Haematologica (Apr 2023)

Germline <i>HAVCR2</i> mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis

  • Chatphatai Moonla,
  • Chantana Polprasert,
  • Patcharee Komvilaisak,
  • Thanawat Rattanathammethee,
  • Sunisa Kongkiatkamon,
  • Kitsada Wudhikarn,
  • Sirorat Kobbuaklee,
  • Pitchayut Boonyabaramee,
  • Nuanrat Tangcheewinsirikul,
  • Samart Pakakasama,
  • Piya Rujkijyanont,
  • Chane Choed-Amphai,
  • Kamon Phuakpet,
  • Saranya Pongudom,
  • Udomsak Bunworasate,
  • Narittee Sukswai,
  • Darintr Sosothikul,
  • Ponlapat Rojnuckarin

DOI
https://doi.org/10.3324/haematol.2022.282419
Journal volume & issue
Vol. 108, no. 10

Abstract

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Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.