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. 2024 Sep;79(9):2458-2469.
doi: 10.1111/all.16084. Epub 2024 Mar 13.

High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy

Peter Korošec  1   2   3 , Gunter J Sturm  4   5 , Jonathan J Lyons  6 , Tinkara Pirc Marolt  1 , Manca Svetina  1   7 , Mitja Košnik  1   8 , Mihaela Zidarn  1   7   8 , Mark Kačar  1   8 , Nina Frelih  1   8 , Nika Lalek  1   8 , Ajda Demšar Luzar  1   7 , Samo Zver  8   9 , Matevž Škerget  8   9 , Ewa Czarnobilska  10 , Wojciech Dyga  10 , Sanja Popović Grle  11 , Miroslav Samarzija  11 , Lisa Arzt-Gradwohl  4 , Urban Čerpes  4 , Grzegorz Porebski  10 , Branko Pevec  11 , Eva Schadelbauer  4 , Peter Kopač  1   8 , Julij Šelb  1   8 , Matija Rijavec  1   7
Affiliations

High burden of clonal mast cell disorders and hereditary α-tryptasemia in patients who need Hymenoptera venom immunotherapy

Peter Korošec et al. Allergy. 2024 Sep.

Abstract

Background: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT.

Methods: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms.

Results: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01).

Conclusions: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT.

Keywords: anaphylaxis; hereditary α‐tryptasemia; hypersensitivity; immunotherapy; mast cell; mastocytosis; venom.

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Conflict of interest statement

Disclosure of potential conflicts of interest

G.J.S. reports lecture fees from ALK-Abellò, Stallergens-Greer and Allergopharma. Other authors declare that they have no relevant conflicts of interest.

Figures

Figure 1.
Figure 1.
KIT p.D816V and/or HαT prevalence in patients who need VIT and in controls. A, All participants who need VIT. B, Grade III-IV HVA. C, Grade II HVA. D, Grade I HVA. E Controls with LLR to Hymenoptera stings or with asymptomatic sensitization to Hymenoptera venoms. HVA: Hymenoptera venom allergy. VIT: venom immunotherapy. LLR: large local reactions. HαT: hereditary alpha tryptasemia.
Figure 2.
Figure 2.
BST levels, KIT p.D816V and/or HαT by severity of HVA (grade I-IV) in patients who need VIT. A, Slovenian cohort. B, Austrian cohort. C, Croatian cohort. D, Polish cohort. BST: basal serum tryptase. HVA: Hymenoptera venom allergy. VIT: venom immunotherapy. HαT: hereditary alpha tryptasemia.
Figure 3.
Figure 3.
Severe sting anaphylaxis and symptoms in patients with KIT p.D816V and/or HαT. A, Grade III-IV reaction. B, Loss of consciousness. C, Absence of urticaria and angioedema. HαT: hereditary alpha tryptasemia.
Figure 4.
Figure 4.
Allele burden of KIT p.D816V in blood leukocytes by severity of HVA (grade I-IV) and symptoms. HVA: Hymenoptera venom allergy.
Figure 5.
Figure 5.
Presence of clonal disease among HVA individuals with detectable KIT p.D816V in blood leukocytes and performed BM studies. A, Classification. B, Classification by allele burden of KIT p.D816V in blood leukocytes. C, Classification by BST. BMM: bone marrow mastocytosis. ISM: indolent systemic mastocytosis. MMAS: monoclonal MC activation syndrome.
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