P1238: germline havcr2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like t-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study

Topic: 20. Lymphoma Biology & Translational Research Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of T-cell non-Hodgkin lymphomas classically present with subcutaneous nodules. Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH). Factors associated with variable manifestations remain undetermined. Aims: We aimed to evaluate clinical variations and associated factors among patients with SPTCL and/or HLH with/without germline HAVCR2 mutations. Methods: We enrolled patients diagnosed with SPTCL and/or HLH from 4 adult hematology centers and 5 pediatric hematology departments. Only patients with idiopathic HLH and SPTCL were eligible. HLH score was defined according to the HLH-2004 criteria. The term HLH-like systemic illness or HPS was applied to those with incomplete HLH-2004 criteria, but clinically consistent with HLH. Direct sequencing of HAVCR2 exon 2 was performed using DNA from patients with SPTCL and/or idiopathic HLH/HLH-like systemic illnesses. Whole exome sequencing was done in 6 cases with HAVCR2Y82C mutation. The systematic review and individual patient data (IPD) level meta-analysis which included this study was subsequently conducted. Descriptive statistics, random-effects meta-analysis, and multivariate logistic regression were analyzed. Results: Among 34 patients enrolled, SPTCL was diagnosed in 28 patients with 10 cases having HLH/HLH-like systemic illnesses. Six cases with germline HAVCR2Y82C mutation manifested as HLH/HLH-like systemic illnesses without panniculitis. The median age of patients at diagnosis was 20.5 yrs. (IQR 12-32), with female gender predominance (65%). Homozygous HAVCR2Y82C mutation was detected in 20 cases (58.8%), heterozygous HAVCR2Y82C mutation in 7 cases (20.6%), while no HAVCR2Y82C mutation was detected in 7 cases (20.6%). Male gender (p=0.03) and age <18 yrs. (p=0.04) were associated with HLH, corresponding to the inverse correlation between ages and HLH-2004 scores (r=-0.4, p=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75% vs 44.4%; p=0.02). Using IPD from this study and other 3 eligible cohorts (n=127), male gender, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by adjusted odds ratio (95% confidence interval) of 2.93 (1.22-7.06), 4.77 (1.05-21.63) and 8.48 (2.98-24.10), respectively (Table 1). Whole exome sequencing was done in 1 heterozygous HAVCR2Y82C mutation case and in 5 homozygous HAVCR2Y82C mutation cases with HLH/HLH-like syndromes. There were no other pathogenic HAVCR2 mutations in a case with heterozygous HAVCR2Y82C mutation. In 5 cases with homozygous HAVCR2Y82C mutation, although there were no other familial HLH genes identified, mutated genes associated with primary immune deficiency disease (PIDD), dysregulated immune activation or proliferation (DIAP) were observed in all cases. Summary/Conclusion: Patients with male gender and/or germline HAVCR2 mutations showed increased risk of developing HLH. Younger patients usually manifested as HLH with/without SPTCL, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.Keywords: T cell lymphoma, Subcutaneous