Clinicopathologic Determinants of Survival in Hemophagocytic Lymphohistiocytosis: Analysis of a Real-World Database

Background

Hemophagocytic lymphohistiocytosis (HLH) is a severe and potentially life-threatening syndrome characterized by uncontrolled activation of lymphocytes and macrophages, leading to excessive cytokine production, hyperinflammation, and tissue damage. HLH can be broadly classified into two forms: primary (familial) HLH, which is an autosomal recessive disorder often associated with genetic mutations affecting cytotoxic function, and secondary (acquired) HLH, which can be triggered by infections, malignancies, autoimmune diseases, and other underlying conditions. We conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in patients with HLH.

Methods

To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, prognostic factors, and survival, we compiled a pooled database of cases that satisfy the diagnostic criteria of HLH. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).

Results

A total of 255 patients with confirmed HLH were identified. The median age was 32. There was a male preponderance with M:F of 1.5. The median duration of symptoms before diagnosis was 3 weeks. Only 8% of our cohort had a primary HLH, 33% involving PRF1. Associated triggering etiologies were unknown (24%), infectious (49%), autoimmune (8%), and malignancies (19%). Tissue hemophagocytosis was seen in 56% of the cases. While liver dysfunction was noted in 58% of the cohort, pulmonary, renal, neurological, and cardiac dysfunction was noted in 25%, 23%, 15%, and 9%, respectively. The median OS of the whole group was 24 months, respectively. Age>50 (p=0.003), splenomegaly (p=0.02), underlying malignant etiology (p=0.0004), LDH>1000 U/L (p=0.003), and sIL2R>5000 U/ml (0.03) were associated with worse OS. Furthermore, patients with pulmonary or renal dysfunction had worse OS. Though lymphadenopathy, hepatomegaly, Ferritin>1000 ng/ml, and CNS involvement were numerically associated with worse OS, they did not reach statistical significance. Sex, fever, HPS, anemia, thrombocytopenia, and triglyceride levels did not impact OS. Compared to supportive care/antibiotics, etoposide-based regimens, and non-chemotherapy immunosuppression resulted in incrementally better median OS (3 vs. 24 vs. NR months, p=0.038). Of note, etoposide-based regimens arm had a greater percentage of high-risk patients. Patients who attained complete response had a superior median OS compared to those with partial and no response, respectively (NR vs. 18 vs. 0.75; p<0.0001). Moreover, patients who relapse <2months had worse survival (6 vs. NR months, p=0.01).

Conclusion

This study presents clinicopathologic data from the largest HLH real-world pooled cohort. It identifies age, splenomegaly, underlying malignant etiology, LDH levels, sIL2R, pulmonary or renal dysfunction, type of therapeutic approach, and quality of response to treatment as critical determinants of OS.

No relevant conflicts of interest to declare.