Combination Chemotherapy and Radiation Therapy in Treating Patients With Acute Lymphoblastic Leukemia That Has Relapsed in the CNS or Testes
Condition: Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional

Summary: 
      RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from
      dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage
      cancer cells. Giving combination chemotherapy together with radiation therapy may kill more
      cancer cells.

      PURPOSE: This clinical trial is studying how well giving chemotherapy together with radiation
      therapy works in treating patients with acute lymphoblastic leukemia that has relapsed in the
      CNS and/or testes.
    

Detailed description: 
      OBJECTIVES:

      Primary

        -  Determine the efficacy of intensified systemic chemotherapy with reduced-dose CNS
           radiotherapy in patients with acute lymphoblastic leukemia and late isolated CNS
           relapse.

        -  Determine the efficacy of intensive systemic chemotherapy without testicular
           radiotherapy in patients with acute lymphoblastic leukemia and late isolated testicular
           relapse.

        -  Determine the toxicity of these regimens in these patients.

      Secondary

        -  Determine whether bone marrow involvement is present at the time of extramedullary
           relapse in patients treated with these regimens.

        -  Correlate pretreatment minimal residual disease with outcomes in patients treated with
           these regimens.

        -  Correlate the role of host gene polymorphisms with toxicity of these regimens and
           incidence and outcome in these patients.

        -  Determine the neuropsychological sequelae associated with isolated CNS relapse and these
           treatment regimens in these patients.

      OUTLINE: This is a pilot, multicenter study. All patients receive common induction,
      consolidation, re-induction, and intensification chemotherapy. Patients are stratified to
      maintenance therapy according to site of extramedullary relapse (CNS vs testicular).

        -  Induction therapy (weeks 1-4): Patients receive vincristine IV on days 1, 8, 15, and 22;
           oral dexamethasone twice daily on days 1-28; daunorubicin* IV over 15 minutes on days 1,
           8, and 15; and intrathecal triple therapy** (ITT) comprising methotrexate,
           hydrocortisone, and cytarabine on days 1, 8, 15, and 22.

      NOTE: *The total dose of anthracyclines on this study is capped at 450 mg/m2. Once this dose
      is reached, all subsequent doses of daunorubicin are omitted.

      NOTE: **Patients with isolated testicular relapse receive ITT on day 1 only.

      In addition to the above, patients with isolated testicular relapse also receive high-dose
      methotrexate IV continuously over 24 hours on day -14. Patients with clinical signs of
      disease at the end of induction undergo testicular biopsy.

      Patients with CNS disease who do not achieve CNS remission after induction therapy receive
      additional ITT as above on days 29 and 36.

        -  Consolidation therapy (weeks 5-10): Patients receive high-dose cytarabine IV over 3
           hours twice daily on days 1-2 and 22-23 and pegaspargase intramuscularly (IM) on days 2
           and 23. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on days 3
           and 24 and continuing until blood counts recover.

      Patients with isolated testicular relapse with positive biopsy results at the end of
      induction undergo testicular radiotherapy once daily for a total of 12 fractions during
      consolidation therapy.

        -  Intensification I (weeks 11-22): Patients receive high-dose methotrexate with leucovorin
           calcium rescue IV over 24 hours on days 1, 22, 43, and 64 and oral mercaptopurine once
           daily on days 2-6, 23-27, 44-48, and 65-69. Patients also receive etoposide IV over 1
           hour and cyclophosphamide IV over 15-30 minutes on days 8, 29, 50, and 71. Patients
           receive ITT* on days 15, 36, 57, and 78.

      NOTE: *Patients with isolated testicular relapse receive ITT on days 36 and 78 only.

        -  Reinduction therapy (weeks 23-26): Patients receive vincristine IV on days 1, 8, 15, and
           22; oral dexamethasone twice daily on days 1-7 and 15-21, and daunorubicin IV over 15
           minutes on days 1, 8, and 15.

        -  Intensification II (weeks 27-50): Patients receive high-dose cytarabine IV over 3 hours
           twice daily on days 1-2, 43-44, 85-86, and 127-128; pegaspargase IM on days 2, 44, 86,
           and 128; ITT* on days 22, 64, 106, and 148; high-dose methotrexate IV continuously over
           24 hours on days 29, 71, 113, and 155; oral mercaptopurine on days 30-34, 72-76,
           114-118, and 156-160; and etoposide IV over 1 hour and cyclophosphamide IV over 15-30
           minutes on days 36, 78, 120, and 162. Patients also receive G-CSF SC beginning on days
           3, 45, 87, and 129 and continuing until blood counts recover.

      NOTE: *Patients with isolated testicular relapse receive ITT on days 22 and 106 only.

        -  Chemotherapy and radiotherapy (weeks 51-54): Patients receive oral dexamethasone twice
           daily on days 1-7 and 15-21, vincristine IV on days 1, 8, and 15, and pegaspargase IM on
           days 1 and 15.

      Patients with isolated CNS relapse also undergo cranial radiotherapy once daily, 5 days a
      week, for a total of 12 fractions.

        -  Maintenance therapy for isolated CNS relapse: (weeks 55-104): Patients receive
           dexamethasone PO orIV twice daily on days 1-5; oral mercaptopurine once daily on days
           1-42; methotrexate IM on days 1, 8, 15, 22, 29, and 36; and vincristine IV and
           cyclophosphamide IV over 1 hour on days 43, 50, 57, and 64. Treatment repeats every 10
           weeks for 5 courses.

        -  Maintenance therapy for isolated testicular relapse:

             -  (Weeks 55-74): Patients receive ITT on day 1 and dexamethasone, mercaptopurine,
                methotrexate, vincristine, and cyclophosphamide as in maintenance therapy for
                isolated CNS relapse. Treatment repeats every 10 weeks for 2 courses.

             -  (Weeks 75-106): Patients receive vincristine IV on day 1; dexamethasone orally or
                IV on days 1-5; oral mercaptopurine on days 1-28; and methotrexate IM on days 1, 8,
                15, and 22. Treatment repeats every 28 days for 8 courses. Patients also receive
                ITT on day 1 every 12 weeks for 3 doses.

      Patients with combined testicular and CNS relapse receive high-dose methotrexate IV
      continuously over 24 hours on day -14 in addition to the same chemotherapy and radiotherapy
      administered during the induction, consolidation, intensification I, reinduction,
      intensification II, and maintenance phases of therapy as isolated CNS relapse patients.

      All patients undergo neuropsychological assessment within 3 months after completion of
      induction therapy (before cranial radiotherapy) and at 2 years after completion of treatment.

      Patients are followed for survival.
    

Intervention name(s): filgrastim; cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; etoposide; leucovorin calcium; mercaptopurine; methotrexate; pegaspargase; therapeutic hydrocortisone; vincristine sulfate; radiation therapy
Intervention type(s): Biological; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Radiation
Intervention description(s): given subcutaneously (SC); IV over 15-30 minutes; IV over 3 hours twice daily; IV over 15 minutes; oral twice daily; IV over 1 hour; rescue IV over 24 hours; oral; intramuscularly (IM); intramuscularly (IM); given IV; Patients with isolated testicular relapse will start Induction with a single dose of high-dose methotrexate (HDMTX) and will not receive either testicular or cranial radiation. Patients with isolated CNS relapse will NOT receive the initial dose of HDMTX prior to Induction, but will receive 1200 cGy of cranial radiation after completing the initial 12 months of intensive systemic chemotherapy.
Other intervention name(s): Granulocyte Colony-Stimulating Factor; r-metHuG-CSF; G-CSF; Neupogen; NSC 614629; CYTOXAN; NSC #26271; Cytosine arabinoside; Ara-C; Cytosar; NSC #6387; Daunomycin; rubidomycin; Cerubidine; NSC #82151; Decadron; Hexadrol; Dexone; Dexameth; NSC #34521; VePesid; Etopophos; VP-16; NSC #141540; LCV; Wellcovorin; citrovorum factor; folinic acid; NSC 03590; 6-MP; Purinethol; 6-mercaptopurine; NSC #000755; MTX; amethopterin; Trexall; NSC #000740; PEG-asparaginase; PEGLA; PEG-L-asparaginase; polyethylene glycol-L-asparaginase; Oncaspar; NSC 624239; Oncovin; VCR; LCR; NSC #67574
Intervention MeSH terms: Leucovorin; Cytarabine; Dexamethasone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Methotrexate; Etoposide; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Pegaspargase; Lenograstim; Levoleucovorin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent childhood acute lymphoblastic leukemia; B-cell childhood acute lymphoblastic leukemia; T-cell childhood acute lymphoblastic leukemia; TdT positive childhood acute lymphoblastic leukemia