OCTET-CY: a phase II study to investigate the efficacy of post-transplant cyclophosphamide as sole graft-versus-host prophylaxis after allogeneic peripheral blood stem cell transplantation.

Acute graft-versus-host disease (GvHD) and chronic GvHD are major barriers to successful allogeneic stem cell transplantation (1). Standard prophylaxis regimens for GvHD comprise combinations of the calcineurin inhibitors cyclosporine or tacrolimus together with either methotrexate or mycophenolate mofetil (2–6). These combination strategies largely contribute to the acute toxicity of the procedure. Despite this prophylaxis, a significant proportion of patients still experiences GvHD (1). Furthermore, continuous immunosuppression (IS) delays immune reconstitution and may diminish the desired graft-versus-tumor effect as well as predispose to infections (7). Based on animal models on tolerance induction by cyclophosphamide (8–10), Luznik et al. (11) pioneered an approach using high-dose cyclophosphamide applied after transplantation in a murine model. Since then, post-transplant cyclophosphamide has been used as component of GvHD prophylaxis in the haploidentical setting (12–19). In the setting of matched donor transplantation, post-transplant cyclophosphamide has been used as single-agent GvHD prophylaxis in bone marrow transplantation after myeloablative conditioning with acceptable rates of acute and chronic GvHD (20–22). In these clinical trials, bone marrow was used as stem cell source, as it contains significantly lower T-cell numbers. Vice versa, based on higher T-cell numbers, the incidence of acute and chronic GvHD could be higher in peripheral blood transplants (23–25). No data have been published so far on post-transplant cyclophosphamide as single-agent GvHD prophylaxis in peripheral blood stem cell transplantation (PBSCT) in the non-haploidentical setting. For haploidentical transplantation, Castagna et al. (18) demonstrated similar results for peripheral blood and bone marrow transplants (acute and chronic GvHD 33% vs. 25% and 13% vs. 13%, respectively). In a matched-control analysis presented at ASH 2012, Alousi et al. (26) reported a significantly higher incidence of grade II–IV and grade III–IV acute GvHD as well as chronic GvHD in matched related or unrelated transplants and post-transplant cyclophosphamide as only GvHD prophylaxis when compared to patients receiving conventional GvHD prophylaxis. Thirty percent of these patients received peripheral blood transplants. A single center study recently demonstrated feasibility of peripheral blood transplants with post-transplant cyclophosphamide followed by short-term sirolimus as GvHD prophylaxis with cumulative incidences of grade II–IV acute GVHD, grade III–IV acute GVHD, all chronic GVHD, and severe chronic GVHD of 41%, 15%, 32%, and 12%, respectively (27). Post-transplant cyclophosphamide on day+3 and +4 after transplant is considered to act mainly on alloreactive T cells rapidly and early dividing upon encounter with patient cells (28–31). In the haploidentical setting, early and favorable immune recovery has been reported (17, 30, 32, 33). In this phase II pilot trial, we assessed the efficacy and safety of post-transplant cyclophosphamide as sole GvHD-prophylaxis as well as its impact on immune recovery in related and unrelated PBSCT following reduced-intensity conditioning in patients with myeloma or lymphoma.