Stem Cell Transplantation Compared With Standard Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia in First Remission
Condition: Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 3

Summary: 
      RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from
      dividing so they stop growing or die. Combining chemotherapy with allogeneic or autologous
      stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and
      kill more cancer cells. It is not yet known whether stem cell transplantation is more
      effective than standard chemotherapy in treating acute lymphoblastic leukemia.

      PURPOSE: This randomized phase III trial is studying how well stem cell transplantation works
      compared to standard combination chemotherapy in treating patients with acute lymphoblastic
      leukemia in first remission.
    

Detailed description: 
      OBJECTIVES:

        -  Compare the duration of complete remission (CR) and survival in patients with acute
           lymphoblastic leukemia in first remission treated with allogeneic or autologous stem
           cell transplantation (SCT) vs conventional consolidation and maintenance chemotherapy.

        -  Compare the overall treatment outcomes in patients treated with these regimens.

        -  Determine the effect of imatinib mesylate given after induction therapy in Philadelphia
           (Ph) chromosome-positive patients in CR.

        -  Determine the benefit of allogeneic or autologous SCT after imatinib mesylate in Ph
           chromosome-positive patients.

        -  Determine the benefit of additional imatinib mesylate administered after allogeneic or
           autologous SCT in Ph chromosome-positive patients.

        -  Determine the minimal residual disease in Ph chromosome-positive patients before and
           after treatment with imatinib mesylate.

        -  Determine the clinical resistance to imatinib mesylate caused by BCR-ABL gene
           amplification or mutation in Ph chromosome-positive patients.

      OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age
      (50 and under vs over 50), time to achieve complete remission (CR) (4 weeks or less vs more
      than 4 weeks), and Philadelphia (Ph) chromosome status (positive vs negative).

        -  First induction therapy: Patients receive daunorubicin (DNR) IV over 15-30 minutes and
           vincristine (VCR) IV over 3-5 minutes on days 1, 8, 15, and 22; oral prednisone (PRED)
           once daily on days 1-28; and asparaginase (ASP) IV over 30 minutes or intramuscularly on
           days 17-28. Patients with CNS leukemia at presentation also receive methotrexate (MTX)
           intrathecally (IT) via an Ommaya reservoir weekly until the CSF is clear. Patients
           without CNS leukemia at presentation receive MTX IT on day 23 only.

        -  Second induction therapy: Beginning immediately after first induction therapy, patients
           receive cyclophosphamide (CTX) IV over 30 minutes on days 1, 15, and 29; cytarabine
           (ARA-C) IV over 30 minutes on days 1-4, 8-11, 15-18, and 22-25; and oral mercaptopurine
           (MP) once daily on days 1-28. Patients with CNS leukemia at presentation also undergo
           concurrent craniospinal irradiation. Patients without CNS leukemia at presentation
           receive MTX IT on days 1, 8, 15, and 22. Patients with Ph chromosome-positive status
           receive oral imatinib mesylate once daily for at least 28 days (days 1-28).

      Patients with Ph chromosome-positive status and CR after second induction therapy proceed to
      group I for autologous or allogeneic stem cell transplantation (SCT). Patients with Ph
      chromosome-negative status and CR after second induction therapy proceed to group II.

        -  Group I (Ph chromosome-positive patients):

             -  Autologous SCT: Patients receive high-dose consolidation/mobilization chemotherapy
                comprising ARA-C IV over 3 hours on days 1-3 and mitoxantrone IV immediately after
                ARA-C administration on days 1 and 2. Patients also receive filgrastim (G-CSF)
                subcutaneously (SC) once daily beginning on day 5 and continuing until blood counts
                recover.

      Patients then undergo peripheral blood stem cell collection or bone marrow harvesting.

      Patients receive preparative therapy comprising total body irradiation twice daily (5-10
      hours apart) on days -6 to -4 and high-dose etoposide (VP-16) IV over 4 hours on day -3. Male
      patients also undergo radiotherapy boost to the testes on day -6.

      Patients undergo autologous SCT on day 0 and receive sargramostim (GM-CSF) SC once daily
      beginning 6 hours after the completion of SCT and continuing until blood counts recover.

        -  Allogeneic SCT: Patients receive the preparative regimen as in autologous SCT and then
           undergo allogeneic SCT on day 0. Patients receive GM-CSF as in autologous SCT.

        -  Post-SCT imatinib mesylate therapy: After recovery from autologous or allogeneic SCT,
           patients receive oral imatinib mesylate once daily. Imatinib mesylate therapy continues
           in the absence of disease progression or unacceptable toxicity.

             -  Group II (Ph chromosome-negative patients):

        -  Intensification therapy: Beginning 4 weeks after the completion of the second induction
           therapy, patients receive high-dose MTX IV over 2 hours on days 1, 8, and 22; leucovorin
           calcium IV every 6 hours for 4 doses and then orally every 6 hours for 12 doses
           beginning 22-24 hours after each MTX infusion; and ASP IV over 30 minutes on days 2, 9,
           and 23.

      Patients who are ≤ 50 years of age with a histocompatible donor proceed to allogeneic SCT and
      undergo allogeneic SCT as in group I. Patients who are ≤ 50 years of age without an
      appropriate donor are randomized to 1 of 2 treatment arms.

        -  Arm I (conventional consolidation/maintenance therapy):

             -  Conventional consolidation therapy: During course 1, patients receive ARA-C IV over
                30 minutes and VP-16 IV over 1 hour on days 1-5; VCR IV on days 1, 8, 15, and 22;
                and oral dexamethasone on days 1-28. During course 2 (which begins 4 weeks after
                initiation of course 1 or when blood counts recover), patients receive ARA-C and
                VP-16 as in course 1. During course 3 (which begins 4 weeks after initiation of
                course 2 or when blood counts recover), patients receive DNR IV on days 1, 8, 15,
                and 22; CTX IV over 30 minutes on day 29; ARA-C IV over 30 minutes on days 31-34
                and 38-41; and oral thioguanine on days 29-42. During course 4 (which begins 8
                weeks after initiation of course 3 or when blood counts recover), patients receive
                treatment as in course 2.

             -  Maintenance therapy: Beginning 4 weeks after initiation of course 4 of
                consolidation therapy or when blood counts recover, patients receive oral MP daily;
                MTX orally or IV once weekly; VCR IV once every 12 weeks; and oral PRED for 5 days
                every 12 weeks. Maintenance therapy continues for 2.5 years after initiation of
                intensification therapy.

        -  Arm II (autologous SCT): Patients undergo autologous SCT as in group I with the
           exception of high-dose consolidation/mobilization chemotherapy.

      Patients are followed every 6 months for 2 years.

      PROJECTED ACCRUAL: Approximately 40 patients per year will be accrued for group I
      (Philadelphia [Ph] chromosome-positive patients) of this study. Approximately 550 patients
      will be accrued for group II (Ph chromosome-negative patients) of this study within 5 years.
    

Intervention name(s): sargramostim; asparaginase; cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; etoposide; imatinib mesylate; leucovorin calcium; mercaptopurine; methotrexate; prednisone; thioguanine; vincristine sulfate; allogeneic bone marrow transplantation; autologous bone marrow transplantation; peripheral blood stem cell transplantation; radiation therapy
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Procedure; Procedure; Procedure; Radiation
Intervention MeSH terms: Leucovorin; Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Methotrexate; Etoposide; Vincristine; Imatinib Mesylate; Daunorubicin; Asparaginase; Mercaptopurine; Thioguanine; Sargramostim; Levoleucovorin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: adult acute lymphoblastic leukemia in remission