Graft-Versus-Host Disease: Have We Solved the Problem?

It has now been more than 40 years since Thomas et alat the Fred Hutchinson Cancer Research Center published their seminal article that demonstrated that patients with refractory acute leukemia could be cured with a combination of high-dose chemoradiotherapy and the allogeneic graft-versus-leukemia effect provided by the infusion of human leukocyte antigen (HLA) –compatible bone marrow from a sibling donor. However, in this early report, the limitations of allogeneic transplantation were obvious. Only the minority of patients with leukemia would have an HLA-compatible donor within their family, and many patients succumbed to the fatal complication of graft-versus-host disease (GVHD) mediated by alloreactive T cells. Much progress has been made in the field of allogeneic stem-cell transplantation (SCT) since that initial report. Reduced-intensity conditioning regimens have allowed the procedure to be extended to older and less-fit patients, and the use of alternative donor sources such as unrelated volunteer donors and cord blood transplantation has extended the ability to perform allogeneic SCT in patients without compatible family donors. Although significant advances have been made in supportive care, HLA typing, and management of many stem-cell transplant complications, a significant proportion of patients continue to have fatal complications primarily related to GVHD, infections, and disease recurrence. The articles that accompany this editorial highlight two potential strategies that might reduce GVHD without increasing the risk of relapse. In the first report by Koreth et al, a novel GVHD prophylaxis regimen, which included a short course of the proteasome inhibitor bortezomib, was used to prevent GVHD in patients undergoing a reduced-intensity-conditioning regimen with a mismatch unrelated donor. Bortezomib, which is a proteosome inhibitor that is extensively used for the treatment of patients with multiple myeloma and mantlecell lymphoma, was administered at doses that ranged from 1 to 1.5 mg/m on days 1, 4, and 7 after SCT in addition to standard tacrolimus and methotrexate. A total of 45 patients were treated in the study; 89% of patients were treated with a one-locus and 11% of patients were treated with a two-loci mismatch. With a median follow-up of 3 years, the 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22%, and the 1-year cumulative incidence of chronic GVHD was 29%. The nonrelapse mortality rate was only 11%, and the relapse rate was 38%. Results were comparable with patients who received HLAmatched transplants with the unexpected observation that bortezomib therapy enhanced immune reconstitution on the basis of measurements of CD8 T cells and natural killer cells. Until recently, it was felt that, in the context of HLA-mismatched transplantation, the only consistently effective measure to prevent serious acute and chronic GVHD reactions was ex vivo or in vivo T-cell depletion (TCD) with monoclonal antibodies, physical techniques, or CD34 purification methods. On the basis of the data presented by Koreth et al, bortezomib-based strategies can potentially join post-transplant cyclophosphamide and antithymocyte globulin as an effective strategy to prevent acute and chronic GVHD in the HLA-mismatch setting without ex vivo TCD. However, only a prospective comparative trial of all these approaches will clarify the relative benefits of one strategy over another. The second report in this issue of Journal of Clinical Oncology was authored by Pasquini et al and is a comparative analysis of transplant outcomes among patients treated in two different groups of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) in which GVHD prophylaxis consisted of either ex vivo TCD by using a CD34 selection device or the standard calcineurin inhibitor (CNI)/ methotrexate prophylaxis. Forty-four patients who received HLAidentical sibling TCD grafts by using a uniform technique for CD34 selection as the sole form of GVHD prophylaxis had their outcomes compared with those of 84 patients who received T-replete grafts and CNI/methotrexate prophylaxis on another BMT CTN protocol. Engraftment rates and kinetics were similar in both groups. Patients who received the TCD graft had significantly lower rates of chronic GVHD (19% v 50%; P .001). There were no differences in rates of graft rejection, leukemia relapse, treatment-related mortality, or disease-free and overall survival rates. The analysis performed by Pasquini et al is a timely report. The last randomized trial of ex vivo TCD versus standard immuneprophylaxis was published more than 5 years ago and involved patients who were treated between 1995 and 2000. In that trial, patients with a variety of hematologic malignancies were randomly assigned to receive an ex vivo TCD marrow transplant by using monoclonal antibody techniques or counter flow elutriation or standard immuneprophylaxis with cyclosporine and methotrexate. As expected, patients who received the TCD marrow had lower rates of acute GVHD grades 2 to 4 (39% v 63%) but surprisingly similar rates of chronic GVHD (29% v 34%). Disease-free survival was similar for patients with acute leukemia but was inferior for patients with chronic myelogenous leukemia because of an increased risk of relapse. Unfortunately, the results of this randomized TCD trial are of little relevance today JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 26 SEPTEMBER 1