Objectives

For the phase II component, to compare the responses of patients with graft-versus-host disease who received sirolimus/calcineurin inhibitor plus prednisone versus sirolimus plus prednisone after 6 months of therapy. For the phase III component, to compare the proportion of subjects with complete resolution of all reversible manifestations at 24 months after starting therapy.

Background

Chronic graft-versus-host disease (cGVHD) is the major treatment-related complication among patients who survive after allogeneic hematopoietic cell transplantation (HCT). Standard immunosuppressive therapy (IST) with prednisone ± a calcineurin inhibitor (CNI) has not changed for three decades, but most patients respond inadequately with slow and most often incomplete control of their disease. Renewed understanding of regulatory T cells (Tregs) led to the hypothesis that experimental therapies permissive of Treg expansion would better abrogate GVHD than CNI-containing (control) IST. Sirolimus and extracorporeal photopheresis (ECP) are permissive of Treg expansion. Because of their acceptance in clinical practice, sirolimus and ECP were considered good candidates for adding to prednisone in clinical trials in cGVHD.

Participants

Adult and pediatric allogeneic HCT recipients were eligible if they had classic cGVHD ± acute GVHD (overlap subtype) that met 2005 NIH diagnostic consensus criteria. This included newly diagnosed patients, defined as individuals who had received <14 days of prednisone (or equivalent) before randomization to the study therapy, or previously treated, but responding inadequately after ≤16 weeks of initial therapy with prednisone and/or a CNI ± an additional non-sirolimus agent started at the time that the chronic GVHD was diagnosed. Patients were ineligible if they had an invasive fungal or viral infection not responding to appropriate therapies.

One hundred patients were evaluated for the phase II primary endpoint after all had completed 6 months of follow-up. All 151 enrolled subjects were followed for phase III endpoints. 77 patients were randomized to the prednisone/sirolimus arm and 74 patients to the prednisone/sirolimus/CNI arm.

Design

The trial was designed as an adaptive phase II/III randomized, open-label, prospective study of three treatments for chronic GVHD. Phase II was to include two parallel, 100-patient, randomized trials, comparing prednisone/sirolimus or prednisone/sirolimus/ECP versus identical (prednisone/sirolimus/CNI) comparator arms, where centers selected only one trial in which to participate. However, the prednisone/sirolimus/ECP arm was closed prematurely due to poor accrual. Comparison of complete/partial response rates did not support proceeding to phase III and further accrual was suspended.

The starting dose of prednisone (or prednisone-equivalent) was 1 mg/kg once daily, unless contraindicated, in which case the prednisone dose began at 0.5–1 mg/kg once daily. It was recommended that the dose of prednisone was tapered down, over 4–8 weeks to reach a dose of 0.5–1 mg/kg every other day, with the tapering starting within 2 weeks after the first evidence of GVHD improvement. Once an every-other-day prednisone (or equivalent) regimen was achieved, this dose remained constant for 10–12 weeks until all reversible chronic GVHD manifestations resolved. The sirolimus therapy began at a dose of 2 mg orally once daily (1 mg/m2 per day if the patient weighed <40 kg).

Health-related quality of life was measured by self-report instruments, including the Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT), Short Form-36 (SF-36).

For phase II, the primary outcome was complete or partial response after 6 months of therapy. For phase III, the primary outcome was complete response at 24 months.

Conclusions

Initial therapy of chronic GVHD with prednisone/sirolimus is an acceptable alternative and better tolerated than therapy with prednisone/sirolimus/CNI.

Carpenter PA, Logan BR, Lee SJ, et al. 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. Haematologica. 2018;103(11):1915-1924. doi:10.3324/haematol.2018.195123

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