Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers

Mohamad Jawhar, Juliana Schwaab, Nicole Naumann, Hans-Peter Horny, Karl Sotlar, Torsten Haferlach, Georgia Metzgeroth, Alice Fabarius, Peter Valent, Wolf-Karsten Hofmann, Nicholas C.P. Cross, Manja Meggendorfer and Andreas Reiter

Key points

  • The complexity and dynamics of mutations significantly impact on response, progression, and prognosis in midostaurin-treated advSM patients.


In advanced systemic mastocytosis (advSM), disease evolution is often triggered by activating KIT mutations (D816V in >80% of cases) and by additional mutations, e.g. in SRSF2, ASXL1 and/or RUNX1 (S/A/Rpos, >60% of cases). In a recently reported phase-II-study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (ORR) of 60% in advSM but biomarkers predictive of response are lacking. We evaluated the impact of molecular markers (KIT D816V, S/A/Rpos) at baseline and during follow-up in 38 midostaurin-treated advSM patients. The median overall survival (OS) was 30 months (95% CI, 6-54) from start of midostaurin. ORR and OS were significantly different between S/A/Rneg (n=12) vs. S/A/Rpos (n=23) patients (ORR: 75% vs. 39%, P=0.04; OS: P=0.01, HR 4.5 [1.3-16.2]). Depending on the relative reduction of the KIT D816V expressed allele burden (EAB) at month 6, patients were classified as KIT-responders (≥25%, n=17) or KIT-non-responders (<25%, n=11). In univariate analyses of clinical and molecular response parameters at month 6, reduction of KIT D816V EAB ≥25%, serum tryptase ≥50% and alkaline phosphatase ≥50% were significantly associated with improved OS. In multivariate analysis, only KIT D816V EAB reduction ≥25% remained an independent on-treatment marker for improved OS (P=0.004, HR 6.8 [1.8-25.3]). Serial NGS analysis of 28 genes in 16 patients revealed acquisition of additional mutations or increasing variant allele frequency in K/NRAS, RUNX1, IDH2 or NPM1 associated with progression in 7 patients. In midostaurin-treated advSM patients, the complexity and dynamics of mutational profiles significantly impact on response, progression, and, prognosis.

  • Submitted January 25, 2017.
  • Accepted April 9, 2017.