Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication following hematopoietic stem cell transplantation (HSCT). Dysregulation of the complement system is implicated in TA-TMA pathogenesis, and eculizumab, a terminal complement inhibitor, has shown significant therapeutic effects. Genetic susceptibility through complement activation gene variations may influence the outcomes of TA-TMA. We hypothesized that the occurrence of TA-TMA is associated with “secondary hit” of disease-susceptible gene that already has embedded in patient’s gene. This study aimed to demonstrate the efficacy of eculizumab in TA-TMA. In addition, this study analyzed the impact of genetic variations on survival in pediatric TA-TMA patients treated with eculizumab.
Methods: A retrospective review of medical records from pediatric TA-TMA patients (aged 0–18 years) treated with eculizumab at Samsung Medical Center between June 2020 and June 2024 was conducted. Genetic analyses included Next-Generation Sequencing (targeting 54 genes associated with atypical hemolytic uremic syndrome) and Multiplex Ligation-dependent Probe Amplification (MLPA) for CFH, CFHR deletions/duplications.
Results: Fourteen patients (mean age 8.6 years, 64% male) were enrolled. Underlying conditions included medulloblastoma, other brain tumors, rhabdomyosarcoma, neuroblastoma, and B-ALL. Genetic abnormalities were identified in 11 patients (79%), involving 13 genes (PROS1, CFH, CFHR5, C3, THBD, SERPIND1, MPL, PLG, C5, KNG1, F5, ADAMTS13, and INF2). One patient exhibited heterozygous CFHR3/CFHR1 deletions. All 14 patients had advanced chronic kidney disease, and there were five deaths and one case requiring peritoneal dialysis. Two-year survival was lower in patients with genetic variants (53%) compared to those without (100%).
Conclusions: Eculizumab is a viable treatment for severe TA-TMA. Genetic susceptibility, even in the absence of pathogenic variants, may adversely impact survival. Pre-HSCT genetic screening may assist in risk stratification and inform treatment strategies. Further studies in larger cohorts are needed.