Good Prognosis of Adult Hemophagocytic Lymphohistiocytosis (HLH) Associated with the HAVCR2 germline Mutation

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal condition caused by excessive immune activation. Known etiologies are malignancies, infections, and autoimmune diseases. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is associated with HLH in approximately 15-20% of cases. Recent studies identified germline HAVCR2 (Hepatitis A Virus-Cellular Receptor 2) mutations in SPTCL and/or HLH. The most commonly reported mutation is HAVCR2 p.Y82C. We aimed to explore the incidence of germline HAVCR2^Y82C mutation in SPTCL-associated and idiopathic HLH and compare clinical outcomes with HLH from other causes.

We collected patients, aged 15 or older, with HLH or HLH-like systemic illness from January 2011 to June 2022. HLH was defined according to the HLH-2004 criteria. The term HLH-like systemic illness was applied to those with incomplete HLH-2004 criteria, but clinically consistent with HLH. Causes of HLH were comprehensively reviewed and documented for baseline characteristics. Direct sequencing to detect germline HAVCR2 p.Y82C (c.245A>G) was done in idiopathic and SPTCTL-associated HLH. DNA was extracted from formalin-fixed paraffin-embedded specimens or blood samples.

Of the 56 HLH or HLH-liked patients, 64% were male with the median age of 46 years old. The median HLH-2004 diagnostic score was 5 (26/56; 46.4%), ranging from 3 - 6 points. We detected germline HAVCR2^Y82C mutations in 9 out of 56 cases (16%), of which 5 cases diagnosed with SPTCL, while 4 cases were idiopathic HLH. Six of 9 mutated cases carried homozygous HAVCR2^Y82C mutation. The other causes of HLH were hematologic malignancies excluding SPTCL (17/56; 30%), idiopathic HLH without HAVCR2 mutation (17/56; 30%), infections (8/56, 14.3%) and autoimmune diseases (5/56; 8.9%). The hematologic malignancy subgroup comprised NK/T cell lymphoma (5/17; 30% ), diffuse large B-cell lymphoma (3/17; 17%), peripheral T-cell lymphoma, not otherwise specified (3/17; 17%), pure erythroid leukemia (2/17; 12%), non-Hodgkin's lymphoma unknown type (2/17; 12%), Hodgkin's lymphoma (1/17; 6%) and myelodysplastic neoplasms (1/17; 6%).

Patients with germline HAVCR2^Y82C mutations showed superior survival than the others (Figure 1). Idiopathic and malignancy-associated HLH showed significant inferior outcomes compared to patients with germline HAVCR2 mutations with hazard ratios (HR) of 5.39 (95% Confidence interval [CI] 1.21-23.99; p=0.027) and 6.53 (95%CI 1.48-28.79; p=0.013), respectively. HLH with germline HAVCR2^Y82C mutation were younger than HLH from other causes (30 vs. 47 years old; p=0.043). Patients with germline HAVCR2^Y82C mutations showed significantly higher hemoglobin levels but lower absolute neutrophil count than HLH with other causes (Table 1).

In conclusion, germline HAVCR2 mutations define a subgroup of HLH with better survival than the others. The mutation test is helpful to determine the prognosis of HLH.

No relevant conflicts of interest to declare.