pegaspargase. Cycles repeat every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive IT MAH every 9 weeks for patients with no prior cranial radiation or every 18 weeks for patients with previous cranial radiation. Patients who have completed 8 cycles with doxorubicin and 30 total weeks of post induction asparaginase proceed to blinatumomab cycle 4 (if B-cell ALL) or continuation. Patients who have not completed this proceed to consolidation cycle 9+ until the above criteria have been completed.

CONSOLIDATION II CYCLE 9+ (IF INDICATED): Patients receive vincristine IV on day 1, dexamethasone IV or PO BID on days 1-5, 6-mercaptopurine PO QD on days 1-14, methotrexate IV on days 1, 8, and 15 and pegaspargase or calaspargase IV on day 1 or 3-weeks after previous dose given during CNS phase and given every 3 weeks until 9 total post-induction doses of calaspargase or 10 total doses of pegaspargase. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity until patients complete 30 total weeks of post induction asparaginase. Patients also receive IT MAH every 9 weeks for patients with no prior cranial radiation or every 18 weeks for patients with previous cranial radiation. Patients then proceed to blinatumomab cycle 4 (if B-cell ALL) or continuation.

BLINATUMOMAB CYCLE 4: Patients receive dexamethasone IV or PO on day 1, blinatumomab IV continuously on days 1-28 and IT MAH continuing per schedule in Consolidation II in the absence of disease progression or unacceptable toxicity. Patients then proceed to continuation.

CONTINUATION: Patients receive vincristine IV on day 1, dexamethasone IV or PO BID on days 1-5, 6-mercaptopurine PO QD on days 1-14, and methotrexate IV on days 1, 8 and 15 of each cycle. Cycles repeat every 21 days until 24 months from date of CR, in the absence of disease progression or unacceptable toxicity. Patients with B-cell ALL with no previous cranial radiation receive IT MAH every 9 weeks for 6 doses post blinatumomab phase doses and then every 18 weeks until completion of therapy. Patients with T-cell ALL with no previous cranial radiation receive IT MAH every 9 weeks until the completion of therapy. Patients (B-cell ALL or T-cell ALL) with previous cranial radiation receive IT MAH every 18 weeks until the completion of therapy, in the absence of disease progression or unacceptable toxicity. Patients who are optimal responders receive vincristine and dexamethasone every 3rd cycle.

Patients undergo echocardiography during screening, dual X-ray absorptiometry scan on study and bone marrow aspiration and biopsy and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days and every 3 months for 4 years then every 6 months until 10 years from registration.