Combination Chemotherapy in Treating Children With Newly Diagnosed 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. Combining more than one drug and giving them in different ways
      may kill more cancer cells. It is not yet known which regimen of combination chemotherapy is
      more effective for acute lymphoblastic leukemia

      PURPOSE: Randomized phase III trial to compare different regimens of combination chemotherapy
      in treating children who have newly diagnosed acute lymphoblastic leukemia.
    

Detailed description: 
      OBJECTIVES: I. Identify response related factors predictive of relapse among children with
      previously untreated standard risk acute lymphoblastic leukemia (ALL). II. Determine the
      prognostic significance of residual leukemic blasts at specific times during induction
      therapy: M3 marrow status (greater than 25% blasts) at day 7; M2 status (5%-25% blasts) at
      day 14; and residual circulating leukemic blasts at days 7 and 14. III. Determine the
      prognostic significance of residual leukemic burden, as measured by fluorescence activated
      cell sorting/leukemic progenitor cell assay, on marrow aspirates acquired at the end of
      induction therapy, at the beginning of maintenance therapy, and at the completion of all
      therapy in patients with B precursor ALL. IV. Determine the prognostic significance of
      residual t(1;19) detected in marrow aspirates by PCR-based analyses of the fusion transcript
      E2A-PBX1 at the end of induction therapy, at the beginning of maintenance therapy, and at the
      completion of all therapy. V. Examine the interrelationships among these response-related
      prognostic factors and their correlation with ploidy, karyotype, and immunophenotype. VI.
      Determine, in a randomized study, whether substitution of oral thioguanine (TG) for oral
      mercaptopurine (MP) during consolidation, interim maintenance, and maintenance therapy
      improves event-free survival for patients with standard-risk ALL. VII. Study and compare the
      cellular pharmacokinetics of oral MP and oral TG during interim maintenance and maintenance
      therapy in selected patients. VIII. Compare the concentrations of MP and TG red blood cell
      metabolites (i.e., nucleotides, nucleosides, free bases, and methylated metabolites) during
      interim maintenance and maintenance therapy, and determine whether low levels of metabolites
      predict relapse in selected patients. IX. Determine the activities of thiopurine
      methyltransferase and hypoxanthine guanine phosphoribosyl transferase several times during
      interim maintenance and maintenance treatment, and compare the activities between the two
      thiopurine treatment groups in selected patients. X. Compare the incidence of central nervous
      system (CNS) relapse and event-free survival in patients receiving intrathecal methotrexate
      (MTX) vs. triple intrathecal chemotherapy (MTX/cytarabine/hydrocortisone) for presymptomatic
      CNS treatment. XI. Determine whether cerebrospinal fluid (CSF) terminal deoxynucleotidyl
      transferase (TdT) positivity predicts for CNS or marrow relapse by measuring TdT activity on
      CSF cytospins in cases with low white blood cell count (less than 5 cells per cubic
      millimeter) and suspected or questionable "blasts" during maintenance therapy. XII. Determine
      event-free survival in patients with standard-risk ALL and M3 marrow at day 14 when treated
      with intensive therapy designed for higher-risk ALL.

      OUTLINE: This is a randomized study. Patients are stratified according to participating
      institution. The following acronyms are used: ARA-C Cytarabine, NSC-63878 ASP Asparaginase
      (E. coli), NSC-109229 CTX Cyclophosphamide, NSC-26271 DM Dexamethasone, NSC-34521 DNR
      Daunorubicin, NSC-82151 DOX Doxorubicin, NSC-123127 HC Hydrocortisone, NSC-10483 MP
      Mercaptopurine, NSC-755 MTX Methotrexate, NSC-740 PEG-ASP Pegaspargase, NSC-624239 PRED
      Prednisone, NSC-10023 TG Thioguanine, NSC-752 TIT Triple Intrathecal Therapy (IT MTX/IT
      ARA-C/IT HC) VCR Vincristine, NSC-67574 Induction: All patients receive oral PRED on days
      0-27, VCR IV on days 0, 7, 14, and 21, and ASP IM 3 times a week for 3 weeks beginning on day
      2-4. ARA-C IT is administered on day 0, and MTX IT is administered on days 7 and 28 (days 7,
      14, 21, and 28 if CNS disease at diagnosis). Following Induction, patients who achieve
      remission are randomly assigned to 1 of 4 treatment arms. Arm I: Consolidation (begins day 28
      of Induction): PRED is tapered from Induction over 10 days. Patients receive VCR IV on day 0,
      oral MP on days 1-27, and MTX IT on days 7, 14, and 21 (only day 7 if CNS disease at
      diagnosis). Interim Maintenance 1 (begins day 28 of Consolidation): Patients receive oral
      PRED on days 0-4 and 28-32, VCR IV days 0 and 28, oral MTX on days 0, 7, 14, 21, 28, 35, 42,
      and 49, and oral MP on days 0-49. Delayed Intensification 1 (begins day 56 of Interim
      Maintenance 1): Patients receive oral DM on days 0-6 and 14-20, VCR IV on days 0, 7, and 14,
      DOX IV over 15-120 min on days 0, 7, and 14, ASP IM twice a week for 2 weeks beginning day
      2-4, CTX IV over 20-30 min on day 28, oral TG on days 28-41, ARA-C IV or SC on days 29-32 and
      36-39, and MTX IT on days 0, 28, and 35. Interim Maintenance 2 (begins day 56 of Delayed
      Intensification 1): Patients receive PRED/VCR/MTX/MP as in Interim Maintenance 1. Delayed
      Intensification 2 (begins day 56 of Interim Maintenance 2): Patients receive DM/VCR/DOX/ASP,
      CTX/TG/ARA-C, and MTX IT as in Delayed Intensification 1. Maintenance (begins day 56 of
      Delayed Intensification 2): Patients receive oral PRED 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 (omitted during wk of IT therapy), and MTX IT on day 0. Treatment continues
      every 84 days for 2 years (girls) or 3 years (boys) from the beginning of Interim Maintenance
      1. Arm II: Patients receive treatment as in arm I, except TIT is TIT substituted for MTX IT.
      Arm III: Patients receive treatment as in arm I with oral TG substituted for oral MTX in
      Consolidation, Interim Maintenance 1 and 2, and Maintenance. If secondary veno-occlusive
      disease occurs, MP is substituted for TG during Maintenance. Arm IV: Patients receive
      treatment as in arm III with TIT substituted for MTX IT. If secondary veno-occlusive disease
      occurs, MP is substituted for TG during Maintenance. Patients with M3 marrow after 2 weeks or
      M2 marrow after 4 weeks of Induction, or with Philadelphia chromosome (t[9;22][q34;q11]),
      t(4;11)(q21;q23), or hypodiploidy, proceed to the following more intensive treatment regimen
      for further therapy: Induction (begins day 14 to day 19 of initial Induction): Patients
      receive oral PRED on days 14-27, VCR IV on days 14 and 21 (day 14 dose omitted if day 14 dose
      from original Induction already given), DNR IV continuously on days 14-16 (48 hours total),
      ASP IM three times a week for 9 total doses (including those received on original Induction),
      MTX IT on days 28 and 35 (days 21, 28, and 35 if CNS disease at diagnosis). Patients with
      M1/M2 bone marrow after day 35 proceed to Consolidation. Consolidation (begins day 28 or 35
      of Induction in this regimen, depending on timing of entry on this regimen): PRED is tapered
      from Induction over 10 days. Patients receive CTX IV 20-30 minutes on days 0 and 28, oral MP
      on days 0-13 and 28-41, ARA-C IV or SC on days 1-4, 8-11, 29-32, and 36-39, VCR IV on days
      14, 21, 42, and 49, PEG-ASP IM on days 14 and 42, and MTX IT on days 7, 14, and 21 (only day
      7 if CNS disease at diagnosis). Patients with M1 or M2 marrow and no extramedullary leukemia
      after day 63 proceed to Interim Maintenance 1. Interim Maintenance 1 (begins day 63 of
      Consolidation): Patients receive VCR IV on days 0, 10, 20, 30, and 40, MTX IV on days 0, 10,
      20, 30, and 40, and PEG-ASP IM on days 1 and 21. Patients with M1 bone marrow after day 56
      proceed to Delayed Intensification I. Delayed Intensification 1 (begins day 56 of Interim
      Maintenance 1): Patients receive oral DM on days 0-6 and 14-20, VCR IV on days 0, 7, 14, 42,
      and 49, DOX IV over 15-120 minutes 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 on days 29-32 and 36-39,
      and MTX IT on days 28 and 35. Interim Maintenance 2 (begins day 56 of Delayed Intensification
      1): Patients receive VCR/MTX/PEG-ASP as in Interim Maintenance 1, and MTX IT on days 0, 20,
      and 40. Delayed Intensification 2 (begins day 56 of Interim Maintenance 2): Patients receive
      DM/VCR/DOX/PEG-ASP, CTX/TG/ARA-C, and MTX IT as in Delayed Intensification 1. Maintenance
      (begins day 56 of Delayed Intensification 2): Patients receive PRED/VCR/MP/MTX, and MTX IT as
      in arm I Maintenance. Patients with CNS or testicular involvement at diagnosis receive
      appropriate radiotherapy concurrent with Consolidation. Radiotherapy begins within 4 days of
      initiation of Consolidation. Craniospinal irradiation is given 5 days a week. Testicular
      irradiation is given to both testes 5 days a week over 2-3 weeks. Patients are followed every
      6-8 weeks during year 1, every 3 months during year 2, every 6 months during year 3, and then
      annually thereafter.

      PROJECTED ACCRUAL: A total of 1970 patients will be accrued for this study within 3.5 years.
    

Intervention name(s): asparaginase; cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; doxorubicin hydrochloride; mercaptopurine; methotrexate; pegaspargase; prednisone; therapeutic hydrocortisone; thioguanine; vincristine sulfate; low-LET cobalt-60 gamma ray therapy; low-LET photon therapy
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Radiation; Radiation
Other intervention name(s): L-Asparaginase - Erwinia; NSC-106977; Cytoxan; NSC-26271.; Cytosine Arabinoside; Ara-C; Cytosar-U; NSC-82151; Decadron; NSC-34521; Adriamycin; NSC-123127; 6-MP; Purinethol; NSC-740; PEG Asparaginase; Oncaspar®; NSC-10023; 6-TG; NSC-752; Oncovin; NSC-67574
Intervention MeSH terms: Cobalt; Cytarabine; Dexamethasone; Prednisone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Pegaspargase; Thioguanine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single
Primary purpose: Treatment
Keywords: untreated childhood acute lymphoblastic leukemia; L1 childhood acute lymphoblastic leukemia; L2 childhood acute lymphoblastic leukemia