Final Results of a Randomized Phase 2 Trial Evaluating Lower-Dose Versus Higher-Dose Pomalidomide as Therapy for Corticosteroid-Refractory Chronic Gvhd
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. 
Published: October 2019

Abstract
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 LD cohort from pneumonia. 9 subjects discontinued ≤ 6 mo because of AEs (n=5) or withdrawal (n=4). More subjects in the HD cohort discontinued early; (HD, n=7; LD, n=2).
ORR at 6 mo in an intent-to-treat analysis was 47% (n=15, PR). ORR increased to 71% in 21 evaluable subjects. ORR in LD and HD were similar 50% (n=8/16) and 44% (n=7/16) respectively. 9 evaluable subjects (43%) had improvement in NIH joint/fascia scores (p=0.004) and median decrease of 10% body surface area involvement with cutaneous cGvHD (p=0.0027 by Wilcoxon signed rank test). Among the NIH response measures, the strongest association with response was the 11-point health care provider severity, median improvement 2 points (p=0.0055 by Jonckheere-Terpstra test), as well as improvements in restrictions in range of motion at elbow (p=0.023) and wrist (p=0.032). 67% (10/15) of the responders also reported clinically significant improvements in self-reported cGvHD symptom bother (Lee scale) and SF-36 physical component summary scores (p<.001).
Median decreases in prednisone dose compared to baseline were 13% (0-67) at 6 mo and 63% (17-81) at 12 mo of Pom. More subjects completed the planned 12 mo of Pom in the LD- vs. HD- cohort (7 vs. 4). After 12 mo of Pom, 3 subjects in the LD arm had progressed cGvHD. Two of those subjects had SD after restarting Pom. A 3rd responded and continued Pom for an additional 12 mo.
Conclusion: This phase 2, randomized trial demonstrates that Pom is an effective salvage therapy for persons with severe, corticosteroid-refractory cGvHD, including sclerotic skin disease. Response rates were similar with 0.5 and 2 mg/d but there were more early discontinuations with 2 mg/d. Organs with most improvement were skin and joints suggesting an anti-fibrotic effect. Pom is a promising new therapy for refractory cGvHD. As HD Pom was less well tolerated without a significant improvement in response, Pom 0.5 mg/d is recommended.
Table. Table.

Disclosures
No relevant conflicts of interest to declare.