Venous Thromboembolism in Patients with Steroid-Refractory Chronic Graft-Versus-Host Disease Receiving Synthetic Retinoid Am80

Abstract

Chronic graft-versus-host disease (GVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of chronic GVHD remains challenging. All-trans retinoic acid (ATRA), a potent vitamin A derivative, can regulate immune responses. Synthetic retinoid Am80, which shows biological activity approximately 10 times more potent than that of ATRA, directly inhibits Th1 cytokine production. We previously reported in an experimental mouse model that Am80 down-regulated both Th1 and Th17 differentiation in donor T cells, resulting in attenuation of chronic GVHD (Nishimori H. et al. Blood 2012). Based on this background, we conducted an open-labeled, multicenter phase II study of Am80 in patients with steroid-refractory chronic GVHD (Maeda Y. et al. Acta Med. Okayama. 2016). Six facilities are participating in this study. Patients take Am80 orally (4 mg/day) for 24 weeks. If any unexpected adverse events with Grade 2 or expected adverse events with Grade 3 develop, the daily dose will be decreased to 2 mg/day, 2 mg every other day, or discontinued.Eighteen patients were enrolled and 5 out of 18 (27.8%) patients experienced venous thromboembolism (VTE). Table 1 shows the patient characteristics of those developed VTEs.It is controversial whether retinoid would enhance the incidence of VTE. Only one patient reported thrombosis when Am80 orally (6 mg/m2) for 2-8 weeks was administrated to approximately 800 patients with acute promyelocytic leukemia. In this study, 5 out of 18 (27.8%) patients experienced thrombosis and the safety committee in this study has stopped the trial due to safety concerns. Recently, a meta-analysis reported the incidence of VTE in chronic GVHD was 35 % (20-54 %). Further studies are needed to confirm the causal relationship between Am80 orally (4 mg/day) for 24 weeks and VTE. And also, alternative treatment schedule in addition to anticoagulants for the prevention of VTE will be investigated in subsequent studies. [Display omitted] DisclosuresNishimori:Toko Pharmaceutical Industries: Other: Investigational drug is provided free of charge.. Maeda:Toko Pharmaceutical Industries: Other: Investigational drug is provided free of charge.