Prospective Multi-Institutional Study of Eculizumab to Treat High-Risk Stem Cell Transplant Associated TMA.

High-risk, complement mediated, untreated transplant-associated thrombotic microangiopathy (hrTMA) has dismal outcomes due to multi-organ dysfunction (MODS). The complement C5 blocker eculizumab shows promising results in hrTMA, but has not been prospectively studied in hematopoietic stem cell transplant (HCT) recipients. We performed the first multi-institutional prospective study in children and young adults to evaluate eculizumab as an early targeted intervention for hrTMA/MODS (NCT03518203). We hypothesized that eculizumab would more than double survival in HCT recipients with hrTMA, compared to our prior study of prospectively screened, untreated hrTMAs serving as historical controls. High-risk TA-TMA features (elevated terminal complement (sC5b-9) and proteinuria measured by random urine protein/creatinine ratio (≥1mg/mg)) were required for inclusion. The primary endpoint was survival at six-months from hrTMA diagnosis. Secondary endpoints were cumulative incidence of MODS six-months after hrTMA diagnosis and one-year post-transplant survival. The eculizumab dosing regimen included intensive loading, induction, and maintenance phases for up to 24 weeks of therapy. All 21 evaluated study subjects with hrTMA had MODS. Primary and secondary study endpoints were met by demonstrating survival of 71% (p<0.0001) six months after hrTMA diagnosis and 62% one year after-transplant. Eleven of fifteen survivors (73%) fully recovered organ function and are well. Our study demonstrates significant improvement in survival and recovery of organ function in hrTMA using an intensified eculizumab dosing regimen and real time TA-TMA biomarker monitoring. This study serves as a benchmark for planning future studies that should focus on preventative measures or targeted therapy that can be initiated prior to organ injury. ClinicalTrials.gov (NCT03518203).