Background and Purpose

Primary hemophagocytic syndrome (pHLH) is a rare hereditary immunodeficiency disease. At present, large-scale, systematic studies based on the Chinese population are lacking. Thus,we conducted a retrospective study analyzed clinical data from pHLH patients at our center to systematically describe the genetic characteristics and prognosis of pHLH in Chinese population，identify factors influencing survival outcomes.

Methods

The study included 116 genetically confirmed pHLH patients diagnosed in the Hematology Departments of Beijing Friendship Hospital, Capital Medical University, and allied hospitals between January 1, 2013, and September 30, 2024. We summarized the genetic characteristics and prognosis of pHLH in China, compared the differences in clinical and laboratory examination characteristics, functional characteristics, and treatment response between between survivors and non-survivors. Kaplan-Meier method was used for survival analysis. Univariate/Multivariate Cox regression models were used to determine the risk factors affecting patient survival outcomes.

Results

Familial HLH-2 (FHL-2) and FHL-3 are the main subtypes of pHLH. Median age of onset was 16.6 years (0.16-70.5 years) and median age at diagnosis was 17.8 years (0.33-70.8 years). Pediatric/adolescent and adult patients each comprised 50% of the cohort. 100 patients (86.2%) fully met the HLH2004 diagnostic criteria, with fever (90.5%) being the most common clinical presentation.Splenomegaly, cytopenia, elevated serum ferritin (SF), and elevated sCD25 were significantly more frequent in adults (all P < 0.05), while CNS involvement was more common in pediatric/adolescent patients (P < 0.05). Reduced NK-cell activity was observed in 68.8% (75/109) of patients. Impaired CD107a expression on NK cells occurred in 39.3% (42/107), and was significantly more prevalent in patients with degranulation-related gene defects (P < 0.001). 97 patients received HLH related induction therapy, with an overall response rate (ORR) of 84.5% (82/97). There was no significant difference in overall survival among pHLH patients of different subtypes. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 56 patients (48.3%) and significantly improved OS (except in XLP-2 patients) (not reached vs. 44 months; χ²=8.905, P=0.003), particularly in FHL patients (not reached vs. 11 months; χ²=10.67, P=0.001) and those with relapsed/refractory disease (not reached vs. 33 months; χ²=4.631, P=0.031). Compared to the survival group, the death group had a higher median age at diagnosis, lower white blood cell (WBC) counts, lower albumin levels, higher SF levels, and a higher prevalence of additional mutated deleterious variants (AMDs) (all P < 0.05). Multivariate Cox regression analysis found that carrying AMDs (HR: 3.664, 95% Cl: 1.113-12.065: P=0.033), CNS involvement (HR: 4.237, 95% CI: 1.434-12.732, P=0.009), and allo HSCT (HR: 0.372, 95% CI: 0.142-0.977, P=0.045) were independent factors affecting OS in patients with pHLH.

Conclusion

Primary HLH may occur in all age demographics, and PRFI and UNC13D are the main pathogenic genes of pHLH patients in China. Allo HSCT significantly improves the prognosis of patients with pHLH (excluding XLP-2), while AMDs, CNS involvement, and transplantation status critically impact survival outcomes.

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2025
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