Response and progression on midostaurin in advanced systemic mastocytosis

• Verfasst von: Jawhar, Mohamad [VerfasserIn]
• Verfasst von: Schwaab, Juliana [VerfasserIn]
• Verfasst von: Naumann, Nicole [VerfasserIn]
• Verfasst von: Metzgeroth, Georgia [VerfasserIn]
• Verfasst von: Fabarius, Alice [VerfasserIn]
• Verfasst von: Hofmann, Wolf-Karsten [VerfasserIn]
• Verfasst von: Reiter, Andreas [VerfasserIn]
• Titel: Response and progression on midostaurin in advanced systemic mastocytosis
• Titelzusatz: KIT D816V and other molecular markers
• Verf.angabe: 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
• E-Jahr: 2017
• Jahr: 13 July 2017
• Umfang: 9 S.
• Fussnoten: Gesehen am 28.05.2018
• Titel Quelle: Enthalten in: Blood
• Ort Quelle: Washington, DC : American Society of Hematology, 1946
• Jahr Quelle: 2017
• Band/Heft Quelle: 130(2017), 2, Seite 137-145
• ISSN Quelle: 1528-0020
• DOI: doi:10.1182/blood-2017-01-764423
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1575547996

Abstract

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/Rpos 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/Rneg (n = 12) and S/A/Rpos (n = 23) patients (ORR: 75% vs 39%, P = .04; OS: P = .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 nonresponders (<25%, n = 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 = .004, HR 6.8 [1.8-25.3]). 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.