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P.A. Carpenter et al.
Introduction
Chronic graft-versus-host disease (GvHD) is the major treatment-related complication among patients who sur- vive after allogeneic hematopoietic cell transplantation. The protracted duration of chronic GvHD and its protean and sometimes irreversible organ manifestations makes it the leading cause of impaired immunity, compromised functional status, and late treatment-related deaths.1,2 Standard immunosuppressive therapy 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. The results of six phase III chronic GvHD trials that tested prednisone or prednisone/CNI backbones with or without an experimental immunosuppressive therapy have not changed clinical practice, because the treatments tested in the experimental arms did not improve outcomes due to lack of efficacy and/or more toxicity.3-8 Between 2005- 2007, reports of phase II trials from single centers showed promising results for prednisone combined with sirolimus, rituximab, mycophenolate mofetil, pentostatin or extracorporeal photopheresis (ECP).9-13 At the same time, renewed understanding of regulatory T cells (Treg) led to the hypothesis that experimental therapies permis- sive of Treg expansion would abrogate GvHD better than CNI-containing (control) immunosuppressive therapy. Sirolimus and ECP are permissive of Treg expansion.14-18 Because of their acceptance in clinical practice sirolimus and ECP were considered good candidates to add to pred- nisone in clinical trials investigating chronic GvHD.
This background, together with the 2005 National Institutes of Health (NIH) chronic GvHD criteria,19 plus other efforts designed to propel the field forward,20,21 moti- vated the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) to conduct an intervention trial for chronic GvHD. The intent was an adaptive phase II/III design to minimize between-phase downtime. The pri- mary purpose of phase II was to select the more promising of two CNI-free approaches (prednisone/sirolimus and prednisone/sirolimus/ECP) in order to proceed seamlessly into a definitive phase III study against a CNI-containing comparator arm (prednisone/sirolimus/CNI). The study also provided an opportunity to use the NIH diagnostic and response criteria prospectively and to validate them.
Methods
Patients
Adult and pediatric allogeneic hematopoietic cell transplant recipients were eligible if they had classic chronic GvHD ± acute GvHD (overlap subtype) that met 2005 NIH diagnostic consen- sus criteria.19 Eligibility criteria were broad and allowed a period of steroid exposure prior to enrollment to ensure congruence with standard practice. Thus, eligible patients were either: 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 inadequate- ly 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. Major reasons for exclusion were patients with late persistent acute GvHD or recurrent acute GvHD only, patients unable to begin prednisone at a dose of 0.5 mg/kg day (or equivalent), patients already receiving sirolimus
for treatment of chronic GvHD, and patients already receiving sirolimus (for prophylaxis or treatment of acute GvHD) along with prednisone at ≥0.25 mg/kg/day (or equivalent) ± additional agents. Patients were also ineligible if they had an invasive fungal or viral infection not responding to appropriate therapies, a crea- tinine clearance <50 mL/min/1.73 m2 based on the Cockcroft- Gault (adults) or Schwartz (age ≤12 years) formula, an absolute neutrophil count <1.5x109/L, a requirement for platelet transfu- sion, or a progressive or recurrent malignancy defined other than by quantitative molecular assays. Institutional review boards at all participating centers provided ethics approval. All patients or their parents signed informed consent to participation in the trial in accordance with the Declaration of Helsinki.
Treatment plan
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 recom- mended 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 equiva- lent) regimen was achieved, this dose remained constant for 10- 12 weeks until all reversible chronic GvHD manifestations resolved. A second taper was then attempted and could follow individual institutional guidelines, but it was recommended that the extent of the tapering be approximately calibrated to the magnitude of an individual patient’s every-other-day prednisone dose. CNI therapy was continued by targeting trough serum lev- els of 5-10 ng/mL for tacrolimus (120-200 ng/mL for cyclosporine). The sirolimus therapy began at a dose of 2 mg orally once daily (1 mg/m2 per day if the patient weighed <40 kg) to target trough serum levels of 3-12 ng/mL. Supportive care was provided in accordance with institutional guidelines reflecting standard practices appropriate for chronic GvHD.22
Study design
The trial was designed as an adaptive phase II/III randomized, open-label, prospective study of three treatments for chronic GvHD (Figure 1, Online Supplementary Figures S1 and S2). Phase II included two parallel, 100-patient, randomized trials, comparing prednisone/sirolimus or prednisone/sirolimus/ECP versus identi- cal (prednisone/sirolimus/CNI) comparator arms. The primary objective of phase II was to estimate the proportion of study sub- jects at 6 months after randomization with complete or partial response, who were alive without relapse or receipt of secondary immunosuppressive therapy. A sufficiently promising phase II result would determine whether the trial would proceed into phase III with additional accrual, would continue as phase II, but be followed for longer phase III endpoints without additional accrual, or would end in failure without further follow-up (Online Supplementary Figure S2). Full details of the study design, endpoint definitions, statistical analysis and study timeline are contained in the Online Supplementary Material.
Results
Patients
One hundred patients were evaluated for the phase II primary endpoint after all had completed 6 months of fol- low-up. The Z-statistic comparing complete/partial response rates (51% versus 50%, Z=0.11, stopping bound- ary Z6≤0.9) did not support proceeding to phase III and, together with pre-specified outcome scenarios, guided the
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haematologica | 2018; 103(11)