Correlates of Organ Damage in Advanced Systemic Mastocytosis Patients Enrolled in Clinical Trials of Avapritinib Open Access

• At avapritinib trial enrollment, AdvSM disease type, prior therapy, and mutational profile impact features of clinical presentation.

• mIWG organ damage is associated with bone marrow mast cell burden, KIT D816V variant allele fraction, and number of S/A/R mutated genes.

Organ damage in patients with advanced systemic mastocytosis (AdvSM) at the time of enrollment on 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 AdvSM patients enrolled on the phase I and II trials of the KIT D816V inhibitor avapritinib (n = 174; systemic mastocytosis with an associated hematologic neoplasm [SM-AHN] 68%, aggressive systemic mastocytosis [ASM] and mast cell leukemia [MCL] both 16%). Forty-seven percent of patients received prior midostaurin. Patients with SM-AHN had the highest absolute monocyte and eosinophil counts, while 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 SRSF2, ASXL1, and/or RUNX1 mutations was associated with older age, shorter interval between diagnosis and enrollment, and fewer number of prior therapies, including midostaurin. AdvSM subtype, the presence and number of additional co-mutated genes beyond KIT D816V, BM mast cell burden, and KIT 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.