Since the development of allogeneic stem cell transplantation in the 1970s, the question of how to optimize the number and activity of donor T cells in the early transplant period has dominated the development of transplant regimens. Given the exquisite sensitivity of the immune system and the substantial genetic differences between siblings, it is no surprise that the donor immune system recognizes the patient as “foreign” and mounts a vigorous immune response. However, this alloreactive response is both damaging, in that it mediates graft-versus-host disease (GVHD), and beneficial, as it underlies the graft-versus-leukemia effect that helps to reduce disease relapse. As with many aspects of life, this balance has proven difficult to achieve, and interventions such as vigorous T-cell depletion, or the early infusion of additional T cells, have both led to clinical problems.
The administration of antithymocyte globulin (ATG) to patients around the time of transplantation is one of several approaches that have been introduced for T-cell depletion. Compared with the sophistication of modern targeted drugs, ATG has an almost elixir-like quality, as it is made from the purified immunoglobulin of rabbits that have been immunized with a human thymocyte cell line. In their article, Dr. Nicolaus Kröger and colleagues performed an open-label study in which ATG was administered in the three days before transplantation in a cohort of 168 patients with a primary diagnosis of acute leukemia who were undergoing myeloablative transplantation from a sibling donor. Clinical trials have been challenging to perform in the transplant setting, and the delivery of this study is therefore a significant achievement in its own right.
The major outcome of the study is that the incidence of chronic GVHD was more than halved, from 68.7 percent in the control group to 32.2 percent in the treatment arm. Chronic GVHD is a poorly understood and often debilitating condition with a wide range of clinical manifestations, and this reduction is therefore of great significance for improving the quality of life for patients. At this stage in reading the article, transplant physicians would probably turn to the information on disease relapse and might anticipate that this benefit of reduced GVHD would be offset by an increase in disease relapse. But the remarkable finding of this study is that there was no statistically significant decrease in two-year relapse-free survival associated with the use of ATG. Indeed, at this point of follow-up, the percentage of patients who had not relapsed and who remained free of chronic GVHD more than doubled from 16.8 percent to 36.6 percent.
In Brief
ATG is a three-day treatment course given prior to transplantation, and the results of this study suggest that it has an important role in this setting. It should be noted that reduced-intensity conditioned transplantation is now a common transplant regimen, and the role of ATG in this setting remains uncertain. This is an important incremental advance for clinical transplantation. However, the observation that only 37 percent of patients remained free of both disease relapse and chronic GVHD at two years after transplantation indicates that further opportunities remain to increase the efficacy and tolerability of this extraordinary procedure.
Competing Interests
Dr. Moss indicated to relevant conflicts of interest.
