To T-cell deplete or not

Comment on Pavletic et al, page 3308

After more than two decades of clinical practice, we finally have results from the first randomized study of T-cell depletion of donor marrow before allogeneic transplantation.

It has been clear for more than 20 years that ex vivo depletion of alloreactive T cells from donor marrow reduces the incidence of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation.¹  However the effect on chronic GVHD has been less well delineated. Single-center studies using T-cell depletion regimens producing a 2- to 4-log depletion report a low incidence of chronic GVHD,^2,3  but other studies using antibodies with narrower specificity have reported a high incidence.⁴  A retrospective registry study also showed that T-cell depletion did not reduce chronic GVHD when narrow specificity antibodies were used.⁵ 

In this issue of Blood, Pavletic and colleagues report the results of a study that for the first time examines the effect of T-cell depletion on the incidence of chronic GVHD in a prospective fashion. They report data from a National Heart, Lung, and Blood Institute (NHLBI)–sponsored phase 3 randomized study that compared outcomes with the use of unmanipulated marrow or T-cell–depleted marrow in unrelated transplant recipients. The authors also studied if there were factors that predict survival in patients with chronic GVHD. They confirm data from previous reports that the incidence of acute GVHD was much lower in the T-cell–depleted cohort but find no significant difference in the incidence of chronic GVHD or survival between recipients of T-cell–depleted or unmanipulated marrow. As the authors point out, this difference may reflect different pathogenesis of these 2 syndromes. Some factors associated with development of chronic GVHD (summarized in Pavletic et al's Table 1 and Figure 1), including older age and prior acute GVHD, have been described previously, but a new observation was the lower incidence seen in patients receiving higher CD34 doses. Prognostic factors for patients who developed chronic GVHD were also analyzed, and factors associated with a better outcome in each group were acute GVHD less than grade II, higher Karnofsky score, and a 6/6 matched donor.

Although this is the first randomized study to address this issue, there are some caveats that limit the conclusions. The first is that 2 T-cell depletion methodologies were used—elutriation and T10B9 antibody mediated with complement. Moreover each marrow manipulation regimen—the 2 T-depletion methods and the use of an unmanipulated product—was associated with a different conditioning regimen. As the authors point out, the comparison is therefore between the whole treatment “package” rather than marrow manipulation alone. An additional issue is that with both methodologies the degree of T-cell depletion was only one log so these conclusions cannot necessarily be extrapolated to other T-cell depletion regimens. A final confounding factor is that this study was initiated in 1995 when marrow was the only source of hematopoietic stem cells used for transplant from unrelated donors, and clinical practice has now changed so that peripheral blood is now a more common source of hematopoietic stem cells. Nevertheless, this report provides a basis for future studies comparing the effects of differing hematopoietic stem cell sources or manipulations on this devastating complication of transplantation. ▪