Combination Chemotherapy in Treating Children With Anaplastic Large Cell Lymphoma (ALCL 99)
Condition: Lymphoma
MeSH terms: Lymphoma; Lymphoma, Large-Cell, Anaplastic
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 more than one drug may kill more tumor cells. It is not
      yet known which combination chemotherapy regimen is more effective for treating anaplastic
      large cell lymphoma.

      PURPOSE: This randomized phase III trial is studying several different regimens of
      combination chemotherapy to compare how well they work in treating children with anaplastic
      large cell lymphoma.
    

Detailed description: 
      OBJECTIVES:

        -  Compare the event-free survival in children with anaplastic large cell lymphoma treated
           with various induction and maintenance chemotherapy regimens with or without
           vinblastine.

        -  Compare the impact of different doses and schedules of methotrexate from the
           Berlin-Frankfurt-Munster-K2 Protocol in terms of overall survival, complete remission
           rate, CNS relapse rate, and nonlymphoma-related death and early death rates in these
           patients.

      OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
      country, vinblastine (VBL) (yes vs no), and prognostic factors (standard-risk (SR) vs
      high-risk (HR) disease).

      Beginning immediately after confirmation of diagnosis, patients receive prephase therapy
      comprising dexamethasone (DM) IV or orally daily on days 1 and 2 and every 12 hours on days
      3-5; cyclophosphamide (CTX) IV over 1 hour on days 1 and 2; and methotrexate (MTX)
      intrathecally (IT), doxorubicin (DOX) IV, and hydrocortisone (HC) IT on day 1.

      Patients are then assigned to one of two treatment groups based on prognosis:

        -  Group 1 (SR disease): Patients are randomized to arm I or III:

             -  Arm I: Patients receive treatment on arm I as defined below on day 1, and then the
                following courses as defined below in the following order beginning on day 6: A1,
                B1, A2, B2, A3, and B3.

             -  Arm III: Patients receive treatment on arm III as defined below on day 1, and then
                the following courses as defined below in the following order beginning on day 6:
                regimen AM1, BM1, AM2, BM2, AM3, and BM3.

        -  Group 2 (HR disease):

             -  First randomization: Patients are randomized to arm I or III:

                  -  Arm I: Patients receive treatment on arm I as defined below on day 1 and then
                     course A1 as defined below on day 6.

                  -  Arm III: Patients receive treatment on arm III as defined below on day 1 and
                     then course AM1 as defined below on day 6.

             -  Second randomization: Patients without disease progression after completion of the
                above therapy are randomized to arm I, II, III, or IV.

                  -  Arm I: Patients receive treatment on arm I as defined below on day 1, and then
                     the following courses as defined below in the following order after blood
                     counts recover: B1, A2, B2, A3, and B3.

                  -  Arm II: Patients receive treatment on arm II as defined below on day 1, and
                     then the following courses as defined below in the following order after blood
                     counts recover: BV1, AV2, BV2, AV3, and BV3.

                  -  Arm III: Patients receive treatment on arm III as defined below on day 1, and
                     then the following courses as defined below in the following order after blood
                     counts recover: BM1, AM2, BM2, AM3, and BM3.

                  -  Arm IV: Patients receive treatment on arm IV as defined below on day 1, and
                     then the following courses as defined below in the following order after blood
                     counts recover: BMV1, AMV2, BMV2, AMV3, and BMV3.

      Patients are followed every 2 months for 1 year, every 4 months for 2 years, every 6 months
      for 2 years, and then annually thereafter.

      DEFINITIONS:

        -  Arms I-IV are defined below:

             -  Arm I: Patients receive lower dose MTX IV over 24 hours and MTX IT.

             -  Arm II: Patients receive lower dose MTX IV over 24 hours and MTX IT. Patients with
                HR disease also receive VBL IV weekly for 1 year beginning 3 weeks after initiation
                of course BV3.

             -  Arm III: Patients receive higher dose MTX IV over 3 hours without intrathecal
                therapy.

             -  Arm IV: Patients receive treatment as in arm III. Patients with HR disease also
                receive VBL IV weekly for 1 year beginning 3 weeks after initiation of course BMV3.

        -  Regimens A, B, AV, BV, AM, BM, AMV, and BMV are defined below:

             -  Regimen A (courses A1, A2, and A3): Patients receive DM IV or orally every 12 hours
                on days 1-5; MTX IV over 24 hours on day 1; MTX IT, DOX IV and HC IT (beginning 2-4
                hours after initiation of MTX infusion) on day 1; leucovorin calcium (CF) IV rescue
                at 42, 48, and 54 hours after initiation of MTX infusion; ifosfamide (IFF) IV over
                1 hour on days 1-5 (before initiation of MTX infusion); cytarabine (ARA-C) IV over
                1 hour every 12 hours and etoposide (VP-16) IV over 2 hours once (beginning after
                completion of ARA-C infusion) on days 4 and 5. Each course lasts 3 weeks.

             -  Regimen B (courses B1, B2, and B3): Patients receive DM, MTX, intrathecal therapy,
                and CF rescue as in regimen A. Patients also receive CTX IV over 1 hour on days 1-5
                and DOX IV over 1 hour on days 4 and 5. Each course lasts 3 weeks.

             -  Regimen AV (courses AV1, AV2, and AV3): Patients receive treatment as in regimen A
                and VBL IV on day 1. Each course lasts 3 weeks.

             -  Regimen BV (courses BV1, BV2, and BV3): Patients receive treatment as in regimen B
                and VBL IV as in regimen AV. Each course lasts 3 weeks.

             -  Regimen AM (courses AM1, AM2, and AM3): Patients receive DM IV or orally every 12
                hours on days 1-5; MTX IV over 3 hours on day 1; and CF IV rescue every 6 hours for
                a total of 12 doses beginning 24 hours after initiation of MTX infusion. Patients
                also receive IFF, ARA-C, and VP-16 as in regimen A. Each course lasts 3 weeks.

             -  Regimen BM (courses BM1, BM2, and BM3): Patients receive CTX and DOX as in regimen
                B. Patients also receive DM, MTX, and CF rescue as in regimen AM. Each course lasts
                3 weeks.

             -  Regimen AMV (courses AMV1, AMV2, and AMV3): Patients receive treatment as in
                regimen AM and VBL as in regimen AV. Each course lasts 3 weeks.

             -  Regimen BMV (courses BMV1, BMV2, and BMV3): Patients receive treatment as in
                regimen BM and VBL as in regimen AV. Each course lasts 3 weeks.

      PROJECTED ACCRUAL: A total of 400 patients will be accrued for this study within 5.4-6.7
      years.
    

Intervention name(s): cyclophosphamide; cytarabine; dexamethasone; doxorubicin hydrochloride; etoposide; ifosfamide; leucovorin calcium; methotrexate; therapeutic hydrocortisone; vinblastine sulfate
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention MeSH terms: Leucovorin; Cytarabine; Dexamethasone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Ifosfamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vinblastine; Levoleucovorin
Allocation: Randomized
Intervention model: Single Group Assignment
Primary purpose: Treatment
Keywords: stage I childhood anaplastic large cell lymphoma; stage II childhood anaplastic large cell lymphoma; stage III childhood anaplastic large cell lymphoma; stage IV childhood anaplastic large cell lymphoma; recurrent childhood anaplastic large cell lymphoma