Comparison of Different Combination Chemotherapy Regimens in Treating Children With Acute Lymphoblastic Leukemia
Condition: Leukemia
MeSH terms: 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 cancer cells from dividing
      so they stop growing or die. Giving more than one drug may kill more cancer cells. It is not
      yet known which combination chemotherapy regimen is more effective in treating childhood
      acute lymphoblastic leukemia.

      PURPOSE: This randomized phase III trial is comparing different combination chemotherapy
      regimens to see how well they work in treating children with acute lymphoblastic leukemia.
    

Detailed description: 
      OBJECTIVES:

        -  Compare the event-free survival and overall survival of children with standard-risk
           acute lymphoblastic leukemia treated with escalating-dose IV methotrexate without
           leucovorin calcium versus oral methotrexate during the interim maintenance phase of
           therapy.

        -  Compare the event-free survival and overall survival of these patients after receiving
           treatment in two delayed intensification phases versus one delayed intensification
           phase.

        -  Compare the toxic effects of oral versus escalating-dose intravenous methotrexate in
           these patients.

        -  Determine the prognostic significance of the rate of disappearance of peripheral
           lymphoblasts and lymphocytes during the first week of treatment in these patients.

        -  Determine the prognostic significance of trisomies of chromosomes 4, 5, 10, and 17 and
           early treatment response in patients treated with these regimens.

        -  Determine the prognostic significance of the TEL-AML1 fusion transcript and early
           treatment response in patients treated with these regimens.

        -  Determine the minimal residual disease (MRD) by polymerase chain reaction in bone marrow
           and cerebrospinal fluid at various stages of therapy in these patients.

        -  Determine the prognostic significance of MRD during various stages of therapy in these
           patients.

        -  Determine whether a second delayed intensification therapy improves the prognosis of
           patients who have MRD at the end of induction therapy.

      OUTLINE: This is a randomized, multicenter study. Patients without CNS disease at diagnosis,
      achieving a specified early marrow response profile and M1 marrow status of less than 5%
      blasts in the bone marrow (regardless of the proportion of mature lymphocytes) by day 28 of
      induction therapy, and remaining event free with favorable bone marrow status and
      cytogenetics between day 21 and 28 of consolidation therapy are randomized to one of four
      treatment arms. Patients with CNS disease at diagnosis are assigned to treatment arm II and
      undergo cranial irradiation. Patients with any of the following unfavorable bone marrow
      features and/or unfavorable cytogenetic features are assigned to the augmented treatment
      regimen by day 21 of induction chemotherapy or at the beginning of consolidation
      chemotherapy:

      NOTE: All T-cell precursor patients that are not more than 4 months past completion of the
      delayed intensification phase of therapy should be switched to the augmented regimen as of
      3/8/2004. These patients may be switched to the augmented regimen. The protocol gives
      specific instructions according to the phase of therapy the patients are actually in.

        -  Unfavorable marrow status:

             -  M2: 5-25% blasts in bone marrow at day 28 of induction chemotherapy (or at day 14
                of induction chemotherapy if day 7 status is M3) OR

             -  M3: More than 25% blast cell in bone marrow, regardless of the proportion of mature
                lymphocytes at day 14 of induction chemotherapy

        -  Unfavorable cytogenetics: Must have 1 of the following:

             -  t(9;22)(q34;q11)

             -  t(4;11)(q21;q23)

             -  Balanced t(1;19)(q23;p13)

             -  Hypodiploidy with less than 45 chromosomes

             -  Other 11q23 translocations involving MLL Patients receive standard induction
                chemotherapy comprising cytarabine (ARA-C) intrathecally (IT) on day 0 or up to 72
                hours before day 0; oral dexamethasone (DM) twice daily on days 0-27; vincristine
                (VCR) IV on days 0, 7, 14, and 21; and pegaspargase (PEG-ASP) intramuscularly (IM)
                once between days 3-5. Patients without CNS disease at diagnosis receive
                methotrexate (MTX) IT on days 7 and 28. Patients with CNS disease at diagnosis
                receive MTX IT on days 7, 14, 21, and 28.

      Patients who have achieved M1 marrow status by day 28 of induction therapy and have favorable
      early bone marrow response and cytogenetics proceed to standard consolidation therapy once
      blood counts have recovered. Patients with M3 bone marrow status at day 28 of induction
      therapy are taken off the protocol. All other patients are assigned to the augmented
      treatment regimen.

      Beginning on day 28 of induction chemotherapy, patients receive standard consolidation
      chemotherapy comprising VCR IV on day 0 and oral mercaptopurine (MP) on days 0-27. Patients
      without CNS disease at diagnosis receive MTX IT on days 7, 14, 21, and 28. Patients with CNS
      disease at diagnosis receive MTX IT on day 7 and cranial irradiation 5 days a week for 2
      weeks. Patients with testicular disease receive bilateral testicular radiotherapy 5 days a
      week for 1 week and then for 3 consecutive days during the next week.

      NOTE: As of 3/8/2004, patients with T-cell disease who did not achieve M1 marrow status by
      day 14 of induction OR who did not receive augmented induction and/or consolidation
      (regardless of early marrow status) receive cranial irradiation.

        -  Arm I: Beginning on day 28 of consolidation chemotherapy, patients receive interim
           maintenance I chemotherapy comprising oral DM twice daily on days 0-4 and 28-32; VCR IV
           on days 0 and 28; oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49; oral MP on days
           0-49; and MTX IT on day 28.

      Beginning on day 56 of interim maintenance I chemotherapy, patients receive delayed
      intensification chemotherapy comprising oral DM twice daily on days 0-6 and 14-20; VCR IV and
      doxorubicin (DOX) IV over 15 minutes to 2 hours on days 0, 7, and 14; PEG-ASP IM on day 3;
      cyclophosphamide (CTX) IV over 20-30 minutes on day 28; oral thioguanine (TG) on days 28-41;
      ARA-C IV or subcutaneously (SC) daily on days 28-31 and 35-38; and MTX IT on days 0 and 28.

      Beginning on day 56 of delayed intensification chemotherapy, patients receive interim
      maintenance II chemotherapy identical to interim maintenance I chemotherapy except patients
      receive MTX IT on days 0 and 28.

      Beginning on day 56 of interim maintenance II chemotherapy, patients receive maintenance
      chemotherapy comprising oral DM twice daily on days 0-4, 28-32, and 56-60; VCR IV on days 0,
      28, and 56; oral MP on days 0-83; oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and
      77; and MTX IT on day 0.

        -  Arm II: Patients receive interim maintenance I chemotherapy, delayed intensification
           chemotherapy, and interim maintenance II chemotherapy as in arm I. Beginning on day 56
           of interim maintenance II chemotherapy, patients then receive a second course of delayed
           intensification chemotherapy followed by maintenance chemotherapy as in arm I.

        -  Arm III: Beginning on day 28 of consolidation chemotherapy, patients receive interim
           maintenance I chemotherapy comprising VCR IV; escalating doses of MTX IV on days 0, 10,
           20, 30, and 40; and MTX IT on day 30. Patients then receive delayed intensification
           chemotherapy as in arm I. Patients receive interim maintenance II chemotherapy as in
           interim maintenance I chemotherapy, but with IV MTX starting at 2/3 of the maximum
           tolerated dose (MTD) attained in interim maintenance I chemotherapy. Patients then
           receive maintenance chemotherapy as in arm I.

        -  Arm IV: Patients receive interim maintenance I chemotherapy as in arm III, delayed
           intensification chemotherapy as in arm I, interim maintenance II chemotherapy as in arm
           III, delayed intensification II chemotherapy as in arm II, and maintenance chemotherapy
           as in arm I.

        -  Augmented Treatment: Patients receive induction chemotherapy comprising daunorubicin IV
           continuously for 48 hours beginning no later than day 21; oral DM twice daily on days
           14-27; and VCR IV on days 14 and 21. Patients without CNS disease at diagnosis receive
           MTX IT on days 21 and 35. Patients with CNS disease at diagnosis receive MTX IT on days
           21 and 28.

      NOTE: Patients with T-cell disease should re-start with augmented consolidation and proceed
      as per the augmented regimen.

      Beginning on day 35 of induction chemotherapy, patients receive consolidation therapy
      comprising CTX IV over 20-30 minutes on days 0 and 28; oral MP on days 0-13 and 28-41; ARA-C
      IV or SC daily on days 0-3, 7-10, 28-31, and 35-38; VCR IV on days 14, 21, 42, and 49; and
      PEG-ASP IM on days 14 and 42. Patients without CNS disease at diagnosis receive MTX IT on
      days 7, 14, and 21. Patients with CNS disease at diagnosis receive MTX IT on day 7 and
      cranial irradiation as in the randomized treatment section. Patients with testicular leukemia
      receive radiotherapy as in the randomized treatment section.

      Beginning on day 63 of consolidation chemotherapy, patients receive interim maintenance I
      chemotherapy comprising VCR IV on days 0, 10, 20, 30, and 40; escalating doses of MTX IV on
      days 10, 20, 30, and 40; PEG-ASP IM on days 1 and 21; and MTX IT on days 0 and 30.

      Beginning on day 56 of interim maintenance I chemotherapy, patients receive delayed
      intensification I chemotherapy comprising oral DM twice daily on days 0-6 and 14-20; VCR IV
      on days 0, 7, 14, 42, and 49; DOX IV over 15 minutes to 2 hours on days 0, 7, and 14; PEG-ASP
      IM on days 3 and 42; CTX IV over 20-30 minutes on day 28; oral TG on days 28-41; ARA-C IV or
      SC daily on days 28-31 and 35-38; and MTX IT on days 0 and 28.

      NOTE: Patients with T-cell disease who are in interim maintenance I chemotherapy with
      escalating IV methotrexate should continue this phase and then proceed as per the augmented
      regimen. If these patients are receiving conventional interim maintenance chemotherapy with
      oral methotrexate, they should stop and restart the interim maintenance as per the augmented
      regimen. These patients receive cranial irradiation starting on day 28 of delayed
      intensification II chemotherapy.

      Beginning on day 56 of delayed intensification I chemotherapy, patients receive interim
      maintenance II chemotherapy as in interim maintenance I chemotherapy, but with IV MTX
      starting at 2/3 of the MTD attained in interim maintenance I chemotherapy.

      NOTE: Patients with T-cell disease who are in delayed intensification I chemotherapy proceed
      with this phase, with the addition of 2 vincristine doses on days 42 and 49 and PEG-ASP on
      day 42. These patients then proceed as per the augmented regimen with the addition of cranial
      irradiation starting on day 28 of delayed intensification II chemotherapy.

      NOTE: Patients with T-cell disease who are within 4 months of completing delayed
      intensification I chemotherapy and have not received interim maintenance II chemotherapy with
      escalating IV methotrexate or delayed intensification II chemotherapy receive a course of
      interim maintenance chemotherapy and delayed intensification II chemotherapy according to the
      augmented regimen. If these patients have received interim maintenance II chemotherapy with
      escalating IV methotrexate, they receive delayed intensification II chemotherapy according to
      the augmented regimen. These patients also receive cranial irradiation starting on day 28 of
      delayed intensification II chemotherapy and then proceed to maintenance therapy.

      Beginning on day 56 of interim maintenance II chemotherapy, patients receive delayed
      intensification II chemotherapy as in delayed intensification I chemotherapy.

      Beginning on day 56 of delayed intensification II chemotherapy, patients receive maintenance
      chemotherapy comprising oral DM twice daily on days 0-4, 28-32, and 56-60; VCR IV on days 0,
      28, and 56; oral MP on days 0-83; oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and
      77; and MTX IT on day 0.

      Patients are followed every 4-8 weeks for one year, every 3 months for one year, every 6
      months for one year, and then annually thereafter.

      PROJECTED ACCRUAL: A total of 2,037 randomized patients will be accrued for this study within
      3.75 years.
    

Intervention name(s): cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; doxorubicin hydrochloride; mercaptopurine; methotrexate; pegaspargase; thioguanine; vincristine sulfate; radiation therapy
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Radiation
Intervention description(s): Given IV; Given IT; Given IV; Given PO; Dose 25 g/m² IV Days 0, 7, 14, given over a period of 15 minutes to 2 hours; Given PO; Given PO and IT; Given IM; Given PO; Given IV; Undergo radiation therapy
Other intervention name(s): Cytoxan; NSC-26271; Cytosine Arabinoside; Ara_C; Cytosar-U; NSC-63878; Cerubidine; NSC-82151; Decadron; DM; NSC-34521; Adriamycin; NSC-123127; 6-MP; MTX; PEG-asparaginase; Oncaspar; L-asparaginase with polyethylene glycol; 6 TG; NSC-752; Oncovin; NSC-67574; VCR; irradiation; radiotherapy; therapy; radiation
Intervention MeSH terms: Cytarabine; Dexamethasone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Pegaspargase; Thioguanine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: untreated childhood acute lymphoblastic leukemia; L1 childhood acute lymphoblastic leukemia; L2 childhood acute lymphoblastic leukemia; L3 childhood acute lymphoblastic leukemia