• Incidence of graft failure 100 days post-transplant
  
• Incidence of acute and chronic graft-vs-host disease100 days post-transplant
  
• Transplant-related mortality 100 days post-transplant
  
• Disease-free survival 100 days post-transplant
  
• Overall survival 100 days post-transplant
  

OBJECTIVES:

• Determine the safety of a preparative regimen comprising total body irradiation, cyclophosphamide, thiotepa, and fludarabine, but without anti-thymocyte globulin, in patients with high-risk leukemia treated with peripheral blood stem cell transplantation from partially matched related donors.
• Determine the incidence of graft failure, acute graft-versus-host disease (GVHD), and treatment-related mortality in patients treated with this regimen.
• Determine rates of chronic GVHD and relapse in patients treated with this regimen.
• Determine disease-free and overall survival in patients treated with this regimen.

OUTLINE: This is a pilot study.

Patients receive a preparative regimen comprising total lymphoid irradiation once daily on days -13 to -11; cyclophosphamide IV over 1 hour on days -8 and -7; thiotepa IV over 4 hours every 12 hours on day -6; fludarabine IV over 30 minutes on days -5 to -1; and total body irradiation once on day -1. Patients also receive cyclosporine IV over 12 hours on days -8 to -1 and methylprednisolone IV twice daily on days -3 and -2. Patients receive CD34-enriched T-cell-depleted allogeneic stem cell infusion on day 0.

Patients with disease progression or uncontrolled infection but without grade II or greater graft-versus-host disease may receive up to 3 donor lymphocyte infusions at least 4 weeks apart until disease regression.

Patients are followed at least weekly until day 100 and then at 6, 12, 18, 24, 36, and 48 months.

PROJECTED ACCRUAL: A total of 20-51 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

  • High-risk myelodysplastic syndromes (MDS), meeting 1 of the following criteria:

    • Transformation to acute leukemia defined by at least 15% blasts
    • Secondary to prior treatment with chemotherapy and/or radiotherapy
    • Presence of complex cytogenetics (at least 3 karyotypic abnormalities)
    • Monosomy or deletion of chromosome 7

  • Acute myeloid leukemia (AML), meeting 1 of the following criteria :

    • High-risk AML in first remission and meeting 1 of the following criteria:

      • At least 3 karyotypic abnormalities
      • Monosomy or deletion of chromosome 5 or 7 = 11q23 chromosomal abnormality
      • Prior diagnosis of MDS
      • Received prior radiotherapy or chemotherapy
    • In second or subsequent remission
    • Primary induction failure or partial remission
    • Untested or sensitive relapse

  • Chronic myelogenous leukemia, meeting 1 of the following criteria:

    • Blast crisis
    • Accelerated phase disease that has failed prior treatment with imatinib mesylate, defined as a failure to achieve hematologic response after 3 months of standard dose (600 mg/day) therapy or disease progression on therapy

  • Myeloproliferative disease

    • The following diagnoses are eligible:

      • Agnogenic myeloid metaplasia
      • Essential thrombocythemia
      • Polycythemia vera
    • Must have evidence of transformation to acute leukemia

  • Acute lymphocytic leukemia (ALL), meeting 1 of the following criteria:

    • High-risk ALL in first remission defined by 1 of the following:

      • t(9;22) or 11q23 chromosomal abnormality
      • Complete response at least 4 weeks after induction therapy OR requiring at least 2 induction regimens
    • Second or subsequent remission
• No relapsed leukemia refractory to appropriate salvage therapy

• Availability of an HLA-mismatched family donor

  • Donor age 75 or under
• No better donor alternative (i.e., HLA-matched related or unrelated stem cell donor) is available

PATIENT CHARACTERISTICS:

Age

• 10 to 50

Performance status

• ECOG 0-1

Life expectancy

• More than 3 months

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin no greater than 4 mg/dL
• Transaminases no greater than 3 times upper limit of normal

Renal

• Creatinine no greater than 2.0 mg/dL OR
• Creatinine clearance at least 60 mL/min

Cardiovascular

• LVEF at least 40%

Pulmonary

• DLCO at least 65% of predicted

Other

• Not pregnant
• Negative pregnancy test
• HIV negative
• No other prior malignancy except basal cell or squamous cell skin cancer or a remote history of cancer now considered cured
• No major organ dysfunction that would preclude transplantation
• No major anticipated illness or organ failure that would preclude transplantation
• No severe psychiatric illness or mental deficiency that would preclude giving informed consent or complying with study
• No uncontrolled infection

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics

Surgery

• Not specified