A randomized phase 2 trial of pomalidomide in subjects failing prior therapy for chronic graft-versus-host disease

Abstract

Steroid-refractory chronic graft-versus-host disease (cGvHD) is a therapeutic challenge. Sclerotic skin manifestations are especially difficult to treat. We conducted a randomized phase-2 clinical trial to determine safety, efficacy, and preferred dose of pomalidomide in persons with moderate to severe cGvHD unresponsive to corticosteroids and/or subsequent lines of therapy. Thirty-four subjects were randomized to receive pomalidomide, 0.5 mg/d; LD) orally (n=17) or 2 mg/d at a starting dose of 0.5 mg/d increasing to 2 mg/d over 6 weeks (n=17, HD). Primary endpoint was overall response rate (ORR) at 6 months according to the 2005 NIH cGvHD Response Criteria. Thirty-two had severe sclerotic skin and received a median of 5 (range, 2-10) prior systemic therapies. ORR was 47% (95% confidence interval [95% CI], 30, 65%) in intent-to-treat analyses. All were partial responses with no difference in ORR between the cohorts. ORR was 67% (45-84%) in the 24 evaluable subjects at 6 months. Nine had improvement in NIH joint/fascia scores (p=0.018). Median change from the baseline in body surface area (BSA) of involved skin cGvHD was -7.5% (-10 to +35; p=0.002). The most frequent adverse events (AEs) were lymphopenia, infection, and fatigue. Eight subjects in the HD cohort had dose decreases because of AEs. There was one death in the LD cohort from bacterial pneumonia. Our data indicate anti-fibrotic effects of pomalidomide and possible association with increases in concentrations of blood regulatory T-cell and IL-2. Pomalidomide, 0.5 mg/d, is a safe and effective therapy of advanced corticosteroid-refractory cGvHD.

Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan

“…Pomalidomide is a thalidomide derivative with 4,000-fold greater inhibition of TNF-alpha, which was originally used in the treatment of multiple myeloma. It has been evaluated in several adult studies for the treatment of SR-cGvHD with 54-67% ORR observed (201,202). Paediatric data are lacking.…”

“…Of note, single-target inhibitors may have a beneficial or detrimental effect at different phases of immune cell development and immune dysfunction. In this regard the results of a randomised phase 2 trial evaluating the response of pomalidomide in 34 adult patients with moderate to severe cGvHD may serve as an example: authors reported that the use of pomalidomide early after HSCT may cause cutaneous inflammation in contrast to the treatment responses observed in late sclerotic cGvHD (201).…”

Ikaros Proteins in Tumor: Current Perspectives and New Developments

“…In another phase III trial, on the basis of BTZ and dexamethasone, pomalidomide was added in the treatment of patients with RRMM to significantly improve PFS (11.20 vs. 7.10 months; HR, 0.61; 95%CI, 0·49–0.77; p < 0·0001), with acceptable hemocyte toxicity (NCT01734928) ( Richardson et al, 2019 ). In addition to malignancy, pomalidomide is a well-tolerated and efficient treatment for advanced steroid-refractory chronic graft-versus-host disease (cGVHD), indicating the antifibrotic effects of pomalidomide are related to the increased levels of blood regulatory T cells and IL-2 (NCT01688466) ( Curtis et al, 2021 ).…”

Severe graft-versus-host disease of the lower intestinal tract after pomalidomide administration in a plasma cell leukemia patient following bone marrow transplantation

“…Therefore, when using IMiDs after allo-HSCT, it is necessary to pay attention to the onset of GVHD, and it may be important to measure cytokines over time and/or analyze lymphocyte subsets. Although IMiDs may also be a treatment option for chronic GVHD 11 , chronic GVHD differs from acute GVHD in the cells, and the mechanisms involved and onset and severity of GVHD might be different depending on the timing of administration and dose.…”