Correlates of organ damage in patients with advanced systemic mastocytosis enrolled in clinical trials of avapritinib

Organ damage in patients with advanced systemic mastocytosis (AdvSM) at the time of enrollment in clinical trials of KIT inhibitors has not been well characterized. We describe the spectrum and clinicopathologic correlates of organ damage as defined by World Health Organization (WHO) and modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (mIWG) criteria among patients with AdvSM enrolled in the phase 1 and 2 trials of the <i>KIT</i> D816V inhibitor avapritinib (n = 174; systemic mastocytosis [SM] with an associated hematologic neoplasm [SM-AHN], 68%; aggressive SM and mast cell leukemia [MCL], both 16%). Notably, 47% of patients received previous midostaurin. Patients with SM-AHN had the highest absolute monocyte and eosinophil counts, whereas those with MCL had the highest serum tryptase level, bone marrow (BM) mast cell burden, and spleen/liver volumes. Treatment-naïve patients were more likely to fulfill WHO and mIWG criteria for hepatic organ damage. The presence of tier 1 <i>SRSF2</i>, <i>ASXL1</i>, and/or <i>RUNX1</i> mutations was associated with older age, shorter interval between diagnosis and enrollment, and fewer number of previous therapies, including midostaurin. AdvSM subtype, the presence and number of additional comutated genes beyond <i>KIT</i> D816V, BM mast cell burden, and <i>KIT</i> D816V variant allele fraction were associated with the presence and/or number of WHO/mIWG organ damage findings. Our study provides a snapshot of the correlates of organ damage in patients enrolled in clinical trials of avapritinib and identifies a key association between molecular profile and burden of organ damage.