Modified Bone Marrow Stem Cell Transplantation for Chronic Myelogenous Leukemia

CML is a disease which progresses to blast crisis within five years of onset despite medical intervention. Allogeneic transplantation has provided a definitive cure for a large number of patients. The International Bone Marrow transplant registry reports a 67% three-year disease free survival for CML patients receiving a matched sibling transplant. However there remains a 17-20% treatment-related mortality and significant long-term complications. Myeloablative regimens with total body irradiation (TBI) are associated with certain sterility, along with a significant incidence of cataracts and second malignancies. Efforts to ameliorate this toxicity have led to the development of regimens lacking total body irradiation. Although the follow-up period for patients receiving these regimens has not been long enough to answer the question of long-term toxicity, it appears that the response rate and the disease free survival are comparable to regimens containing TBI. In addition, transplantation experience with aplastic anemia where TBI is not part of the regimen indicates that treatment related mortality along with the risk of long-term sequela are significantly decreased.

Non-myeloablative allogeneic peripheral blood stem cell transplants are currently being investigated in phase I/II trials assessing engraftment efficacy and toxicity at a number of transplant centers. Preliminary data, including our own experience with 30 patients undergoing this type of procedure, has shown a high rate of complete donor engraftment with a low toxicity profile. Two recent studies investigating non-myeloablative allo-transplantation in standard risk patients revealed an extremely low rate of transplant-related complications and mortality.

In this protocol we investigate non-myeloablative allogeneic PBSC transplantation in patients with CML. The patient group under study would include all patients with chronic phase CML having an HLA-identical sibling. In this protocol, eligible patients would be treated with an allogeneic peripheral blood stem cell transplant from an HLA identical or single HLA antigen-mismatched family donor, using an intensive immunosuppressive regimen without myeloablation ("mini-transplant") in an attempt to decrease the transplant related toxicities while preserving the anti-malignancy and/or anti-host marrow effect of the graft. The low intensity non-myeloablative conditioning regimen should provide adequate immunosuppression to allow stem cell and lymphocyte engraftment. T-cell replete, donor-derived, granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) will be used to establish hematopoietic and lymphoid reconstitution. We will add back lymphocytes in patients with less than 100% donor T-cell chimerism in an attempt to prevent graft rejection and enhance a graft-versus-malignancy effect.

The primary endpoint of this study is transplant related mortality (1 year survival). Other end points include engraftment, degree of donor-host chimerism, incidence of acute and chronic graft versus host disease (GVHD), transplant related morbidity, as well as disease-free and overall survival.