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

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Status: Active

Description

This randomized phase III trial studies risk classification schemes in identifying better treatment options for children and adolescents with acute lymphoblastic leukemia. Risk factor classification may help identify how strong treatment should be for patients with acute lymphoblastic leukemia.

Eligibility Criteria

Inclusion Criteria

  • Diagnosis should be made by bone marrow aspirate or biopsy demonstrating >= 25% involvement by lymphoblasts, with flow cytometry or immunohistochemistry confirming B-precursor or T-ALL phenotype * For patients with circulating blasts in the peripheral blood, flow cytometry confirmation of B-ALL or T-ALL phenotype is sufficient for registration onto the study; bone marrow aspirate and/or biopsy should be performed as soon as feasible, preferably prior to the initiation of any therapy * While myeloid co-expression on blasts determined to be primarily lymphoid is allowed, patients meeting World Health Organization (WHO) diagnostic criteria of mixed phenotype acute leukemia (MPAL) or leukemia of ambiguous lineage are not eligible; patients with mature B-cell phenotype are also not eligible
  • No prior therapy is allowed except for the following: * Short courses of corticosteroid (defined as =< 7 days of corticosteroids within the 4-weeks preceding diagnosis) are allowed ** Participants who have been on corticosteroids chronically (defined as more than 7 days of corticosteroids within the 4-weeks preceding diagnosis or more than 28 days of corticosteroids over the preceding 6 months) are not eligible * A single dose of intrathecal cytarabine (at the time of the diagnostic lumbar puncture) is allowed prior to registration; if patient has received intratumoral (IT) cytarabine prior to informed consent for protocol treatment, day 1 IT cytarabine should not be administered * Emergent radiation to the mediastinum or other life-threatening masses is allowed prior to registration
  • Direct bilirubin < 1.4 mg/dL (23.9 micromoles/L) Note: a total bilirubin of < 1.4 mg/dL (23.9 micromoles/L) is acceptable to meet this requirement
  • Ability of parent or guardian to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Participants with mature B-cell (Burkitt’s) ALL are excluded from study; mature B-cell is defined by the presence of surface immunoglobulin and/or the t(8;14)(q24;q32), t(8;22), or t(2;8) translocation and/or c-myc-gene rearrangement by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR); (FISH/PCR testing for c-myc rearrangements is not required prior to study entry, but it is suggested for patients with surface immunoglobulin expression or L3 morphology)
  • Participants whose leukemia meets WHO diagnostic criteria of mixed phenotype acute leukemia (MPAL) or leukemia of ambiguous lineage are not eligible
  • Participants who have received any chemotherapy or radiotherapy for previous malignancy are not eligible
  • Participants who have ever previously received any anti-neoplastic agent, including methotrexate, 6-mercaptopurine, 6-thioguanine, vincristine cyclophosphamide, cytarabine (except for IT cytarabine), or any anthracycline, for any reason (eg, rheumatologic or autoimmune condition) are not eligible
  • Participants who are receiving any investigational agents are not eligible
  • Participants known to be human immunodeficiency virus (HIV)-positive are excluded (Note: HIV testing is not required prior to enrollment). HIV-positive individuals on combination antiretroviral therapy are ineligible
  • Uncontrolled intercurrent illness including, but not limited to ongoing infection with vital sign instability (hypotension, respiratory insufficiency), life-threatening acute tumor lysis syndrome (eg, with renal failure), symptomatic congestive heart failure, cardiac arrhythmia, intracranial or other uncontrolled bleeding, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is enrolled
  • Individuals with a history of a previous malignancy are ineligible; exception: individuals with a previous malignancy treated with surgery only (no chemotherapy or radiotherapy) more than 5 years prior to registration may be enrolled

Locations & Contacts

Massachusetts

Boston
Boston Children's Hospital
Status: Active
Contact: Lewis Barry Silverman
Phone: 617-632-6191 Email: Lewis_Silverman@dfci.harvard.edu
Dana-Farber Cancer Institute
Status: Active
Contact: Lewis Barry Silverman
Phone: 617-632-6191 Email: Lewis_Silverman@dfci.harvard.edu

New York

Buffalo
Roswell Park Cancer Institute
Status: Active
Contact: Kara M. Kelly
Phone: 716-845-2333 Email: Kara.Kelly@RoswellPark.org
New York
Columbia University / Herbert Irving Cancer Center
Status: Active
Contact: Maria Luisa Sulis
Phone: 212-305-5808 Email: Mls95@cumc.columbia.edu

Quebec

Montreal
Centre Hospitalier Universitaire Sainte-Justine
Status: Active
Contact: Jean-Marie Leclerc
Phone: 514-345-4931ext4639
Quebec
Centre Hospitalier Universitaire de Quebec
Status: Active
Contact: Bruno Michon
Phone: 418-525-4444ext47191

Trial Objectives and Outline

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.

II. 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).

III. 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.

II. 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.

III. 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.

IV. 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).

TERTIARY 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 nonallergic 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.

VIII. To describe toxicity and disease-free survival of very high risk patients treated with an intensified chemotherapy regimen.

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

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

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

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

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

XIV. 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.

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

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

XVII. 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.

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

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

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

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

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

OUTLINE:

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

INDUCTION IA: 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.

INDUCTION IB PART I: 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 intrathecally on day 1.

INDUCTION IB, PART 1: 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.

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.

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 or 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 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 CSN Phase IV every 2 weeks for 15 doses and methotrexate IT, cytarabine IT, and therapeutic hydrocortisone IT every 9 weeks starting on day 1. 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 every 9 weeks starting on day. 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 (courses 1-8), doxorubicin over 15 minutes on day 1 (courses 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 every 9 weeks starting on day. Patients with VHR vincristine sulfate IV on day 1, high dose dexamethasone PD BID on days 1-5 for courses 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 (courses 1-8), doxorubicin over 15 minutes on day 1 (courses 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 every 9 weeks starting on day 1.

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 or IM 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.

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

Trial Phase & Type

Trial Phase

Phase III

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Lewis Barry Silverman

Trial IDs

Primary ID 16-001
Secondary IDs NCI-2017-00431
Clinicaltrials.gov ID NCT03020030