Verstovšek, Srđan

Abstract Background In the primary analysis of the phase III COMFORT-I study, the JAK1/JAK2 inhibitor ruxolitinib (RUX) significantly improved splenomegaly, myelofibrosis (MF)-related symptoms, and quality of life (QoL) measures in patients (pts) with MF versus placebo (PBO). An additional analysis (median follow-up 51 weeks [wks)]) showed RUX was associated with a survival advantage versus PBO (Verstovsek et al. N Engl J Med2012). Longer term follow-up (median 102 wks) showed durable SV reductions and QoL improvements. At this time point, RUX continued to be associated with a survival advantage, despite all pts originally randomized to PBO having discontinued or crossed over to ruxolitinib shortly after the primary analysis (Verstovsek et al. ASH 2012. abstract 800). We report additional longer-term follow-up of pts from COMFORT-I. Methods In COMFORT-I, 309 pts were randomized (1:1) to RUX or PBO. RUX starting dose depended on baseline platelet count (100–200´109/L: 15 mg BID; >200´109/L: 20 mg BID). Doses could be titrated for lack of efficacy or excess toxicity as specified in the protocol. Pts receiving PBO could crossover to RUX after the primary analysis (ie, when all pts completed 24 wks and half the pts completed 36 wks of therapy) or at any time if they met protocol-specified criteria for worsening splenomegaly. The primary endpoint was the proportion of pts who achieved a ≥35% reduction in spleen volume (SV) at wk 24. Symptoms were assessed up to wk 24 using the modified MF Symptom Assessment Form v2.0. QoL continued to be evaluated beyond wk 24 using the EORTC QoL Questionnaire-Core 30 (QLQ-C30). Survival was estimated by Kaplan-Meier analysis according to original randomized treatment. To better understand the effect of crossover on the PBO arm, statistical modeling of survival was conducted using a generalized Gamma distribution. Results Median follow-up was 149 wks at the time of this updated analysis. Of 155 pts originally randomized to RUX, 77 remain on therapy. Of 154 pts originally randomized to PBO, 111 crossed over to RUX; the median time to crossover was 41.1 wks (range, 5.1–65.4). At wk 24, pts originally randomized to RUX had a mean SV reduction of −31.6%; this was durable for pts who continued on RUX, where the mean SV reduction at wk 144 was −34.1%. Fifty-nine percent (91/155) of pts originally randomized to RUX achieved a ≥35% SV reduction at any time during study; for these pts, the probability of maintaining this response for >132 weeks from the time of their initial response was 0.53. Pts originally randomized to RUX who continued on therapy experienced durable improvements in the Global Health Status/QoL and functional domains of the EORTC QLQ-C30. Overall survival favored RUX (HR=0.69; 95% CI: 0.46, 1.03; P= 0.067; Fig 1), with 42 and 54 deaths among pts originally randomized to RUX and PBO, respectively. Modeling of the hazard function of death over time to explore the effect of crossover to RUX in pts originally randomized to PBO showed a decrease in hazard for these pts, which corresponded to an increased proportion of pts crossing over to RUX. In pts originally randomized to RUX who continued on therapy, there was no substantial change in the rate, distribution, or severity of nonhematologic adverse events (AEs) with longer-term therapy; most nonhematologic AEs were grade 1 or 2. Mean and median hemoglobin and platelet count remained stable with longer-term therapy. Consistent with this, the incidence of new onset grade 3 or 4 anemia and thrombocytopenia observed after the first 6 months of RUX therapy decreased relative to that seen in the first 6 months of therapy (Fig 2). With approximately 1 year of additional follow up, 4 new cases of acute myeloid leukemia were reported: 2 pts originally randomized to PBO (376 and 666 days after crossover to RUX) and 2 pts originally randomized to RUX (848 and 1143 days after starting RUX). Conclusions After a median follow-up of 149 wks, the hazard ratio for overall survival favored pts originally randomized to RUX over those originally randomized to PBO, the majority of whom crossed over to RUX. The hazard of death for pts originally randomized to PBO decreased as pts crossed over to RUX. SV reductions and QoL improvements were sustained with longer-term therapy. The incidence of new onset grade 3 or 4 anemia and thrombocytopenia decreased with longer-term therapy. Collectively, these data reinforce the durable efficacy and longer-term safety of RUX in pts with MF. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Mesa:Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Lilly: Research Funding. Gotlib:Incyte Corporation: Travel support, Travel support Other; Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees; Incyte Corporation: Research Funding. Levy:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Gupta:Incyte Corporation: Consultancy; Novartis: Consultancy; Inctye Corporation: Research Funding; Novartis: Research Funding; Novartis: Speakers Bureau. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Miller:Novartis: Consultancy; Incyte Corporation: Consultancy; Novartis: Research Funding; Incyte Corporation: Research Funding; Novartis: Honoraria; Incyte Corporation: Honoraria. Talpaz:Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Winton:Incyte Corporation: Research Funding; Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees. Arcasoy:Incyte Corporation: Research Funding. Lyons:Lilly: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Gilead: Consultancy; Seattle Genetics: Research Funding; Gilead: Research Funding; Ariad: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Paquette:Incyte Corporation: Consultancy. Raza:Novartis: Speakers Bureau; Onconova Inc: Research Funding. Vaddi:Incyte Corporation: Employment; Incyte Corporation: Equity Ownership. Sun:Incyte: Employment; Incyte: Equity Ownership. Peng:Incyte Corporation: Employment; Incyte Corporation: Equity Ownership. Sandor:Incyte: Employment; Incyte: Equity Ownership. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Abstract Abstract 1753 Background: Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life (QoL) in 2 phase 3 studies in patients with myelofibrosis (MF) (the COMFORT studies). These studies compared ruxolitinib with either placebo or best available therapy (BAT). This analysis compares the efficacy outcomes between the placebo arm from COMFORT-I and the BAT arm from COMFORT-II. Methods: COMFORT-I is a randomized (1:1), double-blind, multicenter study comparing ruxolitinib 15 or 20 mg twice daily (bid) with placebo, and COMFORT-II is a randomized (2:1), open-label, multicenter study comparing ruxolitinib 15 or 20 mg bid with BAT (investigator-selected therapy, including no treatment). Both studies met their primary end points with statistical significance (ruxolitinib vs control): the percentage of patients achieving ≥35% reduction in spleen volume at week 24 (COMFORT-I, P <.0001) and week 48 (COMFORT-II, P <.0001). QoL was measured using patient responses with the European Organisation for the Research and Treatment of Cancer (EORTC) QoL Questionnaire–Core 30 (QLQ-C30) as an exploratory end point in both studies. Results: In the COMFORT-I and COMFORT-II studies, 154 patients received placebo (ruxolitinib, n=155) and 73 patients received BAT (ruxolitinib, n=146), respectively, and were included in the primary efficacy analyses. The demographic and baseline characteristics were similar between the control arms of the 2 studies, including spleen size below the costal margin (mean [standard deviation, SD] 16.4 [6.27] cm and 15.8 [6.71] cm in placebo and BAT, respectively). Only 1 patient (0.7%) who received placebo and no patients who received BAT had a ≥35% reduction in spleen volume from baseline at week 24. The median spleen volume increased from baseline at week 24 in both the placebo and BAT groups and was numerically similar (placebo, 8.5% [range, −46.4% to 48.8%]; BAT, 5.1% [range, −33.3% to 29.7%]). In contrast, patients who received ruxolitinib had median reductions in spleen volume from baseline at week 24 of −33.0% (COMFORT-I) and −27.5% (COMFORT-II). The QLQ-C30 provides a measurement of change in QoL and MF-related symptoms, including fatigue, pain, dyspnea, insomnia, and appetite loss. At 24 weeks, neither the placebo nor BAT arms had clinically meaningful changes from baseline (10 points [Osoba et al. J Clin Oncol. 1998]) in any of the QoL (decreases indicate worsening) or symptom scores (increases indicate worsening) (Table). Although differences existed between the placebo and BAT arms, the SDs are large, thus complicating comparisons between the 2 groups. Conclusions: In the COMFORT studies, ruxolitinib demonstrated significantly greater reductions in spleen size compared with placebo or BAT. This post hoc analysis of the 2 studies shows that patients who received BAT in the COMFORT-II study had similar symptom and QoL responses and numerically similar increases in spleen size as those who received placebo in the COMFORT-I study. No clinically meaningful improvements in QoL or symptoms were seen on either the placebo or BAT arms. These new data strongly suggest that current therapies for MF provide little improvement in spleen size, symptoms, or QoL as compared with placebo. Disclosures: Mesa: Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Verstovsek:Incyte Corporation: Research Funding. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Waltzman:Novartis: Employment. Mendelson:Novartis: Employment, Equity Ownership. Martin:Novartis Pharma AG: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Levy:Incyte Corporation: Employment, Equity Ownership. Harrison:Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria.

Abstract Background MF, PV, and ET are neoplasms characterized by activation of JAK2 signaling, and the majority of cases are associated with the gain of function JAK2 V617F mutation. Given that wild-type JAK2 plays a pivotal role in multiple stages of hematopoiesis it is desirable to treat JAK2V617F-positive cases by selectively inhibiting JAK2 V617F while minimizing inhibition of wild-type JAK2 in order not to impede normal marrow function. LY2784544 is a selective inhibitor of JAK2 which demonstrates dose dependent selectivity for JAK2 V617F/STAT5 signaling. LY2784544 entered clinical testing in a Phase I trial in MF, PV, and ET patients (I3X-MC-JHTA, NCT01134120). We have previously reported early interim analysis from this study and provide here an update following completion of study enrollment. Methods The study’s primary objectives were to determine the safety and tolerability of LY2784544 and define a recommended oral daily dose for further study in patients with JAK2 V617F-positive MF, ET, or PV. Secondary objectives included determination of pharmacokinetics and evaluation of response using the IWG-MRT response criteria (2006), European Leukemia Net response criteria for PV and ET (EULN 2009), and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) (Scherber et. al. Blood 2011). Study design included a standard 3+3 dose-escalation to define the maximum tolerated dose (MTD) and was amended to allow cohort expansions at multiple doses demonstrating potential clinical merit. Results Patients Prior to closing to enrollment, 47 patients were consented; 9 did not meet eligibility screening. The 38 treated patients included 31 MF (22 pMF, 6 post-PV MF and 3 post-ET MF), 6 PVs, and 1 ET patient(s), and 86% had received prior systemic therapy for their MPN. Dosing and tolerability of LY2784544: Systemic exposures were approximately dose proportional across the tested range from 30 to 300 mg. Daily doses of 200 mg or greater were associated with CTCAE Grade 3 increases in serum creatinine. In general, increases in serum creatinine occurred within the first 2 weeks of either starting treatment or after an increase in study drug dose. With the available data, the elevations in serum creatinine appear to be fully reversible after dose reduction or drug holiday in the majority of patients. The maximum tolerated daily dose of LY2784544 when given on a continuous daily basis was determined to be 120 mg per day. Serious AEs, across all grades and doses, included increased creatinine/acute renal insufficiency (4 grade 3, 5 grade 2, 1 grade 1), hyperuricemia (2 grade 4, 1 grade 1), hyperkalemia (1 grade 1), and anemia (1 grade 3). This study allowed intrapatient dose escalation, and 34 patients received 120 mg during their study participation. There were 4 patients dosed at 120 mg with SAEs but all were unrelated to study drug treatment (anemia, influenza, enterococcal bacteremia, hematuria and pneumonia). At 120 mg, the most frequently reported drug-related AEs across all grades were diarrhea (44%), nausea (29%), increased creatinine (21%), and anemia, vomiting, fatigue (9% each). Of these related AEs at 120 mg, there was 1 Grade 3 anemia, 3 Grade 3 increased creatinine, and 2 Grade 3 fatigue. There were no Grade 4 AEs. Efficacy Among a cohort of 10 MF patients who only received 120 mg, 3 achieved a clinical improvement. Analyzing across dose levels, a palpable spleen length reduction of ≥50% was seen in 15 of 27 evaluable patients (56%) at any time. The median duration of these responses was 18.3 weeks (range from 0.7 to 148.1 weeks). At 12 weeks, 56% of patients (15/27) reported a ≥50% improvement in Total Symptom Score on the MPN-SAF. Of the 6 PV patients, 3 achieved a clinicohematologic PR. Findings from a central pathology review of serial bone marrow samples will be presented at the meeting. Conclusions A recommended phase II dose for daily dosing of LY2784544 was identified as 120 mg. This dose has been well tolerated and associated with clinical improvements, supporting ongoing Phase II testing of LY2784544 in MPNs. Disclosures: Verstovsek: Eli Lilly and Co: Research Funding. Mesa:Eli Lilly and Co: Research Funding; Genetech: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Sanofi: Research Funding; NS pharma: Research Funding; Celgene: Research Funding. Salama:Eli Lilly and Co: Research Funding. Giles:Eli Lilly and Co: Employment. Pitou:Eli Lilly and Co: Employment. Hayden Zimmermann:Eli Lilly and Co: Employment. Price:Eli Lilly and Co: Employment. Walgreen:Eli Lilly and Co: Employment. Prchal:Eli Lilly and Co: Research Funding.

Abstract Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed by many hematologic malignancies. SL-401 is currently being advanced through clinical trials in patients with a variety of CD123+ malignancies including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML) in remission with high relapse risk, and multiple myeloma. CD123 has been shown to be expressed on myeloproliferative neoplasm (MPN) cells as well as microenvironmental immune cells, namely plasmacytoid dendritic cells (pDCs), in the bone marrows of some patients with MPN including chronic myelomonocytic leukemia (CMML). Microenvironmental pDCs have been implicated in promoting plasma cell disorders and preliminary data suggest that pDCs could play a related role in some myeloid neoplasms. Accordingly, a therapy directed at both CD123-expressing myeloid cells and neighboring CD123-expressing pDCs could provide therapeutic benefit. SL-401 is being evaluated in patients with advanced, high-risk MPN, including systemic mastocytosis (SM), myelofibrosis (MF), primary eosinophilic disorders (PED), and CMML. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of patients with advanced, high risk MPN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients receive SL-401 as a daily IV infusion at 7, 9, 12 ug/kg/day, or higher for days 1-3 of a 21-28 day cycle in a 3x3 design. In stage 2, patients receive SL-401 at the dose determined in stage 1. Study objectives include characterization of the safety profile, including determination of the maximum tolerated or tested dose, and detection of preliminary efficacy signals including evaluation of tumor response and progression free survival by standard criteria. As of 7/20/16, 6 patients with MPN (MF, n=3; CMML-2, n=2; CMML-1, n=1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3). The median age was 66 years (range: 42-81 years). Patients treated at all doses received 1+ to 2+ cycles (ongoing) of SL-401. The most common treatment-related adverse events (AEs) were thrombocytopenia (2/6; 33%) and fatigue (2/6; 33%); the most common ≥ Grade 3 treatment-related AEs were thrombocytopenia (2/6; 33%) and anemia (1/6; 17%); there has been no DLT. Efficacy assessments are ongoing. Patients are currently enrolling in the 12 ug/kg/day cohort. Conclusions: Initial dosing of SL-401 appears to be well-tolerated in patients with MPN and CMML, with no unexpected AEs observed. Given CD123 expression on myeloid neoplastic cells as well as microenvironmental immune cells (namely, pDCs), SL-401 may offer a novel, targeted therapeutic approach in patients with high-risk MPN and CMML of unmet medical need. Enrollment continues in stage 1 of this ongoing Phase 2 trial and updated safety and efficacy data will be presented. Clinical trial information: NCT02268253. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Schiller:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. McCloskey:Novartis: Speakers Bureau; Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Lee:Alexion Pharmaceuticals: Consultancy; Amgen: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer Inc: Consultancy. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Ali:Incyte Corporation: Research Funding. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

Abstract Background: Simtuzumab (SIM) is a humanized monoclonal antibody that inhibits lysyl oxidase-like molecule 2 (LOXL2), an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across many fibrotic diseases. In pre-clinical models, inhibition of LOXL2 blocks fibroblast activation, which plays an important role in the development of organ fibrosis. In Phase 1 studies, SIM was well-tolerated in patients (pts) with advanced solid tumors, liver fibrosis, and idiopathic pulmonary fibrosis (IPF). A Phase 2, open-label study to determine the efficacy of SIM alone (Stage 1) and combined with ruxolitinib (rux) (Stage 2) in pts with primary myelofibrosis (PMF) and post-ET/PV MF was initiated. Methods: Eligible pts had intermediate-1, intermediate-2, or high risk disease and Eastern Cooperative Oncology Group performance status of <2. The primary endpoint was rate of clinical response as defined by a reduction in bone marrow fibrosis score following 24 weeks of treatment with SIM. Patients were randomized in a 1:1 ratio to receive 200 mg or 700 mg SIM by intravenous infusion every 2 weeks as monotherapy (Stage 1, n=24) or combined with rux (Stage 2, n=30). Patients received SIM for up to 24 weeks. Bone marrow biopsies and aspirates were performed approximately every 3 months. Bone marrow fibrosis scoring was performed and quantified at local investigator sites using the European Consensus on Grading Bone Marrow Fibrosis. Myelofibrosis symptoms were evaluated using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and changes in hematologic parameters and splenomegaly were assessed. Results: Between 7/14/11 and 9/22/14, 54 pts were randomized and treated (200 mg SIM [n=12], 700 mg SIM [n=12], 200 mg SIM/rux [n=15], and 700 mg SIM/rux [n=15]). In Stage 1, 0 subjects (0%) in the SIM 200 mg group and 2 subjects (16.7%; 90% CI 3.0%, 43.8%) in the SIM 700 mg group showed a reduction in bone marrow fibrosis score from Baseline to Week 24. In Stage 2, 1 subject (6.7%; 90% CI 0.3%, 27.9%) in the SIM 200 mg/rux group and 2 subjects (13.3%, 90% CI 2.4%, 36.3%) in the SIM 700 mg/rux group showed a reduction in bone marrow fibrosis score from Baseline to Week 24. In an exploratory analysis, similar numbers of subjects showed increases in bone marrow fibrosis scores. SIM treatment was not associated with meaningful improvements in hematologic parameters or reductions in MPN-SAF score or spleen size. The most frequent adverse events were those commonly associated with MF, including constitutional symptoms and reductions in hematological parameters. Conclusions: SIM treatment alone or in combination with rux is safe but does not reliably reduce bone marrow fibrosis in pts with MF. The reason for reduction of marrow fibrosis in some patients and increase in others is unclear and may be sampling variability. Clinical studies of SIM in IPF and liver fibrosis are ongoing. Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Astex Pharmaceuticals, Inc: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Research Funding; Promedior: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Oh:CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Dong:Gilead Sciences: Consultancy, Equity Ownership. Thai:Gilead Sciences: Employment, Equity Ownership. Gotlib:Allakos, Inc.: Consultancy.

Abstract Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, debilitating symptoms, progressive bone marrow fibrosis and shortened survival. Inflammatory cytokines are associated with the disease and monitoring cytokine levels provides information about response to therapy. Momelotinib (MMB) is a JAK1/2 inhibitor under investigation for the treatment of MF that has been shown to be safe and efficacious while providing an anemia benefit to MF patients in the phase I/II studies: CCL09101 (ASH 2013) and YM387-II (EHA 2014). AIMS: To perform an exploratory analysis of the association between cytokines and anemia-related laboratories, 8 week transfusion response, spleen response by MRI at 24 weeks and total symptom score (TSS) reduction (≥50% decrease at week 24) and JAK2 mutation status, in the phase I/II, open-label YM387II trial. METHODS: 61 patients were enrolled and received MMB treatment. Whole blood samples were collected at baseline, 6 and 24 hours post-dose on day 1, and weeks 8 and 20. Plasma levels of 25 cytokines were analyzed by ELISA or MSD. Comparison of post-treatment data with baseline was carried out using Wilcoxon signed rank tests. Significant change from baseline was declared when ≥ 20% change from baseline was observed with Bonferroni adjusted p < 0.05. As this was an exploratory evaluation, comparison between treatment responders and non-responders was carried out using Wilcoxon rank sum test with no multiple testing corrections. Correlations between the cytokines and main biological parameters were investigated using Spearman correlation coefficients. RESULTS: JAK2V617F allele burden. The prevalence of JAK2V617F-positive patients was 68%. A statistically significant decline in JAK2V617F allele burden from baseline in this subgroup was observed at week 12 (median decrease 16.6%; p = 0.0063; n=21) and week 24 (median decrease 21.1%; p = 0.0019; n=18). Higher baseline IGFBP1 was associated with JAK2V617 mutation (48.2% higher in JAK2 mutated patients than in wildtype patients; p = 0.027). Cytokines and iron metabolism markers at baseline At baseline, hepcidin and IL-8 were anti-correlated with anemia-related markers such as transferrin and hemoglobin (Hb) (Spearman correlation coefficients < -0.5). IL-6, CRP and IL-10 showed strong, positive correlation (Spearman correlation coefficients > 0.5). Lower baseline IL-6 was associated with 24 week spleen response (42.3% lower in responders, p = 0.005); higher baseline thrombopoeitin (TPO) was associated with transfusion response at 8 week (3-fold higher in responders, p = 0.002). Baseline ferritin was 63.7% lower in TSS responders compared to non-responders (p = 0.015). On-treatment changes of cytokines and iron markers A significant decrease was observed in CRP, EPO, IL-6, IL-10, IL-12, TNFRII and TNFα following MMB treatment. IL-6 was reduced 30.3% as early as 6 hrs after first dose of MMB and CRP levels were reduced 27.3% after 24 hrs after treatment and continued to decline to 75% by week 4. A peak of IGFBP1 at 24h and increased TPO were observed. Decreased IL-12 and increased IL-8 at week 8 was significantly associated with 24 week spleen response (p < 0.05). Decline of CRP at week 8 was associated with TSS response (p = 0.045). Hb stayed at or above baseline for 6 months. An early peak of Hb was observed at Day 15 which was correlated with a significant increase in red blood cells and decrease in reticulocytes. CONCLUSIONS: In this exploratory analysis, a rapid and sustained reduction in inflammatory cytokines was observed with MMB treatment as expected based on the mechanism of action of MMB through JAK1/2 inhibition. Data from this study suggest an association between IGFBP1 and JAK/STAT signaling in myelofibrosis that will need to be explored in future studies with larger sample sets. Individual baseline biomarkers were correlated with MMB response, but no single biomarker was associated with all responses. Changes in IL-12 and IL-8 were significantly correlated with 24 week spleen response. The Day 15 data suggest that MMB treatment facilitates erythrocyte maturation. These observations, as well as a panel of iron metabolism markers and cellular signaling pathways, will be investigated in a planned Phase 2 translational biology study of MMB in transfusion-dependent subjects with MF (Gilead Sci: GS-US-352-1672). Disclosures Gupta: Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Deininger:Ariad: 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; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zhang:Gilead Sciences: Employment. Xiao:Gilead Sciences: Employment. Collins:Gilead Science: Employment. Kwei:Gilead Sciences: Employment. Joshi:Gilead Sciences: Employment. Brachmann:Gilead Sciences: Employment.

Abstract Background: PRM-151 (PRM) is a recombinant form of pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. 27 patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, or post-polycythemia vera MF and Grade 2 or 3 bone marrow (BM) fibrosis enrolled in the first stage of a 2-stage adaptive trial in which PRM-151 10 mg/kg IV was administered for 24 weeks in four different arms: PRM-151 QW (n=8), PRM-151 Q4W (n=7), PRM-151 QW + ruxolitinib (RUX) (n=6), or PRM-151 Q4W + RUX (n=6). At 24 weeks, reductions in BM fibrosis, improvements in hemoglobin (Hgb) and platelets (PLT), decreases in symptoms (MPN-SAF Total Symptom Score [TSS]), and modest reductions in spleen size by palpation were observed in all arms, with a favorable safety profile (Verstovsek, ASH 2014, Abstract 713). Patients experiencing clinical benefit were allowed to continue beyond 24 weeks. We now report efficacy and safety in 13 patients who have completed at least 72 weeks of treatment. Bone marrow fibrosis status by morphologic WHO grading and computer-assisted image analysis (CIA) are available up to 48 weeks in some patients, as assessed by central hematopathologist reviewers blinded to patient, treatment, and timepoint. BM data through 72 weeks is pending. WHO response was defined as ≥1 grade reduction in MF grade at any time and CIA response was defined as a decrease in the % fibrosis compared to baseline with a negative slope > 1. (Pozdnyakova, EHA 2015, Abstract P677). Baseline Demographics (N=13): Median age 60 (51-76); 46% DIPSS Int-1, 54% DIPSS Int-2; 62% PMF, 15% post-ET MF, 23% post-PV MF; 46% grade 3 BM fibrosis, Hgb < 100 g/L in 38%, PLT < 100 x 109/L in 69% and <50 x 109/L in 38%; 31% JAK inhibitor-naive and 69% received a prior or current JAK inhibitor. Study treatment (N=13): In the first 24 weeks, treatment was PRM-151 QW (n=5), PRM-151 Q4W (n=3), PRM-151 QW + RUX (n=2), PRM-151 Q4W + RUX (n=3). At 28 weeks, treatment changed to PRM-151 QW (n=2), PRM-151 Q4W (n=7), and PRM-151 Q4W + RUX (n=4), with 1 patient stopping RUX for thrombocytopenia. Both PRM-151 QW patients switched to PRM-151 Q4W after 40 and 52 weeks. Two patients missed weeks 64 and 68 due to complications of a motor vehicle accident and abdominal surgery, respectively, but are continuing treatment as of week 72. BM (n=13): 54% had a morphologic response, and 85% had a CIA response. Hgb (g/L): In 5 pts with baseline Hgb < 100, median Hgb increased by 24% from 86 (range 77-97) at baseline to 107 (range 71-113) at Week 72. 3 of 5 patients who were receiving transfusions at baseline became transfusion independent, with durations of 32-60 weeks. (Figure 1) PLT (x 109/L): In 9 pts with baseline < 100, median PLT count increased by 37% from 38 (range 10-89) at baseline to 52 (range 26-159) at Week 72. All 4 patients who were receiving PLT transfusions at baseline became transfusion independent, with durations of 24-44 weeks. (Figure 2) Symptoms (N=13): 69% and 38% of patients had ≥ 50% and 100% reductions from baseline in TSS between 24 and 72 weeks, with durations of up to 48 and 12 weeks, respectively. (Figure 3) Spleen (N= 9 with palpable spleens at baseline): 50% of pts had ≥25% reduction, 2 of whom had ≥50% reduction lasting > 12 weeks. (Figure 4) Safety (N=13): Most common adverse events (AEs) regardless of relatedness were fatigue (4), nausea (3), fever (3), cough (2), diarrhea (2), tooth infection (2), headache (2), upper respiratory infection (2), hyperglycemia (2), and hyperuricemia (2). There were 13 possibly or probably related adverse events in 3 patients from beginning of study through 71 weeks, 11 Grade 1, 1 Grade 2 and 1 Grade 3, with no event occurring in > 1 patient. There were no related serious AEs in these patients. Conclusion: In 13 patients completing at least 72 weeks, PRM-151 treatment was well tolerated, and improvements in Hgb, PLT, symptoms and spleen appeared to increase with longer treatment duration. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Foltz:Promedior: Research Funding. Gupta:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Kalobios: Research Funding; Roche: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Hoffman:All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Silver:Promedior: Research Funding. Pozdnyakova:Promedior: Consultancy. Hasserjian:Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Salama:Promedior: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

Abstract Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2). OBJECTIVE: The purpose of this study is to determine the safety, tolerability and efficacy of orally administered NS-018 in patients with PMF, post-PV MF, or post-ET MF. METHODS: This multicenter, Phase 1/2, 3+3 dose-escalation study of NS-018 enrolled patients with IPSS intermediate-1, intermediate-2, or high risk PMF, post-PV MF, or post-ET MF. The study drug, NS-018, was given orally either daily (QD) or twice daily (BID) in 28-day cycles. In Phase 1, changes in spleen size were assessed by manual palpation, quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF), and responses were assessed according to the IWG-MRT/ELN consensus criteria. Bone marrow fibrosis (BMF) was evaluated by biopsy, according to WHO criteria. Changes in grade of BM fibrosis from baseline were categorized as improvement, stabilization, or worsening. The Phase 1 portion of the study has been completed and data are presented here. RESULTS: In this Phase 1 study, 48 patients were enrolled across 10 dosing cohorts (75-400 mg QD/100-400 mg BID). Characteristics: 37 PMF, 5 post-PV MF, 6 post-ET MF with a median age (range) 69.5 yrs (38-83); M/F:29/19; 35 JAK2V617F+, and 23 previously treated with a different JAK2 inhibitor. At 400 mg QD/BID, NS-018 dosing was associated with drug-related neurologic adverse events (AEs) including dizziness, peripheral neuropathy, headache, disturbance in attention, vertigo, dysesthesia, paresthesia, aphasia, and nervous system disorder (not otherwise specified). The 300 mg QD dose was better tolerated than 250 mg BID or 300 mg BID, with fewer neurologic AEs, and was selected as the recommended phase 2 dose (RP2D). For the 48 phase 1 patients, reductions in MF-SAF score were observed for all symptoms after 3 cycles, including for patients with prior JAK2 inhibitor treatment. In all dose cohorts, ≥ 50% patients achieved ≥ 50% score reduction from baseline in night sweats, pruritus and bone pain after 1 cycle. Moreover, ≥ 50% patients achieved ≥ 50% score reduction from baseline in abdominal pain and inactivity after 3 cycles. In patients who had received prior JAK2 inhibitor, ≥ 50% patients achieved ≥ 50% score reduction from baseline in filling up quickly, inactivity, night sweats and quality of life after 3 cycles. Among 36 patients with baseline splenomegaly ≥ 5 cm and treatment for ≥ 1 cycle, 20 (56%) showed ≥ 50% reduction in spleen size (confirmed for ≥ 8 weeks in 16 patients), including 9/19 (47%) patients with prior JAK2 treatment. According to IWG criteria, 14/36 (39%) patients showed splenic clinical improvement (CI) for ≥ 8 weeks, 4 had hemoglobin CI, and 1 had platelet CI. After 3 cycles of NS-018 treatment, 11/31 (37%) evaluable patients had a reduction in bone marrow fibrosis(BMF) by ≥ 1 grade. At any time during NS-018 treatment, 17/31 (55%) evaluable patients had a reduction in BMF by ≥ 1 grade. Overall, 23% (7/31) patients maintained improvement in BMF for ≥ 12 weeks. Reduction in BMF after 3 cycles was correlated with reduction in splenomegaly and hemoglobin responses. To date, 8 patients with prior JAK inhibitor treatment have been enrolled into the phase 2 portion of the trial. Updated Phase 2 data will presented at the meeting. CONCLUSIONS: The RP2D dose of NS-018 was 300 mg QD. This dose provided an acceptable safety and tolerability profile, and reduction in symptomatic splenomegaly. Phase 2 is ongoing and includes patients previously treated with other JAK2 inhibitors. Disclosures Talpaz: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Sanofi Aventis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Odenike:Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding. Jamieson:GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding. Stein:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Research Funding; CTI Biopharma: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Genentech: Research Funding.

Abstract Abstract 1904 Poster Board I-927 BACKGROUND: Pomalidomide is an IMiDsó immunomodulatory drug that was created by chemical modification of thalidomide with the intent to reduce toxicity and enhance therapeutic activity. In a phase-2 randomized study of patients with myelofibrosis (MF), treatment with pomalidomide alone or in combination with a short course of prednisone was shown to be well tolerated and active in alleviating anemia ( JCO 2009). Herein, we report observations during the longer-term follow-up of those patients who had responded to a pomalidomide-containing treatment regimen. METHODS: Both primary and post polycythemia vera/essential thrombocythemia MF were included in the current study. Protocol eligibility criteria included absolute neutrophil count of × 109/L, platelet count of 50 × 109/L and hemoglobin level of < 10 g/dL. Patients with prior thalidomide or lenalidomide therapy were excluded from study participation. Response was assessed by the International Working Group for Myelofibrosis Research and Treatment criteria (IWG-MRT) (Blood. 2006). Pomalidomide was administered daily and continued indefinitely in responding patients. Prednisone was given for the first 3 months only, in a tapering dose schedule, starting at 30 mg/day. RESULTS: A total of 84 patients were enrolled from April 2007 through May 2008 and received treatment with pomalidomide alone 2 mg/day (n=22), pomalidomide 2 mg/day + prednisone (n=19), pomalidomide 0.5 mg/day + prednisone (n=22) or prednisone alone (n=21). Short-term toxicity details have previously been published (Tefferi et al. JCO 2009) and were remarkable for the lack of neuropathy and low prevalence of grade 3 or 4 myelosuppression (5–16%). Based on an intent-to-treat analysis, 16 (25%) of the 63 patients receiving pomalidomide alone or with a 3-month course of prednisone responded at a median of 1.8 months (range 0.9–6.9) from treatment initiation; all responses represented improvement in anemia with little or no effect on splenomegaly. Specifically, 12 of the 16 treatment responders became transfusion independent and the remaining 4 had a hemoglobin increase of > 2 g/dL (median best hemoglobin response = 11.9 g/dL; range 8.5–15.9). Responding patients usually displayed increases in platelet count but there was no consistent change in serum lactate dehydrogenase level. As of August 2009, ten (63%) of the 16 treatment responders were still in anemia remission and receiving pomalidomide therapy; median time on treatment was 19 months (range, 14–26) and median response duration was 17 months (range, 13-24). No new side effects emerged during this period. Six patients discontinued treatment because of either loss of response (n=5) or progressive splenomegaly/leukocytosis (n=1); 3 patients with continued anemia remission have had substantial increases in their spleen size, which qualifies as spleen progression per IWG-MRT. Among 9 patients with available cytogenetic information, all 3 with unfavorable karyotype relapsed while none of the 6 with favorable karyotype did. A small number of patients (n=7) had follow-up bone marrow examination at 1 to 2 years, at the discretion of their treating physician; none of these patients displayed any change in bone marrow fibrosis or JAK2V617F mutational status. Suppression of a monosomy 7 clone was documented in two patients. In one, the percentage of abnormal metaphases decreased from 90% to 15% after 11 months of treatment with pomalidomide but increased back to 100% four months later, when the patient relapsed while still on treatment. In the second patient, the percentage of abnormal metaphases was 65% at baseline, remained at 75% after 10 months of pomalidomide therapy, but decreased to 7% after one month of treatment discontinuation for relapse; a repeat examination in this patient after another 3 months (still off therapy) showed monosomy 7 and new additional abnormalities (including 4q21q25 deletion) in 65% of metaphases evaluated. CONCLUSION: Longer-term follow-up of pomalidomide-treated patients with myelofibrosis confirm the drug's favorable side effect profile. Also, the majority of treatment responders maintain their remission, which is exclusively anemia remission, for at least one year and several remain in remission after 2 years of therapy. The drug has limited effect on splenomegaly and progressive splenomegaly might occur in some patients despite continued remission in anemia. The presence of unfavorable cytogenetic abnormalities predicts relapse. Disclosures: Gale: Celgene: Employment.

Abstract The impetus for kinase inhibition as a therapeutic endpoint in leukemia research has been driven largely by the success of imatinib mesylate in chronic myelogenous leukemia. However, while imatinib mesylate has been extremely effective in the treatment of chronic phase CML, resistant disease often emerges in both Philadelphia positive ALL and aggressive phase CML patients. Adaphostin is a tyrphostin inhibitor originally developed to target the bcr/abl kinase and demonstrates selectivity in CML patient isolates. Here we show that in vitro, adaphostin is cytotoxic in numerous models that are resistant to imatinib. Features of adaphostin action in bcr/abl containing cells include apoptosis induction via an oxidant dependent mechanism and degradation of bcr/abl protein. Cell lines containing point mutations in p210 bcr/abl which confer imatinib resistance exhibit intracellular peroxide production and DNA fragmentation in response to adaphostin. Bcr/abl degradation also occurs but can be dissociated from peroxide production and subsequent apoptosis signaling. Similar data has also been obtained in cell lines containing p190 bcr/abl. Studies extending these observations into mononuclear and polymorphonuclear cells from imatinib resistant CML patients and Ph+ ALL patients confirm the same mechanism in primary clinical isolates. Collectively, these data suggest that reactive oxygen species generation by adaphostin bypasses imatinib resistance in CML and Ph+ ALL. Further studies dissecting the mechanism of ROS generation by adaphostin in imatinib resistant cells may lead to the identification of new therapeutic targets.