BMT CTN 0302: A Phase II Randomized Trial Evaluating Etanercept, Mycophenolate Mofetil (MMF), Denileukin Diftitox, and Pentostatin in Combination with Corticosteroids in 180 Patients (pts) with Newly Diagnosed Acute Graft Vs. Host Disease (aGVHD)
Authors: Alousi Amin , Weisdorf Daniel J. , Logan Brent R. , Bolanos-Meade Javier , Goldstein Steven C. , Ho Vincent T , Hayes-Lattin Brandon , Wingard John R. , Horowitz Mary M. , Levine John E. 
Published: April 2020

Abstract
On behalf of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) GVHD remains a major limitation of allogeneic hematopoietic cell transplantation (HCT). Steroids are the standard initial therapy yet prior data suggested only 35% complete response (CR) at day 28. We report the results of a randomized, four-arm, phase II trial designed to identify the most promising agent(s) for combination with steroids as initial therapy for aGVHD. Between August, 2005 and March, 2008, 180 pts with newly diagnosed aGVHD were randomized to receive steroids (2 mg/kg/day methylprednisolone) plus either: Etanercept, MMF, Denileukin Diftitox or Pentostatin. Pts who received MMF as GVHD prophylaxis in the preceding 7 days were randomized between the 3 non-MMF arms. The primary objective was to estimate the CR rate at day 28 for each of the four agents and evaluate secondary outcomes pertinent to the best agent for testing in a planned followup phase III trial vs steroids alone.
PATIENTS AND RESULTS: Median age was 50 yrs (range, 7.5–69.9) with 96% &gt;18 yrs; 39% had AML and 63% were male. The graft was peripheral blood (PB) in 61%, bone marrow (BM) in 25% and cord blood (CB) in 14% of pts. HCT was performed with myeloablative conditioning and/or unrelated donor grafts in 66% and 53%, respectively. Forty-four pts (24%) received MMF as aGVHD prophylaxis and were randomized to a non-MMF arm. At enrollment, 68% of patients had grade I-II aGVHD; 32% had grade III/IV. 53% of pts had visceral organ involvement at the time of enrollment. The treatment arms were balanced except CB grafts were more common in the Denileukin Diftitox arm (26%, p=0.006); PB were more common in the Etanercept arm (78%, p=0.006); and the MMF arm had more myeloablative HCT (82%, p=0.04). The proportion of CR at day 28 were: Etanercept (26%), MMF (60%), Denileukin Diftitox (53%) and Pentostatin (38%), and day 56 CR+PR rates were 59%, 78%, 68%, and 71%, respectively. 6 month chronic GVHD (cGVHD) incidence was: Etanercept (21%), MMF (25%), Denileukin Diftititox (29%), and Pentostatin (24%). Overall survival (OS) at 6 months was Etanercept (59%), MMF (71%), Denileukin Diftitox (63%), and Pentostatin (55%), respectively. After excluding pts who received MMF prophylaxis, the MMF arm still had the highest day 28 CR rate and OS. Overall toxicities and post-randomization infections were less frequent in pts randomized to MMF and Etanercept.
CONCLUSIONS: These efficacy and toxicity data, particularly response, survival, cGVHD, and infections, suggest MMF + steroids to be the most promising regimen to compare against steroids alone in a randomized Phase III trial.
Treatment Arm Outcome Etanercept (N=46) MMF (N=45) Denileukin Diftitox (N=47) Pentostatin (N=42) Day 28 CR 12 (26%) Skin: 12/36 (33%) 27 (60%) Skin: 21/35 (60%) 25 (53%) Skin: 17/35 (49%) 16 (38%) Skin: 14/34 (41%) L.G.I.: 4/12 (33%) L.G.I.: 12/18 (67%) L.G.I.: 5/14 (36%) L.G.I.: 7/17 (41%) U.G.I.: 5/10 (50%) U.G.I.: 11/12 (92%) U.G.I.:10/14 (71%) U.G.I.: 8/13 (62%) Liver: 2/6 (33%) Liver: 5/7 (71%) Liver: 3/7 (43%) Liver: 2/5 (40%) Day 28 CR (excl. prior MMF ) 9 (28%) 27 (60%) 15 (48%) 11 (39%) Day 28 CR/PR 22 (48%) 35 (78%) 28 (60%) 26 (62%) Day 56 CR/PR 27 (59%) 35 (78%) 32 (68%) 30 (71%) Day 56Treatment Failures 12 (26%) 4 (9%) 12 (26%) 13 (31%) OS Post-Randomization at 6 months 59% (95% CI: 43%–72%) 71% (95% CI: 54%–82%) 63% (95% CI: 47%–76%) 55% (95% CI: 38%–69%) OS Post-Randomization at 6 months (excl. prior MMF) 70% (95% CI: 51%–83%) 71% (95% CI: 54%–82%) 61% (95% CI: 40%–76%) 54% (95% CI: 33%–71%) Cum Incidence of Initial D/C of steroids at 9 months 34% (95 % CI: 20%–48%) 31% (95% CI: 17%–45%) 20% (95% CI: 8%–32%) 20% (95% CI: 8%–33%) Cum Incidence Day 56 Grade 3–5 Toxicity (%) 76% (95% CI: 63%–88%) 80% (95% CI: 67%–92%) 76% 95% CI: 64%–89%) 67% (95% CI: 52%–81%) Cum Incidence Severe/ Life Threatening/Fatal Infections at Day 270 47% (95% CI: 32%–62%) 44% (95% CI: 29%–59%) 58% (95% CI: 43%–72%) 56% (95% CI: 40%–71%) Cum Incidence of acute GVHD Flare after CR at Day 90 36% (95% CI: 21%–50%) 28% (95% CI: 14%–41%) 35% (95% CI: 21%–49%) 36% (95% CI: 21%–51%) Cum Incidence of cGVHD at Day 180 21% (95% CI: 9%–33%) 25% (95% CI: 11%–39%) 29% (95% CI: 15%–43%) 24% (95% CI: 10%–38%) Cum Incidence of Relapse at Day 180 14% (95% CI: 3%–24%) 10% (95% CI: 1%–19%) 9% (95% CI: 1%–19%) 13% (95% CI: 2%–24%)