A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft- versus-host disease: BMT CTN 0801

Abstract

Initial therapy of chronic graft-versus-host disease is prednisone ± a calcineurin-inhibitor, but most patients respond inadequately. In a randomized, adaptive, phase II/III, multicenter trial we studied whether prednisone/sirolimus or prednisone/sirolimus/photopheresis was more effective than prednisone/sirolimus/calcineurin-inhibitor for treating chronic graft-versus-host disease in treatment-naïve or early inadequate responders. Primary endpoints of this study were proportions of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III. The prednisone/sirolimus/photopheresis arm closed prematurely because of slow accrual and the remaining two-drug versus three-drug study ended in phase II due to statistical futility with 138 evaluable subjects. The two-drug and three-drug arms did not differ in rates of 6-month complete or partial response (48.6% versus 50.0%, P=0.87), or 2-year complete response (14.7% versus 15.5%, P=0.90). Serum creatinine values >1.5 times baseline were less frequent in the calcineurin-inhibitor-free arm at 2 months (1.5% versus 11.7%, P=0.025) and 6 months (7.8% versus 24.0%, P=0.016). Higher adjusted Short Form-36 Physical Component Summary and Physical Functioning scores were seen in the two-drug arm at both 2 months (P=0.02 and P=0.04, respectively) and 6 months (P=0.007 and P=0.001, respectively). Failure-free survival and overall survival rates at 2 years were similar for patients in the the two-drug and three-drug arms (48.6% versus 46.2%, P=0.78; 81.5% versus 74%, P=0.28). Based on similar long-term outcomes, prednisone/sirolimus is a therapeutic alternative to prednisone/sirolimus/calcineurin-inhibitor for chronic graft-versus-host disease, being easier to administer and better tolerated. Clinicaltrials.gov identifier: NCT01106833.

Figure 1.

BMT CTN 0801 Consort flow diagram. ECP: extracorporeal photopheresis; PDN: prednisone; SRL: sirolimus; CNI: calcineurin inhibitor.

Figure 2.

Overall survival, progression-free survival, and failure-free survival. (A) Probability of overall survival by treatment arm (P=0.281). (B) Probability of progression-free survival by treatment arm (P=0.142). Progression-free survival was defined as no clinical evidence of progression or relapsed disease, or any therapy used to treat persistent, progressive, or relapsed disease including withdrawal of immunosuppressive therapy or donor lymphocyte infusion. (C) Probability of failure-free survival in the (C) sirolimus + prednisone (2-drug) arm and (D) control (3-drug) arm. Failure-free survival was defined by the absence of secondary immunosuppressive therapy for chronic graft-versus-host disease, non-relapse mortality, and recurrent or progressive malignancy during treatment. Note: the numbers shown are estimates at each time point for each endpoint. Siro/Pred: sirolimus + prednisone; NRM: non-relapse mortality; FFS: failure-free survival.

Figure 3.

Cumulative incidence of discontinuation of all systemic immunosuppressive therapy without the need to add additional therapy by 2 years.

Figure 4.

Quality of life. Unadjusted graphs are shown for SF-36 quality of life scores:23 (left) Physical Component Summary scores; (right) Physical Functioning subscale scores.

Figure 5.

Six-month landmark analysis. (A) Overall survival after the 6-month landmark with a median follow up for survivors of 30 months. The mortality rates after the 6-month landmark were similar in the complete or partial response group and stable or progressive disease group (hazard ratio, 0.71; 95% confidence interval: 0.17–2.96; P=0.63) or secondary treatment groups (hazard ratio, 0.54; 95% confidence interval: 0.13–2.26; P=0.39), respectively. (B) Cumulative incidence of discontinuation of immunosuppressive therapy after the 6-month landmark. Patients who died or were lost to follow up or experienced relapse before the landmark were excluded (n=19) and no patients ended immunosuppressive therapy before the landmark. CR/PR: patients with complete or partial response without relapse and without secondary therapy at the time of assessment (n=68). SD/PD/Rx: patients not in complete or partial response and alive without relapse and without secondary therapy at the time of assessment (n=31), and patients who had secondary therapy without relapse regardless of response before the landmark (n=16); IST: immunosuppressive therapy.