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

Abstract

Key Points• The complexity and dynamics of mutations significantly impact on response, progression, and prognosis in midostaurintreated advSM patients.In advanced systemic mastocytosis (advSM), disease evolution is often triggered by KIT mutations (D816V in >80% of cases) and by additional mutations (eg, in SRSF2, ASXL1, and/or RUNX1 [S/A/R pos in >60% of cases]). In a recently reported phase 2 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 at baseline and during follow-up in 38 midostaurin-treated advSM patients. The median overall survival (OS) was 30 months (95% confidence interval, 6-54) from start of midostaurin. ORR and OS were significantly different between S/A/R neg (n 5 12) and S/A/R pos (n 5 23) patients (ORR: 75% vs 39%, P 5 .04; OS: P 5 .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 5 17) or KIT nonresponders (<25%, n 5 11). In univariate analyses at month 6, reduction of KIT D816V EAB ‡25%, 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 5 .004,). Serial next-generation sequencing 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 affect response, progression, and prognosis. (Blood. 2017;130(2):137-145)

Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management

“…In this regard, ASXL1 , RUNX1 and SRSF2 mutations that are frequently observed in other myeloid malignancies have been identified as being prognostically detrimental, particularly in advanced SM patients . Further, one study showed inferior clinical outcomes (ie, response rates, survival and disease progression) in advanced SM patients receiving midostaurin treatment, for those harboring poor‐risk mutations as compared to those without such mutations . In a recent study, two complementary risk models for SM were developed, referred to as the Mayo Alliance Prognostic System (MAPS) for SM; one model (clinical) was based on clinical variables alone while the other (hybrid clinical‐molecular) included adverse mutations as an independent risk factor .…”

Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis

“…47 KIT D816V iPSCderived cells were also targeted by midostaurin, avapritinib (BLU-285) and ripretinib (DCC-2618), in agreement with previous reports and clinical trials for these compounds. 17,[19][20][21] Importantly, nintedanib compromised cell viability of SM patient samples and blocked KIT D816V phosphorylation and signaling in primary patient cells.…”

“…11,15 Other TKIs, such as midostaurin, suppress the growth of KIT D816V neoplastic MCs and recently, midostaurin was approved for treatment of advanced SM. [16][17][18] More recently, two further compounds targeting KIT D816V, ripretinib (DCC-2618) and avapritinib (BLU-285), were identified and are being tested in clinical trials for advanced SM. [19][20][21] However, none of the available drugs can induce complete long-lasting remission in all patients and therefore, further efforts to establish preclinical models and to identify new TKIs are needed.…”

Mastocytosis – pathogenesis, clinical manifestation and treatment

“…Common adverse effects are neutropenia or persistent lymphopenia. The majority of patients with ASM or MCL respond to midostaurin, a kinase inhibitor available for oral use . The response is usually only temporary, though.…”