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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

Page last updated: August 23, 2015

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