Second hematopoietic SCT for leukemia relapsing after myeloablative T cell-depleted transplants does not prolong survival.

Patients with leukemia relapsing after allogeneic hematopoietic SCT have a dismal prognosis. A second SCT offers a further opportunity for cure, but has a high rate of treatment failure. To determine the utility of this option, we analyzed 59 consecutive patients relapsing after a myeloablative HLA-matched sibling T cell-depleted (TCD) SCT. Twenty-five patients (13 relapsing within 6 months and 12 relapsing between 6 and 170 months after the first SCT) received a T-replete second SCT. Thirty-eight patients relapsing early had a shorter survival than the 21 patients relapsing later (median 96 vs 298 days, P=0.0002). In patients relapsing early, the second SCT did not improve OS compared with patients receiving non-SCT treatments (median survival 109 vs 80 days, P=0.41). In patients relapsing late, despite an early trend in favor of second SCT, survival was comparable for patients receiving a second SCT compared with non retransplanted patients (median survival 363.5 vs 162 days, P=0.49). Disappointingly, our results do not demonstrate an important survival benefit for a second T-replete allogeneic SCT to treat relapse following a TCD SCT.

Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation.

Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vbeta) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vbeta family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.