No abstract

799 Background: Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) with or without an associated clonal hematologic non-mast cell lineage disease (AHNMD) are myeloproliferative neoplasms (MPN) with inadequate treatment options. The activating KIT D816V mutation occurs in ≈80% of patients (pts) with these advanced forms of SM and is central to disease pathogenesis. Midostaurin is an oral inhibitor of multiple tyrosine kinases, including wild-type and D816-mutated KIT. Promising results of an investigator-initiated trial (Gotlib et al. Blood. 2010;116:316) led to initiation of this multicenter phase 2 study (NCT00782067) of midostaurin in pts with advanced SM. Here, we report the efficacy and preliminary safety results of stage 1 of this trial. Methods: Midostaurin (100 mg BID) was administered continuously in 28-d cycles until progression or intolerable toxicity. Enrollment into an extension phase was permitted if the null hypothesis of an overall response rate (ORR) ≤ 30% was rejected per Fleming 2-stage design. Pts were required to have ≥ 1 measurable C-finding(s) (CF; eg, cytopenias, liver dysfunction) considered related to SM. The primary endpoint was ORR (major response [MR] + partial response [PR] according to Valent criteria) occurring in the first 6 cycles and maintained for ≥ 8 weeks (wk). International Working Group criteria for myelodysplastic syndrome (MDS; with slight modifications) were used to evaluate changes in transfusion dependence. Results: 62 pts were enrolled in stage 1, of whom 40 (65%) were eligible for efficacy evaluation. Reasons for ineligibility included absence of measurable CF (n = 11) or CF considered unrelated to SM (n = 11). Median age of eligible pts (25 males, 63%) was 64.5 y (range: 48–80 y). 33 (83%) pts had ASM (27 with an AHNMD) and 7 (18%) had MCL (3 with an AHNMD). AHNMDs (n=30) included 10 chronic myelomonocytic leukemia (CMML), 10 MDS/MPN-unclassified (MDS/MPN-u), 4 hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL), and 6 other subtypes. 22 (55%) pts received at least 1 prior therapy (median: 1.5; range: 1–4). 28 (70%) pts were KIT D816V/Y–positive, 3 (8%) were KIT D816V/Y–negative, and 9 (23%) were not evaluable for mutation status. The ORR was 60% (24/40), and most responses were MRs (21/24; Table). With a median follow-up of 27 months (mo), the median duration of response and median overall survival (OS) have not been reached. Of the 7 pts with MCL, 4 (57%) achieved an MR, including 3 ongoing incomplete remissions (IR) (19+ mo in 2 pts and 32+ mo in 1 pt). The OS in MCL pts was 22.6 mo. Additionally, 3 of 4 responding ASM/MCL-HES/CEL pts exhibited resolution of blood eosinophilia (mean baseline % and absolute eosinophils: 64% and 15.6 × 109/L). Median change in serum tryptase level among the 40 pts was −61% (range: −97% to 16%), with 16 (40%) pts exhibiting a ' 50% reduction lasting ≥ 8 wk. Median change in marrow mast cell (MC) burden in 32 evaluable pts was −41% (range: −92% to 83%), with 15/32 (47%) pts exhibiting a ≥ 50% reduction. All 62 pts received at least 1 dose of midostaurin and were included in the safety analysis. Grade 3/4 hematologic adverse events (AEs) considered drug-related were neutropenia (11%), anemia (3%), and thrombocytopenia (3%). The most common grade 3/4 drug-related non-hematologic AEs were fatigue (6%), nausea (6%), vomiting (5%), diarrhea (5%), and increased lipase (5%). As of March 15, 2012, therapy was discontinued in 26/40 pts: 7 for AEs (5 drug-related), 12 for disease progression, and 7 for other reasons. 3 of 30 pts with an AHNMD (2 CMML and 1 MDS/MPN-u) developed AML. Conclusion: In advanced SM pts, midostaurin was well tolerated and demonstrated a high rate of durable responses, including in MCL, which historically has a dire prognosis. The drug can produce significant reductions in MC burden, indicating the potential for disease modification. The stage 1 ORR was sufficient to reject the null hypothesis and permitted enrollment in the extension phase, where full accrual of 116 pts has been completed. Disclosures: Gotlib: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. George:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Akin:Novartis: Consultancy. Sotlar:Novartis: Consultancy. Awan:Allos Therapeutics: Speakers Bureau. Morariu:Novartis: Employment. Squier:Novartis: Employment. Villeneuve:Novartis: Employment. Emery-Salbert:Novartis: Employment. Horny:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria. Reiter:Novartis: Consultancy, Honoraria.

Background Patients (pts) with advanced SM, including aggressive SM (ASM) and mast cell leukemia (MCL), often exhibit debilitating mediator symptoms and impaired quality of life (QoL) due to mast cell degranulation and organ damage. Limited treatment options are available for these poor-prognosis conditions. Midostaurin is an oral inhibitor of multiple tyrosine kinases, including wild-type and D816-mutated KIT. In vitro studies have shown that midostaurin inhibits growth and mediator release in human mast cells and basophils. Previously reported results from stage 1 of the ongoing phase 2 study in pts with advanced SM (D2201/NCT00782067; n = 40) showed a high (60%) overall response rate and good safety profile (Gotlib, et al. ASH 2012). Here, we report QoL results and updated duration of response and overall survival (OS) data for these 40 pts. Methods Midostaurin (100 mg twice daily [BID]) was administered continuously in 28-d cycles until progression or unacceptable toxicity. Responses and eligibility were adjudicated by a study steering committee using modified Valent criteria. Symptoms and QoL were assessed at baseline and after each treatment cycle with the Memorial Symptom Assessment Scale (MSAS; ranging from 0 [no symptoms] to 4 [maximum symptom frequency, severity, and distress]) and the Short-Form Health Survey (SF-12; ranging from 0 [worst] to 100 [best]). The total MSAS score (TMSAS), the global distress index score (GDI), the physical score (PHYS), and the psychological score (PSYCH) were derived from the frequency, severity, and distress values of selected symptoms and summarized for the MSAS questionnaire. The composite physical (PCS) and mental health (MCS) scores were summarized for the SF-12 questionnaire. Scores > 50 in the PCS and MCS represent above-average health status. Median values were computed at baseline and for the best value on treatment. In addition, the prevalence of the most frequent symptoms at baseline and at the time of the best TMSAS value was calculated. Results With a median follow-up of 35 mo for all pts (range, 20-46 mo), the median duration of response was 37 mo in the 24 responders (Table). Median OS was 41 mo in the 40 stage 1 pts and not reached in MCL pts. The median best reductions in symptom burden on treatment were 65%, 80%, 68%, and 77% as measured by the TMSAS, GDI, PHYS, and PSYCH assessments, respectively. Compared with baseline, 32% of 37 assessable pts had a > 50% improvement in TMSAS lasting more than 6 cycles, 35% in GDI, 27% in PHYS, and 30% in PSYCH, reached at a median time of 142, 114, 59, and 91 days, respectively. The 6 most prevalent symptoms at baseline were lack of energy, drowsiness, diarrhea, bloating, difficulty concentrating, and difficulty sleeping. The prevalence of all 6 was reduced on treatment from −17% for difficulty sleeping to −35% for bloating. The median PCS and MCS scores at baseline were 36 and 45 compared with 45 and 59, respectively, on treatment. Similar trends were observed in responders, indicating substantial physical and mental improvement. QoL was improved and symptom burden reduced in both pts with ASM and MCL. Conclusion In pts with advanced SM, midostaurin demonstrates a high rate of durable responses that are associated with improvement of disease-related symptoms and QoL. These data are the first systematic analyses of symptom burden and QoL changes with any therapy for ASM and MCL. Disclosures: Gotlib: Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, travel support Other. Off Label Use: This abstract describes a clinical trial evaluating the investigational agent midostaurin for use in patients with advanced systemic mastocytosis. George:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Akin:Novartis: Consultancy. Sotlar:Nanostring: Honoraria; Novartis: laboratory services compensation, laboratory services compensation Other. Hermine:AB Science: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Celgene: Research Funding. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals: Speakers Bureau. Mauro:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Morariu:Novartis: Employment. Squier:Novartis: Employment. Villeneuve:Novartis: Employment. Emery-Salbert:Novartis: Employment. Coombs:Novartis: Employment, Equity Ownership. Hartmann:Novartis: member of a Steering Committee Other. Horny:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding. Reiter:Novartis: Consultancy, Honoraria.

Objectives To describe disease outcome and the influence of treatment modalities in a cohort of patients with polymyositis (PM) and dermatomyositis (DM) prospectively followed by our Internal Medicine Department, between 1985 and 2013. Methods We reviewed the medical notes of 91consecutive patients with PM and DM diagnosed according to the Bohan and Peter criteria. Since the diagnosis each patient have been followed by a standardised protocol. In March-May 2013 all of patients were enrolled in this study with the objective to evaluate a) the disease outcome b) disease activity, c) damage due to disease and treatment d) and the influence of treatment in outcome in the course of the disease. Results The series comprised 91 subjects with either PM (43) or DM (48) (Table 1). Myogenic abnormalities were detected by EMG in all of the cases, whereas muscle biopsy confirmed the diagnosis in 78% of the cases. All patients were treated with glucocorticoids. 72 patients (78%) received one (n=18) or more (n=31) agents, such as immunosuppressants, IVIg (in 39 patients), SCIg (n=18). Twenty-two patients (24%) (12F =55%; mean age 66 years) died after a mean follow-up of 91±84 months. According to the age-adjusted Cox regression model, male sex and a high MITAX value at the onset significantly correlate with mortality [HR =2.4, 95% CI =1.0 to 5.6 and HR =1.5 (95% CI =1.1 to 2.1), respectively]. Kaplan-Meyer estimates higher mortality for patients treated with corticosteroids or with corticosteroids and immunosuppressants as compared to patients treated with IVIG and/or SCIg (LR test p-value =0.3). Five-, 10- and 15-year survivals were higher in patients treated with immunoglobulin as compared with those treated with glucocorticoids or glucocorticoids plus immunosuppressants (p<0.08,0.1 and 0.06,respectively). Conclusions PM and DM represent complex systemic disorders with a high rate of mortality. Patients initially treated with glucocorticoids and/or immunosuppressants had poorer outcome as compared with those treated with immunoglobulin (IV or SC). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3245