Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia
Condition: Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma
Study type: Interventional
Phase: Phase 3

Summary: 
      RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing
      so they stop growing or die. Combining more than one drug and giving the drugs in different
      combinations may kill more cancer cells.

      PURPOSE: Randomized phase III trial to compare the effectiveness of standard combination
      chemotherapy treatment with more intensive combination chemotherapy in treating children with
      acute lymphocytic leukemia.
    

Detailed description: 
      OBJECTIVES: I. Compare the outcomes in children with higher risk acute lymphocytic leukemia
      (ALL) treated with postinduction chemotherapy based on marrow response on day 7 of induction
      therapy: for patients with rapid early response (M1/M2), standard vs intensified
      consolidation chemotherapy and standard vs prolonged duration of intensification
      chemotherapy; for patients with slow early response, addition of doxorubicin vs idarubicin
      and cyclophosphamide to intensification chemotherapy. II. Decrease the incidence of avascular
      necrosis by alternating dexamethasone dosing in patients undergoing 2 courses of delayed
      intensification. III. Assess the impact of day 7 marrow status on outcome in these patients.
      IV. Determine prognosis more precisely by supplementing presenting clinical features,
      immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios,
      pattern of tyrosine kinase activation, leukemic burden following induction and
      intensification therapy, and development of high antibody titer to E. coli asparaginase. V.
      Correlate the traditional prognostic factors of day 7 marrow response, immunophenotype,
      ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios.

      OUTLINE: This is a partially randomized, multicenter study. Patients are stratified by
      center. Patients receive one course of the VPLD regimen comprised of vincristine IV and
      daunorubicin IV over 15 minutes to 2 hours on days 0 and 7, oral prednisone daily on days
      0-7, intrathecal cytarabine on day 0, and asparaginase or pegaspargase intramuscularly on
      days 3, 5, and 7. Patients are assigned to 1 of 2 two postinduction chemotherapy groups based
      on bone marrow response on day 7 of induction. Patients with M1/M2 marrow on day 7 are
      considered rapid early responders. Patients with M3 marrow on day 7 are considered slow early
      responders. Group 1: Rapid early responders Patients receive 2 additional courses of VPLD
      induction chemotherapy. Patients are then randomized to 1 of 4 treatment arms: Arm I:
      Beginning on day 35 of induction therapy, patients receive standard Berlin-Frankfurt-Munster
      (BFM) regimen with standard delayed intensification. Standard BFM for patients in arm I
      consists of the following: consolidation over 5 weeks with cyclophosphamide, cytarabine, and
      mercaptopurine; interim maintenance over 8 weeks with oral methotrexate and mercaptopurine
      (MTX/MP); and delayed intensification over 7 weeks consisting of reinduction with
      vincristine, doxorubicin, oral dexamethasone, and asparaginase or pegaspargase followed by
      reconsolidation with cyclophosphamide, thioguanine, and cytarabine. Arm II: Patients receive
      standard BFM regimen with double delayed intensification. Patients receive therapy similar to
      those in arm I, but dexamethasone is interrupted for 1 week during delayed intensification
      and the intensification regimen is repeated, separated by an 8 week interim maintenance
      course of oral MTX/MP. Arm III: Patients receive augmented BFM regimen with standard delayed
      intensification. Patients receive 9 weeks of consolidation therapy with 2 courses of
      vincristine and pegaspargase alternating with the arm I consolidation therapy. Vincristine,
      intravenous methotrexate, and pegaspargase (the Capizzi I regimen) are substituted for oral
      MTX/MP in the interim maintenance regimen. Pegaspargase is substituted for asparaginase and
      two additional doses of vincristine are administered during delayed intensification. Arm IV:
      Patients receive augmented BFM regimen with double delayed intensification. Patients receive
      intensified chemotherapy throughout, combining the additional therapy given to patients in
      arms II and III. Patients receiving augmented BFM regimen receive pegaspargase instead of
      asparaginase. Patients with CNS disease at diagnosis are treated only on arm IV. Patients who
      are Philadelphia chromosome positive and do not have a bone marrow donor are nonrandomly
      assigned to the treatment group for slow early responders. All RER patients receive the same
      maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal methotrexate is
      administered periodically throughout protocol treatment. Group 2: Slow early responders
      Patients receive augmented BFM consolidation therapy and Capizzi I interim maintenance
      identical to that received by rapid early responders in arm IV. Patients are then randomized
      to receive double delayed intensification with either idarubicin or doxorubicin and
      concurrent cyclophosphamide. All patients receive the same maintenance therapy with
      vincristine/prednisone and oral MTX/MP. Intrathecal MTX is administered periodically
      throughout protocol treatment. Patients with CNS disease at entry receive craniospinal
      irradiation daily for 5 consecutive days beginning on day 0 of consolidation therapy. All
      slow early responders at diagnosis receive cranial irradiation daily for 5 consecutive days
      during consolidation therapy. Patients with testicular leukemia at diagnosis receive
      bilateral testicular irradiation daily for 5 consecutive days during consolidation
      chemotherapy. Groups 1 and 2: Maintenance therapy continues for 2 years for girls or 3 years
      for boys beyond completion of consolidation therapy. Patients are followed every 4-6 weeks
      for 1 year, every 3 months for 1 year, every 6 months for 2 years, and then annually
      thereafter.

      PROJECTED ACCRUAL: Approximately 1,520 patients will be accrued for this study over 4 years.
    

Intervention name(s): asparaginase; cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; doxorubicin hydrochloride; idarubicin; mercaptopurine; methotrexate; pegaspargase; prednisone; thioguanine; vincristine sulfate; radiation therapy
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Radiation
Intervention description(s): Given IV; Given IV; Given IV; Given IV; Given IV; Given IV; Given IV; Given IV; Given PO; Given IV; Given PO; Given IV; Given IV
Other intervention name(s): E. coli; Elspar; NSC-109229; Cytoxan; NSC-26271; Cytosine Arabinoside; Ara-C; Cytosar-U; NSC-63878; Daunomycin Hydrochloride; Cerrubidine; NSC-82151; Decadron; NSC-34521; Adriamycin; NSC-123127; Idarubicin Hydrochloride; Idamycin; NSC-256439; 6-MP; Purinethol; NSC-755; NSC-740; Asparaginase; Oncaspar; NSC-10023; 6-TG; NSC-752; Oncovin; NSC-67574
Intervention MeSH terms: Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Idarubicin; Pegaspargase; Thioguanine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: untreated childhood acute lymphoblastic leukemia; L1 childhood acute lymphoblastic leukemia; L2 childhood acute lymphoblastic leukemia