Abstract
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.