Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation

Abstract

Sirolimus is an effective agent used in graft-versus-host disease (GVHD) prophylaxis after allogeneic transplantation. It also has antiproliferative effects on vascular endothelium when used to coat coronary artery stents. We noted an excess of veno-occlusive disease (VOD) in a clinical trial, and retrospectively reviewed the records of 488 patients to determine the association between sirolimus and VOD. When used with cyclophosphamide/total body irradiation (Cy/TBI) conditioning, sirolimus is associated with an increased incidence of VOD (OR 2.35, P = .005). The concomitant use of methotrexate further increased this rate (OR 3.23, P < .001), while sirolimus without methotrexate was not associated with an increased risk of VOD (OR 1.55, P = .33). Mortality after VOD diagnosis was unaffected, and overall treatment-related mortality was lowest when sirolimus was used without methotrexate. Similar findings were noted in matched, related, and unrelated as well as mismatched donor subgroups. When used with busulfan-based conditioning, sirolimus use was associated with an even higher rate of VOD (OR 8.8, P = .008). Our findings suggest that sirolimus use is associated with VOD after TBI-based transplantation when used with methotrexate after transplantation. Sirolimus-based GVHD prophylaxis without methotrexate is associated with the greatest overall survival. Myeloablative doses of busulfan should not be used with sirolimus-based immunosuppression.

Figure 1

Treatment-related mortality. Treatment-related mortality was examined in a competing risk fashion, with relapse as the competing risk. The 1-year cumulative incidence of TRM in the Tac/Sir group was 13% compared with 30% in the Tac/Sir/Mtx group and 26% in the Tac/Mtx group (P < .001).

Figure 2

Overall survival of Cy/TBI-treated patients. Three-year survival in the Tac/Sir group is 68% in comparison to 37% in the Tac/Sir/Mtx group and 47% in the Tac/Mtx group (P < .001).

Figure 3

Overall survival of MRD and MUD/MM CyTBI patients. (A) Overall survival of MRD (A) and MUD/MM (B) Cy/TBI patients. Overall survival was significantly better in the Tac/Sir group in comparison with the Tac/Sir/Mtx and Tac/Mtx in both the MRD (P = .05) and MUD/MM groups (P = .005).