Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

• Chronic GVHD requiring systemic immunosuppressive treatment [ Time Frame: At 1 year after transplantation ] [ Designated as safety issue: No ]
  Chronic GVHD will be defined by National Institutes of Health (NIH) criteria and requiring systemic treatment. A reduction in the cumulative incidence of GVHD from ~35% to ~15% at 1 year would represent a reasonable goal. A sample size of 42 patients provides 90% power to observe such a difference with one-side 5% type-1 error.
  
  

• Donor engraftment [ Time Frame: At day 28 ] [ Designated as safety issue: No ]
  Descriptive statistics will be used to assess the mean and median proportions of donor myeloid cells and T cells in the blood. In addition, the proportions of patients with full and mixed chimerism will be summarized. Subsequent testing will be done as needed for clinical management. Mixed chimerism will be defined as > 5% and < 95% donor cells, and full chimerism is defined as at least 95% donor cells.
  
  
• Grades II-IV and III-IV acute GVHD [ Time Frame: Through day +100 post-transplant ] [ Designated as safety issue: No ]
  Grades II-IV and III-IV GVHD will be assessed with the use of cumulative incidence plots.
  
  
• Duration of systemic immunosuppressive treatment [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  The need for additional immunosuppressive treatment with agents other than those used for prophylaxis, the reasons for their administration (acute GVHD, chronic GVHD, or other reasons) and the duration of its administration will be determined. Patients will be monitored to determine the duration of systemic immunosuppressive treatment. Primary and secondary treatment of acute GVHD and withdrawal of systemic immunosuppressive treatment will be assessed with the use of cumulative incidence plots.
  
  
• Persistent or recurrent malignancy after HCT [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  Recurrent or progressive malignancy will be assessed with the use of cumulative incidence plots. Recurrent malignancy will be defined by hematologic criteria. Recurrent malignancy will also be defined as any unplanned medical intervention designed to prevent progression of malignant disease in patients who have molecular, cytogenetic or flow-cytometric evidence of malignant cells after transplantation.
  
  
• Non-relapse mortality [ Time Frame: Up to 1 year after transplant ] [ Designated as safety issue: No ]
  Defined as death in the absence of recurrent or progressive malignancy after HCT. Non-relapse morality will be assessed with the use of cumulative incidence plots. This secondary endpoint will be characterized and presented as a cumulative incidence.
  
  
• Overall survival [ Time Frame: At 1 year after transplantation ] [ Designated as safety issue: No ]
  Overall survival will be evaluated as Kaplan-Meier estimates.
  
  
• Disease-free survival [ Time Frame: At 1 year after transplantation ] [ Designated as safety issue: No ]
  Disease-free survival will be evaluated as Kaplan-Meier estimates.
  
  
• Hematologic recovery [ Time Frame: Up to day +100 ] [ Designated as safety issue: No ]
  Descriptive statistics will be used to assess the median days of neutrophil and platelet recovery. The day of neutrophil recovery is defined as the first day of three consecutive lab values on different days, after the conditioning regimen-induced nadir of blood counts, that the absolute neutrophil count is > 500/uL. The day of platelet recovery is defined as the first day of three consecutive lab values on different days, after the conditioning regimen-induced nadir of blood counts, that the platelet count is >= 20,000/uL without platelet transfusion support in the seven days prior.
  
  
• Graft failure [ Time Frame: By greater than or equal to 28 days post-transplant ] [ Designated as safety issue: No ]
  Descriptive statistics will be used to assess the incidence of primary graft failure and secondary graft failure. Primary graft failure is defined as failure to achieve a sustained neutrophil count of >= 500/uL by >= 28 days post-transplant. Secondary graft failure is defined as the decline in neutrophil count to < 500/uL after achieving engraftment which is unrelated to infection or drug effect and is unresponsive to stimulation by growth factors.
  
  

PRIMARY OBJECTIVES:

I. The primary objective of this study is to assess outcomes when high-dose cyclophosphamide (CY) is administered on days 3 and 4 followed by cyclosporine (CSP) after human leukocyte antigen (HLA)-matched related or unrelated mobilized blood cell transplantation with total-body irradiation (TBI) or busulfan (BU)-based conditioning.

SECONDARY OBJECTIVES:

I. The secondary objective of this study is to assess hematopoietic cell transplantation (HCT) outcomes when withdrawal of CSP is accelerated in patients without acute graft-versus-host disease (GVHD).

OUTLINE: Patients' conditioning regimens are determined by the Clinical Coordinator after consultation with the attending physician. Based on disease, patients receive either TBI or fludarabine and busulfan.

PREPARATIVE REGIMEN: Patients receive TBI twice daily (BID) on days -4 or -3 to -1. Some patients also receive fludarabine intravenously (IV) daily on days -5 to -2 and busulfan IV over 3 hours once daily (QD) or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo central nervous system (CNS) prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0 per standard practice.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at day 180 and then annually for 5 years.