Emerging therapeutic and preventive approaches to transplant-associated thrombotic microangiopathy

Transplant-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.

There 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.

Novel 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.