Graft-vs.-lymphoma effect in various histologies of non-Hodgkin's lymphoma

Abstract

Generally, there is a significantly lower risk of lymphoma relapse following allogeneic than after autologous stem cell transplant. Factors contributing to this lower risk of relapse include an absence of the use of ablative conditioning, with a tumor-free graft, and the generation of a graft-vs.-tumor (GVT) immune response. Allogeneic transplantation, however, has the possibility of graft-vs.-host disease (GVHD). The use of autologous and conventional allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma, diffuse large cell lymphoma, chronic lymphocytic leukemia and multiple myeloma is discussed. Due to a 1-year transplant-related mortality of 30-40% and complications caused by GVHD, conventional, myeloablative, allogeneic transplantation is a high-risk option for low-grade lymphoproliferative disorders. Novel applications of allogeneic HSCT are described that take advantage of a GVT effect while reducing the risk of GVHD. Minimally myelotoxic pretransplant conditioning regimens allow host antigen-presenting cells to persist, enabling presentation of host minor histocompatibility antigens to donor T cells, causing a GVT response. Although complications may arise due to GVHD, non-myeloablative HSCT can be offered to patients previously ineligible for conventional high-dose treatment. A protocol developed in Seattle using a low-dose total body irradiation (TBI)-based conditioning regimen with immunosuppression using mycophenolate mofetil in combination with cyclosporin has been used in a multicenter trial. To overcome the problem of graft rejection fludarabine was later added to the protocol. A second protocol from a smaller trial used a preparative, conventional-dose regimen of fludarabine, given with cyclophosphamide. Rituximab was also given to provide synergistic action with the chemotherapy to enhance tumor control in the early post-transplant period to allow time for the establishment of the GVT effect. Following transplantation, GVHD prophylaxis was given using tacrolimus with methotrexate. A trial of a further variation of allogeneic HSCT, tandem auto/allo transplants, is described. First, high-dose therapy with autologous PBSC rescue was used to cytoreduce the disease. This was followed by a reduced-intensity or non-myeloablative allogeneic graft. This procedure was devised to take advantage of high-dose therapy and allogeneic HSCT. Results for non-myeloablative allogeneic HSCT are particularly promising in low-grade NHL and the GVT effect may augment response and delay or prevent relapse. However, for aggressive disease, non-myeloablative regimens are only indicated for patients with minimal disease, as the non-myeloablative regimens are unable to control the tumor before the generation of a GVT effect, and/or lack the ability to control rapidly proliferating disease. Patients with relapsed disease may require a higher-dose regimen or tandem transplant approach.