Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide

Abstract

The intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell-replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.

Figure 1.

Global burden of immunosuppression. (A) The cumulative incidences of initiation of a corticosteroid (left panel), CNI (center panel), or any nonsteroidal systemic pharmacologic or phototherapeutic immunosuppressant agent including a CNI (right panel) are shown for each of the 4 groups: BuCy conditioning with MRD allografting, BuFlu conditioning with MRD allografting, BuCy conditioning with MUD allografting, and BuFlu conditioning with MUD allografting. These analyses included immunosuppression (IS) use for any reason including treatment of acute or chronic GVHD, treatment of engraftment syndrome, treatment of GVHD occurring after DLI or second allogenic transplant, and prophylaxis for second allogeneic transplant in those requiring it for graft failure or relapsed disease. The only competing risk for these cumulative incidence curves was death. (B) The number of immunosuppressive agents with which each patient was being treated at the end of each 30-day interval is shown throughout the first posttransplant year for each of the 4 groups. No patients ever required >4 agents simultaneously. (C) For each of the 4 groups, multistate modeling shows the instantaneous probability of being in 1 of 3 states: (1) alive, not on immunosuppression (Alive, No IS), (2) alive, on immunosuppression (IS), or (3) dead (Death). All patients started in state 1 on day +5 of transplant after receiving cyclophosphamide 50 mg/kg per day on posttransplant days +3 and +4. Patients could transition between the states of being alive and on or off immunosuppression, but death was an absorbing state.