S0333 Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
Condition: Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 2

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), and giving the drugs in different combinations may kill more
      cancer cells.

      PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating
      patients with newly diagnosed acute lymphoblastic leukemia.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the probability of 1-year continuous complete remission in patients with newly
           diagnosed acute lymphoblastic leukemia treated with first induction chemotherapy
           comprising daunorubicin, vincristine, prednisone, and pegaspargase; and second induction
           chemotherapy comprising high-dose cytarabine and mitoxantrone.

      Secondary

        -  Determine the frequency and severity of toxic effects of these induction regimens
           followed by consolidation therapy comprising cyclophosphamide, cytarabine,
           mercaptopurine, and methotrexate and maintenance chemotherapy comprising mercaptopurine,
           methotrexate, vincristine, doxorubicin, dexamethasone, cyclophosphamide, thioguanine,
           and cytarabine in these patients.

      Other objectives (if funding allows):

        -  To evaluate in a preliminary manner the significance of detecting minimal residual
           disease as a prognostic factor for survival and relapse-free survival of patients
           receiving chemotherapy

        -  To evaluate in a preliminary manner the pattern of gene expression of patients entered
           onto the trial and its relationship to cytogenetics/FISH risk classification, overall
           survival, and relapse-free survival

      OUTLINE: This is a multicenter study.

        -  First induction chemotherapy: Patients receive daunorubicin IV on days 1-3; vincristine
           IV on days 1, 8, 15, and 22; prednisone IV or orally on days 1-28, followed by a taper
           to day 35; and pegaspargase IV or subcutaneously (SC) on day 15. Patients with CNS
           leukemia also receive methotrexate intrathecally (IT) or intraventricularly twice weekly
           and oral leucovorin calcium four times daily for 4 doses after each administration of
           methotrexate. When blasts are no longer present in the spinal fluid, patients receive
           methotrexate IT or intraventricularly once weekly for 4 weeks and then once monthly for
           1 year.

      Patients are reevaluated on day 28. Patients who achieve A1 bone marrow status and B1
      peripheral blood status or those with resistant disease proceed to second induction therapy.

        -  Second induction chemotherapy: Patients receive high-dose cytarabine IV on days 1-5;
           mitoxantrone IV on day 3; and filgrastim (G-CSF) SC or IV beginning on day 7 and
           continuing until blood counts recover. Patients with CNS leukemia also receive
           methotrexate and leucovorin calcium as in first induction chemotherapy.

      Patients are reevaluated on day 28. Patients who achieve A1 bone marrow status and B1
      peripheral blood status with no extramedullary disease (other than CNS involvement) proceed
      to consolidation chemotherapy. Patients with resistant disease OR Philadelphia chromosome- or
      BCR/ABL-positive disease are removed from the study after receiving double induction
      chemotherapy.

        -  Consolidation chemotherapy: Patients receive cyclophosphamide IV on days 1, 15, and 29;
           cytarabine IV on days 2-5 and 16-19; oral mercaptopurine on days 1-28; and methotrexate
           IT or intraventricularly on days 2, 9, 16, and 23. Patients with CNS leukemia also
           undergo cranial radiotherapy once daily, 5 days a week, for 2 weeks.

      Patients in complete remission proceed to maintenance chemotherapy.

        -  Maintenance chemotherapy:

             -  Course 1: Patients receive oral mercaptopurine on days 1-63 and oral methotrexate
                on days 1, 8, 15, 22, 29, 36, 43, 50, and 57. Patients proceed to course 2 after
                blood counts recover.

             -  Course 2: Patients receive vincristine IV and doxorubicin IV on days 1, 8, 15, and
                22 and oral dexamethasone on days 1-28. Patients proceed to course 3 after blood
                counts recover.

             -  Course 3: Patients receive cyclophosphamide IV on day 1; oral thioguanine on days
                1-14; and cytarabine IV on days 3-6 and 10-13. Patients proceed to course 4 after
                blood counts recover.

             -  Course 4: Patients receive oral mercaptopurine once daily for 2 years and oral
                methotrexate once weekly for 2 years.

      Treatment continues in the absence of disease relapse or unacceptable toxicity.

      After completion of study therapy, patients are followed every 3 months for 1 year, every 6
      months for 1 year, and then annually for 3 years.
    

Intervention name(s): filgrastim; cyclophosphamide; cytarabine; daunorubicin; dexamethasone; doxorubicin; leucovorin; mercaptopurine; methotrexate; mitoxantrone; Asparaginase; prednisone; thioguanine; vincristine; radiation therapy; allopurinol; bactrim
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Radiation; Drug; Drug
Intervention description(s): As needed per physician discretion; Cyclophosphamide Consolidation: 650 mg/m2; IV; days 1, 15, 29 Post-consolidation course 3: 650 mg/m2; IV; day 1; Induction 2: 3 g/m2; IV over 3 hrs; days 1-5 Consolidation: 75 mg/m2/d; IV push; days 2-5 and 16-19 Post-consolidation course 3: 75 mg/m2/d; IV push; days 3-6 and 10-13; Induction: 60 mg/m2/d; IV; days 1, 2, and 3; Induction 2: 0.1% QID; eye drops; days 1-6 Post consolidation course 2: 10 mg/m2/d; PO; days 1-28; Post consolidation: 25 mg/m2; IV; days 1, 8, 15, and 22; For CNS during induction: 5 mg every 6 hrs for 4 doses; PO; days 1, 4, 8, 11, etx.; after methotrexate if WBC < 3,000; Consolidation: 60 mg/m2; PO; days 1-28 Post-consolidation course 1: 60 mg/m2/d; PO; days 1-63 Post-consolidation course 4: 60 mg/m2/d; PO; daily for 2 yrs; Consolidation: 12 mg; intrathecal or intraventricularly; days 2, 9, 16, and 23 Post-consolidation course 1: 20 mg/m2/wk; PO; days 1, 8 15, 22, 29, 36, 43, 50, 57 Post-consolidation course 4: 20 mg/m2; PO; weekly for 2 yrs; Induction 2: 80 mg/m2; IV; day 3; Induction: 2,000 IU/m2; IM or IV; day 15; Induction: 60 mg/m2/d; PO or IV; days 1-35; Post-consolidation course 3: 60 mg/m2/d; PO; days 1-14; Induction: 1.4 mg/m2/d (2 mg max); IV; days 1, 8, 15, 22; For CNS during consolidation: cranial radiation after blasts are no longer present in spinal fluid. Total dose of 1800 cGy over 2 wks in 10 fractions of 180 cGy 5 days/wk.; 300 mg/d PO Days 1-7; 1 double strenth tablet 2x/d, 2x/wk, PO, begin with prednisone
Intervention MeSH terms: Leucovorin; Cytarabine; Trimethoprim, Sulfamethoxazole Drug Combination; Dexamethasone; Prednisone; Cyclophosphamide; Doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mitoxantrone; Mercaptopurine; Thioguanine; Allopurinol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: L1 adult acute lymphoblastic leukemia; L2 adult acute lymphoblastic leukemia; untreated adult acute lymphoblastic leukemia