Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis (SM) defined by >20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had 'leukemic MCL' (≥ 10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy, administered to 65% of patients, and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded due to low event rates), a diagnosis of MCL-AHN (HR 4.7, 95% CI 1.7 - 13.0, p = 0.001) and abnormal karyotype (HR 5.6, 95% CI 1.4 - 13.3, p = 0.02) were associated with inferior OS; KIT D816V positivity (HR 0.33, 95% CI 0.11 - 0.98, p = 0.04) and midostaurin treatment (HR 0.32, 95% CI 0.08 - 0.72, p = 0.008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.

316 Background: The pathogenetic and high frequency D816V KIT mutation in aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) exhibits in vitro and clinical resistance to imatinib. Midostaurin (PKC412) is an inhibitor of the KIT tyrosine kinase and can block D816V KIT-transformed cell growth at an IC50 of 30–40nM. Herein we report updated results of our fully accrued investigator-initiated, multicenter, phase II study of oral PKC412 in World Health Organization-defined ASM/MCL patients (pts). Method: PKC412 100 mg bid was administered as continuous 28-day cycles until progression/ intolerable toxicity. Lack of a major response (MR) or partial response (PR) per Valent criteria by the end of 2 cycles resulted in discontinuation from the protocol. Result: Efficacy and safety data for all 26 pts (15 male: 11 female) are presented. The distribution of SM pts with one or more “C” findings included ASM (n=4), SM-CMML (n=14), SM-MDS (n=3), SM-MDS/MPN-U (n=1), and MCL (n=4, two with associated MDS). The median age of pts was 62 years (range 24–79 years), and the median # of prior therapies was 1.5 (range 0–4). Responses have been observed in 18/26 pts (69%), consisting of 10 pts (38%) with a MR (6 incomplete remissions and 4 pure clinical responses), 5 pts (19%) with a good partial response (GPR), and 3 pts with a minor PR . Four pts had stable disease, and 4 pts exhibited progressive disease (PD). In subjects with higher quality responses, responses have been durable, with PKC412 administered for a median of 19.5 cycles (1.5 years) for MR pts and 15 cycles (1.2 years) for MR+PR pts (range 4+ - 58+ cycles). Major responses have included normalization of hypoalbuminemia, improvement of hemoglobin and platelet counts, and resolution of liver function abnormalities. High quality responses have also included near complete resolution of pleural effusion and ascites (with reduction of paracentesis), and substantial reversion or normalization of weight loss (including one pt discontinuing TPN). Clinically meaningful responses have been accompanied by reduction of palpable and/or 3-D volumetric CT measurement of hepato/splenomegaly, a >50% decrease in the serum tryptase level and/or marrow mast cell (MC) burden, and improvement in mediator symptoms and ECOG performance status. Cutaneous mast cell lesions faded in 2 pts. One patient with MCL has achieved a near complete remission with RBC transfusion independence, normalization of albumin, disappearance of 18 cm palpable splenomegaly (70% volume reduction by imaging), decrease of serum tryptase from 763 to < 20 ng/mL, and decrease of marrow MC burden from 60–70% to 5%. Of particular interest, in 3 pts with SM-CMML (all D816V KIT+), associated marked eosinophilia normalized (e.g. decreased from 50% to 1% in one pt).The most common grade 1–2 non-hematologic toxicities were nausea and/or vomiting, and less frequently diarrhea and fatigue. Asymptomatic and reversible hyperlipasemia occurred in 5 pts (grade 3, n=1). Hematologic toxicity with a suspected relationship to PKC412 has included ≥ grade 3 worsening of pre-existing anemia, and in one pt, recurrent grade 3 thrombocytopenia despite dose reduction to 50 mg bid. Dose reduction was undertaken in 4 additional pts (N/V, n=2; HA, n=1; transient increase in pre-existing pleural effusion, n=1). Dose re-escalation to 100 mg bid was feasible in 3 of these 4 pts. As of August 5, 2010, 8 pts continue PKC412, and treatment has been discontinued in 18 pts. Among the latter, 2 pts had PKC412 discontinued after 4 cycles (grade 3 fatigue, grade 2 N/V, n=1 each), and 7 initial responders have terminated therapy for PD after 8–39 cycles (1 for progression of CMML). Allele-specific PCR detected D816V KIT in 18/26 (69%) pts, and a novel, activating two–amino acid insertion in MPL was identified in a D816V KIT-negative pt. A statistically significant association was observed between positivity for D816V KIT and achieving a MR versus any other type of response (p=0.0095, Fisher's exact test). Pharmacokinetic data and histopathologic correlates of response (e.g. marrow MC burden and serum tryptase levels) will be presented. Conclusion: PKC412 is well tolerated and exhibits clinically relevant and durable responses which compare very favorably to literature reports of interferon-alpha or cladribine in advanced SM. An ongoing international trial aims to further evaluate the efficacy and safety of PKC412 in this pt population. Disclosures: Gotlib: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. George:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dutreix:Novartis: Employment. Gross:Novartis: Employment. Nikolova:Novartis: Employment. Graubert:Novartis: Research Funding.

There is an unmet need for effective therapies for advanced systemic mastocytosis (advSM). CD30 is expressed on the surface of neoplastic mast cells (MC) in more than 50% of patients with advSM. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate with preclinical evidence supporting both an antineoplastic effect and an attenuation of immunoglobulin E-associated mediator release. These observations are the basis for this phase 2 trial of BV monotherapy (1.8 mg/kg IV every 3 weeks up to 8 cycles) in patients with CD30-positive advSM. The primary objective was to determine the efficacy of BV according to International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria. Secondary objectives included evaluation of safety, changes in bone marrow (BM) MC burden, serum tryptase level, flow cytometric quantification of MC surface expression of CD30, and self-reported symptom burden. The trial enrolled 10 patients with a diagnosis of CD30+ advSM (aggressive SM, SM with an associated hematologic neoplasm [SM-AHN], or mast cell leukemia [MCL]) with 1 or more signs of SM-related organ damage. According to IWG-MRT-ECNM criteria, none of the patients demonstrated better than stable disease with BV. In addition, there were no significant reductions in BM MC burden, serum tryptase levels, or MC surface expression of CD30. Self-reported symptom scores showed no durable improvement with BV treatment. We conclude that BV is not active as a single agent in CD30+ advSM. This trial was registered at www.clinicaltrials.gov as #NCT01807598.

Immunoglobulins were measured in colostral whey from untreated ewes or ewes treated on days 142-145 of gestation with 15 mg oestradiol benzoate (ODB) or 10, 17·5 or 25 mg dexamethasone m-sulfobenzoate (DEX) to induce parturition. DEX at all levels reduced the concentrations of immunoglobulins in colostrum, but ODB had no effect. In a second experiment, similar treatments of ODB and DEX were applied on day 143 of gestation. Lambs were removed from their dams at birth and fed a standard volume of pooled colostrum taken from untreated ewes. They were injected with an antigen (Brucella abortus) at 12 hand 4 weeks of age .. Concentrations of immunoglobulins in blood plasma at 24 h after birth of lambs from DEX-treated ewes were lower than for lambs from untreated ewes or from those treated with ODB. Response to the antigen, monitored to 12 weeks of age, was unaffected by either drug. The impairment of transfer of immunoglobulins from ewe to lamb offers a possible explanation for the higher mortality among older lambs found previously after treatment of ewes with DEX.