Phase III Randomized Trial of Autologous and Allogeneic Stem Cell Transplantation Versus Intensive Conventional Chemotherapy in Acute Lymphoblastic Leukemia in First Remission
- Compare the duration of complete remission (CR) and survival in patients with acute
lymphoblastic leukemia in first remission treated with allogeneic or autologous stem
cell transplantation (SCT) vs conventional consolidation and maintenance chemotherapy.
- Compare the overall treatment outcomes in patients treated with these regimens.
- Determine the effect of imatinib mesylate given after induction therapy in Philadelphia
(Ph) chromosome-positive patients in CR.
- Determine the benefit of allogeneic or autologous SCT after imatinib mesylate in Ph
- Determine the benefit of additional imatinib mesylate administered after allogeneic or
autologous SCT in Ph chromosome-positive patients.
- Determine the minimal residual disease in Ph chromosome-positive patients before and
after treatment with imatinib mesylate.
- Determine the clinical resistance to imatinib mesylate caused by BCR-ABL gene
amplification or mutation in Ph chromosome-positive patients.
OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age
(50 and under vs over 50), time to achieve complete remission (CR) (4 weeks or less vs more
than 4 weeks), and Philadelphia (Ph) chromosome status (positive vs negative).
- First induction therapy: Patients receive daunorubicin (DNR) IV over 15-30 minutes and
vincristine (VCR) IV over 3-5 minutes on days 1, 8, 15, and 22; oral prednisone (PRED)
once daily on days 1-28; and asparaginase (ASP) IV over 30 minutes or intramuscularly
on days 17-28. Patients with CNS leukemia at presentation also receive methotrexate
(MTX) intrathecally (IT) via an Ommaya reservoir weekly until the CSF is clear.
Patients without CNS leukemia at presentation receive MTX IT on day 23 only.
- Second induction therapy: Beginning immediately after first induction therapy, patients
receive cyclophosphamide (CTX) IV over 30 minutes on days 1, 15, and 29; cytarabine
(ARA-C) IV over 30 minutes on days 1-4, 8-11, 15-18, and 22-25; and oral mercaptopurine
(MP) once daily on days 1-28. Patients with CNS leukemia at presentation also undergo
concurrent craniospinal irradiation. Patients without CNS leukemia at presentation
receive MTX IT on days 1, 8, 15, and 22. Patients with Ph chromosome-positive status
receive oral imatinib mesylate once daily for at least 28 days (days 1-28).
Patients with Ph chromosome-positive status and CR after second induction therapy proceed to
group I for autologous or allogeneic stem cell transplantation (SCT). Patients with Ph
chromosome-negative status and CR after second induction therapy proceed to group II.
- Group I (Ph chromosome-positive patients):
- Autologous SCT: Patients receive high-dose consolidation/mobilization chemotherapy
comprising ARA-C IV over 3 hours on days 1-3 and mitoxantrone IV immediately after
ARA-C administration on days 1 and 2. Patients also receive filgrastim (G-CSF)
subcutaneously (SC) once daily beginning on day 5 and continuing until blood
Patients then undergo peripheral blood stem cell collection or bone marrow harvesting.
Patients receive preparative therapy comprising total body irradiation twice daily (5-10
hours apart) on days -6 to -4 and high-dose etoposide (VP-16) IV over 4 hours on day -3.
Male patients also undergo radiotherapy boost to the testes on day -6.
Patients undergo autologous SCT on day 0 and receive sargramostim (GM-CSF) SC once daily
beginning 6 hours after the completion of SCT and continuing until blood counts recover.
- Allogeneic SCT: Patients receive the preparative regimen as in autologous SCT and then
undergo allogeneic SCT on day 0. Patients receive GM-CSF as in autologous SCT.
- Post-SCT imatinib mesylate therapy: After recovery from autologous or allogeneic SCT,
patients receive oral imatinib mesylate once daily. Imatinib mesylate therapy continues
in the absence of disease progression or unacceptable toxicity.
- Group II (Ph chromosome-negative patients):
- Intensification therapy: Beginning 4 weeks after the completion of the second induction
therapy, patients receive high-dose MTX IV over 2 hours on days 1, 8, and 22;
leucovorin calcium IV every 6 hours for 4 doses and then orally every 6 hours for 12
doses beginning 22-24 hours after each MTX infusion; and ASP IV over 30 minutes on days
2, 9, and 23.
Patients who are ≤ 50 years of age with a histocompatible donor proceed to allogeneic SCT
and undergo allogeneic SCT as in group I. Patients who are ≤ 50 years of age without an
appropriate donor are randomized to 1 of 2 treatment arms.
- Arm I (conventional consolidation/maintenance therapy):
- Conventional consolidation therapy: During course 1, patients receive ARA-C IV
over 30 minutes and VP-16 IV over 1 hour on days 1-5; VCR IV on days 1, 8, 15, and
22; and oral dexamethasone on days 1-28. During course 2 (which begins 4 weeks
after initiation of course 1 or when blood counts recover), patients receive ARA-C
and VP-16 as in course 1. During course 3 (which begins 4 weeks after initiation
of course 2 or when blood counts recover), patients receive DNR IV on days 1, 8,
15, and 22; CTX IV over 30 minutes on day 29; ARA-C IV over 30 minutes on days
31-34 and 38-41; and oral thioguanine on days 29-42. During course 4 (which begins
8 weeks after initiation of course 3 or when blood counts recover), patients
receive treatment as in course 2.
- Maintenance therapy: Beginning 4 weeks after initiation of course 4 of
consolidation therapy or when blood counts recover, patients receive oral MP
daily; MTX orally or IV once weekly; VCR IV once every 12 weeks; and oral PRED for
5 days every 12 weeks. Maintenance therapy continues for 2.5 years after
initiation of intensification therapy.
- Arm II (autologous SCT): Patients undergo autologous SCT as in group I with the
exception of high-dose consolidation/mobilization chemotherapy.
Patients are followed every 6 months for 2 years.
PROJECTED ACCRUAL: Approximately 40 patients per year will be accrued for group I
(Philadelphia [Ph] chromosome-positive patients) of this study. Approximately 550 patients
will be accrued for group II (Ph chromosome-negative patients) of this study within 5 years.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
All patients were followed for 2 years
Jacob M. Rowe, MD
Rambam Health Care Campus
United States: Federal Government
|Hurley Medical Center||Flint, Michigan 48503|
|CCOP - Carle Cancer Center||Urbana, Illinois 61801|
|Beth Israel Deaconess Medical Center||Boston, Massachusetts 02215|
|CCOP - Metro-Minnesota||Saint Louis Park, Minnesota 55416|
|Aurora Presbyterian Hospital||Aurora, Colorado 80012|
|Boulder Community Hospital||Boulder, Colorado 80301-9019|
|Penrose Cancer Center at Penrose Hospital||Colorado Springs, Colorado 80933|
|CCOP - Colorado Cancer Research Program||Denver, Colorado 80224-2522|
|Porter Adventist Hospital||Denver, Colorado 80210|
|Presbyterian - St. Luke's Medical Center||Denver, Colorado 80218|
|St. Joseph Hospital||Denver, Colorado 80218|
|Rose Medical Center||Denver, Colorado 80220|
|Swedish Medical Center||Englewood, Colorado 80110|
|St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center||Grand Junction, Colorado 81502|
|Sky Ridge Medical Center||Lone Tree, Colorado 80124|
|Hope Cancer Care Center at Longmont United Hospital||Longmont, Colorado 80502|
|St. Mary - Corwin Regional Medical Center||Pueblo, Colorado 81004|
|North Suburban Medical Center||Thornton, Colorado 80229|
|Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center||Farmington, Connecticut 06360-2875|
|George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus||New Britain, Connecticut 06050|
|Rush-Copley Cancer Care Center||Aurora, Illinois 60507|
|Evanston Northwestern Healthcare - Evanston Hospital||Evanston, Illinois 60201-1781|
|Hinsdale Hematology Oncology Associates||Hinsdale, Illinois 60521|
|Joliet Oncology-Hematology Associates, Limited - West||Joliet, Illinois 60435|
|Carle Cancer Center at Carle Foundation Hospital||Urbana, Illinois 61801|
|Methodist Cancer Center at Methodist Hospital||Indianapolis, Indiana 46202|
|Saint Anthony Memorial Health Centers||Michigan City, Indiana 46360|
|Cedar Rapids Oncology Associates||Cedar Rapids, Iowa 52403|
|Mercy Medical Center - Sioux City||Sioux City, Iowa 51104|
|Siouxland Hematology-Oncology Associates, LLP||Sioux City, Iowa 51101|
|St. Luke's Regional Medical Center||Sioux City, Iowa 51104|
|Tufts-NEMC Cancer Center||Boston, Massachusetts 02111|
|Baystate Regional Cancer Program at D'Amour Center for Cancer Care||Springfield, Massachusetts 01199|
|CCOP - Michigan Cancer Research Consortium||Ann Arbor, Michigan 48106|
|Saint Joseph Mercy Cancer Center||Ann Arbor, Michigan 48106-0995|
|Oakwood Cancer Center at Oakwood Hospital and Medical Center||Dearborn, Michigan 48123-2500|
|Genesys Hurley Cancer Institute||Flint, Michigan 48503|
|Van Elslander Cancer Center at St. John Hospital and Medical Center||Grosse Pointe Woods, Michigan 48236|
|Foote Hospital||Jackson, Michigan 49201|
|Bronson Methodist Hospital||Kalamazoo, Michigan 49007|
|West Michigan Cancer Center||Kalamazoo, Michigan 49007-3731|
|Borgess Medical Center||Kalamazooaa, Michigan 49001|
|Sparrow Regional Cancer Center||Lansing, Michigan 48912-1811|
|Seton Cancer Institute - Saginaw||Saginaw, Michigan 48601|
|St. John Macomb Hospital||Warren, Michigan 48093|
|MeritCare Bemidji||Bemidji, Minnesota 56601|
|Fairview Ridges Hospital||Burnsville, Minnesota 55337|
|Mercy and Unity Cancer Center at Mercy Hospital||Coon Rapids, Minnesota 55433|
|Duluth Clinic Cancer Center - Duluth||Duluth, Minnesota 55805-1983|
|CCOP - Duluth||Duluth, Minnesota 55805|
|Miller - Dwan Medical Center||Duluth, Minnesota 55805|
|Fairview Southdale Hospital||Edina, Minnesota 55435|
|Mercy and Unity Cancer Center at Unity Hospital||Fridley, Minnesota 55432|
|Hutchinson Area Health Care||Hutchinson, Minnesota 55350|
|Meeker County Memorial Hospital||Lichfield, Minnesota 55355|
|Minnesota Oncology Hematology, PA - Maplewood||Maplewood, Minnesota 55109|
|HealthEast Cancer Care at St. John's Hospital||Maplewood, Minnesota 55109|
|Hennepin County Medical Center - Minneapolis||Minneapolis, Minnesota 55415|
|Virginia Piper Cancer Institute at Abbott - Northwestern Hospital||Minneapolis, Minnesota 55407|
|Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center||Robbinsdale, Minnesota 55422-2900|
|St. Francis Cancer Center at St. Francis Medical Center||Shakopee, Minnesota 55379|
|HealthEast Cancer Care at St. Joseph's Hospital||St Paul, Minnesota 55102|
|Park Nicollet Cancer Center||St. Louis Park, Minnesota 55416|
|Regions Hospital Cancer Care Center||St. Paul, Minnesota 55101|
|United Hospital||St. Paul, Minnesota 55102|
|Ridgeview Medical Center||Waconia, Minnesota 55387|
|Minnesota Oncology Hematology, PA - Woodbury||Woodbury, Minnesota 55125|
|HealthEast Cancer Care at Woodwinds Health Campus||Woodbury, Minnesota 55125|
|MeritCare Broadway||Fargo, North Dakota 58122|
|CCOP - MeritCare Hospital||Fargo, North Dakota 58122|
|Aultman Cancer Center at Aultman Hospital||Canton, Ohio 44710-1799|
|Mercy Cancer Center at Mercy Medical Center||Canton, Ohio 44708|
|Jewish Hospital Cancer Center||Cincinnati, Ohio 45236|
|Case Comprehensive Cancer Center||Cleveland, Ohio 44106-5065|
|MetroHealth Cancer Care Center at MetroHealth Medical Center||Cleveland, Ohio 44109|
|St. Rita's Medical Center||Lima, Ohio 45801|
|Natalie Warren Bryant Cancer Center at St. Francis Hospital||Tulsa, Oklahoma 74136|
|Geisinger Medical Center||Danville, Pennsylvania 17822-0001|
|Penn State Cancer Institute at Milton S. Hershey Medical Center||Hershey, Pennsylvania 17033-0850|
|Abramson Cancer Center of the University of Pennsylvania||Philadelphia, Pennsylvania 19104-4283|
|Drexel University College of Medicine - Center City Hahnemann Campus||Philadelphia, Pennsylvania 19102|
|Geisinger Medical Group - Scenery Park||State College, Pennsylvania 16801|
|Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center||Wilkes-Barre, Pennsylvania 18711|
|Sanford Cancer Center at Sanford USD Medical Center||Sioux Falls, South Dakota 57117-5039|
|Medical X-Ray Center, PC||Sioux Falls, South Dakota 57105|
|Avera Cancer Institute||Sioux Falls, South Dakota 57105|
|Vanderbilt-Ingram Cancer Center||Nashville, Tennessee 37232-6838|
|Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center||La Crosse, Wisconsin 54601|
|Dean Medical Center - Madison||Madison, Wisconsin 53717|
|University of Wisconsin Paul P. Carbone Comprehensive Cancer Center||Madison, Wisconsin 53792-6164|
|Marshfield Clinic - Marshfield Center||Marshfield, Wisconsin 54449|
|Medical College of Wisconsin Cancer Center||Milwaukee, Wisconsin 53226|
|Froedtert Hospital and Medical College of Wisconsin||Milwaukee, Wisconsin 53226-3596|
|Marshfield Clinic - Indianhead Center||Rice Lake, Wisconsin 54868|