Gotlib, Jason

Abstract Background: JAK2 inhibition improves splenomegaly and symptoms in patients with myelofibrosis (MF), and the JAK2 inhibitor ruxolitinib has been shown to improve both bone marrow fibrosis and survival in MF patients (Cervantes et al., 2013; Verstovsek et al., 2013). Current prognostic models such as DIPSS plus (Gangat et al., 2011) predict survival in MF based on clinical, laboratory, and cytogenetic information, but predate the era of JAK2 inhibitor use in MF. As such, their value in predicting clinical response or survival during treatment with JAK2 inhibitors remains unknown. We hypothesized that features not considered by DIPSS plus, including bone marrow fibrosis and splenomegaly, have independent effects on therapy response. We therefore conducted a retrospective analysis to create a new model to risk stratify patients with respect to their likelihood of achieving a > 50% reduction in splenic size by palpation with JAK2-inhibitor therapy. Methods: We studied a cohort of 418 patients with bone marrow biopsy-proven MF who were treated with ruxolitinib or one of four other JAK2 inhibitors. An initial cohort of 203 patients seen at University of Michigan, Stanford University, and Mayo Clinic in Scottsdale, AZ was used identify factors that would predict a clinical response to therapy. Response to therapy was evaluated at an early time point (3-4 mos) in 167 patients and at a late time point (5-12 mos) in 138 patients, with 127 patients overlapping between the two. We constructed a multivariable logistic regression model, with Bayesian variable selection, for predicting the probability of early or late splenic response to JAK2 inhibitor therapy. The model was developed with this initial group of 203 patients. The model was then validated with a cohort of 215 patients from the PERSIST1 trial (data supplied by CTI Biopharma). Results: Conclusion: We identified several factors that play a role in predicting whether or not patients with MF are likely to respond to JAK2 inhibitor therapy. The interaction between spleen size and WBC at the time of therapy initiation plays the strongest role in predicting which patients will have an early response to therapy. Additionally, our model suggests that patients who do not have a response to JAK2 inhibitor therapy by about 4 months of treatment are unlikely to develop a later response. Our model is able to discriminate between those likely to benefit after several months of therapy and those for whom a change in therapy should be considered early in their treatment course. Figure 1 The following characteristics were selected for inclusion in the prognostic model based on the data collected from our 418-patient cohort. Spleen size and white blood cell count at the time of therapy initiation were the strongest predictors of early response to JAK2 inhibitor therapy. Achievement of an early response was used to further enhance the model for the late time point (third column) and was the strongest predictor of late response. Interaction terms looked at the interdependence of variables on splenic response. Log odds ratios are provided with 95% credible intervals in parentheses. Figure 1. The following characteristics were selected for inclusion in the prognostic model based on the data collected from our 418-patient cohort. Spleen size and white blood cell count at the time of therapy initiation were the strongest predictors of early response to JAK2 inhibitor therapy. Achievement of an early response was used to further enhance the model for the late time point (third column) and was the strongest predictor of late response. Interaction terms looked at the interdependence of variables on splenic response. Log odds ratios are provided with 95% credible intervals in parentheses. Figure 2 An example of the predicted response for a hypothetical patient. The curves show the interaction of a high initial WBC (red) or a low initial WBC (green) with baseline spleen size (depicted along the X-axis) in predicting whether or not the patient will have a late response to therapy (depicted along the Y-axis). The solid lines show the probability that the patient will respond at the later time point if they had an early response. The dashed lines show the probably of a late response if the patient had not achieved a response by the early time point. Overall, a patient with a higher initial WBC and a larger baseline spleen size is less likely to respond to JAK2 inhibitor therapy. Additionally, the curves clearly separate to show that, for a given baseline WBC and spleen size, a patient who has an early response to therapy is much more likely to have a late response to therapy, whereas a patient who fails to respond early in their treatment course is much less likely to respond with further treatment. Figure 2. An example of the predicted response for a hypothetical patient. The curves show the interaction of a high initial WBC (red) or a low initial WBC (green) with baseline spleen size (depicted along the X-axis) in predicting whether or not the patient will have a late response to therapy (depicted along the Y-axis). The solid lines show the probability that the patient will respond at the later time point if they had an early response. The dashed lines show the probably of a late response if the patient had not achieved a response by the early time point. Overall, a patient with a higher initial WBC and a larger baseline spleen size is less likely to respond to JAK2 inhibitor therapy. Additionally, the curves clearly separate to show that, for a given baseline WBC and spleen size, a patient who has an early response to therapy is much more likely to have a late response to therapy, whereas a patient who fails to respond early in their treatment course is much less likely to respond with further treatment. Disclosures Boonstra: CTI Biopharma: Research Funding. Gowin:Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis: Consultancy; Ariad: Consultancy; Promedior: Research Funding; Celgene: Research Funding; Galena: Consultancy; Incyte: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding. Talpaz:Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding.

Abstract Abstract 3849 Background: CYT387 is a potent JAK-1/2 inhibitor. The maximum tolerated dose (MTD) and preliminary safety and efficacy of once daily dosing of CYT387 were determined in a single center Phase I/II study. Previously reported results from the first 60 subjects enrolled in this study determined a MTD of 300 mg QD and demonstrated improvements in splenomegaly and constitutional symptoms as well as in RBC transfusion requirements. The study was expanded into a multicenter study with planned accrual of 165 subjects at 6 study sites and a twice daily dosing arm was added. The preliminary safety and efficacy results from this expanded multicenter study will be presented. Methods: Subjects with high or intermediate-risk primary myelofibrosis (PMF) and post-polycythemia vera (post-PV) or post-essential thrombocythemia (ET) myelofibrosis were enrolled. In the core expansion study, oral CYT387 was administered either once daily at 150 mg or 300 mg or twice daily at 150 mg for 9 months. Patients who maintained at least stable disease were permitted to continue CYT387 treatment beyond 9 months in an extension phase of the study. Responses were assessed by International Working Group (IWG) Criteria. Results: At present, 163 subjects have been enrolled across the 6 study sites. The diagnoses of enrolled subjects include 64% PMF, 14% post-ET MF and 22% post-PV MF; 67% of the patients were JAK2V617F positive. Starting doses of CYT387 in the dose escalation, confirmation and expansion phases of the study are shown in Table 1. The median duration (range) of treatment was 6.6 months (0.25 to 20.4 months). Patient characteristics were as follows: median age 68 years, 58% male, 87% were spleen evaluable at baseline per IWG criteria (median spleen length was 18 cm by palpation). Sixty three percent (63%) of subjects were anemia evaluable at baseline per IWG criteria; 46% were transfusion dependent. Previous JAK inhibitor and IMiD therapy was reported for 11% and 8% of enrolled subjects, respectively. Reductions in spleen size, improvements in constitutional symptoms and the achievement of transfusion independence were observed in subjects in the expanded multicenter study. CYT387 was well tolerated. Based on currently available data, 73% of subjects reported treatment-related adverse events, with the majority reported as Grade 1. The most common Grade 3–4 treatment related adverse events included thrombocytopenia (16%), and hyperlipasemia (3%). New onset treatment-related Grade 3–4 anemia remains rare (<1%). Grade 1 toxicities included peripheral sensory neuropathy whose incidence and natural history is currently being studied. Twenty-five of 163 subjects (15%) have discontinued from the 9 month core study giving a retention rate of 85%. Conclusions: When examined in an expanded, multicenter study, CYT387 continues to show substantial clinical activity in myelofibrosis, with improvements in splenomegaly, constitutional symptoms and anemia. It appears to be well tolerated when administered in either a once or twice daily dosing regimen. CYT387 continues to demonstrate an ability to induce durable anemia responses in a subset of subjects. Detailed analyses of safety and efficacy will be available at the time of the meeting. Disclosures: Gupta: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith:YM Biosciences: Employment, Equity Ownership. Bavisotto:YM Biosciences: Consultancy. Kowalski:YM Biosciences: Employment, Equity Ownership.

Abstract Abstract 3838 Background: SAR302503 (SAR503, formerly TG101348), a potent, oral JAK2-selective inhibitor was studied in a Phase I/II trial for the treatment of patients with high- or intermediate-risk primary, post-polycythemia vera (PV) and post-essential thrombocythemia (ET) myelofibrosis (MF). SAR503 was administered orally once daily in 28-day cycles. Eligibility criteria included platelet count of ≥50 × 109/L. Interim safety and efficacy data from this study up to April 2010 have been previously published (JCO 2011, 29(7):789–796). The aim of this presentation is to report updated safety and efficacy of ongoing patients as well as an analysis of the JAK2V617F allele burden in this cohort. Results: Overall, 59 subjects (median age 64 years) were treated. Forty four patients had PMF, 12 post-PV MF and 3 post-ET MF; 86% were JAK2 V617F-positive. Median palpable spleen size was 18 cm at study enrollment. Twenty eight patients were treated in the dose-escalation cohort (30–800 mg administered as a single daily dose); thirty one patients were treated at the MTD (680 mg) in the dose confirmation cohort. 43/59 patients (73%) completed 6 cycles of treatment and continued treatment on the extension study. Currently, 22 patients (37%) remain on treatment with a median number of 28.5 cycles (24–41 range) and a median of last dose of 440 mg/day. Safety: Treatment-emergent toxicities in cycle 1–6 have been previously reported; toxicities were dose-dependent and generally alleviated with dose-reduction. Five patients discontinued treatment beyond cycle 6 for treatment-related adverse events: thrombocytopenia, depression, mental status changes, creatinine elevation and subdural hematoma. For the subgroup of patients with a baseline platelet count between 50–100 × 109/L (n =13; median 73, range 51–94); the platelet count at defined times points during follow up was: cycle 3; median 50, range 21–138 (p=0.09) and cycle 6; median 47, range 13–85 (p=0.01). Despite 7 of the 13 patients being treated at ≥680 mg/day, only 2 instances of Grade 4 thrombocytopenia were noted in this group Spleen response: As previously reported, spleen responses were seen early, usually within first 3 cycles, with half or more patients in each dose level ≥240 mg/day showing a durable ≥50% decrease in palpable spleen size. Spleen size (mean, median, range, and proportion with ≥50% reduction) at the following time points was: Baseline (n=58; 18.33cm, 18cm, 4–38cm, NA) ; 6 months (n=57; 9.05cm, 9cm, 0–30cm, 54.4%;) 12 months (n=42; 8.55cm, 9cm, 0–28cm, 66.7%) 18 months (n=36; 8.03cm, 8.5cm, 0–33cm, 52.8%); 24 months (n=31; 8.10cm, 8cm, 0–30cm, 54.8%,) 30 months (n=18; 6cm, 7.5cm, 0–16cm, 61.1%,and) 36 months (n=9; 5.89cm, 3cm, 0–16cm, 66.7%). JAK2V617F allele burden: We previously reported a significant decrease in JAK2V617F allele burden at the end of cycles 6 and 12. A durable decrease was also demonstrable after 24 cycles of treatment (n =21; median 9%, range 0–100%) relative to baseline (n =51; median 20%, range 3–100%) (p=0.03). Similarly, for patients with JAK2 V617F allele burden >20% at baseline; there was a significant decrease after cycle 24 (n =12; median 21%, range 6–100%) relative to baseline (n =23; median 60%, range 23–100%) (p=0.03). Conclusions: SAR503 is safe and efficacious treatment with long term effect on spleen size and JAK2V617F allele burden in patients with high- and intermediate-risk myelofibrosis. Additional follow up information will be updated at the time of meeting. Disclosures: Jamieson: Wintherix: Equity Ownership; Pfizer Oncology: Research Funding; Celgene: Research Funding; Novartis: Honoraria. Gao:Sanofi-Aventis: Employment. Zhang:Sanofi-Aventis: Employment. Neumann:Sanofi-Aventis: Employment.

Abstract Abstract 459 Background: A Phase I study of TG101348, a potent, oral JAK2-selective inhibitor in patients with high- or intermediate-risk primary, post-polycythemia vera (PV) and post-essential thrombocythemia (ET) myelofibrosis (MF) recently completed enrollment. Data from the dose escalation cohort (n=28; 30–800 mg administered as a single daily dose) showed dose-linear plasma exposure, with mean elimination T1/2 at steady state ranging from 16 to 34 hours. The dose-limiting toxicity was reversible asymptomatic grade 3 or 4 amylasemia/lipasemia; the maximum tolerated dose was 680 mg. We now present updated results from an extension study in which subjects continued treatment beyond six 28-day cycles. Result: In the entire study, 59 subjects (median age 64 years) were treated. Forty four patients had PMF, 12 post-PV MF, and 3 post-ET MF; 86% were JAK2V617F-positive. Median palpable spleen size was 18 cm and 21 (36%) patients were transfusion-dependent at study enrollment. Forty three (73%) subjects continued treatment on the extension study; the median (range) cumulative exposure to TG101348 was 380 days (170-767); the number of cycles of treatment completed ranged from 7–29, and the proportion of subjects who completed 12, 18, and 24 cycles of treatment was 72%, 28%, and 14%, respectively. The median (range) treatment dose at data cutoff was 440 mg/day (120 to 680 mg/day; n = 35). Toxicity: TG101348 was well tolerated. Non-hematologic, at least possibly related adverse events included nausea (69%; Grade 3=3%), diarrhea (64%; Grade 3=10%), and vomiting (58%; Grade 3=3%), that were dose-dependent; the symptoms were self-limited or controlled with symptomatic treatment and/or dose reduction. Also observed were asymptomatic increases in serum lipase (27%), AST/ALT (27%/25%), creatinine (24%), and alkaline phosphatase (17%). Grade 3/4 hematological adverse events possibly related to TG101348 included treatment-emergent anemia (35% of patients who were not transfusion dependent at baseline), thrombocytopenia (24%), and neutropenia (10%). Spleen: During cycles 1–6, 42% of patients achieved Clinical Improvement (CI) per the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for spleen response. The CI rate for the 43 subjects who continued treatment beyond 6 cycles was 65%, and the median time (range) to CI was 140 days (77-802). After 12 cycles, 36 (95%) of the 38 evaluable patients had some degree of spleen size reduction; 32 (85%), 26 (68%), and 10 (26%) of subjects had a minimum 25%, 50%, and 100% decrease in palpable splenomegaly. JAK2V617F allele burden: Of the 48 JAK2V617F mutation-positive subjects, 23 (48%) had a baseline mutant allele burden of >20%. Of these, 20 subjects with a baseline median allele burden (range) of 62% (23% to 100%) completed at least 6 cycles of treatment. Sixteen subjects (80%) exhibited a median 62% (range 6% to 96%) decrease in JAK2V617F burden, including 9 (45%) with a ≥50% decrease; 4 subjects (20%) had increases (range 18% to 58%). Eighteen subjects (78%) completed 12 cycles of treatment; 13 (72%) had a median 50% decrease (range 29% to 82%), including 7 (39%) subjects with a ≥50% decrease; 5 subjects (28%) had no change or increases (range 0% to 22%) in JAK2V617F. Constitutional symptoms: For patients with data at baseline and cycle 6, early satiety, fatigue, night sweats, cough, and pruritus were reported by 56%, 47%, 24%, 22%, and 19% of subjects, respectively. Improvement (complete resolution) rates observed at cycle 6 were: 75% (40%), 65% (29%), 89% (89%), 88% (75%), and 100% (57%) for the aforementioned symptoms, respectively. Leukocytosis/Thrombocytosis: Leukocytosis was present at baseline in 33 subjects; following 6 and 12 cycles of therapy, 57% (n=28) and 56% (n=25) achieved normal WBC counts. Thrombocytosis was noted at baseline for 10 (17%) subjects; following 6 and 12 cycles of therapy, 90% (n=10) and 88% (n=8) achieved normal platelet counts. Conclusion: The current study provides proof-of-concept that selective JAK2 inhibition has anti-myeloproliferative/anti-clonal activity in myelofibrosis. The majority of subjects treated with TG101348 for more than 6 cycles experienced a rapid, significant, and durable decrease in splenomegaly, normalization of leukocyte/platelet counts, and improvement of disease-related symptoms, all within the context significantly decreased JAK2V617F burden. Disclosures: Off Label Use: There is no FDA approved drug for Myelofibrosis.All the drugs discussed will be off-label. Stone:Novartis: Consultancy. Silverman:TargeGen: Consultancy. Shorr:TargeGen: Employment, Equity Ownership.

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: 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 Momelotinib (MMB, GS-0387, CYT387) is a JAK1 and JAK2 inhibitor under investigation for the treatment of myelofibrosis. Preliminary results of a phase I/II core study (n=166) were previously reported. Subjects who achieved at least stable disease in the core study could continue MMB treatment in an extension study (n=120). Final data from the phase I/II core study and updated data from the extension study are presented. Methods Subjects with myelofibrosis categorized as IPSS intermediate-2 or high risk, or intermediate-1 risk with symptomatic splenomegaly or hepatomegaly and/or unresponsive to available therapy, were enrolled. Following a dose escalation phase, subjects were treated on a dose expansion phase in the core study with MMB at either 150 mg or 300 mg once-daily, or 150 mg twice-daily for 9 months. In the extension study, MMB was at the same dose the subject tolerated and derived clinical benefit from in the core study. Clinical responses were adjudicated according to IWG-MRT criteria. Spleen Response was defined as ≥ 50% reduction in palpable splenomegaly that lasted ≥ 8 weeks (wks) for baseline splenomegaly ≥ 10 cm, plus resolution of palpable splenomegaly that lasted ≥ 8 wks for baseline splenomegaly > 5 to < 10 cm. Anemia Response was defined as transfusion-free interval of ≥ 12 wks for baseline transfusion dependence, plus ≥ 2 g/dL rise in hemoglobin (Hb) for baseline transfusion independence and Hb < 10 g/dL. Baseline transfusion dependence was defined as ≥ 2U RBC transfusion in the 30 days prior to first dose of MMB or identified as transfusion dependent in medical history. Results As of April 2013, 58 of 120 subjects remained on treatment in the open-label extension study, with median treatment duration of 507 days (range 23-1036) for both core and extension studies. Based on interim analysis, the most common reasons for discontinuation from the extension study were disease progression (n=13), investigator's decision (n=12), and consent withdrawal (n=10), with 2 drug-related adverse events (both peripheral neuropathy) that led to study discontinuation. Efficacy data for the core and extension studies are depicted in table below. Median time to onset of Spleen Response was not yet reached (range 6-693 days), median duration of Spleen Response was 324 days (range 56-936). Median duration of 12-week transfusion independence was not yet reached (91-987 days), median duration of Anemia Response was not yet reached (57-987). Constitutional symptoms assessment at 3 months for the core study showed ≥ 50% improvement in 72%, 46%, 77%, 100%, and 74% of subjects with pruritis, cough, bone pain, fever, and night sweats respectively. Most common Grade 3 or 4 treatment-related events were thrombocytopenia (29%), neutropenia (5%), and elevated lipase (4%) without clinical pancreatitis. Peripheral neuropathy was reported by 38% of subjects, all ≤ Grade 2, with 17 subjects experiencing neuropathy at baseline. Four subjects transformed into acute leukemia (1 in core study, 3 in extension study). There was no treatment-related death. Conclusion Prolonged administration of MMB for treatment of myelofibrosis is well tolerated and has an acceptable safety profile. MMB is efficacious in durably reducing myelofibrosis-related splenomegaly as well as improving transfusion requirement and disease-related symptoms. These data form the basis for the phase 3 randomized study of MMB in myelofibrosis. Disclosures: Gupta: Novartis: Lecture fee, Lecture fee Other; Novartis: Consultancy; Incyte: Consultancy; Novartis: Research Funding; Incyte: Research Funding. Bavisotto:YM Biosciences: Consultancy. Kawashima:Gilead Sciences: Employment. Lee:Gilead Sciences: Employment. Kowalski:Gilead Sciences: Employment. Deng:Gilead Sciences: Employment. Niforos:Gilead Sciences: Employment.

Abstract Introduction Polycythemia vera (PV) is characterized by excessive production of erythroid cells and in most cases a point mutation (V617F) in the Jak2 cytokine signaling kinase. We investigated whether a selective JAK2 inhibitor decreased Jak2 V617F induced erythroid differentiation. Methods Wild-type and mutant Jak2 V617F genes were excised from the retroviral Jak2-mus-MSCV-neo vector (Levine et al), cloned into the lentiviral vector pLV CMV IRES2 GFP and their presence verified by DNA sequencing. Lentiviral vectors bearing the wild-type and mutant Jak2 genes or vector alone were used to transduce human peripheral blood CD34+ cells, which were then divided for plating into megacult medium for megakaryocytic colony growth and methylcellulose culture for enumeration of all other progenitor cell types. Normal cord blood HSC (CD34+/CD38−/CD90+) were clone sorted with the FACS Aria and transduced with no vector, backbone vector, wild-type JAK2 or mutant JAK2 vector in methocult media (Stem Cell Technologies Inc, GF+ H4435) +/− 300 nM of a selective JAK2 inhibitor, TG101348. Colonies were scored at day 14. RNA was isolated from the colonies (Qiagen RNeasy kit) and RT-PCR was performed with wild-type and mutant JAK2 allele specific primers. Results Transduction of cord blood HSC with the mutant Jak2 vector resulted in skewed erythroid colony formation compared to wild-type Jak2, vector alone and untransduced HSC (Figure 1; n=3). RT-PCR with murine Jak2 specific primers resulted in ~900 bp fragments corresponding to murine Jak2 from colonies transduced with the wild-type and mutant Jak2 and confirmed by sequencing, but not those from colonies transduced with the vector alone or the untransduced cells. Like the results in cord blood cells, adult peripheral blood CD34+ cells transduced with the mutant Jak2 developed a skewed developmental pattern, with far greater erythroid colony formation compared to wild-type Jak2 or vector alone. In megacult assays, CD34+ cells transduced with the mutant Jak2 had similar megakaryocytic potential as wild-type Jak2 or vector alone. Addition of TG101348 (300 nM), inhibited mutant kinase-induced erythroid colony formation (Figure 1) in 3 experiments while 100– 300 nM was inhibitory to PV (n=2 patients) HSC and progenitors. Current experiments focus on inhibition of Jak2 in a bioluminescent highly immunocompromised mouse model of Jak2V617F-induced myeloproliferation (Figure 2). Conclusion JAK2 V617F skews differentiation of HSC toward the erythroid lineage and may be inhibited with a selective JAK2 inhibitor - TG101348. Figure 1. In vitro JAK2 Inhibition. Figure 1. In vitro JAK2 Inhibition. Figure 2. Bioluminescent JAK2 V617F-induced Myeloproliferation Model. Figure 2. Bioluminescent JAK2 V617F-induced Myeloproliferation Model.

Abstract 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. PRM has broad anti-fibrotic activity in multiple preclinical models of established fibrotic diseases and no dose limiting toxicities in phase 1 trials. Myelofibrosis (MF: primary (PMF), post-essential thrombocythemia (post-ET MF), and post polycythemia vera (Post PV MF)) is a myeloid malignancy characterized by progressive bone marrow (BM) fibrosis with resultant anemia, abnormal platelet and leukocyte counts, extramedullary hematopoiesis, and a well-defined symptom complex. This study investigated the potential of PRM in MF to reduce BM fibrosis and to improve key disease features including abnormal blood counts, symptoms, and splenomegaly. MF patients (pts) with Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, intermediate-2, or high-risk disease and grade ≥ 2 BM fibrosis, either on no current therapy or on a stable dose of ruxolitinib (RUX) for ≥ 12 weeks and no improvement in spleen for ≥ 4 weeks, were eligible for stage 1 of this open-label adaptive trial. Assignment to one of the 4 treatment arms was per investigator and pt choice: PRM 10 mg/kg IV 1-hour infusion days 1, 3, 5, then weekly (QW) or every 4 weeks (Q4W), alone or with RUX, for 24 weeks. Primary endpoint was overall response rate by IWG-MRT (symptoms by MPN-SAF Total Symptom Score (TSS), spleen by palpation) and/or decrease in BM fibrosis by ≥ 1 grade with otherwise stable disease. BM biopsies were obtained at baseline, 3 and 6 months, and were evaluated centrally by two blinded hematopathologists. Pts with clinical benefit were allowed to continue treatment in an extension. At least one response in any arm was required for that regimen to be evaluated in Stage 2. Twenty seven pts were enrolled: 8 PRM QW, 7 PRM Q4W, 6 PRM QW + RUX, 6 PRM Q4W + RUX. Median age 67 years (52-85); 70% DIPSS Int-2 or High Risk; 52% PMF, 15% post-ET MF, 33% post-PV MF; 63% grade 3 BM fibrosis, Hemoglobin (Hgb) < 100 g/L in 56% and < 85 g/L in 26%, platelet count (PLT)< 100 x 109/L in 52% and < 25 x 109/L in 30%; 22% were JAK inhibitor-naive and 52% had received a prior JAK inhibitor (not including ongoing RUX). Twenty pts completed 24 weeks of therapy; 18 continued extension treatment. PRM-151 was well-tolerated alone and with RUX; most adverse events (AEs) were Grade 1/2 and unrelated, with 3 Grade 3 possibly related AEs and 5 possibly related serious AEs. Nine of 26 evaluable pts responded, for an overall response rate (ORR) of 35%, with 4 IWG symptom clinical improvements (CI) and 6 BM fibrosis responses (Table 1), with ≥ 1 response in each arm. One pt had a CI and BM response. Reduction in BM fibrosis was associated with normal erythroid microarchitecture, normal or decreased myeloid:erythroid ratio, and fewer paratrabecular megakaryocytes, all potential surrogates of improved bone marrow microenvironment. IWG stable disease was observed in 77% of pts, with trends of clinical benefit in Hgb, PLT, peripheral blood blasts, spleen, and symptoms (Table 2). In 14 patients (54%), all parameters were stable or improved. Conclusion: PRM-151 was well-tolerated in patients with advanced MF, with no evidence of drug-related myelosuppression and encouraging trends in both clinical and histologic aspects of the disease. Reduction in BM fibrosis, stable to improved hematologic parameters, symptom responses, and stable to reduced spleen size support further development of PRM-151 in MF. Table 1 Two additional subjects had decrease in bone marrow fibrosis but progressive disease. Number of Patients BM Fibrosis Grade at Last Study Timepoint 3 2 1 BM Fibrosis Grade at Baseline 3 8 3 1 2 1 4 2 Abstract 713. Table 2 Outcome Parameter Denominator (n) Clinical Benefit Pts with Improvement (n/%) ORR (primary endpoint) All evaluable pts (26) IWG-MRT CI AND/OR reduction in BM fibrosis by ≥ 1 grade 9 (35%) Hgb Hgb < 100 g/L (15) ≥10 g/L increase from baseline AND no transfusions or 50% reduction in transfusions if transfusion dependent 6 (40%) PLT PLT < 100 x 109/L (13) > 100 x 109/L AND increase of ≥20 x 109/L ; increase of ≥20 x 109/L if baseline < 50, AND/OR increase of ≥ 10 x 109/L with discontinuation of transfusions 8 (62%) Blasts ≥ 1% peripheral blasts (14) No peripheral blasts 3 (21%) Symptoms All evaluable pts (26) ≥ 25% reduction in TSS ≥ 12 weeks 10 (38%) Spleen Palpable spleen (19) ≥ 25% decrease ≥ 4 weeks AND any decrease ≥ 12 weeks 5 (26%) Disclosures Verstovsek: Incyte: Research Funding; Astrazeneca: Research Funding; Lilly Oncology: Research Funding; Roche: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Promedior: Research Funding; Cell Therapeutics: Research Funding. Mesa:Incyte, CTI, NS pharma, Gilead, Celgene: Research Funding; Promedior: Research Funding. Foltz:Janssen: Consultancy; Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Novartis Pharmaceuticals Corporation: Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding. Ritchie:Celgene, Incyte: Speakers Bureau; Promedior: Research Funding. Hoffman:Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; All Cells LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Pozdnyakova:Sanofi: Consultancy; Incyte: Consultancy; Promedior: Consultancy. Hasserjian:Sanofi: Consultancy; Incyte: Consultancy; Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Gotlib:Novartis: Research Funding, Travel Reimbursement, Travel Reimbursement Other; Sanofi: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Travel Reimbursement Other; Promedior: Research Funding.