Allogeneic hematopoietic stem cell transplantation in ERCC6L2 disease

The hallmark of ERCC6L2 disease (ED) is a highly penetrant progression from bone marrow failure to erythroid-predominant, TP53-mutated myeloid malignancy with a dismal prognosis. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potentially curative option, but concerns exist regarding transplant-related toxicities (TRT) due to the underlying DNA repair defect. To the best of our knowledge, this is the first study to report a systematic analysis of HSCT in ED. We conducted a retrospective multicenter study involving 45 patients with ED who underwent HSCT in 2004-2024. The primary outcomes were overall survival (OS), TRT, and nonrelapse mortality (NRM). The 1-year and 3-year OS were 79% (95% confidence interval [CI], 66-91) and 54% (95% CI, 35-73), respectively. Previous history of excess blasts significantly predicted inferior survival (hazard ratio [HR], 6.8; 95% CI, 2.2-20.3; P< .001), with a median survival of 12 months (95% CI, 0-24). Grade 3 to 5 endothelial toxicities occurred in 27% of patients and were associated with higher NRM (HR, 7.7; 95% CI, 1.5-38.8; P = .016). The use of nontreosulfan-based myeloablative conditioning (MAC) regimens increased the risk of endothelial complications compared with reduced-intensity conditioning (RIC; HR, 4.9; 95% CI, 1.1-22.0; P = .040), whereas outcomes with treosulfan-based MAC were comparable to RIC. In summary, allogeneic HSCT is a viable curative strategy for ED when performed before transformation to an aggressive malignancy, for example myelodysplasia with excess blasts or acute myeloid leukemia. However, the elevated incidence of endothelial toxicity highlights the importance of optimizing conditioning intensity and enhancing peritransplant monitoring in this population.