Final Results of a Randomized Phase 2 Trial Evaluating Lower-Dose Versus Higher-Dose Pomalidomide as Therapy for Corticosteroid-Refractory Chronic Gvhd

• Published in: Blood 2016-12, Vol.128 (22), p.507-507
• Main Authors: Curtis, Lauren M., Venzon, David, Hakim, Fran T., Cowen, Edward W., Hsu, Jennifer, Masuch, Licia, Mays, Jacqueline W., Mitchell, Sandra A., Pirsl, Filip, Pusic, Iskra, Rose, Jeremy J., Kuzmina, Zoya J., Baird, Kristin, Gale, Robert Peter, Fowler, Daniel H., Gress, Ronald E., Pavletic, Steven Z.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V128.22.507.507

Chronic graft-versus-host disease (cGvHD) is the leading cause of late non-relapse morbidity and mortality after allogeneic HCT. There is no standard therapy for steroid-refractory disease. Thalidomide, an immune-modulating drug, showed some activity in advanced sclerotic cGvHD but was difficult to tolerate at active doses. Pomalidomide (Pom) is related to thalidomide, but with higher potency and a more favorable toxicity profile. A pilot study suggested Pom was effective in cGvHD, however doses >2 mg/day were poorly tolerated (Pusic et al, BMT, 2016;51:612). In this randomized phase 2 trial we aimed to determine the optimal dose and to evaluate the efficacy of Pom (NCT01688466). Methods: Subjects were randomized to a low-(LD) 0.5 mg/d or a high-dose (HD) cohort with a starting dose 0.5 mg/d increasing to 2 mg/d over 6 w. Dose reductions for ≥Grade-3 non-hematologic or ≥Grade-4 hematologic adverse events (AEs) on HD-cohort were allowed. There was no crossover. Concomitant stable or tapering systemic therapy for cGvHD was permitted. Venous thrombo-embolism prophylaxis was ASA 325 mg/d. Response was assessed by 2005 NIH response criteria (Filipovich AH et al, 2005;11:945). Primary endpoint was overall response rate (ORR) at 6 mo. Responders could continue at their assigned dose for 6 more mo. Secondary endpoints were safety, PKs and immune studies. The cohort with the higher response rate would be chosen for further evaluation, or if a tie, the LD arm would be favored. Results: From 02/2013 to 05/2016, 32 subjects were randomized (LD, n=16; HD, n=16). Median age was 48 y (range, 20-73 y), 21 (66%) male, median time from transplant 4.1 y (1.5-9.7 y), median time from onset of cGvHD 3.2 y (0.6-8.5 y). Thirty subjects had Global Score Severe. The most severely affected tissues/organs were skin (n=30, 94%), eyes (n=6, 19%) and joints/fascia (n=11, 34%). Most had ≥ 20% body surface area deep sclerosis (n=24, 75%). Pts had received a median 5 (2-9) prior systemic therapies. Baseline characteristics were similar in the two cohorts. Peak/trough levels of Pom were measured at 0.5, 1, 1.5, 2 mg doses and CMax increased in a dose-proportional manner (r2=0.9997), suggesting linear PKs. The most frequent AEs were lymphopenia, infection and fatigue (Table). Six subjects in the HD cohort were dose reduced to 1.5 mg/d because of fatigue (n=3), elevated ALT/AST (n=1), bradycardia (n=1) and neutropenia (n=1), and 2 subjects reduced further to 1 mg/d. There was 1 death in the