Comprehensive Cytokine Profiling of Patients with Advanced Systemic Mastocytosis Treated with Midostaurin

Background: Advanced systemic mastocytosis (AdvSM) comprises a group of hematologic neoplasms primarily driven by the oncogenic KIT D816V mutation. Morbidity and mortality relate to organ damage caused by neoplastic mast cell infiltration and mast cell mediator symptoms. Midostaurin, an oral multikinase/KIT inhibitor, produced reversion of organ damage in 60-70% of AdvSM patients (Gotlib et al, NEJM, 2016; DeAngelo et al, Leukemia, 2018), which was associated with decreases in bone marrow mast cell burden, serum tryptase levels, and splenomegaly in the majority of patients. Similar to myelofibrosis (MF) patients treated with JAK inhibitors, midostaurin improves disease symptoms and quality of life (Gotlib et al, NEJM, 2016). We conducted a cytokine profiling study to better understand the biologic effects of midostaurin in this patient population. Methods: Plasma cytokine levels were analyzed in 19 patients with AdvSM (2 aggressive SM, 10 SM with an associated hematologic neoplasm, and 7 with mast cell leukemia) treated with midostaurin 100 mg twice daily. Seventeen patients were treated on the phase II investigator-initiated trial (DeAngelo et al,Leukemia, 2018), and two were treated on a compassionate-use basis. Cytokine levels were compared to 10 patients with MF (primary MF [n=4]; post PV/ET MF [n=6]), treated with JAK inhibitors (ruxolitinib, fedratinib, or momelotinib) and 10 healthy patients whose age range matched the SM group. Plasma samples were obtained pretreatment, and after 4-8 weeks of therapy. Each patient sample was evaluated for 62 cytokines using a Luminex assay (eBioscience) performed at the Stanford Human Immune Monitoring Center. Sparse partial least squares discriminant analysis (SPLS-DA) was used to identify the most predictive cytokines from the expression data that help classify patient samples based on disease states, and SPLS regression was used to identify cytokines correlated with survival (Rohart et al, mixOmics. R package version 6.3.2). Overall survival was calculated from the time of initiation of midostaurin to time of death. Results: Plasma levels of several cytokines were higher at baseline in AdvSM and MF patients compared to healthy controls (Fig 1A-B). In patients with AdvSM and MF, pretreatment levels of leptin (false discovery rate (FDR) Conclusions: Cytokine expression profiling can distinguish patients with AdvSM or MF from healthy controls. Compared to the use of JAK inhibitors in MF, midostaurin9s activity in AdvSM appears less related to reversion of pro-inflammatory cytokines. Investigation of a larger cohort of patients is needed to determine whether such analyses of plasma cytokines will provide added value to new scoring prognostic systems of AdvSM that incorporate clinical and molecular data. Disclosures DeAngelo:Glycomimetics: Research Funding; Amgen: Consultancy; ARIAD: Consultancy, Research Funding; Takeda: Honoraria; BMS: Consultancy; Incyte: Consultancy, Honoraria; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding. George:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gotlib:Deciphera: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Promedior: Research Funding; Gilead: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.