Combination Chemotherapy in Treating Young Patients With Relapsed or Refractory 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. It is not yet known
      which combination chemotherapy regimen is more effective in treating young patients with
      acute lymphoblastic leukemia.

      PURPOSE: This partially randomized phase III trial is studying how well combination
      chemotherapy works in treating young patients with relapsed or refractory acute lymphoblastic
      leukemia.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Evaluate the progression-free survival (defined as the time from study entry to the
           first occurrence of progression, relapse, death while in complete clinical remission, or
           second malignancy) of United Kingdom patients with relapsed or refractory acute
           lymphoblastic leukemia stratified by risk group.

        -  Evaluate whether a minimal residual disease (MRD) level of 10^-4 is a suitable criterion
           at the end of induction therapy on which to decide whether chemotherapy or stem cell
           transplantation will be most beneficial to patients with intermediate-risk disease.

      Secondary

        -  Use MRD as a surrogate marker for response to therapy.

      OUTLINE: This is a multicenter study. Patients are stratified by risk group (standard vs
      intermediate vs high) and participating country (UK and Ireland vs Australia and New Zealand
      vs The Netherlands).

      Patients with standard-risk disease receive induction therapy, consolidation therapy,
      intensification therapy, interim maintenance therapy, and maintenance therapy. Patients with
      intermediate-risk disease receive induction therapy followed by assessment of minimal
      residual disease (MRD). Those whose MRD status is < 10^-4 at week 5 (after induction therapy)
      proceed to consolidation therapy followed by intensification therapy, interim maintenance
      therapy, and maintenance therapy. Those whose MRD status is ≥ 10^-4 at week 5 (after
      induction therapy) proceed to consolidation therapy followed by intensification therapy and
      assessment of MRD at week 13 (after intensification therapy). Those whose MRD status is ≥
      10^-3 at week 13 proceed to pre-stem cell transplantation cytoreduction (FLAD) followed by
      allogeneic stem cell transplant (ASCT). Those whose MRD status is < 10^-3 at week 13 proceed
      directly to ASCT. Patients with high-risk disease receive induction therapy, consolidation
      therapy, and intensification therapy followed by assessment of MRD at week 13 (after
      intensification therapy). These patients then proceed to further treatment (FLAD and/or ASCT)
      based on the same MRD parameters at week 13 as for patients with intermediate-risk disease.

        -  Induction therapy (weeks 1-4): Patients are randomized to 1 of 2 induction therapy arms.

             -  Arm I: Patients receive idarubicin IV over 1 hour on days 1 and 2; oral
                dexamethasone twice daily on days 1-5 and 15-19; intrathecal (IT) methotrexate on
                days 1 and 8; vincristine sulfate IV on days 3, 10, 17, and 24; and pegaspargase
                intramuscularly (IM) on days 3 and 17 or asparaginase IM on days 3, 5, 7, 9, 11,
                13, 15, 17, 19, 21, 23, and 25.

             -  Arm II: Patients receive mitoxantrone IV over 1 hour on days 1 and 2. Patients also
                receive dexamethasone, methotrexate, vincristine sulfate, and pegaspargase or
                asparaginase as in arm I.

        -  Consolidation therapy (weeks 5-8): Patients receive oral dexamethasone twice daily on
           days 1-5; vincristine sulfate IV on day 3; IT methotrexate on day 8; methotrexate IV
           continuously over 36 hours beginning on day 8; pegaspargase IM on day 9 or asparaginase
           IM on days 9, 11, 13, 15, 17, and 19; leucovorin calcium IV twice on day 10; and
           cyclophosphamide IV over 30 minutes and etoposide phosphate IV over 4 hours on days
           15-19.

        -  Intensification therapy (weeks 9-13): Patients receive oral dexamethasone twice daily on
           days 1-5; vincristine sulfate IV on 3; IT methotrexate on days 1 and 22; cytarabine IV
           over 3 hours twice on days 1, 2, 8, and 9; asparaginase IM on days 2, 4, 9, 11, and 23;
           methotrexate IV continuously over 36 hours beginning on day 22; and leucovorin calcium
           IV twice on day 24.

        -  Interim maintenance therapy (weeks 14-29): Patients receive oral dexamethasone twice
           daily on days 1-5; IT methotrexate* on days 1 and 43; vincristine sulfate IV on day 3;
           high-dose oral methotrexate 4 times on day 22; oral leucovorin calcium twice on day 24;
           oral mercaptopurine once daily on days 1-42; oral methotrexate on days 8, 15, 29, and
           36; oral thioguanine on days 43-49; etoposide phosphate IV over 4 hours and
           cyclophosphamide IV over 30 minutes on days 43 and 50; and cytarabine IV or
           subcutaneously (SC) on days 44-47 and 51-54. Treatment repeats every 56 days (8 weeks)
           for 2 courses.

      Patients undergoing cranial irradiation do so before starting interim maintenance therapy.
      Patients undergoing testicular irradiation do so concurrently with interim maintenance
      therapy.

      NOTE: *Patients who undergo cranial irradiation do not receive IT methotrexate.

        -  Maintenance therapy (weeks 30-117): Patients receive IT methotrexate* on day 15; oral
           dexamethasone twice daily on days 1-5, 29-33, and 57-61; vincristine sulfate IV on days
           1, 29, and 57; oral mercaptopurine once daily on days 1-84; and oral methotrexate on
           days 1, 8, 22, 29, 36, 43, 50, 57, 64, 71, and 78. Treatment repeats every 84 days (12
           weeks) for 7 courses. Patients then receive 4 additional weeks (course 8) of maintenance
           therapy without IT methotrexate.

      NOTE: *Patients who undergo cranial irradiation do not receive IT methotrexate.

        -  Pre-stem cell transplantation cytoreduction (FLAD): Patients receive fludarabine
           phosphate IV over 30 minutes and cytarabine over 4 hours on days 1-5 and liposomal
           daunorubicin citrate IV over 2 hours on day 1. Patients also receive filgrastim IV or SC
           beginning on day 7 and continuing until blood counts recover.

        -  ASCT: Patients undergo ASCT (including conditioning and graft-vs-host disease [GVHD]
           prophylaxis) according to national transplant guidelines based on the type of donor.

        -  Post-transplant immunotherapy: Patients who undergo ASCT may receive incremental doses
           of donor lymphocytes by infusion until a response and/or GVHD has occurred.
    

Intervention name(s): asparaginase; dexamethasone; idarubicin; methotrexate; mitoxantrone hydrochloride; pegaspargase; vincristine sulfate
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Given intramuscularly; Given orally; Given IV; Given intrathecally; Given IV; Given intramuscularly; Given IV
Intervention MeSH terms: Dexamethasone; Methotrexate; Vincristine; Asparaginase; Mitoxantrone; Idarubicin; Pegaspargase
Allocation: Randomized
Primary purpose: Treatment
Keywords: recurrent childhood acute lymphoblastic leukemia; T-cell childhood acute lymphoblastic leukemia