Pharmacological treatment of hematopoietic stem cell transplantation-associated thrombotic microangiopathy with focus on the FDA-approved antibody narsoplimab

INTRODUCTION: Transplantation-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome after allogeneic hematopoietic stem cell transplantation (allo-HSCT), presenting as microangiopathic hemolysis, thrombocytopenia, microvascular thrombosis and multiorgan dysfunction. Dysregulated complement activation is central, rendering complement inhibition a major therapeutic target. AREAS COVERED: This review summarizes the evolving concepts of the pathogenesis, diagnosis, risk stratification, and therapeutic landscape of TA-TMA, emphasizing complement-directed therapies. We discuss terminal complement inhibition with eculizumab and ravulizumab, proximal and alternative pathway inhibition with pegcetacoplan and iptacopan, and lectin pathway inhibition with narsoplimab as the only drug approved by the United States Food and Drug Administration (FDA). We critically appraise narsoplimab with respect to its pivotal trial, expanded access program, and comparative studies with other approaches. Differences in study populations, response definitions, safety ascertainment and regulatory assessments are discussed. EXPERT OPINION: Narsoplimab represents an important advance as the only FDA-approved treatment for TA-TMA, with consistent responses reported in different studies of high-risk patients and an acceptable safety profile. However, current evidence supporting narsoplimab is limited to single-arm studies. Future studies should employ harmonized diagnostic and response criteria, compare complement-directed strategies, and evaluate biomarker-driven early diagnosis and intervention to prevent severe organ damage that may be fatal.