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 the drugs in different combinations may kill more cancer cells. PURPOSE: Randomized phase III trial to compare the effectiveness of standard combination chemotherapy treatment with more intensive combination chemotherapy in treating children with acute lymphocytic leukemia.

Condition	Treatment or Intervention	Phase
L2 childhood acute lymphoblastic leukemia untreated childhood acute lymphoblastic leukemia L1 childhood acute lymphoblastic leukemia	Procedure: chemotherapy  Procedure: radiation therapy  Drug: asparaginase  Drug: cyclophosphamide  Drug: cytarabine  Drug: daunorubicin  Drug: dexamethasone  Drug: doxorubicin  Drug: idarubicin  Drug: mercaptopurine  Drug: methotrexate  Drug: pegaspargase  Drug: prednisone  Drug: thioguanine  Drug: vincristine	Phase III

Further Study Details: 

OBJECTIVES: I. Compare the outcomes in children with higher risk acute lymphocytic leukemia (ALL) treated with postinduction chemotherapy based on marrow response on day 7 of induction therapy: for patients with rapid early response (M1/M2), standard vs intensified consolidation chemotherapy and standard vs prolonged duration of intensification chemotherapy; for patients with slow early response, addition of doxorubicin vs idarubicin and cyclophosphamide to intensification chemotherapy. II. Decrease the incidence of avascular necrosis by alternating dexamethasone dosing in patients undergoing 2 courses of delayed intensification. III. Assess the impact of day 7 marrow status on outcome in these patients. IV. Determine prognosis more precisely by supplementing presenting clinical features, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios, pattern of tyrosine kinase activation, leukemic burden following induction and intensification therapy, and development of high antibody titer to E. coli asparaginase. V. Correlate the traditional prognostic factors of day 7 marrow response, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios.

PROTOCOL OUTLINE: This is a partially randomized, multicenter study. Patients are stratified by center. Patients receive one course of the VPLD regimen comprised of vincristine IV and daunorubicin IV over 15 minutes to 2 hours on days 0 and 7, oral prednisone daily on days 0-7, intrathecal cytarabine on day 0, and asparaginase or pegaspargase intramuscularly on days 3, 5, and 7. Patients are assigned to 1 of 2 two postinduction chemotherapy groups based on bone marrow response on day 7 of induction. Patients with M1/M2 marrow on day 7 are considered rapid early responders. Patients with M3 marrow on day 7 are considered slow early responders. Group 1: Rapid early responders Patients receive 2 additional courses of VPLD induction chemotherapy. Patients are then randomized to 1 of 4 treatment arms: Arm I: Beginning on day 35 of induction therapy, patients receive standard Berlin-Frankfurt-Munster (BFM) regimen with standard delayed intensification. Standard BFM for patients in arm I consists of the following: consolidation over 5 weeks with cyclophosphamide, cytarabine, and mercaptopurine; interim maintenance over 8 weeks with oral methotrexate and mercaptopurine (MTX/MP); and delayed intensification over 7 weeks consisting of reinduction with vincristine, doxorubicin, oral dexamethasone, and asparaginase or pegaspargase followed by reconsolidation with cyclophosphamide, thioguanine, and cytarabine. Arm II: Patients receive standard BFM regimen with double delayed intensification. Patients receive therapy similar to those in arm I, but dexamethasone is interrupted for 1 week during delayed intensification and the intensification regimen is repeated, separated by an 8 week interim maintenance course of oral MTX/MP. Arm III: Patients receive augmented BFM regimen with standard delayed intensification. Patients receive 9 weeks of consolidation therapy with 2 courses of vincristine and pegaspargase alternating with the arm I consolidation therapy. Vincristine, intravenous methotrexate, and pegaspargase (the Capizzi I regimen) are substituted for oral MTX/MP in the interim maintenance regimen. Pegaspargase is substituted for asparaginase and two additional doses of vincristine are administered during delayed intensification. Arm IV: Patients receive augmented BFM regimen with double delayed intensification. Patients receive intensified chemotherapy throughout, combining the additional therapy given to patients in arms II and III. Patients receiving augmented BFM regimen receive pegaspargase instead of asparaginase. Patients with CNS disease at diagnosis are treated only on arm IV. Patients who are Philadelphia chromosome positive and do not have a bone marrow donor are nonrandomly assigned to the treatment group for slow early responders. All RER patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal methotrexate is administered periodically throughout protocol treatment. Group 2: Slow early responders Patients receive augmented BFM consolidation therapy and Capizzi I interim maintenance identical to that received by rapid early responders in arm IV. Patients are then randomized to receive double delayed intensification with either idarubicin or doxorubicin and concurrent cyclophosphamide. All patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal MTX is administered periodically throughout protocol treatment. Patients with CNS disease at entry receive craniospinal irradiation daily for 5 consecutive days beginning on day 0 of consolidation therapy. All slow early responders at diagnosis receive cranial irradiation daily for 5 consecutive days during consolidation therapy. Patients with testicular leukemia at diagnosis receive bilateral testicular irradiation daily for 5 consecutive days during consolidation chemotherapy. Groups 1 and 2: Maintenance therapy continues for 2 years for girls or 3 years for boys beyond completion of consolidation therapy. Patients are followed every 4-6 weeks for 1 year, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 1,520 patients will be accrued for this study over 4 years.

Ages Eligible for Study:  1 Year   -   21 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Acute lymphocytic leukemia (ALL) with M3 bone marrow; No FAB L3 morphology; CNS or overt testicular leukemia at diagnosis allowed
• High risk status; 10-21 years old with any white blood count (WBC); 1-9 years old with WBC of 50,000/mm3 or greater

--Prior/Concurrent Therapy--

• No prior therapy for ALL except: Emergency therapy for blast crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration
• Biologic therapy: Not specified
• Chemotherapy: Intrathecal cytarabine or methotrexate allowed at diagnostic lumbar puncture; Induction therapy must begin within 72 hours after intrathecal injection
• Endocrine therapy: At least 1-2 months since prior prednisone, for less than 48 hours, for reactive airway disease; Inhalational steroids allowed
• Radiotherapy: Not specified
• Surgery: Not specified

--Patient Characteristics--

• Age: 1 to 21
• Performance status: Not specified
• Life expectancy: 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,  92868,  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,  94143-0128,  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,  60637-1470,  United States
Indiana
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5289,  United States
Iowa
      Holden Comprehensive Cancer Center at The University of Iowa, Iowa City,  Iowa,  52242-1009,  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,  Missouri,  64108,  United States
Nebraska
      University of Nebraska Medical Center, Omaha,  Nebraska,  68198-3330,  United States
New Jersey
      Saint Peter's University Hospital, New Brunswick,  New Jersey,  08901-1780,  United States
New York
      Herbert Irving Comprehensive Cancer Center, New York,  New York,  10032,  United States
      Memorial Sloan-Kettering Cancer Center, New York,  New York,  10021,  United States
      Mount Sinai School of Medicine, New York,  New York,  10029,  United States
      NYU School of Medicine's Kaplan Comprehensive Cancer Center, New York,  New York,  10016,  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-Ingram Cancer Center, Nashville,  Tennessee,  37232-6838,  United States
Texas
      University of Texas - MD Anderson Cancer Center, Houston,  Texas,  77030-4009,  United States
Washington
      Children's Hospital and Regional Medical Center - Seattle, Seattle,  Washington,  98105,  United States
      Fred Hutchinson Cancer Research Center, Seattle,  Washington,  98109-1024,  United States
Wisconsin
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792-6164,  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 Health Centre, Halifax,  Nova Scotia,  B3J 3G9,  Canada

Study chairs or principal investigators

Nita Louise Seibel,  Study Chair,  Children's Cancer Group   

Study ID Numbers:  CDR0000064953; CCG-1961
Record last reviewed:  November 2003
Last Updated:  October 13, 2004
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002812
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08