A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation

Abstract

Improvement of graft-versus-host disease prophylaxis remains an important goal in allogeneic hematopoietic stem cell transplantation. Based on reports of possibly preferential properties of sirolimus, we compared the standard regimen of cyclosporine and methotrexate (n=106) with a combination of tacrolimus and sirolimus (n=103) as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation in a prospective, open, randomized trial. The hypothesis was that the tacrolimus/sirolimus regimen would lead to less acute graft-versus-host disease and reduced transplant-related mortality. There was no significant difference in the cumulative incidence of acute graft-versus-host disease of grades II-IV (41% vs. 51%; P=0.19) or grades III-IV (13% vs. 7%; P=0.09) between the groups. Time to neutrophil engraftment (18 days vs. 17 days; P=0.24) was similar, but time to platelet engraftment was longer in cyclosporine/methotrexate patients (14 vs. 12 days; P<0.01). No significant differences in incidence of oropharyngeal mucositis, time to full donor chimerism, or number of cytomegalovirus infections were seen between the two treatment arms, and transplant-related toxicities were equally distributed. Triglyceride (P=0.005) and cholesterol (P=0.009) levels were higher in tacrolimus/sirolimus patients. Transplant-related mortality (18% vs. 12%; P=0.40) and 5-year overall survival (72% vs. 71%; P=0.71) were similar. Five-year relapse-free survival in patients with malignant diagnoses was 65% in the cyclosporine/methotrexate group and 63% in the tacrolimus/sirolimus group (P=0.73). We conclude that tacrolimus/sirolimus remains a valid and safe alternative to cyclosporine/methotrexate as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation, with comparable transplant-related outcomes. The trial was registered at clinicaltrials.gov identifier: 00993343.

Trial registration: ClinicalTrials.gov NCT00993343.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

CONSORT diagram and end points. Flow of patients enrolled in the trial. CR: complete remission; CP: chronic phase; RIC: reduced intensity conditioning; MAC: myeloablative conditioning; MUD: matched unrelated donor; CsA: cyclosporine; Mtx: methotrexate; Tac: tacrolimus; Sir: sirolimus; GvHD: graft-versus-host disease; HSCT: allogeneic hematopoietic stem cell transplantation; TRM: transplant-related mortality; OS: overall survival.

Figure 2.

Graft-versus-host disease (GvHD) outcomes. (A) Cumulative incidence of acute GvHD of grades II–IV. (B) Cumulative incidence of acute GvHD of grades III–IV. (C) Cumulative incidence of chronic GvHD. CsA: cyclosporine; Mtx: methotrexate; Tac: tacrolimus; Sir: sirolimus; GvHD: graft-versus-host disease; HSCT: allogeneic hematopoietic stem cell transplantation.

Figure 3.

Engraftment outcomes. (A) Cumulative incidence of neutrophil engraftment. (B) Cumulative incidence of platelet engraftment. CsA: cyclosporine; Mtx: methotrexate; Tac: tacrolimus; Sir: sirolimus; HSCT: allogeneic hematopoietic stem cell transplantation.

Figure 4.

Survival outcomes. (A) Overall survival (all patients). (B) Relapse-free survival (malignant diagnoses). CsA: cyclosporine; Mtx: methotrexate; Tac: tacrolimus; Sir: sirolimus; HSCT: allogeneic hematopoietic stem cell transplantation.