Non-Myeloablative Allogeneic Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Hematologic Malignancies in High Risk Patients and in Patients With Debilitating Hematologic Diseases

Patients with malignant and non-malignant hematologic diseases including severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), acute and chronic leukemias, Hodgkin's and non-Hodgkin's lymphoma and multiple myeloma (MM) can now be cured by allogeneic bone marrow transplantation (BMT). This curative effect has been ascribed to the use of high dose chemo-radiotherapy and the anti-tumor or anti-bone marrow effect of the allograft. Dose intensification of conditioning regimens in attempts to reduce disease recurrence has been largely unsuccessful because of increased toxicity and mortality. Indeed, most evidence now points to donor-derived T-cells as being the principal modality leading to the complete eradication of both malignant and non-malignant host hematopoietic cells. The assumption that successful allogeneic BMT relies on the myeloablative effect of intensive but hazardous chemo-radiotherapy has largely restricted this therapeutic modality to patients with malignant or life-threatening hematologic disorders under the age of 55 years. Treatment-related mortality increases substantially with age, prior intensive treatment with chemo-radiotherapy, worsening performance status, and co-morbid medical conditions. An unacceptable risk of death from conventional BMT renders many patients ineligible for what may otherwise be curative therapy. Several in vitro studies have demonstrated the existence of donor-derived CD4 and CD8 positive lymphocytes with specific reactivity for the patient s leukemia. These cells provide a potent graft-versus-leukemia (GVL) effect. This GVL effect is best seen in patients with CML relapsing after BMT, where a single infusion of donor lymphocytes has been shown to induce complete remission. In addition to the potent anti-leukemia effect of these cells, there is now strong evidence that donor T-cells are capable of completely eradicating residual host hematopoietic cells in a non-myeloablative transplant setting (graft-versus-marrow) leading to successful and complete donor hematopoietic engraftment. Non-myeloablative allogenic 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 greater than 150 patients undergoing this type of procedure, have 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. The decreased risk of transplant-related complications associated with non-myeloablative transplants expands the eligibility of transplant candidates as well as opens the possibility to evaluate non-myeloablative regimens in patients at high risk for complications with standard transplantation. Besides hematologic malignancies, allogeneic BMT has been shown to be curative in a number of debilitating hematologic diseases which may behave in a relatively indolent fashion, such as paroxysmal nocturnal hemoglobinuria (PNH) and refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS). However, the 30% risk of treatment-related mortality (TRM) with standard myeloablative allotransplantation usually precludes these patients from potentially curative therapy, because of concerns about shortening life in patients with these disorders. In this protocol we investigate non-myeloablative allogeneic peripheral blood stem cell (PBSC) transplantation in two groups of subjects where standard allogeneic transplantation is considered to have unacceptable toxicity. Group A: Subjects with hematologic malignancies with factors putting them at high risk for transplant related complications and mortality, including prior intensive chemo-radiotherapy and co-morbid diseases. Group B: Subjects with hematologic diseases (both clonal and non-clonal) associated with reasonable longevity not currently considered for allogeneic BMT because of prohibitive procedural mortality with conventional BMT (enrollment closed October 2010). In this protocol, eligible subjects are treated with an allogeneic PBSC transplant from an HLA identical or single HLA antigen-mismatched family donor, using an intensive immunosuppressive regimen without myeloablation 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 PBSCs will be used to establish hematopoietic and lymphoid reconstitution. We will add back lymphocytes in recipients 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 (200 day 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.