Abstract: Background: Aggressive Systemic Mastocytosis (ASM) and the related disorders, SM with associated hematologic non-mast cell disorder (SM-AHNMD) and mast cell leukemia (MCL), are mast cell (MC) neoplasms that cause debilitating allergy symptoms, markedly impair organ function and decrease life expectancy. Although the oncogenic KIT D816V mutant is recognized as an important driver in about 95% of advanced SM (ASM, SM-AHNMD, MCL), no currently approved therapy effectively targets KIT D816V. A phase 1 study (NCT02561988) was initiated in advanced SM to assess the safety, PK, and preliminary clinical activity of BLU-285, a potent, highly-selective oral inhibitor designed to target KIT D816V (IC50 = 0.27 nM). Methods: Adult patients (pts) with ASM, SM-AHNMD or MCL per WHO diagnostic criteria were given BLU-285 once daily on a 4-week cycle following a 3+3 escalation design. Adverse events (AEs) per CTCAE, PK and biomarkers including serum tryptase, D816V mutant allele fraction in blood and bone marrow and co-occurring mutations (Illumina TruSight panel) were assessed. Liver and spleen size were measured serially via CT or MRI. All cases will undergo central pathology review to confirm SM diagnosis and subtype. Results: At a 21-JUL-2016 cutoff, 6 pts (5 ASM; 1 SM-CMML) have been treated with BLU-285 in 2 cohorts at doses of 30 and 60 mg/day. All pts had confirmed D816V mutation in blood and bone marrow and all pts had ≥ 1 co-occurring mutation(s) in bone marrow (range 4-9, most frequently TET2 (5), DNMT3A (4) and GATA1 (4)). All pts had MC-related organ damage as evidenced by ≥ 1 C-finding (bone marrow dysfunction with ≥ 1 cytopenia; hepatomegaly with impaired liver function, ascites and/or portal hypertension; osteolytic skeletal lesions; splenomegaly with hypersplenism; malabsorption with weight loss). The median number of C-findings was 1.5 (range 1-3). 4 pts had urticaria pigmentosa. Concomitant medications for MC-related symptoms included anti-histamines (5), corticosteroids (2), leukotriene receptor antagonist (2) and/or cromolyn (1). 2 pts had received prior anti-neoplastic therapy with pegylated interferon (1) or midostaurin (1). Although early in dose escalation, marked improvements in disease symptoms and burden were seen in all pts across both dose levels. This included symptomatic relief of allergy symptoms with decreased use of corticosteroids (2), improved urticaria pigmentosa (3 of 4), and increased albumin (5)/weight gain (6), indicative of diminished malabsorption. Objective decreases in mast cell burden were also observed including decline in peripheral blood and bone marrow KIT D816V DNA levels (6), decreased splenomegaly (3), tryptase decline (5), and decreased bone marrow MCs (2 of 2) (1 pt had bone marrow aspirate MCs decline from 30% at baseline to 3%; 1 pt had bone marrow biopsy MCs decline from 80% to 20%, both at C3D1). Tryptase decline appears to be dose related, with 〉 50% decrease in 1/3 patients in the 30 mg cohort and 〉 50% decrease in 3/3 patients in the 60 mg cohort. Updated diagnostic, biomarker, bone marrow and response data will be presented at the time of the meeting. An MTD has not been determined and dose escalation continues. BLU-285 was well tolerated with most AEs being CTCAE grade 1 and no grade ≥ 4 events. Grade 2 AEs included fatigue, dizziness, headache, rash, shingles, anemia, elevated GGT and thrombocytopenia (1 patient each). Grade 3 alkaline phosphatase elevation was observed in 3 patients and grade 3 back pain in 1 patient. All pts remain on treatment, with duration of therapy ranging from 2-5 cycles. Initial PK data show that BLU-285 is rapidly absorbed (Tmax 2-4 h), and half-life is 〉 19 h supporting once daily dosing. Mean steady-state AUC and Cmax at the 30 mg dose level were 1,845 ng*h/mL and 89 ng/mL, which are below the maximally active exposure in KIT D816-mutant xenograft models. Conclusion: Currently approved therapies do not effectively target KIT D816V, a key genomic-driver in approximately 95% of SM. BLU-285, a potent, highly-selective inhibitor of this mutant has been well tolerated and demonstrates clinical activity early in dose escalation with objective decreases in MC burden and improvements in MC-related organ damage in advanced SM. These encouraging phase 1 data support selective targeting of KIT D816V and further clinical testing of BLU-285 in SM. Disclosures Drummond: BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau. DeAngelo:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Ariad: Consultancy; Baxter: Consultancy; Celgene: Consultancy. Deininger:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Radia:Novartis: Honoraria; Pfizer: Honoraria. Hexner:Blueprint medicines: Membership on an entity's Board of Directors or advisory committees; novartis: Research Funding. Shi:Blueprint Medicines: Employment, Equity Ownership. Alvarez-Diez:Blueprint Medicines: Employment, Equity Ownership. Evans:Blueprint Medicines: Employment, Equity Ownership. Healy:Blueprint Medicines: Employment, Equity Ownership. Wolf:Blueprint Medicines: Employment, Equity Ownership.

Abstract: Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a devastating disorder with protean clinical manifestations caused by the overproduction of T-cell derived cytokines. Cytokine-dependent activation of the Janus family kinases (JAK) is a hallmark of the final common pathway in HLH pathogenesis. Therefore, we initiated a single center, open-label, investigator-initiated trial to assess the efficacy and safety of ruxolitinib in adult patients with secondary HLH. Methods: Adult patients (≥18 years) who fulfilled 5 of 8 diagnostic criteria were eligible. Patients with CNS involvement or an active malignancy were ineligible. Patients who had received any prior systemic therapy (excluding corticosteroids) within 7 days of treatment were ineligible. Patients with normal renal function received oral ruxolitinib 15 mg twice daily on a continuous, 28-day cycle. Dose reductions for renal insufficiency and toxicity are permitted. Treatment was continued indefinitely until disease progression, unacceptable toxicity, or any other conditions for treatment discontinuation were met. The first patient was enrolled in February, 2016 and enrollment is ongoing. The primary endpoint is overall survival at 2 months. Secondary endpoints include the response rate, duration of response, progression-free and overall survival. Adverse events were graded and attributed in accordance with the National Cancer Institute Guidelines for the Cancer Therapy Evaluation Program. Disease parameters evaluable for response included all quantifiable signs and laboratory abnormalities included in the diagnostic criteria for HLH. A complete response (CR) required normalization of all signs and laboratory abnormalities. At least 25% improvement in two or more signs/laboratory abnormalities was required for a partial response (PR). At least a 50% worsening in two or more signs/laboratory abnormalities was considered progressive disease (PD), while failure to fulfill any of these criteria was considered stable disease (SD). Results: A total of 4 patient have been enrolled, all of whom fulfilled at least 5 of 8 diagnostic criteria for HLH. Hemophagocytosis, a pathologic hallmark of HLH, was observed in every patient. At the time of treatment initiation, all patients were anemic [median hemoglobin 7.1 g/dL (range: 6.2-7.5 g/dL)] and thrombocytopenic [median platelet count 47 K/uL (range: 14-107 K/uL)] . Three patients were neutropenic [median ANC 0.95 K/uL (range: 0-1.9 K/uL)]. HLH was secondary to an autoimmune disorder (n=3), infection (n=1), and a homozygous mutation in the STXBP2 gene, recently identified as a causative defect in primary HLH, was observed in one patient. Cytopenias significantly improved within the first week of treatment in all patients. On day +7, the mean increase in hemoglobin was 1.88 g/dL (0.2-3 g/dL), in ANC was 1.53 K/uL (range 0.1-5.3 K/uL) and platelet count was 74 K/uL (range 17-116 K/uL). Neutropenia resolved by day +40 and thrombocytopenia resolved by day +47 in all patients. Three of four patients became transfusion independent within 2 days of treatment initiation. Three of four patients received corticosteroids prior to and after initiation of ruxolitinib. The mean corticosteroid (prednisone equivalent) dose prior to treatment initiation was 225 mg/day (range: 60-391 mg/day) and was 38 mg/day (range: 0-75 mg/day) on day +30. Within 47 days of treatment initiation, corticosteroids were discontinued in 2 patients, and were discontinued in all patients by day +54. Significant improvements in ferritin and sIL-2R were also observed with a median 92.6% decrease in ferritin by day +30 (range 86.4-92.6%) and 86% median decrease in sIL-2R by day +30 (range 66.6-92.7%). All patients achieved at least a PR, and 2 patients remain on treatment ( 〉 2 months, 〉 8 months). Two patients discontinued treatment, one for progressive disease (due to recurrent symptoms), and another for drug intolerance (neuropathic foot pain). No severe adverse events have been observed. In addition to the patients enrolled in this study, two additional patients who met eligibility criteria were similarly treated (off study) at another institution. Both of these patients achieved at least a PR and remain on treatment ( 〉 8 months, 〉 14 months). Conclusions: Ruxolitinib led to rapid and durable responses and was well tolerated in adult patients with secondary HLH. Disclosures Devata: Affimed: Research Funding. Phillips:Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy. Sood:Bayer: Research Funding. Wilcox:Incyte, Corp: Research Funding.