Patterns of Response to Eculizumab in High-Risk Transplant-Associated Thrombotic Microangiopathy

Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation driven by endothelial injury with complement activation and is a leading cause of non-relapse mortality. Terminal complement (C5) blockade with eculizumab improves outcomes in high-risk TA-TMA, yet about one third of patients fail to respond. We studied 85 children and young adults with high-risk TA-TMA treated with pharmacokinetic/pharmacodynamic (PK/PD) guided eculizumab, comparing responders (n=55) and non-responders (n=30). Non-responders exhibited more severe systemic organ injury and markedly inferior survival. PK/PD analysis demonstrated that non-responders required intensified eculizumab dosing to suppress terminal complement activity (sC5b-9). Durable complement control, defined as sustained sC5b-9 normalization reflecting resolution of ongoing complement activation rather than drug-dependent transient suppression, required median 35 days (IQR 21.5-55) of therapy. Non-responders demonstrated persistently elevated proteinuria along with markers of endothelial stress and interferon signaling, including ST2 and CXCL9, despite sustained suppression of sC5b-9 consistent with ongoing endothelial injury not solely explained by circulating terminal complement activity. A subset of patients treated with eculizumab and interferon-γ blocker (emapalumab) demonstrated improved complement pharmacodynamics despite greater baseline complement activation, supporting a pathogenic interaction between interferon signaling and complement-mediated endothelial injury. sC5b-9 remains the only clinically relevant complement biomarker consistently associated with disease risk and outcomes, whereas other quantitative complement component levels did not distinguish responders. Together, these findings indicate that eculizumab non-responders have persistent endothelial injury, identifiable with clinically available biomarkers, and support further investigation of interferon signaling as a potential contributor to treatment resistance.