Objectives

To estimate the difference in day 28 complete response/partial response rates for sirolimus vs prednisone as initial treatment of patients with standard risk acute graft-versus-host disease.

Background

Acute graft-versus-host disease (GVHD) frequently occurs after allogeneic hematopoietic cell transplantation (HCT). The standard treatment has been high-dose corticosteroids, which are only effective in about half of patients and have significant toxicities.

Recently, clinical and blood biomarker-based tools have been developed to estimate the likelihood of initial response to steroid treatment and subsequent risk for mortality in acute GVHD. The Minnesota (MN) GVHD Risk Score uses acute GVHD organ involvement and severity to identify standard-risk (SR) vs high-risk (HR) status at onset of GVHD. The Ann Arbor (AA) biomarker risk uses 2 serum biomarkers at acute GVHD onset to generate a score from 1 to 3, with higher scores indicating greater mortality risk. Although published clinical trials have examined varied initial steroid doses according to acute GVHD severity, prospective multicenter trials employing novel clinical and biomarker tools for risk-adapted GVHD therapy have not been performed.

The BMT CTN 1501 study was initiated to examine the activity of sirolimus vs prednisone therapy in the initial treatment of patients with a combined SR (MN-SR; AA1/2 biomarker risk) acute GVHD profile.

Participants

Eligible patients had MN-SR acute GVHD not previously treated with systemic acute GVHD therapy. An absolute neutrophil count higher than 500/μL was required for participation. Patients were excluded if they had prior therapy with sirolimus within 14 days of enrollment, prior donor lymphocyte infusion, or transplant associated microangiopathy (TMA) within 7 days of enrollment.

A total of 127 subjects were enrolled. Of the 122 subjects identified as AA1/2 risk status, 64 were randomized to the prednisone group and 58 to the sirolimus group.

Design

The BMT CTN 1501 study was a multicenter, randomized, phase 2 trial comparing sirolimus vs standard prednisone therapy among patients with newly diagnosed MN-SR, AA biomarker 1/2 acute GVHD. Randomization was performed in a 1:1 ratio, using permuted blocks and stratified by HCT center. Randomized therapy began within 24 hours of randomization. A 5-mL blood sample was collected at randomization to centrally assess biomarker status. Those identified as AA1/2 risk status continued their randomized therapy and informed all primary and secondary outcome analyses.
Sirolimus (as tablet or oral solution) was given as a loading dose (6 mg orally once for those aged >12 years, or 5 mg/m2 orally once for those aged ≤12 years), followed by maintenance to continue therapeutic levels through at least 56 days (10-14 ng/mL until acute GVHD resolution, then 5-10 ng/mL after resolution until at least day 56). Prednisone (or prednisone dose-equivalent) was initiated at 2 mg/kg/day and required to remain at this dose for 3 days. A suggested taper was provided that decreased to 1 mg/kg/day after 7 days, 0.5 mg/kg/day at week 2, 0.25 mg/kg/day at week 3, 0.2 mg/kg/day at week 4, 0.1 mg/kg/day at week 5, 0.1 mg/kg/day every other day at week 6, and off at week 7. This suggested taper would allow patients with treatment-responsive GVHD in the prednisone group of the trial to reach less than 0.25 mg/kg by the day 28 assessment.

The primary objective was to estimate the difference in day 28 complete response (CR)/partial response (PR) rates. A score of 0 in all GVHD organs was considered a CR. Improvement in target organ(s) without progression in others was considered a PR. A predefined key secondary end point was the rate of day 28 CR/PR with prednisone dose 0.25 mg/kg/day or less. Prednisone use after randomization to sirolimus was considered a failure for the primary outcome, but not for the key secondary outcome, provided it remained below the threshold.

Conclusions

For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life.

Pidala J, Hamadani M, Dawson P, et al. Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial. Blood. 2020;135(2):97-107. doi:10.1182/blood.2019003125

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