Stem Cell Transplantation Compared With Standard Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia in First Remission

Phase 3

Completed

• Conditions: Leukemia
• Interventions: Biological: sargramostim; Drug: cyclophosphamide; Drug: asparaginase; Drug: cytarabine; Drug: dexamethasone; Drug: daunorubicin hydrochloride; Drug: etoposide; Drug: imatinib mesylate; Drug: leucovorin calcium; Drug: mercaptopurine; Drug: methotrexate; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Procedure: allogeneic bone marrow transplantation; Radiation: radiation therapy; Procedure: autologous bone marrow transplantation; Procedure: peripheral blood stem cell transplantation

• Registration Number: NCT00002514
• Lead Sponsor: Eastern Cooperative Oncology Group

Brief 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.

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.

Study Timeline

• Study Start: 1993-05-07
• Study First Submitted: 1999-11-01
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2006-12
• Status Verified: 2023-06
• Last Update Submitted: 2023-06-14
• Last Update Posted: 2023-06-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1929

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Transplant	imatinib mesylate	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	vincristine sulfate	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Conventional Consolidation/Maintenance	cyclophosphamide	Consolidation/Maintenance Therapy
Conventional Consolidation/Maintenance	dexamethasone	Consolidation/Maintenance Therapy
Conventional Consolidation/Maintenance	mercaptopurine	Consolidation/Maintenance Therapy
Conventional Consolidation/Maintenance	methotrexate	Consolidation/Maintenance Therapy
Transplant	prednisone	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	cytarabine	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	daunorubicin hydrochloride	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	methotrexate	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	sargramostim	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	etoposide	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	allogeneic bone marrow transplantation	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Conventional Consolidation/Maintenance	daunorubicin hydrochloride	Consolidation/Maintenance Therapy
Transplant	asparaginase	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	peripheral blood stem cell transplantation	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Conventional Consolidation/Maintenance	leucovorin calcium	Consolidation/Maintenance Therapy
Transplant	leucovorin calcium	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Conventional Consolidation/Maintenance	vincristine sulfate	Consolidation/Maintenance Therapy
Conventional Consolidation/Maintenance	radiation therapy	Consolidation/Maintenance Therapy
Transplant	autologous bone marrow transplantation	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Transplant	cyclophosphamide	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Conventional Consolidation/Maintenance	prednisone	Consolidation/Maintenance Therapy
Transplant	mercaptopurine	Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
Conventional Consolidation/Maintenance	asparaginase	Consolidation/Maintenance Therapy
Conventional Consolidation/Maintenance	cytarabine	Consolidation/Maintenance Therapy
Conventional Consolidation/Maintenance	etoposide	Consolidation/Maintenance Therapy
Conventional Consolidation/Maintenance	thioguanine	Consolidation/Maintenance Therapy

Primary Outcome Measures

Name	Time	Method
Overall Survival	All patients were followed for 2 years

Trial Locations

Locations (94)

Drexel University College of Medicine - Center City Hahnemann Campus; 🇺🇸 Philadelphia, Pennsylvania, United States

MetroHealth Cancer Care Center at MetroHealth Medical Center; 🇺🇸 Cleveland, Ohio, United States

Swedish Medical Center; 🇺🇸 Englewood, Colorado, United States

Virginia Piper Cancer Institute at Abbott - Northwestern Hospital; 🇺🇸 Minneapolis, Minnesota, United States

Hennepin County Medical Center - Minneapolis; 🇺🇸 Minneapolis, Minnesota, United States

Vanderbilt-Ingram Cancer Center; 🇺🇸 Nashville, Tennessee, United States

Boulder Community Hospital; 🇺🇸 Boulder, Colorado, United States

St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center; 🇺🇸 Grand Junction, Colorado, United States

Hope Cancer Care Center at Longmont United Hospital; 🇺🇸 Longmont, Colorado, United States

Sky Ridge Medical Center; 🇺🇸 Lone Tree, Colorado, United States

St. Mary - Corwin Regional Medical Center; 🇺🇸 Pueblo, Colorado, United States

Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center; 🇺🇸 Farmington, Connecticut, United States

Rush-Copley Cancer Care Center; 🇺🇸 Aurora, Illinois, United States

Evanston Northwestern Healthcare - Evanston Hospital; 🇺🇸 Evanston, Illinois, United States

Hinsdale Hematology Oncology Associates; 🇺🇸 Hinsdale, Illinois, United States

Joliet Oncology-Hematology Associates, Limited - West; 🇺🇸 Joliet, Illinois, United States

CCOP - Carle Cancer Center; 🇺🇸 Urbana, Illinois, United States

Carle Cancer Center at Carle Foundation Hospital; 🇺🇸 Urbana, Illinois, United States

Methodist Cancer Center at Methodist Hospital; 🇺🇸 Indianapolis, Indiana, United States

Saint Anthony Memorial Health Centers; 🇺🇸 Michigan City, Indiana, United States

Mercy Medical Center - Sioux City; 🇺🇸 Sioux City, Iowa, United States

Cedar Rapids Oncology Associates; 🇺🇸 Cedar Rapids, Iowa, United States

Siouxland Hematology-Oncology Associates, LLP; 🇺🇸 Sioux City, Iowa, United States

St. Luke's Regional Medical Center; 🇺🇸 Sioux City, Iowa, United States

Tufts-NEMC Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Baystate Regional Cancer Program at D'Amour Center for Cancer Care; 🇺🇸 Springfield, Massachusetts, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

Oakwood Cancer Center at Oakwood Hospital and Medical Center; 🇺🇸 Dearborn, Michigan, United States

Genesys Hurley Cancer Institute; 🇺🇸 Flint, Michigan, United States

Hurley Medical Center; 🇺🇸 Flint, Michigan, United States

Van Elslander Cancer Center at St. John Hospital and Medical Center; 🇺🇸 Grosse Pointe Woods, Michigan, United States

Foote Hospital; 🇺🇸 Jackson, Michigan, United States

Borgess Medical Center; 🇺🇸 Kalamazoo, Michigan, United States

Seton Cancer Institute - Saginaw; 🇺🇸 Saginaw, Michigan, United States

Bronson Methodist Hospital; 🇺🇸 Kalamazoo, Michigan, United States

Sparrow Regional Cancer Center; 🇺🇸 Lansing, Michigan, United States

St. John Macomb Hospital; 🇺🇸 Warren, Michigan, United States

MeritCare Bemidji; 🇺🇸 Bemidji, Minnesota, United States

Fairview Ridges Hospital; 🇺🇸 Burnsville, Minnesota, United States

Mercy and Unity Cancer Center at Mercy Hospital; 🇺🇸 Coon Rapids, Minnesota, United States

Duluth Clinic Cancer Center - Duluth; 🇺🇸 Duluth, Minnesota, United States

Miller - Dwan Medical Center; 🇺🇸 Duluth, Minnesota, United States

CCOP - Duluth; 🇺🇸 Duluth, Minnesota, United States

Fairview Southdale Hospital; 🇺🇸 Edina, Minnesota, United States

Hutchinson Area Health Care; 🇺🇸 Hutchinson, Minnesota, United States

Meeker County Memorial Hospital; 🇺🇸 Litchfield, Minnesota, United States

Minnesota Oncology Hematology, PA - Maplewood; 🇺🇸 Maplewood, Minnesota, United States

Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center; 🇺🇸 Robbinsdale, Minnesota, United States

Park Nicollet Cancer Center; 🇺🇸 Saint Louis Park, Minnesota, United States

CCOP - Metro-Minnesota; 🇺🇸 Saint Louis Park, Minnesota, United States

Regions Hospital Cancer Care Center; 🇺🇸 Saint Paul, Minnesota, United States

HealthEast Cancer Care at St. Joseph's Hospital; 🇺🇸 Saint Paul, Minnesota, United States

St. Francis Cancer Center at St. Francis Medical Center; 🇺🇸 Shakopee, Minnesota, United States

United Hospital; 🇺🇸 Saint Paul, Minnesota, United States

Ridgeview Medical Center; 🇺🇸 Waconia, Minnesota, United States

CCOP - MeritCare Hospital; 🇺🇸 Fargo, North Dakota, United States

Minnesota Oncology Hematology, PA - Woodbury; 🇺🇸 Woodbury, Minnesota, United States

MeritCare Broadway; 🇺🇸 Fargo, North Dakota, United States

Mercy Cancer Center at Mercy Medical Center; 🇺🇸 Canton, Ohio, United States

Aultman Cancer Center at Aultman Hospital; 🇺🇸 Canton, Ohio, United States

Jewish Hospital Cancer Center; 🇺🇸 Cincinnati, Ohio, United States

Case Comprehensive Cancer Center; 🇺🇸 Cleveland, Ohio, United States

Natalie Warren Bryant Cancer Center at St. Francis Hospital; 🇺🇸 Tulsa, Oklahoma, United States

Geisinger Medical Center; 🇺🇸 Danville, Pennsylvania, United States

Penn State Cancer Institute at Milton S. Hershey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

Abramson Cancer Center of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Geisinger Medical Group - Scenery Park; 🇺🇸 State College, Pennsylvania, United States

Avera Cancer Institute; 🇺🇸 Sioux Falls, South Dakota, United States

Medical X-Ray Center, PC; 🇺🇸 Sioux Falls, South Dakota, United States

Sanford Cancer Center at Sanford USD Medical Center; 🇺🇸 Sioux Falls, South Dakota, United States

Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center; 🇺🇸 La Crosse, Wisconsin, United States

Marshfield Clinic - Marshfield Center; 🇺🇸 Marshfield, Wisconsin, United States

Marshfield Clinic - Indianhead Center; 🇺🇸 Rice Lake, Wisconsin, United States

Porter Adventist Hospital; 🇺🇸 Denver, Colorado, United States

Presbyterian - St. Luke's Medical Center; 🇺🇸 Denver, Colorado, United States

Rose Medical Center; 🇺🇸 Denver, Colorado, United States

St. Joseph Hospital; 🇺🇸 Denver, Colorado, United States

CCOP - Colorado Cancer Research Program; 🇺🇸 Denver, Colorado, United States

Mercy and Unity Cancer Center at Unity Hospital; 🇺🇸 Fridley, Minnesota, United States

HealthEast Cancer Care at St. John's Hospital; 🇺🇸 Maplewood, Minnesota, United States

HealthEast Cancer Care at Woodwinds Health Campus; 🇺🇸 Woodbury, Minnesota, United States

Penrose Cancer Center at Penrose Hospital; 🇺🇸 Colorado Springs, Colorado, United States

North Suburban Medical Center; 🇺🇸 Thornton, Colorado, United States

Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center; 🇺🇸 Wilkes-Barre, Pennsylvania, United States

West Michigan Cancer Center; 🇺🇸 Kalamazoo, Michigan, United States

Aurora Presbyterian Hospital; 🇺🇸 Aurora, Colorado, United States

CCOP - Michigan Cancer Research Consortium; 🇺🇸 Ann Arbor, Michigan, United States

Saint Joseph Mercy Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

Froedtert Hospital and Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Medical College of Wisconsin Cancer Center; 🇺🇸 Milwaukee, Wisconsin, United States

George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus; 🇺🇸 New Britain, Connecticut, United States

Dean Medical Center - Madison; 🇺🇸 Madison, Wisconsin, United States

University of Wisconsin Paul P. Carbone Comprehensive Cancer Center; 🇺🇸 Madison, Wisconsin, United States

St. Rita's Medical Center; 🇺🇸 Lima, Ohio, United States