Clonal Mast Cell Disorders and Mutation Profile in Adults Initially Presenting with Mast Cell Activation (Anaphylaxis) versus Non-Anaphylactic Presentations: A Joint Allergy–Hematology Cohort

Purpose: To compare the diagnostic yield, clinical, and molecular features of clonal mast cell disorders (CMCDs) in adults presenting with mast cell activation (MCA)/anaphylaxis versus non-anaphylactic phenotypes in a joint Allergy-Hematology cohort. Patients and Methods: In this single-center retrospective study, we reviewed clinician-selected adults (≥ 18 years) evaluated at a Thai tertiary center (2019– 2024) who completed joint Allergy-Hematology evaluation and targeted 66-gene myeloid next-generation sequencing (NGS). Index presentations were classified as MCA/anaphylaxis versus non-MCA. Final diagnoses followed WHO 5th/International Consensus Classification criteria. Results: Of 24 sequenced adults, 14 (58.3%) had MCA/anaphylaxis and 10 (41.7%) had non-MCA presentations. Among sequenced MCA/anaphylaxis presentations, final diagnoses included idiopathic anaphylaxis (IA, n=11), secondary anaphylaxis (n=2), and systemic mastocytosis (SM, n=1). Conversely, all 10 non-MCA cases had CMCD (SM 6, cutaneous mastocytosis 4). Compared to non-mastocytosis cases, mastocytosis patients were older, predominantly male, with higher basal tryptase (median 22.4 vs 3.2 ng/mL). Pathogenic variants occurred in 12/24 (50%) patients: KIT D816V in 6/24 (25%), with heterogeneous TET2 co-mutations, DNMT3A R882H, and SRSF2 P95 hotspots clustering in SM. IA rarely harbored driver mutations. Conclusion: CMCD showed a low diagnostic yield (1/14, 7.1%) in the clinician-selected MCA/anaphylaxis subgroup escalated to marrow/NGS, but was universal in the hematologic non-MCA subset (10/10, 100%). These findings suggest that REMA-based, risk-stratified selection may be useful in this setting, but larger prospective studies are needed. While TET2 was the most frequently mutated gene overall, the mutational profile within the SM subgroup—characterized by KIT D816V and frequent TET2, DNMT3A , and SRSF2 co-mutations—parallels established molecular signatures in Western systemic mastocytosis cohorts, suggesting KIT -targeted therapies are biologically applicable in Thai patients. A clinician-selected cohort undergoing NGS includes 24 patients. In the MCA/Anaphylaxis group (n=14), the CMCD yield is 7.1 percent, mainly idiopathic anaphylaxis. In the Non-MCA group (n=10), the CMCD yield is 100 percent, with systemic mastocytosis (SM) in 6 and cutaneous mastocytosis (CM) in 4. The most frequent driver mutation is KIT D816V, dominant in SM at 85.7 percent. Frequent co-mutations in SM (n=7) include TET2 at 71 percent, SRSF2 at 57 percent and DNMT3A at 29 percent. Pathogenic variants are detected in 50 percent of the cohort, while IA driver mutations are rare. The patient profile shows mastocytosis (n=11) with a mean age of 63, tryptase median of 22.4 ng/mL and 72.7 percent male. Non-mastocytosis (n=13) has a mean age of 40, tryptase median of 3.2 ng/mL and 7.7 percent male. Conclusion highlights risk stratification and therapeutic applicability, with REMA/NICAS scores optimizing patient selection for bone marrow and NGS and Thai SM profiles suggesting potential applicability of KIT-targeted therapies.Infographic comparing CMCDs in MCA vs. non-MCA presentations with patient profiles and mutation data. Keywords: anaphylaxis, KIT D816V, systemic mastocytosis, mast cell activation syndrome, next-generation sequencing, REMA score