The Role of Purine Analogues in Low-Intensity Regimens With Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Host conditioning prior to allogeneic bone marrow transplantation (BMT) has traditionally involved the use of high-dose, myeloablative chemotherapy and irradiation, focusing on maximal tumor cytoreduction as well as adequate immunosuppression to allow engraftment of allogeneic stem cells. High-dose chemoradiation conditioning regimens have been associated with a significant incidence of organ toxicity and acute and chronic graft-versus-host disease (GVHD). Recent efforts to diminish the acute transplant-associated toxicities have focused on the development of relatively nontoxic, nonmyeloablative, or less myeloablative conditioning regimens, with the emphasis being predominantly on induction of immunosuppression to enable engraftment. Without ablative chemotherapy, disease control in these regimens is largely relegated to the graft-versus-leukemia/lymphoma (GVL) effect. While the evolution these regimens has resulted in successful engraftment of allogeneic stem cells with minimal toxicity, acute and chronic GVHD occurs in 20% to 50% of patients and remains a major cause of transplant-associated morbidity. Strategies to lower the incidence of acute GVHD have primarily focused on more precise molecular donor/recipient matching, alternative stem cell sources, and T-cell depletion of the graft. While successful in lowering the frequency and severity of GVHD, T-cell-depleted grafts have been associated with compromised the graft-versus-disease effect. Recent studies have suggested that, in addition to T-effector cells within the graft, donor and host dendritic cells may play a role in GVHD. Purine analogues have been evaluated as part of these regimens. While fludarabine and cladribine have been shown to be effective, these agents have been associated with an increased incidence of serious infection and severe acute GVHD. Pentostatin has a different mechanism of action and was also investigated as part of these preparative regimens. Regimens using pentostatin/extracorporeal photopheresis (ECP)/total body irradiation (TBI) have been shown to be well tolerated and associated with early full donor engraftment with a predominance of donor dendritic cell (DC)2 cells and a low incidence of acute GVHD. Further investigation evaluating this preparative regimen is warranted.