Emerging therapeutic and preventive approaches to transplant-associated thrombotic microangiopathy

• Authors: Satheesh Chonat, Emory University; Michelle Schoettler, Emory University; Kirsten Williams, Emory University; Leslie Lehmann, Boston Children’s/Dana Farber Cancer and Blood Disorders Center, Pediatric Hematopoietic Cellular Therapies
• Journal Title: CURRENT OPINION IN HEMATOLOGY
• Volume: Volume 28, Number 6
• Publisher: LIPPINCOTT WILLIAMS & WILKINS | 2021-11-01, Pages 408-416
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1097/MOH.0000000000000687
• Subjects: Health Sciences, Oncology; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Hematology; complement inhibition; endothelial dysfunction; haematopoietic cellular therapy; transplant-associated thrombotic microangiopathy; STEM-CELL TRANSPLANTATION; PROTECTS ENDOTHELIAL-CELLS; VERSUS-HOST-DISEASE; RISK-FACTORS; VITAMIN-D; VENOOCCLUSIVE DISEASE; GVHD PROPHYLAXIS; TA-TMA; COMPLEMENT; DEFIBROTIDE

Abstract

Purpose of reviewTransplant-associated thrombotic microangiopathy (TA-TMA) is a complication that can occur in both allogeneic and autologous haematopoietic cellular therapy (HCT) recipients and is associated with significant morbidity and mortality. Although TA-TMA is a complex disease, there is emerging evidence that complement activation and endothelial dysfunction play a key role in the pathophysiology of the disease. The use of eculizumab has improved survival in patients with high risk and severe disease, but mortality rates in treated patients still exceed 30%, highlighting the need for novel approaches.Recent findingsThere are multiple ongoing and planned clinical trials investigating novel complement agents in TA-TMA and other TMAs. Drugs vary by targets of the complement system, mechanism, and form of administration. Clinical trial designs include single arm studies that span across multiple age groups including children, and double-blind, randomized, placebo-controlled studies. These studies will provide robust data to inform the care of patients with TA-TMA in the future. In addition to multiple promising therapeutic agents, preventing TA-TMA is an emerging strategy. Agents known to protect the endothelium from damage and augment endothelial function by promoting anti-inflammatory and antithrombotic effects may have a role in preventing TA-TMA or ameliorating the severity, though additional studies are needed.SummaryNovel therapeutic agents for TA-TMA inhibition of the complement system are under investigation and prophylactic strategies of endothelial protection are emerging. Further understanding of the pathophysiology of the disease may identify additional therapeutic targets. Multiinstitutional, collaborative clinical trials are needed to determine the safety and efficacy of these agents going forward.