Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: Incidence, clinical characteristics and survival.

Malignancy-associated hemophagocytic lymphohistiocytosis (mal-HLH) is a severe hyperinflammatory syndrome with poor prognosis. We evaluated mal-HLH in Sweden with regard to population-based incidence, clinical features, and survival. Using the Swedish Patient Registry for 1997-2018, we identified 307 adults (≥18-years) and 9 children (209 males, 107 females; p<0.001), with both an HLH-related diagnosis and malignant disease according to ICD-10, corresponding to 0.19/100,000 adults/year (0.15/100,000 for the entire population); increasing from 0.026 1997-2007 to 0.34 2008-2018 (p<0.001). The most recent 7-year period (2012-2018), the incidence was 0.45/100,000 adults/year (n=246). This incidence varied between the six health care regions in Sweden, from 0.18 to 0.71 (Region Stockholm) per 100,000 adults/year (p<0.001), likely due to variable awareness. Mal-HLH was reported in 0.6% of all hematological malignancies with highest proportion (2.8%) in males aged 25-29 years. Among all 316 patients, 1-month probability of survival, likely representing the HLH-episode, increased significantly from 52% (confidence interval (CI) 40-63) 1997-2007 to 71% (CI=65-76) 2008-2018, while 2-year survival remained poor (25%; 20-30%). Altogether 52% were lymphomas; 29% leukemias; 8% other hematological malignancies; and 11% solid tumors. Men were more affected than females by mal-HLH, also taking the overrepresentation of men with hematological malignancies into account (p=0.0012). Notably, validation by review of medical files 1997-2011 revealed 13% over-reporting of the diagnosis HLH. We conclude that the annual mal-HLH incidence increased ten-fold 1997-2018, was at least 0.71/100,000 adults 2012-2018, i.e., 0.62/100,000 adults considering 13% estimated HLH over-reporting, and that early survival improved significantly, likely due to increased awareness and more HLH-directed therapy.