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: Randomized phase III trial to compare the effectiveness of stem cell transplantation with that of standard combination chemotherapy in treating patients who have acute lymphoblastic leukemia in first remission.

Condition	Treatment or Intervention	Phase
adult acute lymphoblastic leukemia in remission	Drug: asparaginase  Drug: cyclophosphamide  Drug: cytarabine  Drug: daunorubicin  Drug: dexamethasone  Drug: etoposide  Drug: filgrastim  Drug: imatinib mesylate  Drug: leucovorin calcium  Drug: mercaptopurine  Drug: methotrexate  Drug: mitoxantrone  Drug: prednisone  Drug: sargramostim  Drug: thioguanine  Drug: vincristine  Procedure: allogeneic bone marrow transplantation  Procedure: autologous bone marrow transplantation  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: bone marrow transplantation  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: enzyme inhibitor therapy  Procedure: high-dose chemotherapy  Procedure: peripheral blood stem cell transplantation  Procedure: protein tyrosine kinase inhibitor therapy  Procedure: radiation therapy	Phase III

Further Study Details: 

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.
• 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 and CR after second induction therapy proceed to group I. Patients with Ph chromosome-negative status and CR after second induction therapy proceed to group II.
• Patients receive oral imatinib mesylate once daily on days 1-28. Patients who are not ready to proceed to transplantation after the 28-day treatment period with imatinib mesylate, may receive imatinib mesylate for an additional 30-60 days. Patients then proceed directly to allogeneic or autologous stem cell transplantation (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.
• 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.
• 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.

Ages Eligible for Study:  15 Years   -   65 Years,  Genders Eligible for Study:  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
• 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%

Pulmonary:

• Induction therapy:
• Not specified
• Postinduction therapy:
• FEV_1 ≥ 60% of predicted
• DLCO ≥ 50% of predicted

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

Colorado
      Boulder Community Hospital, Boulder,  Colorado,  80301-9019,  United States; Recruiting
      CCOP - Colorado Cancer Research Program, Incorporated, Denver,  Colorado,  80224,  United States; Recruiting
      Hope Cancer Care Center at Longmont United Hospital, Longmont,  Colorado,  80501,  United States; Recruiting
      Medical Center of Aurora - South Campus, Aurora,  Colorado,  80012-0000,  United States; Recruiting
      Penrose Cancer Center at Penrose Hospital, Colorado Springs,  Colorado,  80933,  United States; Recruiting
      Porter Adventist Hospital, Denver,  Colorado,  80210,  United States; Recruiting
      Presbyterian - St. Luke's Medical Center, Denver,  Colorado,  80218,  United States; Recruiting
      Rocky Mountain Cancer Centers - Denver Rose, Denver,  Colorado,  80220,  United States; Recruiting
      Rocky Mountain Cancer Centers - Thornton, Thornton,  Colorado,  80229,  United States; Recruiting
      Sky Ridge Medical Center, Lone Tree,  Colorado,  80124,  United States; Recruiting
      St. Joseph Hospital, Denver,  Colorado,  80218-1191,  United States; Recruiting
      St. Mary-Corwin Regional Medical Center, Pueblo,  Colorado,  81004,  United States; Recruiting
      Swedish Medical Center, Englewood,  Colorado,  80112,  United States; Recruiting
Florida
      University of Florida Shands Cancer Center, Gainesville,  Florida,  32610-0296,  United States; Recruiting
Illinois
      CCOP - Carle Cancer Center, Urbana,  Illinois,  61801,  United States; Recruiting
      CCOP - Evanston, Evanston,  Illinois,  60201,  United States; Recruiting
      CCOP - Illinois Oncology Research Association, Peoria,  Illinois,  61615-7828,  United States; Recruiting
      Hinsdale Hematology Oncology Associates, Hinsdale,  Illinois,  60521,  United States; Recruiting
      Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago,  Illinois,  60611,  United States; Recruiting
Indiana
      Indiana University Cancer Center, Indianapolis,  Indiana,  46202-5289,  United States; Recruiting
Iowa
      CCOP - Cedar Rapids Oncology Project, Cedar Rapids,  Iowa,  52403-1206,  United States; Recruiting
Maryland
      Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore,  Maryland,  21231,  United States; Recruiting
Massachusetts
      Beth Israel Deaconess Medical Center, Boston,  Massachusetts,  02215,  United States; Recruiting
      Cancer Center at Tufts - New England Medical Center, Boston,  Massachusetts,  02111,  United States; Recruiting
Michigan
      CCOP - Kalamazoo, Kalamazoo,  Michigan,  49007-3731,  United States; Recruiting
      CCOP - Michigan Cancer Research Consortium, Ann Arbor,  Michigan,  48106,  United States; Recruiting
      West Michigan Cancer Center, Kalamazoo,  Michigan,  49007-3731,  United States; Recruiting
Minnesota
      CCOP - Duluth, Duluth,  Minnesota,  55805,  United States; Recruiting
      CCOP - Metro-Minnesota, Saint Louis Park,  Minnesota,  55416,  United States; Recruiting
      Mayo Clinic Cancer Center, Rochester,  Minnesota,  55905,  United States; Recruiting
Nebraska
      CCOP - Missouri Valley Cancer Consortium, Omaha,  Nebraska,  68106,  United States; Recruiting
New Jersey
      CCOP - Northern New Jersey, Hackensack,  New Jersey,  07601,  United States; Recruiting
New York
      Albert Einstein Cancer Center at Albert Einstein College of Medicine, Bronx,  New York,  10461,  United States; Recruiting
      MBCCOP-Our Lady of Mercy Cancer Center, Bronx,  New York,  10466,  United States; Recruiting
Ohio
      MetroHealth's Cancer Care Center at MetroHealth Medical Center, Cleveland,  Ohio,  44109,  United States; Recruiting
Pennsylvania
      Abramson Cancer Center at the University of Pennsylvania, Philadelphia,  Pennsylvania,  19104,  United States; Recruiting
      CCOP - Geisinger Clinic and Medical Center, Danville,  Pennsylvania,  17822-2001,  United States; Recruiting
      Penn State Cancer Institute at Milton S. Hershey Medical Center, Hershey,  Pennsylvania,  17033-0850,  United States; Recruiting
South Dakota
      CCOP - Sioux Community Cancer Consortium, Sioux Falls,  South Dakota,  57104,  United States; Recruiting
Tennessee
      Vanderbilt-Ingram Cancer Center at Vanderbilt Medical Center, Nashville,  Tennessee,  37232-6307,  United States; Recruiting
Wisconsin
      CCOP - Marshfield Clinic Research Foundation, Marshfield,  Wisconsin,  54449,  United States; Recruiting
      CCOP - St. Vincent Hospital Cancer Center, Green Bay, Green Bay,  Wisconsin,  54301,  United States; Recruiting
      Medical College of Wisconsin Cancer Center, Milwaukee,  Wisconsin,  53226-3596,  United States; Recruiting
      University of Wisconsin Comprehensive Cancer Center, Madison,  Wisconsin,  53792-0001,  United States; Recruiting
United Kingdom, England
      University College Hospital, London,  England,  WC1E 6AU,  United Kingdom; Recruiting

Study chairs or principal investigators

Jacob M. Rowe, MD,  Study Chair,  Rambam Medical Center   
Mark R. Litzow, MD,  Mayo Clinic Cancer Center   
Antony H. Goldstone, FRCP,  Study Chair,  University College Hospital   

Study ID Numbers:  CDR0000078099; ECOG-2993; MRC-LEUK-UKALL-XII; EST-4491; NCT00002514
Record last reviewed:  February 2005
Last Updated:  April 4, 2005
Record first received:  November 1, 1999
ClinicalTrials.gov Identifier:  NCT00002514
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08