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 may kill more cancer cells. It is
not yet known which regimen of chemotherapy is more effective for acute lymphoblastic
leukemia.
PURPOSE: This randomized phase III trial is comparing four regimens of combination
chemotherapy to see how well they work in treating children with newly diagnosed acute
lymphoblastic leukemia.
- Determine if multidrug delayed-intensification therapy improves outcome in children
- Compare the efficacy and toxicity of methotrexate administered over 4 hours vs
methotrexate administered over 24 hours in this patient population.
- Determine the correlation between event-free survival, minimal residual disease, and
early response in this patient population treated with this multiple drug regimen.
OUTLINE: This is a randomized, multicenter study.
- Consolidation (weeks 5-32): Patients are randomized to one of four treatment arms.
- Arm I (weeks 5-24): Patients receive IT methotrexate (MTX) on day 1 followed by
MTX IV over 20 minutes followed by MTX continuously over 23. 6 hours on weeks 7,
10, 13, 16,19, and 22. At 42 hours after the beginning of the MTX infusion,
patients receive oral leucovorin calcium every 6 hours for a total of 3 doses.
Patients also receive oral mercaptopurine daily beginning on week 5 and continuing
until the completion of consolidation therapy; oral dexamethasone twice daily on
days 1-7 of weeks 8 and 17; and vincristine IV on day 1 of weeks 8, 9, 17, and 18.
- Arm II (weeks 5-24): Patients receive MTX IV over 4 hours on weeks 7, 10, 13, 16,
19, and 22. At 42 hours after the beginning of the MTX infusion, patients receive
oral leucovorin calcium as in arm I. Patients also receive mercaptopurine,
dexamethasone, vincristine, and IT MTX as in arm I.
- Arm III (weeks 5-32): Patients receive MTX IV as in arm I on weeks 7, 10, 13, 24,
27, and 30; leucovorin calcium as in arm I; pegaspargase IM on day 2, 3, OR 4 of
week 16; and oral mercaptopurine daily on weeks 5-13, and from week 24 until the
completion of consolidation therapy. Patients also receive IT MTX as in arm I on
weeks 7, 10, 13, 16, 20, 21, and 30; oral dexamethasone twice daily on weeks 8,
16-18, and 28 for a total of 35 days; vincristine IV on day 1 of weeks 8, 9, 16,
17, 18, 28, and 29; daunorubicin IV on day 1 of weeks 16-18; cyclophosphamide IV
over 30 minutes on day 1 of week 20; cytarabine IV or subcutaneously daily on days
2-5 of weeks 20 and 21; and oral thioguanine daily on weeks 20-21.
- Arm IV (weeks 5-32): Patients receive MTX IV as in arm II on weeks 7, 10, 13, 24,
27, and 30; leucovorin calcium as in arm I; and pegaspargase, mercaptopurine, IT
MTX, dexamethasone, vincristine, daunorubicin, cyclophosphamide, cytarabine, and
thioguanine as in arm III.
- Intensive continuation (weeks 25-80): At weeks 25-72 for arms I and II, and at weeks
33-80 for arms III and IV, patients receive oral MTX every 6 hours for 4 doses on weeks
1, 3, 5, 7, 9, and 11; oral mercaptopurine daily; oral leucovorin calcium every 12
hours for 2 doses beginning 48 hours after the start of MTX; IT MTX and vincristine IV
on day 1 of week 12; and oral dexamethasone twice daily on days 1-7, beginning with the
administration of vincristine. Treatment repeats every 12 weeks for 4 courses.
- Additional continuation (weeks 73-130): At weeks 73-130 for arms I and II, and at weeks
81-130 for arms III and IV, patients receive oral MTX weekly; oral mercaptopurine
daily; vincristine IV on day 1 every 12 weeks; oral dexamethasone as during intensive
continuation therapy; and IT MTX on day 1 every 12 weeks, beginning with the last week
of the first course (in place of oral MTX).
Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1
year, every 6 months for 1 year, and then every 6-12 months for 1 year.
PROJECTED ACCRUAL: A total of 1,014 patients will be accrued for this study within 3. 22
years.
University Medical Center Groningen, Groningen 9700 RB, Netherlands
San Jorge Children's Hospital, Santurce 00912, Puerto Rico
Swiss Pediatric Oncology Group Bern, Bern CH 3010, Switzerland
Swiss Pediatric Oncology Group Geneva, Geneva CH 1211, Switzerland
Comprehensive Cancer Center at University of Alabama at Birmingham, Birmingham, Alabama 35233, United States
University of South Alabama Cancer Research Institute, Mobile, Alabama 36604, United States
Alberta Children's Hospital, Calgary, Alberta T2T 5C7, Canada
Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada
Arizona Cancer Center at University of Arizona Health Sciences Center, Tucson, Arizona 85724, United States
Arkansas Cancer Research Center at University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States
Rebecca and John Moores UCSD Cancer Center, La Jolla, California 92093-0658, United States
Stanford Cancer Center at Stanford University Medical Center, Palo Alto, California 94304-1812, United States
Sutter Cancer Center, Sacramento, California 95816, United States
University of California Davis Cancer Center, Sacramento, California 95817, United States
Children's Hospital and Health Center, San Diego, San Diego, California 92123-4282, United States
Kaiser Permanente Medical Center/Kaiser Foundation Hospital - San Diego, San Diego, California 92120, United States
Kaiser Permanente Medical Center - Santa Clara, Santa Clara, California 95051-5386, United States
Yale Comprehensive Cancer Center, New Haven, Connecticut 06520-8064, United States
Broward General Medical Center, Fort Lauderdale, Florida 33316, United States
Children's Hospital of Southwest Florida, Fort Myers, Florida 33908, United States
University of Florida Shands Cancer Center, Gainesville, Florida 32610-0296, United States
Joe DiMaggio Children's Hospital at Memorial, Hollywood, Florida 33021, United States
Nemours Children's Clinic, Jacksonville, Florida 32207, United States
Baptist-South Miami Regional Cancer Program, Miami, Florida 33176-2197, United States
Miami Children's Hospital, Miami, Florida 33155, United States
University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida 30101, United States
Florida Hospital Cancer Institute, Orlando, Florida 32804, United States
Nemours Children's Clinic-Orlando, Orlando, Florida 32806, United States
Sacred Heart Children's Hospital, Pensacola, Florida 32504, United States
All Children's Hospital, St. Petersburg, Florida 33701, United States
St. Joseph's Children's Hospital, Tampa, Florida 33677-4227, United States
Kaplan Cancer Center at St. Mary's Medical Center, West Palm Beach, Florida 33407, United States
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus, Atlanta, Georgia 30342, United States
MBCCOP-Medical College of Georgia Cancer Center, Augusta, Georgia 30912-4000, United States
Cancer Research Center of Hawaii, Honolulu, Hawaii 96813, United States
Tripler Army Medical Center, Honolulu, Hawaii 96859-5000, United States
Children's Memorial Hospital - Chicago, Chicago, Illinois 60614, United States
Rush University Medical Center, Chicago, Illinois 60612, United States
Advocate Hope Children's Hospital, Oak Lawn, Illinois 60453, United States
Saint Jude Midwest Affiliate, Peoria, Illinois 61637, United States
Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center, Kansas City, Kansas 66160-7357, United States
CCOP - Wichita, Wichita, Kansas 67214-3882, United States
Via Christi Cancer Center at Via Christi Regional Medical Center, Wichita, Kansas 67214, United States
Wesley Medical Center, Wichita, Kansas 67214, United States
Children's Hospital of New Orleans, New Orleans, Louisiana 70118, United States
MBCCOP - LSU Health Sciences Center, New Orleans, Louisiana 70112, United States
Ochsner Cancer Institute at Ochsner Clinic Foundation, New Orleans, Louisiana 70121, United States
Tulane Cancer Center at Tulane University Hospital and Clinic, New Orleans, Louisiana 70112, United States
Pediatric Specialty Clinic at Eastern Maine Medical Center, Bangor, Maine 04401, United States
Maine Children's Cancer Program, Scarborough, Maine 04074-9308, United States
Greenebaum Cancer Center at University of Maryland Medical Center, Baltimore, Maryland 21201-1595, United States
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States
Walter Reed Army Medical Center, Silver Spring, Maryland 20910, United States
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute, Boston, Massachusetts 02115, United States
Floating Hospital for Children, Boston, Massachusetts 02111, United States
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114-2696, United States
UMASS Memorial Cancer Center - University Campus, Worcester, Massachusetts 01655, United States
Children's Hospital of Michigan, Detroit, Michigan 48201, United States
Van Elslander Cancer Center at St. John Hospital and Medical Center, Detroit, Michigan 48236, United States
Hurley Medical Center, Flint, Michigan 48503, United States
University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, United States
Keesler Medical Center - Keesler Air Force Base, Keesler AFB, Mississippi 39534-2511, United States
University of Missouri - Columbia, Columbia, Missouri 65203, United States
Cardinal Glennon Children's Hospital, Saint Louis, Missouri 63104, United States
St. Louis Children's Hospital, Saint Louis, Missouri 63110, United States
Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, United States
Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey 07601, United States
University of New Mexico Cancer Research and Treatment Center, Albuquerque, New Mexico 87131, United States
Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia
Roswell Park Cancer Institute, Buffalo, New York 14263-0001, United States
Schneider Children's Hospital, New Hyde Park, New York 11042, United States
Beth Israel Medical Center - Singer Division, New York, New York 10128, United States
Mount Sinai Medical Center, New York, New York 10029, United States
James P. Wilmot Cancer Center at University of Rochester Medical Center, Rochester, New York 14642, United States
Long Island Cancer Center at Stony Brook University Hospital, Stony Brook, New York 11794, United States
SUNY Upstate Medical University Hospital, Syracuse, New York 13210, United States
Mission Hospitals - Memorial Campus, Asheville, North Carolina 28801, United States
Blumenthal Cancer Center at Carolinas Medical Center, Charlotte, North Carolina 28232-2861, United States
Presbyterian Cancer Center at Presbyterian Hospital, Charlotte, North Carolina 28233, United States
Duke Comprehensive Cancer Center, Durham, North Carolina 27710, United States
Leo W. Jenkins Cancer Center at Pitt County Memorial Hospital, Greenville, North Carolina 27858-4354, United States
Comprehensive Cancer Center at Wake Forest University, Winston-Salem, North Carolina 27157-1081, United States
Oklahoma University Medical Center, Oklahoma City, Oklahoma 73104, United States
Natalie Warren Bryant Cancer Center at St. Francis Hospital, Tulsa, Oklahoma 74136, United States
McMaster Children's Hospital at Hamilton Health Sciences, Hamilton, Ontario L8S 4J9, Canada
Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada
Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
CCOP - Columbia River Oncology Program, Portland, Oregon 97225, United States
Legacy Emanuel Hospital and Health Center & Children's Hospital, Portland, Oregon 97227, United States
St. Christopher's Hospital for Children, Philadelphia, Pennsylvania 19134-1095, United States
Hopital Sainte Justine, Montreal, Quebec H3T 1C5, Canada
Montreal Children's Hospital at McGill University Health Center, Montreal, Quebec H3G 1A4, Canada
Centre de Recherche du Centre Hospitalier de l'Universite Laval, Sainte Foy, Quebec GIV 4G2, Canada
Royal Children's Hospital, Brisbane, Queensland 4029, Australia
Rhode Island Hospital, Providence, Rhode Island 02903, United States
Hollings Cancer Center at Medical University of South Carolina, Charleston, South Carolina 29425-0721, United States
Children's Hospital of Greenville Hospital System, Greenville, South Carolina 29605, United States
East Tennessee State University Cancer Center at Johnson City Medical Center, Johnson City, Tennessee 37614-0622, United States
St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States
Driscoll Children's Hospital, Corpus Christi, Texas 78466, United States
Medical City Dallas Hospital, Dallas, Texas 75230, United States
Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas, Dallas, Texas 75390-9063, United States
Cook Children's Medical Center - Fort Worth, Fort Worth, Texas 76104, United States
University of Texas Medical Branch, Galveston, Texas 77555-0209, United States
Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital, Houston, Texas 77030-2399, United States
San Antonio Military Pediatric Cancer and Blood Disorders Center, Lackland Air Force Base, Texas 78236, United States
MBCCOP - South Texas Pediatrics, San Antonio, Texas 78229-3900, United States
University of Texas Health Science Center at San Antonio, San Antonio, Texas 78207, United States
CCOP - Scott and White Hospital, Temple, Texas 76508, United States
Center for Cancer Prevention and Care at Scott and White Clinic, Temple, Texas 76508, United States
Vermont Cancer Center at University of Vermont, Burlington, Vermont 05401-3498, United States
Royal Children's Hospital, Parkville, Victoria 3052, Australia
Cancer Center at the University of Virginia, Charlottesville, Virginia 22908, United States
INOVA Fairfax Hospital, Falls Church, Virginia 22042-3300, United States
Naval Medical Center - Portsmouth, Portsmouth, Virginia 23708-5100, United States
Massey Cancer Center at Virginia Commonwealth University, Richmond, Virginia 23298-0212, United States
Carilion Medical Center for Children at Roanoke Community Hospital, Roanoke, Virginia 24029, United States
Madigan Army Medical Center, Tacoma, Washington 98431-0001, United States
West Virginia University - Robert C. Byrd Health Sciences Center - Charleston Division, Charleston, West Virginia 25302, United States
Mary Babb Randolph Cancer Center at West Virginia University Hospitals, Morgantown, West Virginia 26506-9300, United States
St. Vincent Hospital, Green Bay, Wisconsin 54307-9070, United States
CCOP - Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, United States
Midwest Children's Cancer Center, Milwaukee, Wisconsin 53226, United States
Chen IM, Harvey RC, Mullighan CG, Gastier-Foster J, Wharton W, Kang H, Borowitz MJ, Camitta BM, Carroll AJ, Devidas M, Pullen DJ, Payne-Turner D, Tasian SK, Reshmi S, Cottrell CE, Reaman GH, Bowman WP, Carroll WL, Loh ML, Winick NJ, Hunger SP, Willman CL. Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children's Oncology Group study. Blood. 2012 Apr 12;119(15):3512-22. doi: 10.1182/blood-2011-11-394221. Epub 2012 Feb 24.
Rabin KR, Gramatges MM, Borowitz MJ, Palla SL, Shi X, Margolin JF, Zweidler-McKay PA. Absolute lymphocyte counts refine minimal residual disease-based risk stratification in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2012 Sep;59(3):468-74. doi: 10.1002/pbc.23395. Epub 2011 Nov 18.
Xu H, Cheng C, Devidas M, Pei D, Fan Y, Yang W, Neale G, Scheet P, Burchard EG, Torgerson DG, Eng C, Dean M, Antillon F, Winick NJ, Martin PL, Willman CL, Camitta BM, Reaman GH, Carroll WL, Loh M, Evans WE, Pui CH, Hunger SP, Relling MV, Yang JJ. ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol. 2012 Mar 1;30(7):751-7. doi: 10.1200/JCO.2011.38.0345. Epub 2012 Jan 30.
Borowitz MJ, Devidas M, Hunger SP, et al.: Prognostic signficance of end consolidation minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL): A report from the Children's Oncology Group (COG). [Abstract] J Clin Oncol 26 (Suppl 15): A-10000, 2008.
Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM; Children's Oncology Group. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood. 2008 Jun 15;111(12):5477-85. doi: 10.1182/blood-2008-01-132837. Epub 2008 Apr 3.
Davies SM, Borowitz MJ, Rosner GL, Ritz K, Devidas M, Winick N, Martin PL, Bowman P, Elliott J, Willman C, Das S, Cook EH, Relling MV. Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 15;111(6):2984-90. doi: 10.1182/blood-2007-09-114082. Epub 2008 Jan 8.
Hinds PS, Hockenberry MJ, Gattuso JS, Srivastava DK, Tong X, Jones H, West N, McCarthy KS, Sadeh A, Ash M, Fernandez C, Pui CH. Dexamethasone alters sleep and fatigue in pediatric patients with acute lymphoblastic leukemia. Cancer. 2007 Nov 15;110(10):2321-30.
Winick N, Martin PL, Devidas M, et al.: Delayed intensification (DI) enhances event-free survival (EFS) of children with B-precursor acute lymphoblastic leukemia (ALL) who received intensification therapy with six courses of intravenous methotrexate (MTX): POG 9904/9905: a Children's Oncology Group study (COG). [Abstract] Blood 110 (11): A-583, 2007.
