Low-Dose or High-Dose Vincristine and Combination Chemotherapy in Treating Young Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia

• Efficacy of therapy [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
  Efficacy of therapy of an intensive chemotherapy regimen. (based on POG 9412) for patients with intermediate-risk relapse of childhood B-precursor ALL. Power calculations are based on the assumption of proportional hazards, and using the log rank test (alpha=0.1, one-sided test). The efficacy stopping boundaries to be used will be based on the alpha x (time)^2 spending function. The study will also be monitored for futility. The lower boundaries are based on testing the alternative hypothesis at the 0.005 level.
• Event-free survival at 3 years [ Time Frame: At 3 years ] [ Designated as safety issue: No ]
  A 95% confidence interval will be constructed using data on the standard dosing VCR arm at the time of study completion. If the lower bound of the confidence interval is larger than 40%, then the intensified chemotherapy will be deemed as efficacious. correlation between MRD and EFS will be essentially descriptive.

• Frequency and severity of adverse effects assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 107 weeks ] [ Designated as safety issue: Yes ]
  If 7 or more of the first 30 patients (combined in both arms) experience Grade 3 peripheral neurotoxicity then the accrual of adolescents will be temporarily closed. A one-sided Z-test for testing the equality of proportions with alpha=0.05 and with early stopping boundaries based on the t1/2 alpha spending function will be used. Osteonecrosis will be closely monitored on this study - overall and among patients less than ten years and those greater than or equal to ten years of age at the time of enrollment on study.
• Gene expression profile of early versus late marrow relapse by DNA microarray [ Time Frame: Up to 36 months ] [ Designated as safety issue: No ]
  Genes predictive of outcome will be identified using statistical methods and multiple supervised machine learning algorithms with rigorous cross validation. Profiles will be correlated with time of relapse (early vs. late). Expression profiles derived from relapse samples will be compared to the gene expression classifiers derived from pretreatment samples. Three-year EFS for these two groups varies from less than 20% for early marrow relapse to 40% - 50% for late relapse

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) and giving the drugs in different ways and different doses may kill more cancer cells. It is not yet known whether low-dose vincristine is more effective than high-dose vincristine (closed to accrual as of 09/2010) when given together with different combination chemotherapy regimens in treating acute lymphoblastic leukemia.

PURPOSE: This randomized phase III trial is studying low-dose vincristine to see how well it works compared with high-dose vincristine(closed to accrual as of 09/2010) when given together with different combination chemotherapy regimens in treating young patients with intermediate-risk relapsed B-cell acute lymphoblastic leukemia.

OBJECTIVES:

Primary

• Determine the efficacy of an intensive chemotherapy regimen (based on POG-9412) for pediatric patients with intermediate-risk relapsed B-precursor acute lymphoblastic leukemia.

Secondary

• Compare the 3-year event-free survival and frequency and severity of adverse effects in patients treated with high-dose (closed to accrual as of 9/2010) vs low-dose vincristine.
• Compare, descriptively, the outcomes of patients treated with combination chemotherapy vs those treated with matched sibling-related donor hematopoietic stem cell transplantation (for those with eligible donors).

OUTLINE: This is a multicenter, randomized study. Patients are randomized to 1 of 2 treatment arms (randomization closed as of 09/2010).

• Induction therapy 1 (weeks 1-5):

  • Arm I: Patients receive low-dose vincristine IV on days 1, 8, 15, and 22; oral prednisone 3 times daily on days 1-28; doxorubicin hydrochloride IV over 15 minutes on day 1; pegaspargase intramuscularly (IM) on days 2, 8, 15, and 22; cytarabine intrathecally (IT) on day 1; and methotrexate IT* on days 15 and 29.
  • Arm II (closed to accrual as of 09/2010)***: Patients receive high-dose vincristine IV on days 1, 8, 15, and 22 and prednisone, doxorubicin hydrochloride, pegaspargase, cytarabine, and methotrexate* as in arm I.

NOTE: *CNS-positive patients do not receive methotrexate IT. In both arms, CNS-positive patients receive intrathecal triple therapy (ITT) comprising methotrexate IT, hydrocortisone IT, and cytarabine IT on days 1, 8, 15, 22, and 29. CNS-positive patients not achieving remission after induction therapy 1 receive one additional dose of ITT on day 36.

Patients in both arms then proceed to induction therapy 2**.

NOTE: **Patients who are CNS-positive at relapse receive induction therapy 3 BEFORE induction therapy 2.

NOTE: *** Patients already enrolled on arm II are crossover to arm I.

• Induction therapy 2 (weeks 6-10 or 7-11): Once blood counts recover, all patients receive etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on days 1-5; high-dose methotrexate IV continuously over 24 hours on day 22; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; and methotrexate IT* on days 1 and 22. Patients also receive filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 22.

Patients with testicular-relapse with persistent testicular disease at the end of induction therapy 1 undergo testicular radiotherapy once daily, 5 days a week, for 12 days during induction therapy 2**.

NOTE: **Radiotherapy should be completed before beginning high-dose methotrexate (week 9) chemotherapy.

All patients then proceed to induction therapy 3.

• Induction therapy 3 (weeks 11-15 or 12-16): All patients receive high-dose cytarabine IV over 3 hours on days 1, 2, 8, and 9, and asparaginase IM on days 2 and 9. Patients also receive G-CSF IV or SC beginning on day 10 and continuing until blood counts recover.

Patients with a suitable HLA-matched related donor are removed from study and proceed to stem cell transplantation. Patients without a suitable HLA-matched related donor proceed to intensification therapy 1 (as per their randomized arm in induction therapy 1).

• Intensification therapy 1 (weeks 16-27 or 17-28):

  • Arm I: Patients receive low-dose vincristine IV and high-dose methotrexate IV continuously over 24 hours on day 1; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 2-6; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 8; and methotrexate IT* on day 15. Treatment repeats every 21 days for 4 courses (with the exception of IT methotrexate which repeats for only 3 courses).
  • Arm II(closed to accrual as of 09/2010)**: Patients receive high-dose vincristine IV on day 1 and high-dose methotrexate, leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide, and methotrexate IT* as in arm I.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 15. ITT repeats every 3 weeks for 3 courses.

NOTE: ** Patients already enrolled on arm II are crossover to arm I.

Patients in both arms then proceed to reinduction therapy (as per their randomized arm in induction therapy 1).

• Reinduction therapy (weeks 28-32 or 29-33):

  • Arm I: Patients receive low-dose vincristine IV and doxorubicin hydrochloride IV over 15 minutes on days 1, 8, and 15, oral dexamethasone twice daily on days 1-7 and 15-21, pegaspargase IM on days 2 and 15, and methotrexate IT* on days 1 and 28.
  • Arm II (closed to accrual as of 09/2010)**: Patients receive high-dose vincristine IV on days 1, 8, and 15 and doxorubicin hydrochloride, dexamethasone, pegaspargase, and methotrexate IT* as in arm I.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on days 1 and 28.

NOTE: ** Patients already enrolled on arm II are crossover to arm I.

Patients in both arms then proceed to intensification therapy 2 (as per their randomized arm in induction therapy 1).

• Intensification therapy 2 (weeks 33-56 or 34-57):

  • Arm I: Once blood counts recover, patients receive high-dose cytarabine IV over 3 hours on days 1 and 2; pegaspargase IM on day 2; low-dose vincristine IV on days 22 and 29; high-dose methotrexate IV on day 22; leucovorin calcium IV or orally beginning 42 hours after start of high-dose methotrexate and continuing every 6 hours for at least 3 doses; oral mercaptopurine once daily on days 23-27; etoposide phosphate IV over ≥ 1 hour and cyclophosphamide IV over 1 hour on day 29; and methotrexate IT* on day 36. Patients also receive G-CSF IV or SC beginning on day 3 and continuing until blood counts recover. Treatment repeats every 42 days for 4 courses (with the exception of IT methotrexate which only repeats for 3 courses).
  • Arm II: Patients receive high-dose cytarabine, high-dose methotrexate, leucovorin calcium, pegaspargase, mercaptopurine, etoposide phosphate, cyclophosphamide, methotrexate IT*, and G-CSF as in arm I. Patients also receive high-dose vincristine IV on days 22 and 29.

NOTE: *CNS-positive patients do not receive methotrexate IT. CNS-positive patients receive ITT on day 36. Treatment repeats every 6 weeks for 3 courses.

Patients in both arms then proceed to maintenance therapy (as per their randomized arm in induction therapy 1).

• Maintenance therapy (week 57-106 or 58-107):

  • Arm I: Patients receive methotrexate IT on day 1* and then orally on days 8, 15, 22, 29, and 36; oral mercaptopurine once daily on days 1-42; oral dexamethasone twice daily on days 1-5; and low-dose vincristine IV and cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 70 days for 5 courses.
  • Arm II: Patients receive methotrexate*, mercaptopurine, dexamethasone, and cyclophosphamide as in arm I. Patients also receive high-dose vincristine IV on days 43, 50, 57, and 64.

NOTE: *CNS-positive patients receive methotrexate IT on day 1, instead of oral methotrexate.

Beginning in week 1 of the first maintenance therapy course, patients with CNS relapse undergo cranial radiotherapy once daily, 5 days a week, for 10 days. Patients with CNS relapse do not receive any IT therapy during maintenance therapy.

After completion of study therapy, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 418 patients will be accrued for this study.

• Biological: filgrastim
  Given IV, subcutaneously
  Other Names:

  • Granulocyte Colony-Stimulating Factor
  • r-metHuG-CSF
  • G-CSF
  • Neupogen
  • NSC #614629
• Drug: asparaginase
  Given IM
  Other Names:

  • E. coli L-asparaginase
  • EC 3.5.2.2
  • colaspase
  • L-asnase
  • Elspar
  • Kidrolase
  • Crasnitin
  • Leunase
  • NSC#109229
• Drug: cyclophosphamide
  Given IV
  Other Names:

  • Cytoxan
  • NSC#26271
• Drug: cytarabine
  Given IV, intrathecally
  Other Names:

  • Cytosine arabinoside
  • Ara-C
  • Cytosar
  • NSC #063878
• Drug: dexamethasone
  Given orally
  Other Names:

  • Decadron
  • Hexadrol
  • Dexone
  • Dexameth
  • NSC #34521
• Drug: doxorubicin hydrochloride
  Given IV
  Other Names:

  • Adriamycin
  • NSC #123127
• Drug: etoposide phosphate
  Given IV
  Other Names:

  • VePesid
  • Etopophos
  • VP-16
  • NSC #141540
• Drug: leucovorin calcium
  Given IV or orally
  Other Names:

  • LCV
  • Wellcovorin
  • citrovorum factor
  • folinic acid
  • NSC#003590
• Drug: mercaptopurine
  Given orally
  Other Names:

  • 6-MP
  • Purinethol
  • 6-mercaptopurine
  • NSC #000755
• Drug: methotrexate
  Given orally, intrathecally
  Other Names:

  • MTX
  • amethopterin
  • Trexall
  • NSC #000740
• Drug: pegaspargase
  Given IM
  Other Names:

  • PEG-asparaginase
  • PEGLA
  • PEG-L-asparaginase
  • polyethylene glycol-L-asparaginase
  • Oncaspar
  • NSC #624239
• Drug: prednisone
  Given orally 3 times daily
  Other Names:

  • Deltasone
  • Meticorten
  • Orasone
  • Liquid Pred
  • Pediapred
  • Sterapred
  • NSC 010023
• Drug: therapeutic hydrocortisone
  Given intrathecally
  Other Names:

  • INTRATHECAL TRIPLES
  • Methotrexate/Hydrocortisone/Cytarabine
  • IT-3
• Drug: vincristine sulfate
  Given IV
  Other Names:

  • Oncovin
  • VCR
  • LCR
  • NSC #67574
• Radiation: radiation therapy
  Beginning in week 1 of the first maintenance therapy course, patients with CNS relapse undergo cranial radiotherapy once daily, 5 days a week, for 10 days.

• Active Comparator: Arm I (low-dose vincristine and combination chemotherapy)
  Pts receive cranial radiation therapy. Induction of low-dose vincristine sulfate in combo chemotherapy (etoposide phosphate, prednisone, doxorubicin hydrochloride, pegaspargase, cytarabine, methotrexate) on wks 1-5. CNS+ pts receive (ITT-methotrexate, therapeutic hydrocortisone, cytarabine). They also receive additional induction (etoposide phosphate, cyclophosphamide, methotrexate, leucovorin calcium, cytarabine, asparaginase and filgrastim) on wks 6-10 & 11-15, an intensified regimen (vincristine, methotrexate, leucovorin calcium, mercaptopurine, etoposide phosphate, cyclophosphamide) on wks 16-7, re-induction regimen on wks 28-32 (vincristine,doxorubicin,dexamethasone,pegaspargase, methotrexate), intensified regimen on wks 33-56 (cytarabine, pegaspargase, vincristine sulfate, methotrexate, leucovorin calcium,mercaptopurine,etoposide and cyclophosphamide), a maintenance regimen on wks 57-106 (methotrexate, mercaptopurine, dexamethasone, vincristine, cyclophosphamide).
  Interventions:

  • Biological: filgrastim
  • Drug: asparaginase
  • Drug: cyclophosphamide
  • Drug: cytarabine
  • Drug: dexamethasone
  • Drug: doxorubicin hydrochloride
  • Drug: etoposide phosphate
  • Drug: leucovorin calcium
  • Drug: mercaptopurine
  • Drug: methotrexate
  • Drug: pegaspargase
  • Drug: prednisone
  • Drug: therapeutic hydrocortisone
  • Drug: vincristine sulfate
  • Radiation: radiation therapy
• Experimental: Arm II (high-dose vincristine and combination chemotherapy)
  Patients receive induction therapy comprising high-dose vincristine sulfate in combination with chemotherapy on weeks 1-5. They also receive additional induction therapy on weeks 6-10 and 11-15, an intensified chemotherapy regimen on weeks 16-7, a re-induction regimen on weeks 28-32, an intensified regimen on weeks 33-56, and a maintenance regimen on weeks 57-106.(closed to accrual as of 09/2010).
  Interventions:

  • Biological: filgrastim
  • Drug: asparaginase
  • Drug: cyclophosphamide
  • Drug: cytarabine
  • Drug: dexamethasone
  • Drug: doxorubicin hydrochloride
  • Drug: etoposide phosphate
  • Drug: leucovorin calcium
  • Drug: mercaptopurine
  • Drug: methotrexate
  • Drug: pegaspargase
  • Drug: prednisone
  • Drug: therapeutic hydrocortisone
  • Drug: vincristine sulfate
  • Radiation: radiation therapy

DISEASE CHARACTERISTICS:

• Diagnosis of acute lymphoblastic leukemia (ALL)

  • Bone marrow with > 25% L1 or L2 lymphoblasts (M3 marrow)

    • Patients with > 25% L3 marrow lymphoblasts and/or evidence of c-myc translocation are not eligible (considered Burkitt's or mature B-cell leukemia)

• Intermediate-risk relapsed disease, meeting 1 of the following criteria:

  • Bone marrow relapse ≥ 36 months after initial diagnosis (defined as M3 marrow after previous remission from ALL)
  • Combined bone marrow and extramedullary (CNS* and/or testicular**) relapse ≥ 36 months after initial diagnosis
  • Isolated extramedullary (CNS* and/or testicular**) relapse < 18 months after initial diagnosis NOTE: *CNS relapse is defined as WBC ≥ 5/mm³ in cerebral spinal fluid (CSF) with blasts present on cytospin OR any number of WBC in CSF with immunophenotypic proof of leukemic relapse (defined as identifiable blasts plus [for B-lineage] TdT or CD-10 positivity on 2 consecutive CSF samples obtained 4 weeks apart)

NOTE: **Testicular relapse is defined as unilateral or bilateral testiculomegaly with biopsy-proven testicular involvement OR unilateral or bilateral testiculomegaly with concurrent relapse in the bone marrow and/or CNS

• The following subtypes are not allowed:

  • T-lineage ALL
  • Mature B-cell (Burkitt's) leukemia (defined as L3 morphology and/or evidence of c-myc translocation)
  • Philadelphia-chromosome positive disease
• No Down syndrome (trisomy 21)

PATIENT CHARACTERISTICS:

• Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
• Bilirubin < 3.0 mg/dL
• Not pregnant
• Fertile patients must use effective contraception
• No history of peripheral neuropathy ≥ grade 3 within the past month
• No toxicity (i.e. peripheral neuropathy) ≥ grade 3 attributable to vincristine within the past month

PRIOR CONCURRENT THERAPY:

• At least 5 days since prior intrathecal chemotherapy
• No prior hematopoietic stem cell or marrow transplantation
• No prior cranial radiotherapy > 1200 cGy (for patients with CNS relapse)
• No concurrent stem cell transplant
• No concurrent alternative therapy
• No concurrent itraconazole in patients receiving vincristine
• No concurrent intensity-modulated radiotherapy