A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease

Abstract

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01680965.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract

Figure 1.

Clinician- and NIH-based responses at 6 months among evaluable subjects compared with the benchmarks. Lower limit of 1-sided 90% CI for both MD- and NIH-defined ORR of 62.5% was 51.5% (Atkinson-Brown estimate), which exceeded benchmark estimate from BMT CTN 0801 (48.6%). Trial MD was the trial clinician–assessed response rate at 6 months; Trial H0 was the trial null hypothesis based on prior published clinician-assessed 6-month response rates in phase III cGVHD therapy trials; Trial NIH was the trial NIH 6-month response rate; CTN 0801 was the published NIH 6-month response rate in BMT CTN 0801 trial. *Atkinson-Brown 1-sided CI limit was 51.5%.

Figure 2.

Clinician-reported (MD) or NIH-calculated (NIH) responses at serial time points on trial. MR, mixed response; PD, progressive disease; SD, stable disease.

Figure 3.

Long-term study outcomes as measured by treatment failure and OS and FFS. (A) Cumulative incidence of treatment failure (death, relapse, and new systemic IST). (B) Overall and FFS.