A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation

Abstract

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).

Trial registration: ClinicalTrials.gov NCT00105001.

Figure 1.

Donor granulocyte and T-cell chimerism. Percent donor granulocyte (A) and T-cell chimerism (B) in arm 1 (n=69), arm 2 (n=71) and arm 3 (n=68). Horizontal lines represent medians, and dots represent the individual data points. P values are two-tailed.

Figure 2.

Graft-versus-host disease and use of systemic steroids. Cumulative incidence of grade II to IV acute (A) and chronic (B) GvHD among patients in arm 1 (n=69), arm 2 (n=71) and arm 3 (n=68). (C) Cumulative incidence of use of systemic steroids in arm 1 (n=69), arm 2 (n=71) and arm 3 (n=68).

Figure 3.

Viral infections. Cumulative incidence of cytomegalovirus reactivation in arm 1 (n=69), arm 2 (n=71) and arm 3 (n=68).

Figure 4.

Non-relapse mortality and relapse or progression. (A) Cumulative incidence of non-relapse mortality among patients in arm 1 (n=69), arm 2 (n=71) and arm 3 (n=68). (B) Cumulative incidence of relapse or progression among patients in arm 1 (n=69), arm 2 (n=71) and arm 3 (n=68).

Figure 5.

Progression-free and overall survival. Cumulative incidences of progression-free survival (A) and overall survival (B) among patients in arm 1 (n=69), arm 2 (n=71) and arm 3 (n=68).