Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network

Abstract

Acute graft-versus-host disease (aGVHD)is the primary limitation of allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard initial therapy, yet only 25% to 41% of patients completely respond. This randomized, 4-arm, phase 2 trial was designed to identify the most promising agent(s) for initial therapy for aGVHD. Patients were randomized to receive methylprednisolone 2 mg/ kg per day plus etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), or pentostatin. Patients (n ‫؍‬ 180) were randomized; their median age was 50 years (range, 7.5-70 years). Myeloablative conditioning represented 66% of transplants. Grafts were peripheral blood (61%), bone marrow (25%), or umbilical cord blood (14%); 53% were from unrelated donors. Patients who received MMF for prophylaxis (24%) were randomized to a non-MMF arm. At randomization, aGVHD was grade I to II (68%), III to IV (32%), and (53%) had visceral organ involvement. Day 28 complete response rates were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival was 47%, 64%, 49%, and 47%, respectively.

State-of-the-art acute and chronic GVHD treatment

“…In a retrospective study, infliximab has been shown to be associated with significant response although the proportion of patients with grade III-IV aGVHD was low and treatment was complicated by infections particularly aspergillus which could be explained by elimination of monocytes-macrophages by infliximab [97,98]. Etanercept also increased infections in clinical trials but not as much as infliximab [81,86]. In a phase III randomized trial of high-dose corticosteroids with or without infliximab including 63 newly diagnosed GVHD patients, no statistically significant difference was found in GVHD-related mortality, non-relapse mortality or overall survival [87].…”

“…In a largescale phase II trial conducted by BMT Clinical Trial Network (BMT-CTN) patients were randomized into 4 arms to receive methylprednisolone 2 mg/kg/day and CI in addition to either etanercept, mycophenolate (MMF), denileukin or pentostatin as the initial therapy. Complete response rates at 28 days were 26, 60, 53 and 38 %, respectively, with overall survival of 47, 64, 49 and 47 % at 9 months [81]. Based on these encouraging results, a randomized phase III trial of steroid and CI with MMF vs steroid and CI has started (BMT CTN Study 0802), but the study was terminated as preliminary results did not show any difference with addition of MMF [82].…”

“…It is available in both oral and IV forms. There have been multiple published studies, both retrospective and prospective, using MMF in the treatment of steroid-refractory aGVHD [81,107]. In one study it was associated with responses in 9 out of 19 patients, but this did not translate into long-term overall survival [108].…”

Prophylactic and therapeutic treatment of graft-versus-host disease in Japan

“…A retrospective study comparing a PSL-equivalent steroid dose of 1 and 2 mg/kg/day demonstrated no disadvantage of low-dose PSL at 1 mg/kg/day for patients with mild grade II acute GVHD [114]. Comparative studies evaluating a combination of PSL and other immunosuppressants, including antibodies against interleukin-2, ATG, etanercept, and infliximab [115][116][117][118][119][120], did not demonstrate an advantage of the addition of these immunosuppressants to PSL. Oral beclomethasone dipropionate (BDP) allowed PSL to be rapidly tapered, with fewer recurrences of gastrointestinal GVHD [121].…”

Response as an end point in treatment trials for acute GVHD

“…[11][12][13][14] In a recent issue of Bone Marrow Transplantation, Saliba and colleagues 15 from the MD Anderson Cancer Center present a study validating therapy response as an outcome measure in 83 predominantly hematological malignancy patients who had been enrolled on two clinical trials testing upfront therapy for acute GVHD. 16,17 They assessed acute GVHD responses on days 7, 14 and 28 after starting primary steroid-based therapy. About 60% of the patients responded to the therapy; however, the proportion of complete responses increased from 53% on day 7 to 92% on day 28.…”