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

This study has been completed.
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Medical Research Council
Information provided by (Responsible Party):
Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:
NCT00002514
First received: November 1, 1999
Last updated: November 21, 2012
Last verified: August 2007
History of Changes

November 1, 1999
November 21, 2012
April 1993
December 2006   (final data collection date for primary outcome measure)
Overall Survival [ Time Frame: All patients were followed for 2 years ] [ Designated as safety issue: No ]
Not Provided
Complete list of historical versions of study NCT00002514 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
Not Provided
Not Provided
 
Stem Cell Transplantation Compared With Standard Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia in First Remission
Phase III Randomized Trial of Autologous and Allogeneic Stem Cell Transplantation Versus Intensive Conventional Chemotherapy in Acute Lymphoblastic Leukemia in First Remission

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.

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.
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Leukemia
  • Biological: sargramostim
  • Drug: 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
  • Procedure: allogeneic bone marrow transplantation
  • Procedure: autologous bone marrow transplantation
  • Procedure: peripheral blood stem cell transplantation
  • Radiation: radiation therapy
  • Experimental: Transplant
    Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant
    Interventions:
    • Biological: sargramostim
    • Drug: asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: etoposide
    • Drug: imatinib mesylate
    • Drug: leucovorin calcium
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: prednisone
    • Drug: vincristine sulfate
    • Procedure: allogeneic bone marrow transplantation
    • Procedure: autologous bone marrow transplantation
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: Conventional Consolidation/Maintenance
    Consolidation/Maintenance Therapy
    Interventions:
    • Drug: asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: etoposide
    • Drug: leucovorin calcium
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: radiation therapy

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
1929
Not Provided
December 2006   (final data collection date for primary outcome measure)

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
Both
15 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00002514
CDR0000078099, E2993, MRC-LEUK-UKALL-XII, EST-4491
Yes
Eastern Cooperative Oncology Group
Eastern Cooperative Oncology Group
  • National Cancer Institute (NCI)
  • Medical Research Council
Study Chair: Jacob M. Rowe, MD Rambam Health Care Campus
Principal Investigator: Mark R. Litzow, MD Mayo Clinic
Study Chair: Antony H. Goldstone, FRCP University College London Hospitals
Eastern Cooperative Oncology Group
August 2007

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP