Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

Abstract

We conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versus-host disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00089141 on August 4, 2004.

Figure 1

Flow diagram summarizing results of the randomization, administration of the study drug, and analysis of results at the end of the study.

Figure 2

Cumulative incidence of treatment success and treatment failure. The lower black curves and left scale represent the cumulative incidence of discontinued systemic treatment for chronic GVHD without secondary therapy for chronic GVHD, development of bronchiolitis obliterans, recurrent malignancy during primary treatment for chronic GVHD, or death during primary treatment for chronic GVHD; upper gray curves and right scale, cumulative incidence of treatment failure, including secondary therapy for chronic GVHD, development of bronchiolitis obliterans, recurrent malignancy during primary treatment for chronic GVHD, or death during primary treatment for chronic GVHD. The gap between the lower and upper curves indicates the proportion of patients continuing primary treatment for chronic GVHD without recurrent malignancy or development of bronchiolitis obliterans. Vertical line at 2 years represents the prespecified interval time designated for assessment of the primary endpoint; —, MMF group; and ----, control group.

Figure 3

Mean steroid doses, mean GVHD severity scores, and percentages of patients with complete response after randomization show no benefit of MMF for initial treatment of chronic GVHD. (A) Prednisone doses. (B) Mean National Institutes of Health severity scores and (C) prevalence of complete response (CR) across time among surviving patients without recurrent malignancy. (A,B) Bars represent ± SD. (C) The upper black curves represent relapse-free survival for reference. Changes in prevalence of CR (gray lines) can occur either with the onset or end of CR or with death or recurrent malignancy in the presence or absence of CR. In all panels: —, MMF group; and ----, control group.

Figure 4

Analysis of major outcomes shows no benefit of MMF for initial treatment of chronic GVHD. (A) Outcomes according to treatment arm. (B) Hazard ratio estimates and 95% confidence intervals for outcomes among patients in the MMF arm compared with those in the control arm. (A) — represent the MMF group; and ----, control group. (B) Hazard ratio estimates and confidence intervals were derived from Cox regression analysis stratified on the number of involved sites at onset (1 vs > 1) and conditioning regimen (myeloablative vs nonmyeloablative).