P1036: real-world efficacy and safety of midostaurin-treatment in patients with advanced systemic mastocytosis

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Midostaurin is an approved multikinase/KIT inhibitor for treatment of patients with advanced systemic mastocytosis (AdvSM). Aims: Within the complex field of a variety of response criteria, we sought to identify the most valuable baseline and on-treatment parameters for improved prediction of survival. Methods: On basis of the ´German Registry on Disorders of Eosinophils and Mast Cells`(GREM), we retrospectively evaluated response, survival and safety of midostaurin in 79 consecutive patients with AdvSM (treatment period between 2009 and 2022). Beside common serological, morphological and molecular response parameters, we also assessed a recurrently observed early flare-up of the alkaline phosphatase, which was defined as ≥25% increase within 3 months after start of treatment and a subsequent decline below baseline within 6 months. Results: The median times from diagnosis to initiation of midostaurin, median duration of treatment and median overall survival (OS) were 0.8, 1.0 and 3.0 years, respectively. The median follow-up time from diagnosis and start of treatment was 3.3 and 3.2 years, retrospectively. Midostaurin was used in first-line (1L) or second and further lines (2L+; median 1 prior treatment line, range 0-4) in 63 (80%) and 16 (20%) patients, respectively. In median 1 (range 0-2) subsequent treatment line was applied. The recommended dose of 100mg BID was initiated in 63/79 (80%) patients. At month 12, 29/44 (66%) patients remained at this dose. Overall, 60 adverse events (AE) led to dose-adjustment (including temporary or permanent discontinuation) in a total observation time of 239 patient-years. Most common reasons for dose-adjustment were nausea/emesis (n=22, 37%) and neutropenia (n=8, 13%). Thrombocytopenia and anemia accounted for n=6 (10%) and n=4 (7%) AEs with subsequent dose-adjustment. No new safety signals occurred. At baseline, the presence of additional somatic mutations in SRSF2 (n=36, 46%, HR 2.0 [1.2-3.6], P=0.014), ASLX1 (n=15, 19%, HR 2.0 [1.0-3.9], P=0.043), and EZH2 (n=6, 8%, HR 4.3 [1.7-11.3], P=0.003) significantly stratified patients according to their hazard ratio-weighted risk (median OS, 5.8 vs. 2.9 vs. 1.0 years; P<0.001; Figure 1A). Durable responses (complete, partial, clinical improvement) according to modified Valent criteria, IWG-MRT-ECNM criteria or Pure Pathological Response (PPR) criteria over a median duration between 12 and 24 months were achieved in 60%, 29% and 13% of patients, respectively. Within the first 12 months, achievement of a response was dose-dependent (100mg BID vs. reduced dose, P<0.05) and the duration of response was associated with an OS benefit (P<0.001). An AP flare-up occurred in 22 (28%) patients, was associated with a subsequent decrease of the serum tryptase (median -35%, range -82-191%) and conferred into improved OS (median 5.8 vs. 2.2 years, P=0.007). Multivariable analysis identified the AP flare-up (P=0.029), a ≥25% reduction of bone marrow (BM) mast cell (MC) infiltration (P=0.046) and a ≥25% reduction of the KIT D816V expressed allele burden (EAB; P=0.034) as independent markers for improved OS (best response at any time within the first 6 months; Figure 1B). Summary/Conclusion: In midostaurin-treated AdvSM-patients, absence of mutations in the SRSF2/ASXL1/EZH2 gene panel at baseline and the on-treatment parameters AP flare-up, and >25% reduction of BM MC infiltration and of KIT D816V EAB at any time within the first 6 months were identified as the most valuable parameters for prediction of improved OS.Figure 1. Kaplan-Meier estimates of overall survival in hazard-weighted risk scoring systems based on (A) additional somatic mutations beyond KIT D816V at baseline and (B) independent on-treatment parameters. Keywords: Mast cell, Systemic mastocytosis, Mast cell disease, Mastocytosis