Combination Chemotherapy With or Without Peripheral Stem Cell Transplant in Treating Children With Acute Lymphoblastic Leukemia
Condition: Childhood Acute Lymphoblastic Leukemia in Remission; Recurrent Childhood Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 3

Summary: 
      This phase II trial is studying how well combination chemotherapy with or without donor
      peripheral stem cell transplant works in treating children with acute lymphoblastic leukemia.
      Giving combination chemotherapy before a donor peripheral stem cell transplant helps stop the
      growth of cancer cells. It also helps stop the patient's immune system from rejecting the
      donor's stem cells. When the healthy stem cells from a donor are infused into the patient
      they may help the patient's bone marrow make stem cells, red blood cells, white blood cells,
      and platelets.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. Determine the feasibility of treatment with intensified chemotherapy, in terms of toxicity
      and patient accrual, in children with very high-risk acute lymphoblastic leukemia.

      II. Determine the feasibility and efficacy of following intensified chemotherapy with
      allogeneic hematopoietic stem cell transplantation in patients with HLA-matched related
      donors.

      III. Determine the toxicity of imatinib mesylate in combination with intensified chemotherapy
      in Philadelphia chromosome-positive patients.

      IV. Determine the event-free survival of patients treated with this regimen. V. Determine
      whether minimal residual disease (MDR) after induction therapy and prior to intensification
      therapy can predict relapse in these patients.

      VI. Determine whether MDR after intensification is prognostically significant. VII. Determine
      whether gene expression patterns predict disease recurrence or response to imatinib mesylate.

      OUTLINE: This is a multicenter study. This is also a dose-escalation study of imatinib
      mesylate in Philadelphia chromosome-positive (Ph+) patients. Patients are stratified
      according to Philadelphia chromosome (Ph) status (Ph-positive vs Ph-negative or
      indeterminate), hypodiploidy (yes vs no), MLL translocation (11q23) AND slow early response
      to prior induction therapy (yes vs no), and failed prior induction therapy (yes vs no).

      Cohorts of 8-12 Ph+ patients receive escalating doses of imatinib mesylate, according to the
      guidelines for each treatment block of this study, until the maximum tolerated dose (MTD) for
      each treatment combination is determined. The MTD is defined as the dose preceding that at
      which 2 of 6 patients experience dose-limiting toxicity. An additional 35 patients are
      treated at the MTD.

      CONSOLIDATION BLOCK 1: Patients receive etoposide IV over 1 hour followed by ifosfamide IV
      over 1.5 hours on days 1-5. Patients also receive methotrexate intrathecally on day 1 and
      filgrastim (G-CSF) subcutaneously (SC) on days 6-15 or until blood counts recover. Patients
      with CNS 2/3 at diagnosis also receive intrathecal triple therapy comprising methotrexate,
      hydrocortisone, and cytarabine (ITT) on days 8 and 15. Ph+ patients in cohorts 3, 4, and 5
      receive oral imatinib mesylate on days 1-21. Within 4 days of starting consolidation therapy,
      patients with biopsy-proven testicular leukemia undergo radiotherapy daily for 12 days.

      CONSOLIDATION BLOCK 2: Patients receive high-dose methotrexate IV over 24 hours and ITT on
      day 1 followed by high-dose cytarabine IV over 3 hours, every 12 hours on days 2 and 3.
      Patients also receive leucovorin calcium IV or orally every 6 hours for 3 doses beginning on
      day 2, and G-CSF SC on days 4-13 or until blood counts recover. Ph+ patients in cohorts 2, 3,
      4, and 5 receive oral imatinib mesylate as in consolidation block 1. Patients undergoing
      allogeneic hematopoietic stem cell transplantation (HSCT) proceed to preparative
      chemotherapy. All other patients proceed to reinduction block 1.

      REINDUCTION BLOCK 1: Patients receive vincristine IV on days 1, 8, and 15; daunorubicin IV on
      days 1 and 2; cyclophosphamide IV over 30 minutes, every 12 hours on days 3 and 4;
      pegaspargase intramuscularly (IM) on day 4; and ITT on days 1 and 15. Patients also receive
      oral dexamethasone twice daily on days 1-7 and 15-21 and G-CSF SC on days 5-14 or until blood
      counts recover. Ph+ patients in cohorts 2, 4, and 5 receive imatinib mesylate as in
      consolidation block 1.

      INTENSIFICATION BLOCK 1: Patients receive high-dose methotrexate IV over 24 hours on days 1
      and 15 and ITT on days 1 and 22. Patients also receive leucovorin calcium IV or orally every
      6 hours for 3 doses beginning on days 2 and 16. Patients receive etoposide IV over 2 hours
      followed by cyclophosphamide IV over 30 minutes on days 22-24; G-CSF SC on days 27-36 or
      until blood counts recover; high-dose cytarabine IV over 3 hours, every 12 hours on days 43
      and 44; and asparaginase IM on day 44. Ph+ patients in cohorts 1 and 4 receive oral imatinib
      mesylate on days 43-63, and patients in cohort 5 receive oral imatinib mesylate on days 1-56.

      REINDUCTION BLOCK 2: Patients receive vincristine, daunorubicin, cyclophosphamide,
      pegaspargase, dexamethasone, and G-CSF as in reinduction block 1. Patients also receive ITT
      on days 1 and 15. Ph+ patients receive imatinib mesylate as in reinduction block 1.

      INTENSIFICATION BLOCK 2: Patients receive methotrexate, leucovorin calcium, etoposide,
      cyclophosphamide, filgrastim, cytarabine, and asparaginase as in intensification block 1. Ph+
      patients receive imatinib mesylate as in intensification block 1.

      MAINTENANCE 1: Patients receive high-dose methotrexate IV and leucovorin calcium as in
      consolidation block 2. Patients also receive ITT and vincristine IV on days 1 and 29; oral
      dexamethasone twice daily on days 1-5 and 29-33; oral methotrexate on days 8, 15, and 22;
      oral mercaptopurine on days 8-28; etoposide IV over 2 hours followed by cyclophosphamide IV
      over 30 minutes on days 29-33; and G-CSF SC on days 34-43. Ph+ patients in cohorts 1-4
      receive oral imatinib mesylate on days 29-49 and patients in cohort 5 receive oral imatinib
      mesylate on days 1-56. Treatment repeats every 8 weeks for 4 courses in the absence of
      disease progression or unacceptable toxicity.

      MAINTENANCE 2: Patients receive vincristine and dexamethasone as in maintenance 1. Beginning
      on day 1, patients undergo cranial radiotherapy once daily, 5 days a week, for approximately
      2 weeks. Patients also receive oral methotrexate on days 8, 15, 22, 29, 36, 43, and 50 and
      oral mercaptopurine on days 11-56. Ph+ patients in cohorts 1-4 receive oral imatinib mesylate
      on days 1-21 and 29-49, and patients in cohort 5 receive oral imatinib mesylate on days 1-56.

      MAINTENANCE 3: Patients receive vincristine and dexamethasone as in maintenance 2. Patients
      also receive oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, and 50; and oral
      mercaptopurine on days 1-56. Ph+ patients receive imatinib mesylate as in maintenance 2.
      Treatment repeats every 8 weeks for 7 courses (12 courses total in maintenance 1, 2, and 3)
      in the absence of disease progression or unacceptable toxicity.

      Patients may undergo allogeneic HSCT after consolidation block 2 if there is an available
      HLA-DR matched or HLA-A or -B matched or 1 antigen mismatched relative donor.

      Patients with CNS leukemia undergo cranial radiotherapy 3 times daily on days -10 to -8. All
      patients undergo radiotherapy twice daily on days -7 to -5 and receive etoposide IV on day -4
      and cyclophosphamide IV on days -3 and -2. Patients undergo allogeneic bone marrow,
      peripheral blood stem cell, or umbilical cord blood transplantation on day 0. Patients
      receive cyclosporine IV beginning on day -1 and continuing every 12 hours, switching to oral
      administration when possible, until day 60 and tapering thereafter. Patients also receive
      methotrexate on days 1, 3, and 6. Beginning 16-24 weeks after transplantation, Ph+ patients
      receive oral imatinib mesylate once daily for 24 weeks.

      Patients are followed every 4-8 weeks for 1 year, every 3 months for 1 year, every 6 months
      for 1 year, and then annually thereafter. Patients undergoing HSCT are followed weekly for
      the first year.
    

Intervention name(s): filgrastim; asparaginase; cyclophosphamide; cyclosporine; cytarabine; daunorubicin hydrochloride; dexamethasone; etoposide; ifosfamide; imatinib mesylate; leucovorin calcium; mercaptopurine tablet; methotrexate; pegaspargase; vincristine sulfate; allogeneic bone marrow transplantation; peripheral blood stem cell transplantation; umbilical cord blood transplantation; radiation therapy
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Procedure; Procedure; Procedure; Radiation
Intervention description(s): Given SC; Given IM; Given IV; Given IV; Given IT and IV; Given IV; Given orally; Given IV; Given IV; Given orally; Given IV or orally; Given orally; Given IT, IV, and orally; Given IM; Given IV; Undergo allogeneic bone marrow, peripheral blood stem cell, or umbilical cord blood transplantation; Undergo allogeneic bone marrow, peripheral blood stem cell, or umbilical cord blood transplantation; Undergo allogeneic bone marrow, peripheral blood stem cell, or umbilical cord blood transplantation; Undergo radiation therapy
Other intervention name(s): G-CSF; Neupogen; ASNase; Colaspase; Crasnitin; Elspar; L-ASP; CPM; CTX; Cytoxan; Endoxan; Endoxana; ciclosporin; cyclosporin; cyclosporin A; CYSP; Sandimmune; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Cytosar-U; cytosine arabinoside; Cerubidin; Cerubidine; daunomycin hydrochloride; daunorubicin; RP-13057; Aeroseb-Dex; Decaderm; Decadron; DM; DXM; EPEG; VP-16; VP-16-213; Cyfos; Holoxan; IFF; IFX; IPP; CGP 57148; Gleevec; Glivec; CF; CFR; LV; 6-mercaptopurine; 6-MP; Leukerin; MP; amethopterin; Folex; methylaminopterin; Mexate; MTX; L-asparaginase with polyethylene glycol; Oncaspar; PEG-ASP; PEG-L-asparaginase; leurocristine sulfate; VCR; Vincasar PFS; bone marrow therapy, allogeneic; bone marrow therapy, allogenic; transplantation, allogeneic bone marrow; transplantation, allogenic bone marrow; PBPC transplantation; PBSC transplantation; peripheral blood progenitor cell transplantation; transplantation, peripheral blood stem cell; cord blood transplantation; transplantation, umbilical cord blood; UCB transplantation; irradiation; radiotherapy; therapy, radiation
Intervention MeSH terms: Leucovorin; Cytarabine; Cyclosporine; Dexamethasone; Cyclophosphamide; Ifosfamide; Methotrexate; Etoposide; Vincristine; Etoposide phosphate; Imatinib Mesylate; Daunorubicin; Asparaginase; Mercaptopurine; Pegaspargase; Cyclosporins; Levoleucovorin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment