Reduced intensity allogeneic transplantation: updated results using alternative regimens

The use of reduced-intensity conditioning (RIC) regimens for hematologic malignancies and solid tumors has been designed to reduce treatment-related mortality (TRM) and provide a platform of durable donor engraftment in order to exploit a graft-versus-tumor effect. First-generation regimens were designed to be primarily immunosuppressive in an effort to facilitate donor engraftment. However, the lack of significant antitumor effects of some regimens has been a problem, allowing disease progression prior to the development of any graft-versus-tumor effects. Furthermore, graft-versus-host disease (GVHD) remains a significant clinical problem.

In this issue of Blood, 2 reports of alternative RIC regimens are included. Faulkner and colleagues (page 428) evaluated 65 patients with lymphoproliferative disorders treated with an RIC regimen consisting of alemtuzumab (Campath) and BEAM (BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], etoposide, cytarabine, and melphalan) followed by transplantation involving an HLA-matched sibling (n = 57) or a matched unrelated donor (n = 6). At a median follow-up of 1.4 years, 37 of 65 patients remain alive in complete remission. Acute GVHD (grades I-II) occurred in 11 (17%) of 64 patients. The estimated one-year TRM was 8% for patients receiving their first transplant but 57% for those patients who had received a prior autologous transplant. Histologic diagnosis of aggressive non-Hodgkin lymphoma and age at transplantation of older than 46 years were significantly associated with a higher relapse rate and worse event-free survival.

In a second report, Blaise and colleagues (page 435) evaluated a regimen consisting of fludarabine, antithymocyte globulin (ATG), and busulfan for the treatment of refractory solid tumors consisting of renal cell carcinoma, breast carcinoma, malignant melanoma, and ovarian carcinoma. The TRM with this regimen was low at 9%, and the overall response rate was 14%. Patients without disease progression at the time of transplantation had an improved response. Responses were seen in all tumor types with the overall cumulative incidence of acute GVHD at 65% and chronic GVHD at 44%.

Both of these studies demonstrate a proof of principle for the RIC regimens. Continuous alterations in an attempt to increase the antitumor effects while decreasing GVHD are evolving. The data so far have demonstrated promising results in the indolent lymphoproliferative disorders and Hodgkin disease in some patients; however, most studies in aggressive non-Hodgkin lymphomas and solid tumors have not demonstrated as much disease responsiveness. Alterations with a moderate increase in the antitumor effects and the addition of immune suppressive agents and/or monoclonal antibodies may improve the disease control while decreasing the GVHD associated with allogeneic transplantation. These 2 studies represent a step in the right direction; however, additional improvements will be needed to increase the antitumor effects, particularly in patients with aggressive lymphoma and solid tumors.