Stem Cell Transplantation Compared With Standard Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia in First Remission
Information source: Eastern Cooperative Oncology Group
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Leukemia
Intervention: sargramostim (Biological); asparaginase (Drug); cyclophosphamide (Drug); cytarabine (Drug); daunorubicin hydrochloride (Drug); dexamethasone (Drug); etoposide (Drug); imatinib mesylate (Drug); leucovorin calcium (Drug); mercaptopurine (Drug); methotrexate (Drug); prednisone (Drug); thioguanine (Drug); vincristine sulfate (Drug); allogeneic bone marrow transplantation (Procedure); autologous bone marrow transplantation (Procedure); peripheral blood stem cell transplantation (Procedure); radiation therapy (Radiation)
Phase: Phase 3
Status: Completed
Sponsored by: Eastern Cooperative Oncology Group Official(s) and/or principal investigator(s): Jacob M. Rowe, MD, Study Chair, Affiliation: Rambam Health Care Campus Mark R. Litzow, MD, Principal Investigator, Affiliation: Mayo Clinic Antony H. Goldstone, FRCP, Study Chair, Affiliation: University College London Hospitals
Summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from
dividing so they stop growing or die. Combining chemotherapy with allogeneic or autologous
stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs
and kill more cancer cells. It is not yet known whether stem cell transplantation is more
effective than standard chemotherapy in treating acute lymphoblastic leukemia.
PURPOSE: This randomized phase III trial is studying how well stem cell transplantation
works compared to standard combination chemotherapy in treating patients with acute
lymphoblastic leukemia in first remission.
Clinical Details
Official title: Phase III Randomized Trial of Autologous and Allogeneic Stem Cell Transplantation Versus Intensive Conventional Chemotherapy in Acute Lymphoblastic Leukemia in First Remission
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Overall Survival
Detailed description:
OBJECTIVES:
- 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
chromosome-positive patients.
- 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
counts recover.
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.
Eligibility
Minimum age: 15 Years.
Maximum age: 65 Years.
Gender(s): Both.
Criteria:
DISEASE CHARACTERISTICS:
- Histologically confirmed acute lymphoblastic leukemia (ALL)
- More than 25% lymphoblasts in bone marrow
- Patients with myeloid antigen expression AND unequivocal lymphoid
immunophenotype are eligible
- Philadelphia (Ph) chromosome status determined by cytogenetics, fluorescence in situ
hybridization (FISH), and/or RNA analysis
- Patients determined to be Ph chromosome negative by cytogenetics, but positive
for BCR-ABL by FISH or polymerase chain reaction are considered Ph chromosome
positive
- Patients with Ph chromosome-positive disease may be up to age 65
- No myelodysplasia or other antecedent hematologic disorder
- Patients age 50 and under must be HLA typed during induction therapy of study
treatment OR provide a written explanation for not undergoing HLA typing
- A and B typing required
- C and DR typing done if feasible
- Allogeneic stem cell transplantation patients must meet the following criteria:
- Appropriate HLA histocompatible donor available
- Ph chromosome-negative patients must have HLA identical sibling
- Ph chromosome-positive patients must have HLA identical, HLA-matched
unrelated, or haploidentical related donor
- Postinduction therapy:
- CSF negative for leukemia
- No occult or overt leukemic meningitis
- Documented complete remission
PATIENT CHARACTERISTICS:
Age:
- 15 to 65
Performance status:
- Induction therapy:
- Not specified
- Postinduction therapy:
- 0-1
Life expectancy:
- Not specified
Hematopoietic:
- See Disease Characteristics
Hepatic:
- Induction therapy:
- Direct bilirubin ≤ 2. 0 mg/dL
- Postinduction therapy:
- Direct bilirubin < 2. 0 mg/dL
- SGPT or SGOT < 3 times normal
Renal:
- Induction therapy:
- Creatinine < 2 mg/dL
- Postinduction therapy:
- Creatinine ≤ 2 mg/dL
- Creatinine clearance ≥ 60 mL/min
Cardiovascular:
- Induction and postinduction therapy:
- No significant cardiac disease requiring digoxin and/or diuretics
- No major ventricular dysrhythmia requiring medication
- No ischemic heart disease requiring medication
- Postinduction therapy:
- Cardiac ejection fraction ≥ 50% for patients under consideration for
transplantation
Pulmonary:
- Induction therapy:
- Not specified
- Postinduction therapy:
- FEV_1 ≥ 60% of predicted for patients under consideration for transplantation
- DLCO ≥ 50% of predicted for patients under consideration for transplantation
Other:
- Induction and postinduction therapy:
- HIV negative
- No concurrent organ damage or other medical problem (e. g., psychiatric disorder
or drug abuse) that would preclude study therapy
- Not pregnant
- Postinduction therapy:
- No persistent infection
PRIOR CONCURRENT THERAPY:
Biologic therapy:
- No concurrent umbilical cord allogeneic transplantation
Chemotherapy:
- Not specified
Endocrine therapy:
- Prior corticosteroids for ALL allowed
Radiotherapy:
- Not specified
Surgery:
- Not specified
Other:
- Induction and postinduction therapy:
- No other prior therapy for ALL
- Postinduction therapy:
- No concurrent antibiotics
Locations and Contacts
Aurora Presbyterian Hospital, Aurora, Colorado 80012, United States
Boulder Community Hospital, Boulder, Colorado 80301-9019, United States
Penrose Cancer Center at Penrose Hospital, Colorado Springs, Colorado 80933, United States
CCOP - Colorado Cancer Research Program, Denver, Colorado 80224-2522, United States
Porter Adventist Hospital, Denver, Colorado 80210, United States
Presbyterian - St. Luke's Medical Center, Denver, Colorado 80218, United States
Rose Medical Center, Denver, Colorado 80220, United States
St. Joseph Hospital, Denver, Colorado 80218, United States
Swedish Medical Center, Englewood, Colorado 80110, United States
St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center, Grand Junction, Colorado 81502, United States
Sky Ridge Medical Center, Lone Tree, Colorado 80124, United States
Hope Cancer Care Center at Longmont United Hospital, Longmont, Colorado 80502, United States
St. Mary - Corwin Regional Medical Center, Pueblo, Colorado 81004, United States
North Suburban Medical Center, Thornton, Colorado 80229, United States
Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center, Farmington, Connecticut 06360-2875, United States
George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus, New Britain, Connecticut 06050, United States
Rush-Copley Cancer Care Center, Aurora, Illinois 60507, United States
Evanston Northwestern Healthcare - Evanston Hospital, Evanston, Illinois 60201-1781, United States
Hinsdale Hematology Oncology Associates, Hinsdale, Illinois 60521, United States
Joliet Oncology-Hematology Associates, Limited - West, Joliet, Illinois 60435, United States
Carle Cancer Center at Carle Foundation Hospital, Urbana, Illinois 61801, United States
CCOP - Carle Cancer Center, Urbana, Illinois 61801, United States
Methodist Cancer Center at Methodist Hospital, Indianapolis, Indiana 46202, United States
Saint Anthony Memorial Health Centers, Michigan City, Indiana 46360, United States
Cedar Rapids Oncology Associates, Cedar Rapids, Iowa 52403, United States
Mercy Medical Center - Sioux City, Sioux City, Iowa 51104, United States
Siouxland Hematology-Oncology Associates, LLP, Sioux City, Iowa 51101, United States
St. Luke's Regional Medical Center, Sioux City, Iowa 51104, United States
Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, United States
Tufts-NEMC Cancer Center, Boston, Massachusetts 02111, United States
Baystate Regional Cancer Program at D'Amour Center for Cancer Care, Springfield, Massachusetts 01199, United States
CCOP - Michigan Cancer Research Consortium, Ann Arbor, Michigan 48106, United States
Saint Joseph Mercy Cancer Center, Ann Arbor, Michigan 48106-0995, United States
Oakwood Cancer Center at Oakwood Hospital and Medical Center, Dearborn, Michigan 48123-2500, United States
Genesys Hurley Cancer Institute, Flint, Michigan 48503, United States
Hurley Medical Center, Flint, Michigan 48503, United States
Van Elslander Cancer Center at St. John Hospital and Medical Center, Grosse Pointe Woods, Michigan 48236, United States
Foote Hospital, Jackson, Michigan 49201, United States
Borgess Medical Center, Kalamazooaa, Michigan 49001, United States
Bronson Methodist Hospital, Kalamazoo, Michigan 49007, United States
West Michigan Cancer Center, Kalamazoo, Michigan 49007-3731, United States
Sparrow Regional Cancer Center, Lansing, Michigan 48912-1811, United States
Seton Cancer Institute - Saginaw, Saginaw, Michigan 48601, United States
St. John Macomb Hospital, Warren, Michigan 48093, United States
MeritCare Bemidji, Bemidji, Minnesota 56601, United States
Fairview Ridges Hospital, Burnsville, Minnesota 55337, United States
Mercy and Unity Cancer Center at Mercy Hospital, Coon Rapids, Minnesota 55433, United States
CCOP - Duluth, Duluth, Minnesota 55805, United States
Duluth Clinic Cancer Center - Duluth, Duluth, Minnesota 55805-1983, United States
Miller - Dwan Medical Center, Duluth, Minnesota 55805, United States
Fairview Southdale Hospital, Edina, Minnesota 55435, United States
Mercy and Unity Cancer Center at Unity Hospital, Fridley, Minnesota 55432, United States
Hutchinson Area Health Care, Hutchinson, Minnesota 55350, United States
Meeker County Memorial Hospital, Lichfield, Minnesota 55355, United States
HealthEast Cancer Care at St. John's Hospital, Maplewood, Minnesota 55109, United States
Minnesota Oncology Hematology, PA - Maplewood, Maplewood, Minnesota 55109, United States
Hennepin County Medical Center - Minneapolis, Minneapolis, Minnesota 55415, United States
Virginia Piper Cancer Institute at Abbott - Northwestern Hospital, Minneapolis, Minnesota 55407, United States
Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center, Robbinsdale, Minnesota 55422-2900, United States
CCOP - Metro-Minnesota, Saint Louis Park, Minnesota 55416, United States
St. Francis Cancer Center at St. Francis Medical Center, Shakopee, Minnesota 55379, United States
HealthEast Cancer Care at St. Joseph's Hospital, St Paul, Minnesota 55102, United States
Park Nicollet Cancer Center, St. Louis Park, Minnesota 55416, United States
Regions Hospital Cancer Care Center, St. Paul, Minnesota 55101, United States
United Hospital, St. Paul, Minnesota 55102, United States
Ridgeview Medical Center, Waconia, Minnesota 55387, United States
HealthEast Cancer Care at Woodwinds Health Campus, Woodbury, Minnesota 55125, United States
Minnesota Oncology Hematology, PA - Woodbury, Woodbury, Minnesota 55125, United States
CCOP - MeritCare Hospital, Fargo, North Dakota 58122, United States
MeritCare Broadway, Fargo, North Dakota 58122, United States
Aultman Cancer Center at Aultman Hospital, Canton, Ohio 44710-1799, United States
Mercy Cancer Center at Mercy Medical Center, Canton, Ohio 44708, United States
Jewish Hospital Cancer Center, Cincinnati, Ohio 45236, United States
Case Comprehensive Cancer Center, Cleveland, Ohio 44106-5065, United States
MetroHealth Cancer Care Center at MetroHealth Medical Center, Cleveland, Ohio 44109, United States
St. Rita's Medical Center, Lima, Ohio 45801, United States
Natalie Warren Bryant Cancer Center at St. Francis Hospital, Tulsa, Oklahoma 74136, United States
Geisinger Medical Center, Danville, Pennsylvania 17822-0001, United States
Penn State Cancer Institute at Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033-0850, United States
Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, United States
Drexel University College of Medicine - Center City Hahnemann Campus, Philadelphia, Pennsylvania 19102, United States
Geisinger Medical Group - Scenery Park, State College, Pennsylvania 16801, United States
Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center, Wilkes-Barre, Pennsylvania 18711, United States
Avera Cancer Institute, Sioux Falls, South Dakota 57105, United States
Medical X-Ray Center, PC, Sioux Falls, South Dakota 57105, United States
Sanford Cancer Center at Sanford USD Medical Center, Sioux Falls, South Dakota 57117-5039, United States
Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-6838, United States
Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center, La Crosse, Wisconsin 54601, United States
Dean Medical Center - Madison, Madison, Wisconsin 53717, United States
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin 53792-6164, United States
Marshfield Clinic - Marshfield Center, Marshfield, Wisconsin 54449, United States
Froedtert Hospital and Medical College of Wisconsin, Milwaukee, Wisconsin 53226-3596, United States
Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin 53226, United States
Marshfield Clinic - Indianhead Center, Rice Lake, Wisconsin 54868, United States
Additional Information
Clinical trial summary from the National Cancer Institute's PDQ® database
Related publications: Wang H, Chen XQ, Geng QR, Liu PP, Lin GN, Xia ZJ, Lu Y. Induction therapy using the MRC UKALLXII/ECOG E2993 protocol in Chinese adults with acute lymphoblastic leukemia. Int J Hematol. 2011 Aug;94(2):163-8. doi: 10.1007/s12185-011-0891-y. Epub 2011 Jul 6. Goldstone AH. Transplants in Adult ALL--? Allo for everyone. Biol Blood Marrow Transplant. 2009 Jan;15(1 Suppl):7-10. doi: 10.1016/j.bbmt.2008.11.017. Review. Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A, Rowe J, Webb D. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2007 Mar;48(3):254-61. Paietta E, Ferrando AA, Neuberg D, Bennett JM, Racevskis J, Lazarus H, Dewald G, Rowe JM, Wiernik PH, Tallman MS, Look AT. Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood. 2004 Jul 15;104(2):558-60. Epub 2004 Mar 25. Ferrando AA, Neuberg D, Dodge RK, et al.: Adult T-cell ALL patients whose lymphoblasts express the HOX11 oncogene have an excellent prognosis when treated with chemotherapy and are not candidates for allogeneic bone marrow transplantaton in first remission. [Abstract] Blood 100 (11 pt 1): A-578, 2002.
Starting date: April 1993
Last updated: November 21, 2012
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