Predicting the clinical course of advanced systemic mastocytosis on treatment with avapritinib or midostaurin

Advanced systemic mastocytosis (AdvSM) is driven by KIT D816V in approximately 95% of cases. Accurate assessment and prediction of clinical course and disease outcome before and during treatment with the KIT inhibitors midostaurin and avapritinib may facilitate optimization of treatment strategies. We retrospectively evaluated clinical, morphologic, laboratory, and genetic predictors of outcome in 79 midostaurin- and 176 avapritinib-treated patients. The number of mutations at baseline in SRSF2/ASXL1/EZH2 (midostaurin) and in SRSF2/RUNX1/SETBP1 (avapritinib) delineated highly predictive 3-tier risk classification systems. Treatment with avapritinib was associated with an early response of the KIT D816V variant allele frequency; a ≥10% reduction in peripheral blood at day 15 indicated improved overall survival (OS). Within 3 months of starting treatment, a ≥25% increase in alkaline phosphatase (AP) levels (AP flare) was observed in 46/47% of midostaurin/avapritinib-treated patients and was associated with longer OS. Multivariable analyses identified a ≥25% reduction in the KIT D816V allele burden (midostaurin), normalization of serum albumin levels (avapritinib), and normalization of hemoglobin and/or platelet levels (midostaurin and avapritinib) within 6 months as significant predictors for prolonged OS. In conclusion, genetic profiling, dynamic laboratory parameters, and KIT D816V monitoring improve outcome prediction in patients with AdvSM on midostaurin or avapritinib.