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.

Condition	Treatment or Intervention	Phase
L1 childhood acute lymphocytic leukemia L2 childhood acute lymphocytic leukemia untreated childhood acute lymphocytic leukemia	Drug: asparaginase  Drug: cyclophosphamide  Drug: cytarabine  Drug: daunorubicin  Drug: dexamethasone  Drug: doxorubicin  Drug: hydrocortisone  Drug: mercaptopurine  Drug: methotrexate  Drug: pegaspargase  Drug: prednisone  Drug: thioguanine  Drug: vincristine	Phase III

Further Study Details: 

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.

PROTOCOL 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 recevie 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, 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.

Ages Eligible for Study:  1 Year   -   9 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Newly diagnosed acute lymphoblastic leukemia (ALL) obtained by bone marrow aspirate or bone marrow biopsy
• No greater than 25% L3 blasts
• Initial white blood cell count less than 50,000/mm3 (performed at CCG institution)
• Massive lymphadenopathy, massive splenomegaly, and/or large mediastinal mass allowed
• CNS or testicular leukemia allowed
• Allogeneic bone marrow transplant should be considered (if donor available) for patients with Philadelphia chromosome (t[9;22][q34;q11]) or translocation (4;11)(q21;q23)

--Prior/Concurrent Therapy--

• No prior treatment for ALL
• Biologic therapy: Not specified
• Chemotherapy: Intrathecal cytarabine (IT ARA-C) may begin prior to registration provided systemic chemotherapy initiated within 72 hours after IT ARA-C
• Endocrine therapy: See Radiotherapy; At least 1 month since prior systemic steroids; Steroids given for less than 48 hours allowed; Inhaled corticosteroids allowed at any time
• Radiotherapy: Radiotherapy or dexamethasone for mediastinal mass causing superior mediastinal syndrome allowed prior to registration, if indicated
• Surgery: Not specified

--Patient Characteristics--

• Age: 1 through 9
• Performance status: Not specified
• Hematopoietic: See Disease Characteristics
• Hepatic: Not specified
• Renal: Not specified

California
      Children's Hospital Los Angeles, Los Angeles,  California,  90027-0700,  United States
      Children's Hospital of Orange County, Orange,  California,  92668,  United States
      Jonsson Comprehensive Cancer Center, UCLA, Los Angeles,  California,  90095-1781,  United States
      Long Beach Memorial Medical Center, Long Beach,  California,  90806,  United States
      UCSF Cancer Center and Cancer Research Institute, San Francisco,  California,  94115-0128,  United States
Colorado
      Children's Hospital of Denver, Denver,  Colorado,  80218,  United States
District of Columbia
      Children's National Medical Center, Washington,  District of Columbia,  20010-2970,  United States
Illinois
      University of Chicago Cancer Research Center, Chicago,  Illinois,  60637,  United States
Indiana
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5265,  United States
Iowa
      University of Iowa Hospitals and Clinics, Iowa City,  Iowa,  52242,  United States
Michigan
      University of Michigan Comprehensive Cancer Center, Ann Arbor,  Michigan,  48109-0752,  United States
Minnesota
      Mayo Clinic Cancer Center, Rochester,  Minnesota,  55905,  United States
      University of Minnesota Cancer Center, Minneapolis,  Minnesota,  55455,  United States
Missouri
      Children's Mercy Hospital - Kansas City, Kansas City,  Missouri,  64108,  United States
Nebraska
      University of Nebraska Medical Center, Omaha,  Nebraska,  68198-3330,  United States
New York
      Herbert Irving Comprehensive Cancer Center, New York,  New York,  10032,  United States
      Kaplan Cancer Center, New York,  New York,  10016,  United States
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States
North Carolina
      Lineberger Comprehensive Cancer Center, UNC, Chapel Hill,  North Carolina,  27599-7295,  United States
Ohio
      Children's Hospital Medical Center - Cincinnati, Cincinnati,  Ohio,  45229-3039,  United States
      Children's Hospital of Columbus, Columbus,  Ohio,  43205-2696,  United States
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5065,  United States
Oregon
      Doernbecher Children's Hospital, Portland,  Oregon,  97201-3098,  United States
Pennsylvania
      Children's Hospital of Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States
      Children's Hospital of Pittsburgh, Pittsburgh,  Pennsylvania,  15213,  United States
Tennessee
      Vanderbilt Cancer Center, Nashville,  Tennessee,  37232-6838,  United States
Texas
      University of Texas - MD Anderson Cancer Center, Houston,  Texas,  77030,  United States
Utah
      Huntsman Cancer Institute, Salt Lake City,  Utah,  84132,  United States
Washington
      Children's Hospital and Medical Center - Seattle, Seattle,  Washington,  98105,  United States
      Fred Hutchinson Cancer Research Center, Seattle,  Washington,  98109,  United States
Wisconsin
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792,  United States
Australia, Western Australia
      Princess Margaret Hospital for Children, Perth,  Western Australia,  6001,  Australia
Canada, British Columbia
      British Columbia Children's Hospital, Vancouver,  British Columbia,  V6H 3V4,  Canada
Canada, Nova Scotia
      IWK Grace Health Centre, Halifax,  Nova Scotia,  B3J 3G9,  Canada

Study chairs or principal investigators

Linda C. Stork,  Study Chair,  Children's Cancer Group   

Study ID Numbers:  CDR0000064665; CCG-1952
Record last reviewed:  August 2004
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002744
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08