Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk Acute Lymphoblastic Leukemia

• Improvement in 5-year disease-free survival (DFS) from 93% to 96% in average-risk (AR) patients based on the methotrexate randomization [ Designated as safety issue: No ]
• Determination of whether the 5-year DFS in AR patients is adversely affected by the reduced pulses in maintenance [ Designated as safety issue: No ]
• Determination of whether less intensive therapy will maintain a 5-year DFS ≥ 95% for low-risk patients randomized to 1 of 2 low-intensity regimens [ Designated as safety issue: No ]
• 5-year DFS for Down syndrome patients [ Designated as safety issue: No ]

• Burden of therapy in AR patients overall at different time points during and at the end of therapy [ Designated as safety issue: No ]
• Burden of therapy in AR patients randomized to every 4-week vs every 12-week pulses during maintenance therapy [ Designated as safety issue: No ]

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 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.

PURPOSE: This partially randomized phase III clinical trial is studying different combinations of risk-adapted chemotherapy regimens and their side effects and comparing how well they work in treating younger patients with newly diagnosed standard-risk acute lymphoblastic leukemia.

OBJECTIVES:

Primary

• To determine if a maintenance regimen containing once 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 pediatric patients with standard-risk (SR) B-precursor acute lymphoblastic leukemia (ALL).
• To determine whether a reduced-pulses maintenance regimen with 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 SR B-precursor ALL.
• To confirm that patients in the low-risk (LR) subset of SR B-precursor ALL, based on clinical and cytogenetic features and minimal residual disease (MRD) criteria, can attain a 5-year DFS of ≥ 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 sulfate/dexamethasone pulses at 12-week intervals during maintenance (Arm LR-C).
• To provide standardized treatment and enhanced supportive care to children with SR Down syndrome-ALL in order to improve outcomes and facilitate further study of this biologically and clinically unique patient subgroup.

Secondary

• To assess the burden of AR-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 overall at different time points during and at the end of therapy.
• To assess the burden of AR-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 by comparing children randomized to every 4-week vs every 12-week dexamethasone/vincristine sulfate pulses during maintenance therapy.
• To characterize the onset, severity, and natural history of vincristine-associated neuropathy by physical therapists (or occupational therapists) in children undergoing therapy for AR-ALL, 1) overall at different time points during and at the end of therapy, and by 2) comparing children randomized to every 4 weeks vs every 12 weeks dexamethasone/vincristine pulses during Maintenance.

OUTLINE: This is a multicenter study.

All patients receive induction therapy comprising intrathecal (IT) cytarabine on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone orally 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; oral mercaptopurine on days 1-28; IT methotrexate on days 1, 8, and 15; and oral leucovorin calcium 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 oral leucovorin calcium every 12 hours on days 36-34.
  • Delayed-intensification therapy (8 weeks): Patients receive dexamethasone orally 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; oral thioguanine on days 29-42; cytarabine IV over 15-30 minutes or subcutaneously (SC) on days 29-32 and 33-39; IT methotrexate on days 1 and 29; and oral leucovorin calcium 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 oral leucovorin calcium every 12 hours on days 3-4 and 33-34.
  • Maintenance therapy: Patients receive vincristine sulfate IV on day 1; oral dexamethasone BID on days 1-5; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine 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).

• Average-risk:

  • 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 orally 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; oral thioguanine on days 29-42; cytarabine IV over 15-30 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; oral dexamethasone BID on days 1-5, 29-33, and 57-61; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine on days 1-84; and IT methotrexate on day 1.
    • Arm B: Patients receive vincristine sulfate IV on days 1, 29, and 57; oral dexamethasone BID on days 1-5, 29-33, and 57-61; higher-dose oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine on days 1-84; and IT methotrexate on day 1.
    • Arm C: Patients receive vincristine sulfate IV on day 1; oral dexamethasone BID on days 1-5; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine on days 1-84; and IT methotrexate on day 1.
    • Arm D: Patients receive vincristine sulfate IV on day 1; oral dexamethasone BID on days 1-5; higher-dose oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine 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 orally or IV on days 9-10, 30-31, 51-52, 72-73, 93-94, and 114-115; dexamethasone orally or IV BID on days 15-21 and 78-84; and oral mercaptopurine on days 1-133.
    • Maintenance therapy: Patients receive vincristine sulfate IV on days 1 and 8; oral dexamethasone BID on days 1-7; oral methotrexate* on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, and 106; and oral mercaptopurine 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; oral dexamethasone BID on days 1-7; oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, 50, 57, and 64; and oral mercaptopurine on days 1-70. Treatment continues for 2½ years (timed from the date of diagnosis).

NOTE: *Patients do not receive oral methotrexate 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 orally 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; oral thioguanine on days 29-42; cytarabine IV over 15-30 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; oral dexamethasone BID on days 1-5; oral methotrexate on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78; oral mercaptopurine 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).

During the Maintenance phase of therapy, health-related quality-of-life (HRQOL) measures, parent's perception of child's health vulnerability, fewer missed days of school/daycare by patients and work by parents, and peripheral neurological functioning may be compared in children receiving different vincristine sulfate/dexamethasone pulses frequencies to systematically assess the impact of treatment.

Blood samples may be collected periodically for research studies and patients may complete quality-of-life surveys periodically.

After completion of study treatment, patients are followed up periodically for 10 years.

• Drug: cyclophosphamide
  Given IV or orally
• Drug: cytarabine
  Given IV or orally
• Drug: dexamethasone
  Given IV or orally
• Drug: doxorubicin hydrochloride
  Given IV or orally
• Drug: leucovorin calcium
  Given IV or orally
• Drug: mercaptopurine
  Given IV or orally
• Drug: methotrexate
  Given orally
• Drug: pegaspargase
  Given IV or orally
• Drug: thioguanine
  Given IV or orally
• Drug: vincristine sulfate
  Given IV or orally

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

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

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

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

  • Drug: dexamethasone
  • Drug: methotrexate
  • Drug: vincristine sulfate
• Experimental: Arm LR-M
  Patients receive consolidation and maintenance therapy.
  Interventions:

  • Drug: dexamethasone
  • Drug: leucovorin calcium
  • Drug: mercaptopurine
  • Drug: methotrexate
  • Drug: vincristine sulfate
• Experimental: Arm LR-C
  Patients receive consolidation, interim maintenance I, delayed intensification, interim maintenance II, and maintenance therapy.
  Interventions:

  • Drug: cyclophosphamide
  • Drug: cytarabine
  • Drug: dexamethasone
  • Drug: doxorubicin hydrochloride
  • Drug: mercaptopurine
  • Drug: methotrexate
  • Drug: pegaspargase
  • Drug: thioguanine
  • Drug: vincristine sulfate

DISEASE CHARACTERISTICS:

• Enrolled on COG-AALL08B1

• Newly diagnosed B-precursor acute lymphoblastic leukemia (ALL)

  • NCI standard-risk (SR) disease

• Meets the criteria for one of the following risk groups after induction therapy††:

  • Low-risk (LR) disease, defined as meeting the following criteria:

    • Favorable genetics: the presence of simultaneous trisomies of chromosome 4 and 10 (double trisomy; DT) or ETV6/RUNX1 fusion
    • Day 8 peripheral blood (PB) minimal residual disease (MRD) < 0.01%
    • Day 29 bone marrow (BM) MRD < 0.01%
    • No CNS2*, CNS3*, or testicular† leukemia
    • No steroid pretreatment
    • No Down syndrome (DS)

    • No unfavorable genetic characteristics, defined as:

      • iAMP21 as identified by fluorescence in-situ hybridization (FISH)
      • MLL rearrangements as identified by cytogenetics, FISH, or molecular studies
      • Hypodiploidy: Fewer than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone
      • Induction failure: M3 marrow on Day 29

      • Philadelphia chromosome positive (Ph+) ALL

        • BCR-ABL1 (formerly known as BCR-ABL) fusion transcript determined by FISH or RT-PCR
        • t(9;22)(q34;q11) determined by cytogenetics

  • Average-risk disease, defined as meeting one of the following sets of criteria:

    • Favorable genetics: the presence of DT or ETV6/RUNX1 fusions
    • Day 8 PB MRD ≥ 0.01% or CNS2* status
    • Day 29 BM MRD < 0.01%
    • No CNS3* or testicular† leukemia
    • No DS OR
    • Neither favorable nor unfavorable cytogenetics
    • Day 8 PB MRD < 1%
    • Day 29 BM MRD < 0.01%
    • No CNS3* or testicular† leukemia
    • No DS

  • Standard-risk with Down syndrome (DS), defined as meeting the following criteria:

    • No mixed-lineage leukemia (MLL)-rearrangement, hypodiploidy, or Philadelphia chromosome-positive (Ph+) disease
    • Day 29 BM MRD < 0.01%‡‡
    • No CNS3* or testicular† leukemia NOTE: ‡‡DS-ALL patients who have day 29 BM MRD > 0.01% will be eligible for post-induction therapy on the DS stratum of the high-risk trial.

NOTE: *CNS2 disease is defined as, in cerebrospinal fluid (CSF), presence of < 5/mm3 WBCs and cytospin positive for blasts, or traumatic lumbar puncture (LP) ≥ 5/mm3 WBCs cytospin positive for blasts, but negative by Steinherz/Bleyer algorithm. CNS3 disease is defined as, in CSF, after traumatic LP presence of ≥ 5/mm3 WBCs and cytospin positive for blasts and/or clinical signs of CNS leukemia. The CNS status must be determined based on a sample obtained before administration of any systemic or intrathecal chemotherapy.

NOTE: †Testicular leukemia is defined as unilateral or bilateral testiculomegaly. Biopsy is required if clinical findings are equivocal or suggestive of hydrocele or a non-leukemic blast.

NOTE: †† Patients entered on this study who are later found to meet eligibility criteria for the COG-AALL0622 Ph+ ALL study should be immediately be taken off study therapy before day 15 of induction therapy if they are eligible to transfer to COG-AALL06222 or its successor study or otherwise, at the end of induction therapy.

• Patients enrolled in AALL0932 who are identified to have iAMP21 will be classified as Very High Risk and will not be eligible to continue on AALL0932 after Induction therapy, but will be eligible to enroll in AALL1131 for post-Induction therapy

PATIENT CHARACTERISTICS:

• WBC count < 50,000/mm^3

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior cytotoxic chemotherapy for the current diagnosis of ALL or any cancer diagnosed previously

  • Steroids* and intrathecal cytarabine for the current diagnosis of ALL allowed

    • Inhalational steroids are not considered as pretreatment NOTE: *If steroids are given for 24 hours in the 2 weeks before diagnosis and a complete blood count (CBC) is obtained within 3 days before the initiation of the steroid, the patient will be assigned to induction based on NCI risk group using the pre-steroid WBC count. If there is no pre-steroid CBC obtained, the patient will be assigned to receive induction therapy on the COG high-risk study. Post-induction risk assignment will be refined by leukemia-specific genetic features and the level of bone marrow minimal residual disease at day 29, except that SR patients in this group will not be eligible for the LR arm. Any amount of steroid pretreatment at any time before 2 weeks before diagnosis will not affect initial induction assignment as long as the patient meets all other eligibility criteria. SR patients in this group may be eligible for the LR arm only if they did not receive steroids within the month before diagnosis.