Chemotherapy With or Without Bone Marrow Transplantation in Treating Patients With Acute Lymphoblastic Leukemia
Condition: Leukemia; Lymphoma
MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 3

Summary: 
      RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so
      they stop growing or die. Combining chemotherapy with radiation therapy may kill more tumor
      cells. Bone marrow transplantation can replace immune cells that were destroyed by
      chemotherapy.

      PURPOSE: Randomized phase III trial to study the effectiveness of chemotherapy compared with
      or without bone marrow transplantation in treating patients with acute lymphoblastic
      leukemia.
    

Detailed description: 
      OBJECTIVES:

        -  Compare the remission induction, toxicity, and duration of remission in patients with
           newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma treated with
           prednisone vs dexamethasone plus cyclophosphamide, daunorubicin, and vincristine as
           induction.

        -  Compare the survival and disease-free survival of patients treated with autologous bone
           marrow transplantation (BMT) followed by low- or high-intensity maintenance chemotherapy
           with cranial irradiation after consolidation.

        -  Determine the relative and disease-free survival of patients treated with autologous or
           allogeneic BMT after identical induction, consolidation, and conditioning regimens.

      OUTLINE: This is a randomized, multicenter study. Patients are stratified according to center
      and risk group (high vs standard).

      Induction

        -  Patients are randomized to 1 of 2 treatment arms.

             -  Arm I:Patients receive daunorubicin IV on days 1-3 and 15 and 16; cyclophosphamide
                (CTX) IV on days 1 and 8; vincristine (VCR) IV on days 1, 8, 15, and 22; and
                prednisone IV or orally every 8 hours on days 1-7 and 15-21.

             -  Arm II: Patients receive daunorubicin, CTX, and VCR as in arm I and dexamethasone
                IV or orally on days 1-8 and 15-22.

        -  Patients on both arms without CNS disease at presentation receive CNS prophylaxis
           comprising methotrexate (MTX) intrathecally (IT) on days 1, 8, 15, and 22. Patients on
           both arms with CNS disease at presentation receive CNS therapy comprising hydrocortisone
           (HC) IT and MTX IT alternating with cytarabine (ARA-C) IT twice a week until CSF clears.
           After induction, patients on both arms proceed to consolidation, regardless of response.

      Consolidation

        -  Patients receive ARA-C IV over 2 hours every 12 hours on days 29-34 and mitoxantrone IV
           on days 33-35. Patients without CNS disease at presentation receive CNS prophylaxis
           comprising MTX IT on day 29. Patients with CNS disease at presentation receive CNS
           therapy comprising HC IT and MTX IT alternating with ARA-C weekly for 6 weeks. Patients
           who achieve complete response (CR) at day 55-60 receive MTX IV on days 64 and 79,
           leucovorin calcium IV or orally every 6 hours on days 65-67 and 80-82, and asparaginase
           IV over 1 hour or intramuscularly on days 65 and 80.

        -  Standard-risk patients who are under age 20 and achieve CR after day 80 are assigned to
           arm IV of group A. Patients who achieve CR after day 80 and have a genotypically or
           phenotypically HLA-matched family donor, a family donor mismatched at only 1 locus (A,
           B, or DR), or an HLA-matched unrelated donor proceed to group B. Patients who achieve CR
           after day 80 and are eligible for autologous bone marrow transplantation (BMT) proceed
           to group A. Patients found to be at extremely high risk are taken off study.

      Group A

        -  Patients are randomized to 1 of 2 treatment arms.

             -  Arm III: Autologous bone marrow is harvested. Patients receive bone marrow ablation
                comprising CTX IV over 1 hour on days -4 and -3 and total body irradiation on day
                -1. Autologous bone marrow is reinfused on day 0. Beginning at month 8 (4 months
                after BMT), patients receive first maintenance comprising VCR IV, doxorubicin IV,
                and dexamethasone IV (VAD) or VCR IV, doxorubicin IV, and prednisolone IV (VAP) on
                days 1-4 and 29-32. Patients receive second maintenance comprising oral
                mercaptopurine daily and oral MTX daily beginning at month 10 and continuing
                through year 3. Patients without CNS disease at presentation receive CNS
                prophylaxis comprising MTX IT on days 1 and 29. Patients with CNS disease at
                presentation receive CNS therapy comprising ARA-C IT, MTX IT, and HC IT beginning
                at 1 month after BMT and continuing monthly for 1 year and then every 3 months
                through year 3.

             -  Arm IV: Patients receive CTX IV and ARA-C IV continuously on day 1, oral
                mercaptopurine on days 8-28, and oral MTX on days 8, 15, and 22 during months 4, 7,
                11, 13, 17, 21, 25, and 29. Patients receive MTX IV over 30 minutes on day 1,
                leucovorin calcium IV or orally every 6 hours on days 2-4, asparaginase IV over 1
                hour or intramuscularly on day 2, oral mercaptopurine on days 8-28, and oral MTX on
                days 8, 15, and 22 during months 6, 10, 12, 15, 19, 23, and 27. Patients receive
                VAD or VAP as in arm III beginning at month 8. Patients without CNS disease at
                presentation receive CNS prophylaxis comprising whole brain radiotherapy and MTX IT
                on day 1 of radiotherapy during month 5. Patients with CNS disease at presentation
                receive CNS therapy as in arm III.

      Group B

        -  Allogeneic bone marrow is harvested. Patients receive bone marrow ablation as in arm III
           beginning on day 100. Allogeneic bone marrow is infused over 15-30 minutes on day 0.

             -  Patients in groups A and B with CNS disease at presentation undergo radiotherapy to
                focal infiltration at entry or concurrently with total body irradiation, or whole
                brain radiotherapy during maintenance (if no prior CNS irradiation). At any time
                during the study, patients who develop marrow relapse (more than 5% leukemic blasts
                in bone marrow on 2 occasions), CNS relapse (blasts in CSF, cranial nerve palsy, or
                CNS mass), or testis or other extramedullary relapse are taken off study.

      PROJECTED ACCRUAL: A total of 392 patients will be accrued for this study within
      approximately 6 years.
    

Intervention name(s): asparaginase; cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; doxorubicin hydrochloride; leucovorin calcium; mercaptopurine; methotrexate; mitoxantrone hydrochloride; prednisolone; prednisone; therapeutic hydrocortisone; vincristine sulfate; allogeneic bone marrow transplantation; autologous bone marrow transplantation; radiation therapy
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Procedure; Procedure; Radiation
Intervention MeSH terms: Leucovorin; Cytarabine; Dexamethasone; Prednisone; Prednisolone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mitoxantrone; Mercaptopurine; Levoleucovorin
Allocation: Randomized
Primary purpose: Treatment
Keywords: untreated adult acute lymphoblastic leukemia; stage I adult lymphoblastic lymphoma; stage III adult lymphoblastic lymphoma; stage IV adult lymphoblastic lymphoma; contiguous stage II adult lymphoblastic lymphoma; noncontiguous stage II adult lymphoblastic lymphoma