Combination Chemotherapy in Treating Patients with Acute Lymphoblastic Leukemia or Lymphoma

PRIMARY OBJECTIVES:

I. To improve the event-free survival of provisional standard- or high-risk patients with genetically or immunologically targetable lesions or minimal residual disease (MRD) >= 5% at day 15 or day 22 or >= 1% at the end of remission induction, by the addition of molecular and immunotherapeutic approaches including tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T cells / blinatumomab for refractory B-acute lymphoblastic leukemia (B-ALL) or B-lymphoblastic lymphoma (B-LLy), and the proteasome inhibitor bortezomib for those lacking targetable lesions.

II. To improve overall treatment outcome of T acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LLy) by optimizing pegaspargase and cyclophosphamide treatment, by the addition of new agents in patients with targetable genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the addition of bortezomib for those who have a poor early response to treatment but no targetable lesions, and by administering nelarabine to T-ALL and T-LLy patients with leukemia/lymphoma cells in cerebrospinal fluid at diagnosis or MRD >= 0.01% at the end of induction.

III. To determine in a randomized study design whether the incidence and/or severity of acute vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of vincristine in patients with the high-risk CEP72 TT genotype or by shortening the duration of vincristine therapy in standard/high-risk patients with the CEP72 CC or CT genotype.

SECONDARY OBJECTIVES:

I. To estimate the event-free survival and overall survival of children with acute lymphoblastic leukemia (ALL) and to assess the non-inferiority of total therapy study XVII (TOTXVII) compared to the historical control given by total therapy study XVI (TOTXVI).

II. To estimate the event-free survival and overall survival of children with acute lymphoblastic lymphoma (LLy) when ALL diagnostic and treatment approaches are used.

III. To evaluate the efficacy of blinatumomab in B-ALL patients with end of induction MRD >= 0.01% to < 1% and those (regardless of MRD level or TOTXVII risk category) with the genetic subtypes of BCR-ABL1, ABL-class fusion, JAK-STAT activating mutation, hypodiploid, iAMP21, ETV6-RUNX1–like, MEF2D, TCF3-HLF, or BCL2/MYC or with Down syndrome, by comparing event-free survival to historical control from TOTXVI.

IV. To determine the tolerability of combination therapy with ruxolitinib and early Intensification therapy in patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib and day 15 or day 22 MRD >= 5%, day 42 MRD >= 1%, or LLy patients without complete response at the end of induction and all patients with early T cell precursor leukemia.

BIOLOGICAL OBJECTIVES:

I. To use data from clinical genomic sequencing of diagnosis, germline/remission and MRD samples to guide therapy, including incorporation of targeted agents and institution of genetic counseling and cancer surveillance.

II. To evaluate and implement deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequencing-based methods to monitor levels of MRD in bone marrow, blood, and cerebrospinal fluid.

III. To assess clonal diversity and evolution of pre-leukemic and leukemic populations using DNA variant detection and single-cell genomic analyses in a non-clinical, research setting.

IV. To identify germline or somatic genomic variants associated with drug resistance of ALL cells to conventional and newer targeted anti-leukemic agents in a non-clinical, research setting.

V. To compare drug sensitivity of ALL cells from diagnosis to relapse in vitro and in vivo and determine if acquired resistance to specific agents is related to specific somatic genome variants that are not detected or found in only a minor clone at initial diagnosis.

SUPPORTIVE CARE OBJECTIVES:

I. To conduct serial neurocognitive monitoring of patients to investigate the neurocognitive trajectory, mechanisms, and risk factors.

II. To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover.

EXPLORATORY OBJECTIVES:

I. To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors of treatment outcome (host toxicity or in vivo efficacy).

II. To perform a detailed assessment of thiopurine metabolism and to correlate with 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome.

III. To establish xenografts of representative subtypes of ALL, including high-risk, poorly responsive, refractory and relapsed cases, and to correlate diagnosis, interim and relapse genomic features.

IV. To prospectively determine the risk and epidemiology of breakthrough infection or febrile neutropenia and adverse effects of antibiotics administered as prophylaxis or treatment.

V. To use cell phenotyping and genomic approaches to characterize the non-tumor microenvironment and correlate with responses to conventional and immunotherapeutic approaches.

VI. To estimate the treatment response and event-free survival and overall survival of children with mixed phenotype acute leukemia (MPAL) when ALL diagnostic and treatment approaches are used.

OUTLINE:

B/myeloid MPAL patients are treated as B-ALL and T/myeloid MPAL patients are treated as early T cell precursor-ALL.

TRIPLE INTRATHECAL CHEMOTHERAPY (ITT): Patients receive methotrexate intrathecally (IT), therapeutic hydrocortisone IT, and cytarabine IT on days 1 and 15. Patients may receive additional ITT on days 8 and 22, on days 4, 8, 11, and 22, or day 43.

REMISSION INDUCTION: Patients receive prednisone or prednisolone orally (PO) on days 1-28, vincristine sulfate IV on days 1, 8, 15, and 22, daunorubicin hydrochloride intravenously (IV) on days 2 and 8, pegaspargase IV, or intramuscularly (IM), or calaspargase pegol-mknl IV on day 3 or pegaspargase IV, or intramuscularly (IM) on days 3 and 15 for patients with MRD >= 1%, cyclophosphamide IV on day 22, cytarabine IV or subcutaneously (SC) on days 22-25 and 29-32, mercaptopurine PO on days 22-35, dasatinib PO daily starting day 15 until the end of therapy, and bortezomib IV or SC on days 29 and 32. Patients with T lymphoblastic leukemia/lymphoma also receive daunorubicin hydrochloride IV on day 15.

EARLY INTENSIFICATION THERAPY: Patients receive cyclophosphamide IV on day 43, cytarabine IV or SC on days 43-46 and 50-53, mercaptopurine PO on day 43-56, ITT on day 43, dasatinib PO daily starting on day 43 until the end of therapy, ruxolitinib PO twice daily (BID) starting on days 43-56, and bortezomib IV or SC on days 43 and 46.

CONSOLIDATION: Patients receive high-dose methotrexate on days 1, 15, 29, and 43, mercaptopurine PO on days 1-56, ITT on days 1, 15, 29, and 43, and dasatinib PO daily and ruxolitinib PO BID until end of therapy.

IMMUNOTHERAPY: Patients with standard-risk B-ALL/LLy with positive MRD at the end of induction, high-risk genetics, or Down syndrome receive blinatumomab continuously IV on days 1-28 and ITT on day 29, after consolidation or at some timepoint before week 30 of continuation. For participants who have already passed this point in therapy (prior to amendment 4.0), blinatumomab may be given any time during Continuation Therapy. Patients with high-risk B-ALL/LLy receive CAR T-cell therapy. Patients with high-risk B-ALL/B-LLy who are not able to receive CAR T-cell therapy can receive blinatumomab.

REINTENSIFICATION I: Patients with non-early T cell precursor (ETP) ALL and LLy receive dexamethasone PO or IV BID on days 1-6, cytarabine IV every 12 hours on days 1-2, etoposide IV over 1 hour every 12 hours on days 3-5, ITT on day 5, and pegaspargase IV or IM on day 6. Patients with high-risk ETP ALL receive vorinostat PO three times daily on days 1-3, idarubicin IV over 1 hour on days 4-6, cytarabine IV over 2 hours every 12 hours on days 4-6, and ITT on day 1 or earlier.

REINTENSIFICATION II: Patients receive clofarabine IV over 2 hours, etoposide IV over 2 hours, cyclophosphamide IV over 30-60 minutes, and dexamethasone IV or PO BID on days 1-5. Patients also receive ITT on day 1 or earlier.

CONTINUATION: Prior to initiation of continuation therapy, T-ALL patients with leukemia cells in cerebrospinal fluid or positive MRD at the end of remission induction receive nelarabine IV on days 1-5 of week 1, cyclophosphamide IV on day 1 of week 2, cytarabine on day 1 of week 2. T-ALL patients receive nelarabine IV continuation weeks 22, 27, 32, 37, and 42.

Patients with standard/high-risk ALL and LLy receive dexamethasone PO BID on days 1-5 of weeks 1, 4, 14, 25, 29, 33, 37, 41, 45, and 49, doxorubicin IV on day 1 of weeks 1, 4, 11, and 14, mercaptopurine PO on days 1-7 of weeks 1-6, 10-16, 21-23, 26-27, 30-31, 34-35, 38-39, 42-43, and 46-47, calaspargase pegol-mknl on day 1 of weeks 1, 4, 10, 13 or pegaspargase IV or IM on day 1 of weeks 1, 3, 5, 11, 13, and 15, methotrexate IV, PO, or IM on days 1 of weeks 21-23, 26-27, 30-31, 34-35, 38-39, 42-43, and 46-47, cyclophosphamide IV on day 1 of weeks 24, 28, 32, 36, 40, 44, and 48, cytarabine IV on days 1 of weeks 24, 28, 32, 36, 40, 44, and 48, and vincristine sulfate IV on day 1 of weeks 1, 4, 11, 14, 25, 29, 33, 37, 41, 45, and 49. Patients may also receive ITT at weeks 3, 7, 12, 17, 25, 29, 33, 37, 41, 45 and 49. Additional intrathecal therapy will be given based on the risk factors of central nervous system relapse at weeks 57, 65, 73, 81, 89, and 97.

Patients with low risk ALL and LLy receive dexamethasone PO BID on days 1-5 of weeks 1, 4, 14, 25, 29, 33, 37, 41, 45, and 49, mercaptopurine PO on days 1-7 of weeks 1-6, 10-16, 20, 21-49, and 50-57, methotrexate IV, PO, or IM on day 1 of weeks 2, 3, 5, 6, 10-13, 15, 16, 20-24, 26-28, 30-32, 34-36, 38-40, 42-44, 46-48, and vincristine sulfate IV on day 1 of weeks 1, 4, 14, 25, 29, 33, 37, 41, 45, and 49. Patients may also receive ITT at weeks 3, 7, 12, 17, 25, 29, 33, 37, 41, 45, and 49.

Patients are then randomized into 1 of 2 arms.

ARM I: Patients with standard/high-risk ALL and LLy receive mercaptopurine PO on days 1-7 and methotrexate IV, PO, or IM on day 1 of weeks 50-51, 53-55, and 57-120, and cyclophosphamide IV on day 1 and cytarabine IV on day 1 of weeks 52 and 56.

ARM II: Patients with standard/high-risk ALL and LLy receive mercaptopurine PO on days 1-7 of weeks 50-51, 54-55, and 58-120, and methotrexate IV, PO, or IM on day 1 of weeks 50-51, 54-55, 58-60, 62-64, 66-68, 70-72, 74-76, 78-80, 82-84, 86-88, 90-92, 94-96, 98-100, and 102-120, cyclophosphamide IV on day 1 and cytarabine IV on day 1 of weeks 52 and 56, dexamethasone PO BID on days 1-5 and vincristine sulfate IV on day 1 on weeks 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, and 101.

All patients with low-risk ALL and LLy receive mercaptopurine PO on days 1-7 and methotrexate IV, PO, or IM on day 1 of weeks 50-120.

REINDUCTION I (weeks 7-9 of Continuation): Patients receive dexamethasone PO BID on days 1-8 and 15-21, calaspargase pegol-mknl IV on day 1 or pegaspargase IV or IM, on days 1 and 15, and vincristine sulfate IV on days 1, 8, and 15. Patients with standard/high-risk ALL and LLy also receive doxorubicin IV on day 1.

REINDUCTION II (weeks 17-19 of Continuation): Patients receive dexamethasone PO BID on days 1-8 and 15-21, calaspargase pegol-mknl on day 1 or pegaspargase IV or IM on days 1 and 15, and vincristine sulfate IV on days 1, 8, and 15. Patients with standard/high-risk ALL and LLy also receive high-dose cytarabine IV over 3 hours every 12 hours on days 15 and 16.

Treatment continues in the absence of disease progression or unexpected toxicity.