Risk-Adapted Chemotherapy in Treating Younger Patients With Newly Diagnosed Standard-Risk Acute Lymphoblastic Leukemia or Localized B-Lineage Lymphoblastic Lymphoma
Risk-Adapted Chemotherapy in Treating Younger Patients With Newly Diagnosed Standard-Risk Acute Lymphoblastic Leukemia or Localized B-Lineage Lymphoblastic Lymphoma
This partially randomized phase III trial studies the side effects of different combinations
 of risk-adapted chemotherapy regimens and how well they work in treating younger patients
 with newly diagnosed standard-risk acute lymphoblastic leukemia or B-lineage lymphoblastic
 lymphoma that is found only in the tissue or organ where it began (localized). Drugs used in
 chemotherapy work in different ways to stop the growth of cancer cells, either by killing the
 cells, by stopping them from dividing, or by stopping them from spreading. Giving more than
 one drug (combination chemotherapy), giving the drugs in different doses, and giving the
 drugs in different combinations may kill more cancer cells.
PRIMARY OBJECTIVES:

 l. To determine if a maintenance regimen containing weekly oral methotrexate at 40
 mg/m^2/week will result in an improved disease free survival (DFS) compared to that
 containing weekly oral methotrexate at 20 mg/m^2/week in the average-risk (AR) subset of
 patients with standard-risk B-precursor acute lymphoblastic leukemia (ALL). (Complete
 effective January 13, 2017) II. To determine whether a reduced-pulses maintenance regimen
 with vincristine (vincristine sulfate)/dexamethasone pulses delivered every 12 weeks can be
 used without adversely impacting DFS as compared to pulses given every 4 weeks in the AR
 subset of patients with standard risk B-precursor ALL.

 III. To confirm that patients in the low-risk (LR) subset of standard risk B-precursor ALL,
 based on clinical and cytogenetic features and minimal residual disease (MRD) criteria, can
 attain a 5 year DFS of at least 95% with either a P9904 based regimen that includes 6 courses
 of intermediate dose (1 g/m^2 over 24 hours) methotrexate without alkylating agents or
 anthracyclines (Arm LR-M), or an outpatient based regimen identical to that of AR patients
 with reduced vincristine/dexamethasone pulses at 12 week intervals during maintenance (Arm
 LR-C).

 IV. To provide standardized treatment and enhanced supportive care to children with
 standard-risk (SR) Down syndrome B-ALL in order to improve outcomes and facilitate further
 study of this biologically and clinically unique patient subgroup.

 V. To improve understanding of the biology of localized B-lineage lymphoblastic lymphoma
 (B-LLy) and Down syndrome (DS) B-LLy by obtaining biologic data, including fluorescence in
 situ hybridization (FISH) for recurrent cytogenetic lesions on paraffin specimen, and banking
 tissue for future research.

 VI. To describe the 5-year event free survival (EFS) and overall survival (OS) of patients
 with Murphy stage I and II B-LLy receiving modified AR B-ALL therapy.

 SECONDARY OBJECTIVES:

 I. To assess the burden of AR B-ALL therapy as measured by surveys of the child's quality of
 life, missed days of school/daycare/work by children and parents, family functioning,
 parental perception of the child's health vulnerability, physical functioning, and emotional
 distress, 1) overall at different time points during and at the end of therapy, and by 2)
 comparing children randomized to every 4 week vs. every 12 week dexamethasone/vincristine
 pulses during maintenance. (Closed to accrual as of April 19, 2013) II. To characterize the
 onset, severity, and natural history of vincristine associated neuropathy by physical
 therapists (or occupational therapists) in children undergoing therapy for AR B-ALL, 1)
 overall at different time points during and at the end of therapy, and by 2) comparing
 children randomized to every 4 week vs. every 12 week dexamethasone/vincristine pulses during
 maintenance. (Closed to accrual as of March 15, 2013)

 TERTIARY OBJECTIVES:

 I. To explore the correlation of minimal marrow disease (MMD) at diagnosis and outcome for
 patients with B-LLy. (Closed effective Amendment #5)

 OUTLINE:

 All patients receive induction therapy comprising intrathecal (IT) cytarabine on day 1;
 vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) or IV twice daily
 (BID) on days 1-28; pegaspargase IV over 1-2 hours on day 4; and IT methotrexate* on days 8
 and 29. Patients with Philadelphia chromosome-positive disease are eligible to transfer to
 COG-AALL0622 by day 15 of induction therapy and patients with high-risk (HR) or very
 high-risk (VHR) disease are eligible to transfer to a COG HR or VHR trial at the end of
 induction therapy. Patients with standard-risk disease with Down syndrome (DS) who have bone
 marrow minimal residual disease 0.01% are eligible to transfer to the DS stratum of the HR
 trial. Patients with induction failure (defined as M3 [> 25% lymphoblasts] on day 29) may be
 eligible for the COG VHR-acute lymphoblastic leukemia study.

 NOTE: *Patients with DS also receive oral leucovorin calcium every 12 hours on days 10-11 and
 31-32.

 STANDARD-RISK WITH DOWN SYNDROME:

 Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1;
 mercaptopurine PO on days 1-28; IT methotrexate on days 1, 8, and 15; and leucovorin calcium
 PO every 12 hours on days 3-4, 10-11, and 17-18. Interim maintenance I therapy (8 weeks):
 Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11,
 21, 31, and 41; IT methotrexate on day 31; and leucovorin calcium PO every 12 hours on days
 36-34. Delayed-intensification therapy (8 weeks): Patients receive dexamethasone PO or IV BID
 on days 1-7 and 15-21; vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15
 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV
 over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 1-30 minutes
 or subcutaneously (SC) on days 29-32 and 33-39; IT methotrexate on days 1 and 29; and
 leucovorin calcium PO every 12 hours on days 3-4 and 31-32. Interim maintenance II therapy (8
 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days
 1, 11, 21, 31, and 41; IT methotrexate on days 1 and 31; and leucovorin calcium PO every 12
 hours on days 3-4 and 33-34. Maintenance therapy: Patients receive vincristine sulfate IV on
 day 1; dexamethasone PO BID on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. Courses
 repeat every 12 weeks for 2 years (timed from the start of interim maintenance I therapy).

 B-LLy:

 Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1;
 mercaptopurine PO on days 1-28; IT methotrexate on days 1, 8, and 15; and leucovorin calcium
 PO every 12 hours on days 3-4, 10-11, and 17-18. Interim maintenance I therapy (8 weeks):
 Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11,
 21, 31, and 41; IT methotrexate on day 31; and leucovorin calcium PO every 12 hours on days
 36-34. Delayed-intensification therapy (8 weeks): Patients receive dexamethasone PO or IV BID
 on days 1-7 and 15-21; vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15
 minutes on days 1, 8, and 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV
 over 30-60 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 1-30 minutes
 or subcutaneously (SC) on days 29-32 and 33-39; IT methotrexate on days 1 and 29; and
 leucovorin calcium PO every 12 hours on days 3-4 and 31-32. Interim maintenance II therapy (8
 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days
 1, 11, 21, 31, and 41; IT methotrexate on days 1 and 31; and leucovorin calcium PO every 12
 hours on days 3-4 and 33-34. Maintenance therapy: Patients receive vincristine sulfate IV on
 day 1; dexamethasone PO BID on days 1-5; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1. Courses
 repeat every 4 weeks for 2 years (timed from the start of interim maintenance I therapy).

 AVERAGE-RISK:

 Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on day 1;
 mercaptopurine PO on days 1-28; and IT methotrexate on days 1, 8, and 15.Interim maintenance
 I therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15
 minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on day 31. Delayed intensification
 therapy (8 weeks): Patients receive dexamethasone PO or IV BID on days 1-7 and 15-21;
 vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15 minutes on days 1, 8, and
 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV over 30-60 minutes on day
 29; thioguanine PO on days 29-42; cytarabine IV over 1-30 minutes or SC on days 29-32 and
 36-39; and IT methotrexate on days 1 and 29. Interim maintenance II therapy (8 weeks):
 Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days 1, 11,
 21, 31, and 41 and IT methotrexate on days 1 and 31. Maintenance therapy: Patients are
 randomized to 1 of 4 maintenance therapy treatment arms.

 Arm A: Patients receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone PO BID on
 days 1-5, 29-33, and 57-61; methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71,
 and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1.

 Arm B: Patients receive vincristine sulfate IV on days 1, 29, and 57; dexamethasone PO BID on
 days 1-5, 29-33, and 57-61; higher-dose methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT methotrexate on day 1.

 Arm C: Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5;
 methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on
 days 1-84; and IT methotrexate on day 1.

 Arm D: Patients receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5;
 higher-dose methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78;
 mercaptopurine PO on days 1-84; and IT methotrexate on day 1.

 In all arms, maintenance therapy courses repeat every 12 weeks for 2 years for girls and for
 3 years for boys (timed from the start of interim maintenance I therapy).

 LOW-RISK: Patients are randomized to 1 of 2 treatment arms.

 Arm I (LR-M): Consolidation therapy (19 weeks): Beginning one week after completion of
 induction therapy, patients receive vincristine sulfate IV on days 15, 22, 78, and 85;
 methotrexate IV over 24 hours and IT methotrexate on days 8, 29, 50, 71, 92, and 113;
 leucovorin calcium PO or IV on days 9-10, 30-31, 51-52, 72-73, 93-94, and 114-115;
 dexamethasone PO BID or IV on days 15-21 and 78-84; and PO mercaptopurine on days
 1-133.Maintenance therapy: Patients receive vincristine sulfate IV on days 1 and 8;
 dexamethasone PO BID on days 1-7; methotrexate* PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57,
 64, 71, 78, 85, 92, 99, and 106; and mercaptopurine PO on days 1-112. Courses repeat every 16
 weeks. Patients also receive IT methotrexate on days 1 and 85 (courses 1 and 4), day 57
 (courses 2 and 5), or day 29 (courses 3 and 6). Patients then receive course 7 comprising
 vincristine sulfate IV on days 1 and 8; dexamethasone PO BID on days 1-7; methotrexate PO on
 days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64; and mercaptopurine PO on days 1-70. Treatment
 continues for 2 and Â½ years (timed from the date of diagnosis).NOTE: *Patients do not
 receive methotrexate PO on the days that they receive IT methotrexate.

 Arm II (LR-C): Consolidation therapy (4 weeks): Patients receive vincristine sulfate IV on
 day 1; oral mercaptopurine on days 1-28; and IT methotrexate on days 1, 8, and 15. Interim
 maintenance I therapy (8 weeks): Patients receive vincristine sulfate IV and methotrexate IV
 over 2-15 minutes on days 1, 11, 21, 31, and 41 and IT methotrexate on day 31.
 Delayed-intensification therapy (8 weeks): Patients receive dexamethasone PO or IV BID on
 days 1-7 and 15-21; vincristine sulfate IV and doxorubicin hydrochloride IV over 1-15 minutes
 on days 1, 8, and 15; pegaspargase IV over 1-2 hours on day 4; cyclophosphamide IV over 30-60
 minutes on day 29; thioguanine PO on days 29-42; cytarabine IV over 1-30 minutes or SC on
 days 29-32 and 36-39; and IT methotrexate on days 1 and 29.Interim maintenance II therapy (8
 weeks): Patients receive vincristine sulfate IV and methotrexate IV over 2-15 minutes on days
 1, 11, 21, 31, and 41 and IT methotrexate on days 1 and 31. Maintenance therapy: Patients
 receive vincristine sulfate IV on day 1; dexamethasone PO BID on days 1-5; methotrexate PO on
 days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; mercaptopurine PO on days 1-84; and IT
 methotrexate on day 1. Courses repeat every 12 weeks for 2 years for girls and for 3 years
 for boys (timed from the start of interim maintenance I therapy).

 After completion of study treatment, patients are followed up periodically for 10 years from
 study entry.
Inclusion Criteria:

 -  B-ALL patients must be enrolled on AALL08B1 or APEC14B1 (if open for the
 classification of newly diagnosed ALL patients) prior to treatment and enrollment on
 AALL0932

 -  Note: B-LLy patients are not eligible for AALL08B1, and can enroll directly onto
 AALL0932

 -  B-ALL patients must have an initial white blood cell count < 50,000/uL

 -  Patients must have newly diagnosed National Cancer Institute (NCI) Standard Risk B-ALL
 or B-LLy Murphy stages I or II; patients with Down syndrome are also eligible

 -  Note: for B-LLy patients with tissue available for flow cytometry, the criterion
 for diagnosis should be analogous to B-ALL; for tissue processed by other means
 (i.e. paraffin blocks), the methodology and criteria for immunophenotypic
 analysis to establish the diagnosis of B-LLy defined by the submitting
 institution will be accepted

 -  All patients and/or their parents or legal guardians must sign a written informed
 consent

 -  All institutional, Food and Drug Administration (FDA), and NCI requirements for human
 studies must be met

 Exclusion Criteria:

 -  With the exception of steroid pretreatment (defined below) or the administration of
 intrathecal cytarabine, patients must not have received any prior cytotoxic
 chemotherapy for either the current diagnosis of B-ALL or B-LLy or for any cancer
 diagnosed prior to initiation of protocol therapy on AALL0932

 -  Patients receiving prior steroid therapy may be eligible for AALL0932

 -  Patients with central nervous system 3 (CNS3) leukemia

 -  CNS status must be known prior to enrollment; (Note: the CNS status must be
 determined based on a sample obtained prior to administration of any systemic or
 intrathecal chemotherapy, except for steroid pretreatment); B-LLy patients with
 CNS3 disease are not eligible for this protocol or the COG HR ALL protocol; it is
 recommended that intrathecal cytarabine be administered at the time of the
 diagnostic lumbar puncture; this is usually done at the time of the diagnostic
 bone marrow or venous line placement to avoid a second lumbar puncture; this is
 allowed prior to registration; systemic chemotherapy must begin within 72 hours
 of the first dose of intrathecal therapy

 -  B-ALL patients with testicular leukemia are not eligible for AALL0932

 -  For B-LLy patients the following additional exclusion criteria apply:

 -  T-lymphoblastic lymphoma

 -  Morphologically unclassifiable lymphoma

 -  Absence of both B-cell and T-cell phenotype markers in a case submitted as
 lymphoblastic lymphoma

 -  CNS3-positive disease or testicular involvement

 -  M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow

 -  Female patients who are pregnant are ineligible

 -  Lactating females are not eligible unless they have agreed not to breastfeed
 their infants

 -  Female patients of childbearing potential are not eligible unless a negative
 pregnancy test result has been obtained

 -  Sexually active patients of reproductive potential are not eligible unless they
 have agreed to use an effective contraceptive method for the duration of their
 study participation