Secondary Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome Following Allo‐ HCT : Features, Outcomes, and Risk Stratification

Background Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) is a rare but highly fatal complication after allogeneic hematopoietic cell transplantation (allo‐HCT), frequently diagnosed under conditions of clinical uncertainty. We aimed to characterize post‐transplant sHLH/MAS and to identify clinically accessible factors associated with early mortality. Methods We retrospectively analyzed adult patients who developed sHLH/MAS after allo‐HCT between 2018 and 2025. Inclusion required an HScore ≥ 169. Overall survival within 60 days from sHLH/MAS onset was the primary endpoint. Clinical and laboratory variables were evaluated using Cox proportional‐hazards models, and patients were stratified according to the number of adverse prognostic factors identified. Results Seventy‐two patients met inclusion criteria. Median time from allo‐HCT to sHLH/MAS onset was 22 days. Sixty‐day overall survival was poor. In univariable and multivariable analyses, vasopressor‐dependent sepsis (HR 7.77, p < 0.001) and ferritin > 15 000 μg/L (HR 3.48, p = 0.002) were independently associated with early mortality. Stratification based on these two factors separated patients into low‐, intermediate‐, and high‐risk groups with 60‐day survival of 92%, 52%, and 9%, respectively ( p < 0.001). Conclusions Post‐transplant sHLH/MAS is associated with extremely high early mortality. Vasopressor‐dependent sepsis and extreme hyperferritinemia identify patients at particularly high risk. These findings require confirmation in independent cohorts.