Determinants of Eculizumab Response in High-Risk Transplant-Associated Thrombotic Microangiopathy

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT), driven by endothelial injury and complement activation. Eculizumab, a terminal complement C5 inhibitor, improves survival in high-risk TA-TMA, yet one-third of patients fail to respond. To determine mechanisms of eculizumab non-response and early predictors of outcome in TA-TMA that are critical for improving therapy. We studied 90 children and young adults with high-risk TA-TMA, comparing eculizumab responders (n=60) and non-responders (n=30). All HSCT recipients were prospectively screened for TA-TMA. TA-TMA risk group and response to eculizumab was determined based on published criteria (Fig1). All patients with high-risk TA-TMA received PK/PD-guided eculizumab dosing. We performed novel PK/PD modeling to determine complete complement blockade (“equilibrium”). Complement blockade, PK/PD dynamics, biomarker trajectories for sC5b-9, CXCL9, ST2, proteinuria by random urine protein/creatine ratio (rUPCR), and outcomes were compared in responders and non-responders. Non-responders displayed greater systemic organ injury and worse survival despite optimized eculizumab dosing and PK/PD monitoring (Fig 2A). PK/PD modeling confirmed that complement blockade can be achieved with intensified dosing, but steady blockade state (equilibrium) requires approximately six weeks of therapy, underscoring that short-term biomarker normalization is not sufficient to declare response (Fig 2B). Importantly, non-responders exhibited persistently elevated rUPCR and rising ST2 despite suppression of sC5b-9, indicating ongoing complement-independent endothelial injury. Longitudinal biomarker profiling showed that non-responders had progressive CXCL9 elevation despite sC5b-9 control, and that adding IFNγ blockade with emapalumab improved eculizumab PK/PD, accelerated complement suppression, and enhanced survival, underscoring the pathogenic role of the complement-interferon loop (Fig3). We showed that elevated sC5b-9 is associated with TA-TMA risk, higher therapy needs and poor outcomes, whereas comprehensive profiling of other complement components did not differentiate responders, and normal C3/C4 values did not exclude TA-TMA highlighting the need for functional biomarkers. These findings reveal that eculizumab non-response reflects complement independent persistent endothelial injury. Early monitoring of ST2, CXCL9, rUPCR, may identify patients at risk for suboptimal eculizumab response and guide precision therapies that can be integrated with complement blockade. Such strategies will be essential to improve survival and prevent irreversible vascular injury in high-risk TA-TMA.