Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To test a novel risk group classification scheme with the goal of reducing rates of treatment-related toxicity without compromising complete remission rates and overall event-free survival.

Ia. To test whether remission induction can be de-intensified in low-risk B-acute lymphoblastic leukemia (ALL) patients without adversely impacting complete remission rates or proportion of patients classified as very high-risk on the basis of high minimal residual disease (MRD levels).

Ib. To determine rates of event-free survival, disease-free survival and overall survival associated with novel risk group classification scheme.

SECONDARY OBJECTIVES:

I. To determine the feasibility of treating children and adolescents with a reduced dose of pegaspargase (Oncaspar) every 2-weeks for 30 weeks during post-induction therapy.

Ia. To determine whether treatment with reduced doses of pegaspargase decreases the proportion of patients with very high nadir serum asparaginase activity (NSAA) (defined as >= 1.0 IU/mL) compared with standard fixed dosing during post-induction therapy.

Ib. To determine the proportion of patients who maintain NSAA at or above 0.4 IU/mL with a reduced dose of pegaspargase (1750 IU/m^ 2 or 2000 IU/m^2 every 2-weeks) during post-induction therapy.

Ic. To determine the rate of non-allergic asparaginase-related toxicities (including pancreatitis, thromboembolic events, hyperbilirubinemia, hypertriglyceridemia and hyperglycemia) associated with reduced dose of pegaspargase during post-induction therapy, and to compare this rate to that observed with standard fixed dosing pegaspargase (2500 IU/m^2 every 2 weeks).

II. To estimate disease-free survival (DFS) in patients assigned to very high risk (VHR) group.

EXPLORATORY OBJECTIVES:

I. To compare disease-free survival for patients treated on Dana-Farber Cancer Institute (DFCI) 16-001 with patients treated on previous DFCI protocol 05-001.

II. To describe rates of non-asparaginase-related toxicities (including infections, mucositis, bone fracture and osteonecrosis) and compare these rates to those observed on previous DFCI protocol 05-001.

III. To determine whether there is an association between peak SAA levels and non-allergic asparaginase-related toxicities.

IV. To describe rates of silent inactivation in patients treated with pegaspargase (Oncaspar).

V. To pilot a strategy of re-challenging patients with pegaspargase after initial infusion reaction/clinical hypersensitivity to this agent.

VI. To evaluate concordance of MRD results assessed by two methodologies: next generation sequencing (NGS) and multi-parameter flow cytometry.

VII. To pilot an intensified regimen for very high-risk patients.

VIIa. To describe toxicity of very high-risk patients treated with an intensified chemotherapy regimen.

VIIb. To explore the feasibility of characterizing TKI-targetable fusions in real-time and administering targeted therapy to very high-risk patients with these fusions.

VIII. To prospectively characterize subclinical changes in cognitive function during treatment for ALL.

VIIIa. To assess the relationship of biomarkers in the spinal fluid measured during treatment and standardized measures of cognition.

VIIIb. To estimate the rate of adherence to 6-mercaptopurine and dexamethasone in pediatric and adolescent patients during the consolidation II and continuation phases of therapy.

VIIIc. To explore the association between adherence to 6-mercaptopurine and adherence to dexamethasone during consolidation II and during continuation therapy.

VIIId. To explore the relationship between adherence to 6-mercaptopurine and dexamethasone and patient-related sociodemographic predictors including: age (>= 15 years), ethnicity and primary caregiver level of health literacy.

VIIIe. To assess the impact of adherence to 6-mercaptopurine and dexamethasone on disease-free survival (DFS).

VIIIf. To assess concordance of self-reported adherence rates and MEMS (medication event monitoring systems) cap measured adherence rates.

IX. To prospectively characterize the trajectory of household material hardship (HMH) from initiation through completion of therapy and to explore its impact on disease outcome and chemotherapy receipt.

IXa. To describe prevalence at HMH at baseline and at 3 additional time points during therapy.

IXb. To explore association between baseline HMH and disease outcome (relapse, event-free survival, overall survival).

IXc. To assess relationship between HMH and adherence to 6-mercaptopurine.

IXd. To explore the association between baseline area-based socioeconomic measures (ABSM) and disease outcome (relapse, event-free survival, overall survival).

IXe. To explore the relationship between HMH and ABSM at baseline and over the course of therapy.

X. To describe dexamethasone and vincristine-associated toxicity during the continuation phase, through targeted data capture and patient reported outcomes/quality of life assessments.

OUTLINE:

STEROID PROPHASE: Patients receive dexamethasone intravenously (IV) twice daily (BID) on days 1-3 and cytarabine intrathecally (IT) on day 1.

INDUCTION IA PHASE: Patients with initial low risk (LR) without high-risk (HR) or very high-risk (VHR) features receive dexamethasone PO BID or IV on days 4-25 with taper staring on day 26 and completing on day 32, vincristine sulfate IV on day 4, 11, 18, and 25, pegaspargase IV over 1-2 hours on day 6, cytarabine IT, methotrexate IT, and therapeutic hydrocortisone IT on day 18. Patients diagnosed with CNS-2 also receive cytarabine IT twice weekly starting on days 4, 5, or 6 for 3 doses and on days 14, 21, 25, and 28, methotrexate IT and therapeutic hydrocortisone IT on days 21, 25, and 28. Patients may receive methotrexate IT on day 32. Patients with initial LR with HR or VHR or unknown HR or VHR features also receive doxorubicin IV over 15 minutes on days 11 and 12. Patients with initial HR features receive dexamethasone, vincristine sulfate, pegaspargase as in initial LR without HR or VHR. Patients also receive doxorubicin IV over 15 minutes and dexrazoxane hydrochloride IV over 15 minutes on days 4 and 5, and cytarabine IT, methotrexate IT, and therapeutic hydrocortisone IT on day 18. Patients diagnosed with central nervous system (CNS)-2 or CNS-3 also receive cytarabine IT twice-weekly between days 4 and 15 and on days 21, 25, 28, methotrexate IT and therapeutic hydrocortisone IT on days 21, 25, and 28. Patients may receive methotrexate IT on day 32. VHR patients with dasatinib-sensitive Ph-like fusion receive dasatinib PO QD.

INDUCTION IB PART 1: All patients receive cyclophosphamide IV over 1 hour on day 1, cytarabine IV or subcutaneously (SC) on days 1-4 and 8-11, mercaptopurine PO once daily (QD) on days 1-14, and methotrexate IT on day 1. VHR patients with dasatinib-sensitive fusion receive dasatinib PO QD.

INDUCTION IB, PART 2: Patients who are then determined to be high-risk or very high-risk receive cyclophosphamide IV on day 22, cytarabine IV or SC on days 22-25 and 29-32, mercaptopurine PO QD on days 22-35, and methotrexate IT on day 22. VHR patients with dasatinib-targetable gene fusion receive dasatinib PO QD.

CONSOLIDATION IA: Patients with B-ALL receive vincristine sulfate IV, high dose methotrexate IV over 24 hours, and methotrexate IT on day 1. Patients also receive mercaptopurine PO QD on days 1-14. Patients with T-ALL receive vincristine sulfate IV on days 1 and 15, mercaptopurine PO QD on days 1-7 and 15-21, methotrexate IT on day 1, and high dose methotrexate IV over 24 hours on days 1 and 15.

CONSOLIDATION IB: Patients with B-ALL receive vincristine sulfate IV on day 1, dexamethasone IV or PO BID on days 1-5, methotrexate IT on day 1, high dose methotrexate IV over 24 hours on day 1, cyclophosphamide IV over 30 minutes on days 8-12, etoposide IV over 2 hours on days 8-12, and filgrastim or pegfilgrastim SC starting on day 13. Patients with T-ALL receive nelarabine IV over 1 hour, etoposide IV over 2 hours, and cyclophosphamide IV over 30 minutes on days 1-5. Patients also receive filgrastim or pegfilgrastim SC starting on day 6. For both B-ALL and T-ALL, VHR patients with dasatinib-targetable gene fusion receive dasatinib PO QD.

CONSOLIDATION IC: Patients with HVR receive dexamethasone IV or PO BID on days 1-5, high dose cytarabine IV on days 1-2, etoposide over 1-2 hours on days 3-5, methotrexate IT on day 1, filgrastim or pegfilgrastim SC starting on day 6, and pegaspargase IV over 1-2 hours on 8 and then every 2 weeks. VHR patients with dasatinib-targetable gene fusion receive dasatinib PO QD.

CNS PHASE: Patients are randomized to 1 of 2 arms.

ARM A: Patients with LR, intermediate risk (IR), and HR receive vincristine sulfate IV on day 1, dexamethasone PO BID on days 1-5, and mercaptopurine PO QD on days 1-14. Patients also receive fixed dose pegaspargase IV over 1-2 hours on day 8, then once every 2 weeks for 15 doses, methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT twice weekly for 4 doses starting on day 1. VHR patients with dasatinib-targetable gene fusion receive dasatinib PO QD.

ARM B: Patients with LR, IR, and HR receive vincristine sulfate, dexamethasone, mercaptopurine, methotrexate, cytarabine, therapeutic hydrocortisone, and dasatinib as in Arm A. Patients also receive dose adjusted pegaspargase IV over 1-2 hours on day 8 and then every 2 weeks for 15 doses.

Patients who decline or are ineligible for randomization are assigned to 1 of 3 arms.

ARM X: Patients with LR, IR, and HR receive vincristine sulfate, dexamethasone, mercaptopurine, methotrexate, cytarabine, therapeutic hydrocortisone, dasatinib, and pegaspargase as in Arm A.

ARM Y: Patients with LR, IR, and HR receive vincristine sulfate, dexamethasone, mercaptopurine, methotrexate, cytarabine, therapeutic hydrocortisone, and dasatinib as in Arm A.

ARM Z: Patients with LR, IR, and HR receive vincristine sulfate, dexamethasone, mercaptopurine, methotrexate, cytarabine, therapeutic hydrocortisone, and dasatinib as in Arm A. Patients also receive pegaspargase intramuscularly (IM) twice weekly or IV thrice weekly.

CONSOLIDATION II: Patients with LR receive vincristine sulfate IV on day 1, dexamethasone PO BID on days 1-5, mercaptopurine PO QD on days 1-14, and methotrexate IV, IM or PO on days 1, 8, and 15. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive pegaspargase as in CNS Phase IV every 2 weeks for 15 doses and methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT as close to every 9 weeks starting on day 1 of cycle 3. Patients with LR assigned to Arm Y receive vincristine sulfate IV on day 1, dexamethasone PD BID on days 1-5, mercaptopurine PO QD on days 1-14 dexrazoxane hydrochloride IV over 15 minutes on day 1, and doxorubicin over 15 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT as close to every 9 weeks starting on day 1 of cycle 3. Patients with IR and HR receive vincristine sulfate IV on day 1, dexamethasone PD BID on days 1-5, mercaptopurine PO QD on days 1-14 dexrazoxane hydrochloride IV over 15 minutes on day 1 (cycles 1-8), doxorubicin over 15 minutes on day 1 (cycles 1-8), and methotrexate IV or IM on days 1, 8, and 15. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive pegaspargase as in CNS Phase and methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT as close to every 9 weeks (no prior cranial radiation) or 18 weeks (previously irradiated) starting on day 1 of cycle 3. Patients with VHR vincristine sulfate IV on day 1, high dose dexamethasone PD BID on days 1-5 for cycles 1-8 and then standard dose dexamethasone PO BID on day 1-5, mercaptopurine PO QD on days 1-14 dexrazoxane hydrochloride IV over 15 minutes on day 1 (cycles 1-8), doxorubicin over 15 minutes on day 1 (cycles 1-8), and methotrexate IV, IM, or PO on days 1, 8, and 15. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive pegaspargase as in CNS Phase and methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT as close to every 9 weeks (no prior cranial radiation) or 18 weeks (previously irradiated) starting on day 1 of cycle 3.

CONTINUATION PHASE: Patients receive vincristine sulfate IV on day 1, dexamethasone PO BID on days 1-5, mercaptopurine PO QD on days 1-14, methotrexate IV, IM, or PO on days 1, 8, and 15. Patients also receive methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT every 9 or 18 weeks starting on day 1. VHR patients with dasatinib-targetable gene fusion receive dasatinib PO QD.

Additionally, patients undergo blood sample collection, bone marrow aspiration and biopsy and echocardiography on study.

After completion of study treatment, patients are followed up monthly for 6 months, every 2 months for the next 6 months, every 4 months for 1 year, then every 6 months for another year, and then annually for up to 10 years.