Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With Acute Lymphoblastic Leukemia
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 the growth of cancer
      cells, either by killing the cells or by stopping them from dividing. Giving more than one
      drug (combination chemotherapy) may kill more cancer cells. It is not yet known which
      combination chemotherapy regimen is more effective in treating young patients with acute
      lymphoblastic leukemia.

      PURPOSE: Thisphase III trial is studying several different combination chemotherapy regimens
      to compare how well they work in treating young patients with acute lymphoblastic leukemia.
    

Detailed description: 
      OBJECTIVES:

        -  Compare the relative efficacy of induction therapy comprising dexamethasone or
           prednisone, in terms of a higher rate of event-free survival (EFS) and overall survival
           and a reduced rate of relapse, in pediatric patients with intermediate-risk or high-risk
           acute lymphoblastic leukemia (ALL).

        -  Compare the relative safety of a reduced-intensity reintensification regimen comprising
           dexamethasone, vincristine, cyclophosphamide, and anthracyclines vs a standard treatment
           regimen in pediatric patients with standard-risk ALL identified by fast clearance of
           leukemic cells.

        -  Compare the efficacy of a second delayed reintensification regimen vs standard
           reintensification therapy, in terms of improved EFS, in pediatric patients with
           intermediate-risk ALL.

        -  Compare the efficacy of extended reintensification therapy (triple reinduction) vs
           standard reintensification therapy (intensive pulses and one reintensification) in
           pediatric patients with high-risk ALL.

      OUTLINE: This is a randomized, multicenter study.

        -  Prednisone prephase therapy: Patients receive oral prednisone on days 1-7 and one dose
           of methotrexate (MTX) intrathecally (IT) on day 1.

        -  Induction/consolidation therapy, protocol I: Patients are randomized to 1 of 2 treatment
           arms.

             -  Arm I (closed to accrual as of 6/30/2006): Patients receive prednisone (PRED) on
                days 8-28.

             -  Arm II (closed to accrual as of 6/30/2006): Patients receive dexamethasone (DEXA)
                on days 8-28.

      Patients in both arms also receive vincristine (VCR) and daunorubicin hydrochloride (DNR)
      once weekly in weeks 2-5; asparaginase (ASP) on days 12-33; cyclophosphamide (CPM) on days 36
      and 64; cytarabine (ARA-C) in weeks 6-9; mercaptopurine (MP) on days 36-63; and MTX IT on
      days 1, 15, 29,38 and 52.* NOTE: *Patients with CNS disease also receive MTX IT on days 8 and
      22. After completion of induction/consolidation therapy, patients are stratified according to
      risk group based on disease response (standard-risk [SR] group [negative minimal residual
      disease (MRD) on day 33 and before protocol M, day 78] vs high-risk [HR] group [MRD ≥ 10^-³
      on day 78] vs intermediate-risk [IR] group [all nonSR/nonHR]).* Patients with SR and IR
      disease proceed to consolidation therapy-protocol M. Patients with HR disease proceed to HR
      block therapy.

      NOTE: *Patients meeting any of the following criteria are placed in the HR group regardless
      of MRD response: Philadelphia chromosome-positive disease (BCR/ABL or t[9;22]; translocations
      [t4;11][q11;q23] or MLL/AF4); "prednisone-poor-response" (≥ 1,000 blasts/mm³ in the
      peripheral blood on day 8 after prednisone prephase therapy); or no response to study
      induction therapy (M2/3 at day 33).

      • Consolidation, protocol M: Patients receive MP on days 1-56 and MTX on days 8, 22, 36, and
      50.

      After completion of extracompartment therapy, SR and IR patients proceed to reintensification
      therapy. SR patients are randomized to arms I or II. IR patients are randomized to arms I or
      III. HR patients who have completed induction/consolidation therapy are randomized to arms IV
      or V.

        -  Reinduction therapy:

           o Arm I (standard reinduction therapy, protocol II [closed to accrual as of 6/30/2006]):
           SR and IR patients receive DEXA on days 1-22; VCR and doxorubicin hydrochloride (DOX) in
           weeks 2-5; ASP on days 8, 11, 15, and 18; CPM on day 36; ARA-C and thioguanine (TG) on
           days 36-49; and MTX IT on days 38 and 45. Patients then proceed to maintenance therapy.

        -  Arm II (reduced-intensity reinduction therapy, protocol III [closed to accrual as of
           6/30/2006]): SR patients receive DEXA on days 1-15; VCR and DOX on days 1 and 8; ASP on
           days 1, 4, 8, and 11; CPM on day 15; ARA-C and TG on days 15-28; and MTX IT on days 16
           and 23. Patients then proceed to maintenance therapy.

        -  Arm III (reduced-intensity reinduction/second delayed reinduction therapy [double
           reintensification therapy] [closed to accrual as of 6/30/2006]): IR patients receive
           reduced-intensity reintensification therapy as in arm II. After a 10-week interim
           maintenance phase, treatment repeats once for a second delayed course of
           reintensification therapy. Patients then proceed to maintenance therapy.

        -  Arm IV (standard reintensification therapy [closed to accrual as of 6/30/2006]): HR
           patients receive one sequence of the following HR therapy elements, in this order: 1, 2,
           3, following standard reinduction therapy protocol II repeated twice after a four weeks
           Interim Maintenance phase. Patients then proceed to maintenance therapy.

             -  Element HR-1: Patients receive DEXA on days 1-5; VCR on days 1 and 6; ARA-C twice
                on day 5; MTX and CPM every 12 hours on days 2-4 (5 doses); ASP on day 6 ; and
                MTX/ARA-C/PRED IT on day 1.

             -  Element HR-2: Patients receive DEXA on days 1-5; vindesine on days 1 and 6; DNR on
                day 5; MTX and ifosfamide every 12 hours on days 2-4 (5 doses); ASP on day 6; and
                MTX/ARA-C/PRED IT on day 1.

             -  Element HR-3: Patients receive DEXA on days 1-5; ARA-C every 12 hours on days 1-2
                (4 doses); etoposide five times daily on days 3-5; ASP on day 5; and MTX/ARA-C/PRED
                IT on day 1.

        -  Arm V (extended reintensification therapy [triple protocol III] [closed to accrual as of
           6/30/2006]): HR patients receive HR therapy elements 3, 2, and 1 following
           reintensification therapy repeated the therapy element three times with 4-week interim
           maintenance phases in between. Patients then proceed to maintenance therapy.

             -  Interim maintenance/maintenance therapy: Patients receive MTX once weekly and MP
                daily until week 104 plus IT MTX every eight weeks.

             -  Radiotherapy: HR patients or patients with T-cell acute lymphoblastic leukemia or
                CNS disease undergo CNS radiotherapy.

      PROJECTED ACCRUAL: A total of 2,039 patients has been accrued for this study.
    

Intervention name(s): dexamethasone; asparaginase; Asparaginase; cyclophosphamide; cytarabine; daunorubicin; doxorubicin; Etoposide; Ifosfamide; mercaptopurine; Methotrexate; prednisone; thioguanine; Vincristine; Vindesine
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 10 mg/sqm/day from for 21 days; native E-coli Asparaginase 5,000 IU/sqm x 8 doses; native E-Coli Asparaginase 10,000 IU/sqm x 4 doses; 1,000 mg/sqm i.v. 2 doses in Induction phase 1000 mg/sqm i.v. 1 dose in Protocoll II 500 mg/sqm i.v. 1 dose in protocol III; 75 mg/sqm i.v.or s.c. 4 doses/week for 4 weeks in Induction phase 75 mg/sqm i.v.or s.c. 4 doses/week for 2 weeks in Protocol II and III; 30 mg/sqm i.v. 4 doses in Induction phase; 30 mg/sqm i.v. x 4 doses in Protocol II and III; 100 mg/sqm i.v. for 3 doses in HR block 3; 800 mg/sqm i.v.q12h x 5 in HR block 2; 60 mg/sqm p.o. c 28 days in Induction phase 60 mg/sqm p.o. x 56 days in Protocol M 50 mg/sqm daily in Maintenance phase; by age i.t. in Induction/Protocol M/Protocol II/Protocol III/HR Blocks and maintenance; 60 mg/sqm daily p.o. for 28 days then tapered in Induction phase; 60 mg/sqm p.o. x 14 days in Protocol II and Protocol III; 1.5 mg/sqm i.v. x 4 doses in Induction phase and Protocol II 1.5 mg/sqm i.v. x 2 doses in Protocol III and HR block 1; 3 mg/sqm i.v. x 2 doses in HR block 2
Intervention MeSH terms: Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Ifosfamide; Doxorubicin; Methotrexate; Etoposide; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Thioguanine; Vindesine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment