Outpatient allografting in hematologic malignancies and nonmalignant disorders--applying lessons learned in the...

The novel allogeneic transplant approach outlined in this chapter proposes the dual concepts that currently used intensive cytoreductive conditioning programs can be successfully replaced by nonmyeloblative immunosuppression and that stem cell grafts create marrow space for engraftment through subclinical GVH reactions. Immunosuppression can be conceptually divided into two parts, one targeted exclusively towards host cells before transplantation, and the other aimed at both host and donor T lymphocytes after transplantation. The resultant effect is to either establish mutual graft-host tolerance as reflected by stable mixed donor-host chimerism or accomplish complete donor chimerism. Preclinical studies have demonstrated the feasibility of this new approach in the context of MHC-identical transplants in young canines. Early data from the dog model of severe hereditary hemolytic anemia suggest that mixed chimerism can partially correct the phenotypic expression of disease, but that complete chimerism will be necessary to halt the continued hemolytic process of the host type minority red blood cell population. In contrast, mixed chimerism would be expected to correct disease manifestations of other severe hereditary red blood cell disorders such as sickle cell disease. The early results in human patients with hematological malignancies have demonstrated the feasibility of establishing hematopoietic engraftment using a nonmyeloblative conditioning regimen. Using this regimen, transplants were performed in the outpatient setting, and the need for transfusion support was minimal. Preliminary information suggests that mixed chimerism does not appear to be stable in this older patient population, with most patients progressing to full donor chimerism and a small minority rejecting. Complete disease responses and molecular remissions have been observed in a significant proportion of patients, suggesting that adoptive immunotherapy may not be necessary in most cases. However, in those patients that engraft with at least mixed chimerism and develop progression of the underlying malignancy, DLIs can be used for subsequent adoptive immunotherapy. The feasibility and safety of the outpatient approach for MHC-nonidentical transplantation has been demonstrated. Graft rejection appears to have been corrected by the addition of fludarabine to the nonmyeloablative conditioning regimen for the recipients of HLA-identical sibling allografts. Despite most recipients of MHC-nonidentical transplantation having sustained engraftment, some rejections have been observed. Studies are ongoing to identify the risk factors for rejection after unrelated HSCT to ensure uniform engraftment in future studies.