Combination Chemotx in Treating Children or Adolescents With Newly Diagnosed Stg III or Stg IV Lymphoblastic Lymphoma
Condition: Lymphoma
MeSH terms: Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Non-Hodgkin
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. It is not yet known which regimen of combination chemotherapy is
      most effective for lymphoblastic lymphoma.

      PURPOSE: This randomized phase III trial is studying different regimens of combination
      chemotherapy to compare how well they work in treating children or adolescents with newly
      diagnosed stage III or stage IV lymphoblastic lymphoma.
    

Detailed description: 
      OBJECTIVES:

        -  Compare the event-free survival and overall survival of children or adolescents with
           newly diagnosed disseminated stage III or IV lymphoblastic lymphoma treated with 4
           chemotherapy regimens*.

        -  Determine whether treatment with a regimen without methotrexate maintains the same
           disease-free survival as NHL/BFM 90 in these patients.

        -  Determine whether intensification with anthracycline and cyclophosphamide improves
           disease-free survival in these patients.

        -  Collect outcome data on uniformly treated patients with localized disease or
           CNS-positive disease.

        -  Determine whether rapid reduction in tumor volume by chest radiography and CT scan is
           predictive of improved outcome in patients treated with these regimens.

        -  Determine the prevalence of bone marrow involvement at presentation in these patients.

        -  Determine whether peripheral blood can replace bone marrow in the initial staging of
           these patients.

        -  Determine the clinical significance of bone marrow and peripheral blood involvement in
           these patients.

      NOTE: *All patients as of 4/2006 receive treatment on Arm III regimen only

      OUTLINE: Patients are stratified by disease characteristics (disseminated lymphoblastic
      lymphoma vs localized lymphoblastic lymphoma [localized lymphoblastic lymphoma is closed to
      accrual as of 10/2005]) and age. Patients with CNS negative disseminated lymphoblastic
      lymphoma are randomized to 1 of 4 treatment arms*. Patients with testicular involvement at
      diagnosis are nonrandomly assigned to arm IV and do not receive testicular radiotherapy.
      Patients with localized lymphoblastic lymphoma (closed to accrual as of 10/2005) are not
      randomized.

      NOTE: *All patients as of 4/2006 receive treatment on Arm III only

        -  Localized lymphoblastic lymphoma (closed to accrual as of 10/2005):

             -  Induction (5 weeks): Patients receive vincristine IV and daunorubicin IV over 15
                minutes to 2 hours on days 0, 7, 14, and 21; oral prednisone on days 0-27; and
                asparaginase intramuscularly (IM) on days 3, 5, and 7 and then 3 times a week for 9
                doses (during days 8-21). Patients also receive methotrexate intrathecally (IT) on
                days 7 and 28 and cytarabine IT on day 0.

             -  Consolidation (5 weeks): Patients receive methotrexate IT on days 0, 7, 14, and 21
                followed by cyclophosphamide IV over 1 hour on days 0 and 14; cytarabine IV on days
                0-3, 7-10, 14-17, and 21-24; oral mercaptopurine on days 0-27; and oral prednisone
                over 10 days.

             -  Interim maintenance (8 weeks): Patients receive methotrexate IT on days 0 and 28;
                oral mercaptopurine on days 0-41; and oral methotrexate on days 7, 14, 21, and 35.

             -  Delayed intensification (7 weeks): Patients receive vincristine IV and doxorubicin
                IV over 15 minutes to 2 hours on days 0, 7, and 14; asparaginase IM on day 3 and
                then 3 times a week for 6 doses; oral dexamethasone on days 0-30; cyclophosphamide
                IV over 1 hour on day 28; and cytarabine IV or SC on days 28-31 and 35-38. Patients
                also receive oral thioguanine on days 28-41 and methotrexate IT on days 28 and 35.

             -  Maintenance (84 day course): Patients receive vincristine IV on days 0, 28, and 56;
                oral prednisone on days 0-4, 28-32, and 56-60; oral methotrexate on days 7, 14, 21,
                28, 35, 42, 49, 56, 63, 70, and 77; oral mercaptopurine on days 0-83; and
                methotrexate IT on day 0.

        -  Disseminated lymphoblastic lymphoma:

             -  Arm I (closed to accrual as of 4/2006): Patients receive same induction,
                consolidation, and interim maintenance therapy schedule as localized lymphoblastic
                lymphoma patients.

                  -  Delayed intensification (7 weeks): Patients receive vincristine IV and
                     doxorubicin IV over 15 minutes to 2 hours on days 0, 7, 14, and 21;
                     asparaginase IM on day 3 and then 3 times a week for 6 doses; and oral
                     dexamethasone on days 0-28. Patients also receive cyclophosphamide IV over 1
                     hour on day 35; cytarabine IV or SC on days 35-38 and 42-45; oral thioguanine
                     on days 35-48; and methotrexate IT on days 35 and 42.

                  -  Maintenance (84 day course): Patients receive same therapy as localized
                     lymphoblastic lymphoma patients, except methotrexate IT is administered on day
                     0 and 28 (for first 4 courses).

             -  Arm II (closed to accrual as of 4/2006): Patients receive consolidation, interim
                maintenance, and maintenance therapy as in arm I.

                  -  Induction (5 weeks): Patients receive vincristine IV on days 0, 7, 14, and 21;
                     daunorubicin IV over 48 hours on days 0-2; oral prednisone on days 0-27; and
                     asparaginase IM on days 3, 5, and 7 and then 3 times a week for 9 doses
                     (during days 8-21). Patients also receive methotrexate IT on days 7 and 28;
                     cyclophosphamide IV over 1 hour on day 2; and cytarabine IT on day 0.

                  -  Delayed intensification (7 weeks): Patients receive vincristine IV on days 0,
                     7, 14, 21; daunorubicin IV over 48 hours on days 0-2; asparaginase IM on day 3
                     and then 3 times a week for 6 doses; and oral dexamethasone on days 0-28.
                     Patients also receive cyclophosphamide IV over 1 hour on days 2 and 35;
                     cytarabine IV or SC on days 35-38 and 42-45; oral thioguanine on days 35-48;
                     and methotrexate IT on days 35 and 42.

             -  Arm III:

                  -  Induction (5 weeks): Patients receive vincristine IV and daunorubicin IV over
                     1 hour on days 0, 7, 14, and 21 and oral prednisone on days 0-37. Patients
                     also receive asparaginase IM on day 11 and then 3 times a week for 9 doses;
                     methotrexate IT on days 7 and 28; and cytarabine IT on day 0.

                  -  Consolidation (5 weeks): Patients receive methotrexate IT and cyclophosphamide
                     IV over 1 hour on days 0 and 14; cytarabine IV or SC on days 0-3, 7-10, 14-17,
                     and 21-24; oral mercaptopurine on days 0-27; and oral prednisone over 10 days.

                  -  Interim maintenance (9 weeks): Patients receive methotrexate IT and IV on days
                     7, 21, 35, and 49; oral mercaptopurine on days 0-55; and leucovorin calcium IV
                     at 42, 48, and 54 hours after methotrexate IV.

                  -  Delayed intensification (10 weeks): Patients receive vincristine IV and
                     doxorubicin IV over 1 hour on days 0, 7, 14, and 21; asparaginase IM on day 3
                     and then 3 times a week for 6 doses; and oral dexamethasone on days 0-29.
                     Patients also receive cyclophosphamide IV over 1 hour on day 35; cytarabine IV
                     on days 35-38 and 42-45; oral thioguanine on days 35-48; and methotrexate IT
                     on days 35 and 42.

                  -  Maintenance (84 day courses): Patients receive vincristine IV on days 0, 28,
                     and 56; oral prednisone on days 0-4, 28-32, and 56-60; oral methotrexate on
                     days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77; and oral mercaptopurine on
                     days 0-83.

             -  Arm IV (closed to accrual as of 4/2006): Patients receive consolidation and interim
                maintenance therapy as in arm III.

                  -  Induction: Patients receive vincristine IV on days 0, 7, 14, and 21;
                     daunorubicin IV over 48 hours on days 0-2; oral prednisone on days 0-37;
                     asparaginase IM on day 11 and then 3 times a week for 9 doses; methotrexate IT
                     on days 7, 14, 21, and 28; cyclophosphamide IV on day 2; and cytarabine IT on
                     day 0.

                  -  Delayed intensification (10 weeks): Patients receive vincristine IV on days 7,
                     14, 21, and 28; daunorubicin IV over 48 hours on days 0-2; asparaginase IM on
                     day 3 and then 3 times a week for 6 doses; and oral dexamethasone on days
                     0-29. Patients also receive cyclophosphamide IV over 1 hour on days 2 and 35;
                     cytarabine IV on days 35-38 and 42-45; oral thioguanine on days 35-48; and
                     methotrexate IT on days 35 and 42.

                  -  Maintenance (84 day courses): Patients receive therapy as in arm III. Patients
                     who are over 1 year of age and have CNS disease at diagnosis undergo cranial
                     radiotherapy once daily 5 days a week beginning on day 0. Patients over 2
                     years of age undergo radiotherapy over 11-14 days (6-9 days for 1-2 years of
                     age).

      Patients are followed monthly for one year, every 3 months for 1 year, every 6 months for 1.5
      years, and then annually thereafter.

      PROJECTED ACCRUAL: Approximately 250-400 patients will be accrued for this study within 5
      years.
    

Intervention name(s): asparaginase; cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; doxorubicin hydrochloride; leucovorin calcium; mercaptopurine; methotrexate; prednisone; thioguanine; vincristine sulfate; radiation therapy
Intervention type(s): 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 IV; Given IV; Given PO; Given IV
Other intervention name(s): E.coli L-asparaginase; EC 3.5.2.2; colaspase; L-asnase; Elspar; Kidrolase; Crasnitin; Leunase; NSC#109229; Cytoxan; NSC #26271; cytosine arabinoside; Ara-C; Cytosar; NSC #63878; daunomycin; rubidomycin; Cerubidine; NSC #82151; Decadron; Hexadrol; Dexone; Dexameth; NSC #34521; Adriamycin; NSC #123127; LCV; Wellcovorin; citrovorum factor; folinic acid; NSC #003590; 6-MP; Purinethol; 6-mercaptopurine; NSC #000755; MTX; amethopterin; Trexall; NSC #000740; Deltasone; Meticorten; Orasone; Liquid Pred; Pediapred; Sterapred; NSC #010023; 6-thioguanine; 2-amino-1,7-dihydro-6H-purine-6-thione; WR-1141; Tabloid; Lanvis; NSC # 751; Oncovin; VCR; LCR; NSC #67574
Intervention MeSH terms: Leucovorin; Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Thioguanine; Levoleucovorin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: stage III childhood lymphoblastic lymphoma; stage IV childhood lymphoblastic lymphoma