Citations

Abstract Background: Patients with the myeloproliferative neoplasm (MPN) polycythemia vera (PV) require treatment to manage blood cell counts and reduce the risks of cardiovascular/thromboembolic events. Hydroxyurea (HU) is a common cytoreductive treatment; however, some patients discontinue HU treatment because of resistance, intolerance, or frequently a combination of both limitations. Patients may also continue to receive HU despite diminishing or nonexistent clinical benefit, sometimes in combination with persistent need for phlebotomy procedures. This analysis of MPN Landmark survey data examined patient-reported quality of life (QoL) outcomes in patients with PV who were naive to HU (HU-N), were continuing HU (HU-C), or had discontinued HU (HU-D). Methods: Patients with an MPN under active management in the US were eligible to complete an online survey (fielded May - July 2014). This is a report of responses given by patients with PV to questions about symptom burden, QoL, activities of daily living (ADL), and work/productivity. PV-related effects on patients feeling depressed/discouraged, patients feeling anxious/worried, or interference with ADLs were considered to be at high levels if the patient-reported score was ≥4 on a scale of 1 (not at all) to 5 (a great deal). Symptom severity was rated on a scale of 0 (absent) to 10 (worst imaginable). Results: The survey respondents included 380 patients with PV (HU-N, n=159; HU-C, n=181; HU-D, n=40). Mean age was 62.2 years, 65.1 years, and 64.2 years in the HU-N, HU-C, and HU-D groups, respectively. Mean duration of PV was 8.3 years, 10.3 years, and 13.9 years in the HU-N, HU-C, and HU-D groups, respectively. Patients who had not received HU were currently or previously treated with phlebotomy (87.4%), interferon (11.3%), or anagrelide (9.4%); 66.0% of HU-N patients were classified as high-risk based on information provided by the patients in the survey (ie, age 60 or older or history of thrombosis). Among HU-C and HU-D patients, treatment history included phlebotomy (89.5% and 100%, respectively), interferon (7.2% and 52.5%), or anagrelide (15.5% and 35.0%); 79.6% and 82.5%, respectively, were classified as high-risk. Ruxolitinib was not FDA-approved for PV at the time of this survey. Patients reported high levels of feeling anxious/worried and depressed/discouraged as a result of their PV across all subgroups: HU-N, 27.7% and 15.1%, respectively; HU-C, 22.7% and 15.5%; HU-D, 32.5% and 22.5%. Many patients also experienced a high level of PV-related interference with ADLs, which was more common in the HU-D group (30.0%) than the HU-N (11.3%) or HU-C (18.2%) groups. HU-D patients were more likely to have reported ever reducing their work hours (54.2% of the patients who responded) compared with the HU-N (33.3%) and HU-C groups (36.8%). Among all patients, HU-D patients reported a mean of 8.3 doctor visits in the past 12 months, compared with 5.6 in the HU-N group and 6.6 in the HU-C group. Most patients had experienced PV-related symptoms in the past 12 months (Table 1), particularly fatigue, itching, and day/night sweats; fatigue was ranked first as the symptom that patients would most like to resolve. Conclusion: Patients with PV in a large retrospective real-world survey across the US are found to experience burdensome PV-related symptoms and reduced QoL. The findings from this study also show that standard treatments do not address these aspects of PV in many patients, and patients who have discontinued HU may experience an even greater disease burden, possibly because of a lack of effective and/or safe alternative treatment options. Importantly, while 66.0% of the patients in the HU-N group were classified as high-risk, the majority of the high-risk patients in the HU-N group (81.0%) were not treated with cytoreductive agents, suggesting a potential knowledge deficit regarding recommendations for PV management. Collectively, these results illustrate the adverse impact of PV-related symptom burden on patient QoL and reinforce the importance of unmet control of PV-related symptoms in choosing PV therapy. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Gilead: Research Funding. Miller:Incyte Corporation: Honoraria, Research Funding. Mascarenhas:Promedior: Research Funding; Roche: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Kalobios: Research Funding. Thyne:Incyte Corporation: Speakers Bureau. Paranagama:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Naim:Incyte Corporation: Employment, Equity Ownership. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees.

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 Abstract 3850 Background: We have recently shown that primary myelofibrosis (PMF) was associated with increased plasma levels of IL-1b/IL-1RA/IL-2R/IL-6/IL-8/IL-10/IL-12/IL-13/IL-15/TNF-α/G-CSF/INF-α/MIP-1α/MIP-1b/HGF/IP-10/MIG/MCP-1/VEGF in PMF (J Clin Oncol 2011; 29: 1356). In addition, increased levels of IL-8, IL-2R, IL-12, IL-15 and IP-10 were independently associated with inferior survival. In the current study, we focused on the plasma cytokine profile in polycythemia vera (PV) and examined how it compares with PMF or in a cohort of PV patients whose samples were collected during follow-up. We also looked for phenotypic and prognostic correlates. Methods: Study inclusion for patients with PV required availability of archived plasma within one year of diagnosis. Samples from PV patients seen at different points post-diagnosis were also collected, in order to compare their cytokine profile with that of patients whose samples were collected within one year of diagnosis. Standard procedures were followed to centrifuge peripheral blood samples at 4°C and store aliquots at −80°C. Concentrations of 30 plasma cytokines/chemokines were analyzed in duplicates using Multiplex Bead-based Luminex Technology (Invitrogen, Carlsbad, CA, USA): IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, EGF, eotaxin, FGF-b, GM-CSF, G-CSF, HGF, IFN-α, IFN-γ, IP-10, MCP-1, MIG, MIP-1α, MIP-1β, RANTES, TNF-α, and VEGF. Measurements were performed on a Luminex 200 analyzer (Luminex Corporation, Austin, TX, USA) and resulting data were evaluated using STarStation Software Version 2.3 (Luminex Corporation, Austin, TX, USA). Results I: Plasma cytokines in PV (n=36 for samples collected within one year of diagnosis and n=40 for samples collected beyond that time point) vs. PMF (n=92) vs. normal controls (n=35) There was no significant difference between the three groups in the plasma levels of the following cytokines: IL-1β, IL-2, IL-4, EGF, and IL-17. PV and normal controls had similar levels of IL-2R, IL-5, FGF-b, and TNF-α; all four cytokines were elevated in PMF. The levels of the following cytokines were equally increased in PV and PMF: IL-1RA, IL-7, HGF, MIG, and VEGF. The following cytokines were also elevated in both PMF and PV but predominantly so in PV (MIP-1α) or PMF (IL-6, IL-8, IL-12, IL-13, IL-15, MIP-1β, IP-10, and MCP-1). Eotaxin and GM-CSF were elevated in PV but not PMF. Compared to normal controls, significantly lower levels were noted for IL-10 in PV and IFN-α and IFN-γ for PMF. IFN-α and IFN-γ levels were both elevated in PV. Comparison of PV samples collected within one year of diagnosis (n =36) vs. those collected beyond that time point (n =40) showed significantly increased levels of IL-8 (p=0.0005) and borderline significant increases in IP-10 (p=0.09) and IL-2R (p=0.09). Results II: Clinical correlates of plasma cytokines in PV Among the above-listed cytokines that were abnormally increased or decreased in PV, significant correlations were seen with sex (IP-10 and GM-CSF), age (IP-10, eotaxin), platelet count (MIG), hemoglobin level (IL-6), arterial thrombosis (IFN-γ, IL-1RA, VEGF, MIP-1α), and abnormal karyotype (IL-13, MIP-1α). None of the cytokines correlated with leukocyte count, venous thrombosis, pruritus or microvascular symptoms. The following, treated as continuous variables, were associated with inferior survival: IL-7, HGF, IFN-α, MCP-1, GM-CSF and IL-10 (p<0.05 for all). The number of events and sample size were too small to perform multivariable analysis. Conclusions: Plasma cytokine levels in PV are markedly abnormal and show both similarities and differences with PMF; the similarities became more pronounced in patients whose samples were examined at later stages of their disease. The current study suggests prognostic implications that warrant validation in a larger number of patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Polycythemia Vera (PV) constitutes one of the three BCR-ABL1-negative myeloproliferative neoplasms and is characterized by clonal erythrocytosis and the almost invariable presence of JAK2 mutation. An absolute monocyte count (AMC) of ≥1 x 10(9)/L defines chronic myelomonocytic leukemia (CMML) but can also be seen in other myeloid disorders including myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The presence or development of monocytosis has previously been shown to confer poor prognosis in both primary myelofibrosis (PMF), which is one of the three BCR-ABL1-negative MPN (Leukemia Research 2007;31:1503, Mod Pathol. 2013 Feb;26(2):204) and MDS (Haematologica. 1997;82:25). In the current study, we examined the clinical, prognostic and molecular correlates of monocytosis in PV. Methods Study patients were selected from our institutional database of MPN and fulfilled the 2008 World Health Organization (WHO) criteria for the diagnosis of PV (Blood. 2009;114:937). Cytogenetic and mutational analyses were performed according to conventional methods (Leukemia. 2014;28:2206) any assignment as unfavorable karyotype was per PMF criteria (Leukemia. 2011;25:82). Mutation screening included TET2, ASXL1 and SRSF2 because of their known association with CMML (Leukemia. 2014;28:2206) Statistical analyses considered clinical and laboratory parameters obtained at time of diagnosis. Results Patient characteristics: Analysis was conducted on 587 patients (median age 60 years; 48% males) who met WHO criteria for diagnosis of PV. Amongst them, accurate documentation of AMC was available in 237 patients, cytogenetic information in 239, and ASXL1, TET2 and SRSF2 mutational status in 133 patients. Median (range) values were for AMC 0.6 x 10(9)/L (0-4.7) and leukocytes 11.6 x 10(9)/L (3.8-171.6). 31% of 506 informative patients had palpable splenomegaly, 34% of 551 had microcirculatory symptoms, 30% of 566 had pruritus, 8% of 504 had erythromelalgia, 42% of 581 had hypertension, 9% of 584 had diabetes and 11% of 575 were active tobacco users. 25% of the patients presented with history of thrombosis and 22% developed thrombosis after diagnosis. Cytogenetic findings were abnormal in 19%, of whom 20% were unfavorable. TET2, ASXL1 and SRSF2 mutations were documented in 18%, 11% and 3%, respectively. During follow-up, 224 (38%) patients died and median follow-up for living patients was 109 months. Median survival was 16 years and leukemic or fibrotic transformations were documented in 4% and 14%, respectively. Comparison of patients with and without monocytosis: Among 237 informative patients, 32 (14%) displayed monocytosis (AMC ≥1 x 10(9)/L) at time of diagnosis. PV patients with monocytosis were older (p=0.006) and displayed higher leukocyte count (p<0.0001) and higher incidences of leukocytosis (p=0.024) and unfavorable cytogenetic abnormalities (p=0.02). There was no association between monocytosis and mutations for TET2 (p=0.1), ASXL1 (p=0.7) and SRSF2 (p=0.3) or thrombosis before (p=0.9) or after (p=0.5) diagnosis (p=0.5), palpable splenomegaly (p=0.6), pruritus (p=0.7) or microcirculatory symptoms (p=0.1). Among the 237 PV patients in whom information regarding AMC was available, 70 (30%) died during follow-up and 49 (21%), 23 (10%), 9 (4%) developed thrombosis, leukemic transformation or fibrotic progression, respectively. In univariate analysis, overall (p=0.009; HR 2.0, 95% CI 1.2-3.4) but not leukemia-free (p=0.79), myelofibrosis-free (p=0.13) or thrombosis-free (p=0.48) survivals were different between patients with or without monocytosis. Furthermore, the significant difference in survival was no longer apparent when analysis was adjusted for age (p=0.13), unfavorable karyotype (0.17) or leukocytosis (p=0.06). Conclusions Monocytosis (AMC ≥1 x 10(9)/L) is not infrequent in PV (14%). However, the presence of monocytosis does not appear to represent a significantly different phenotype in terms of molecular characteristics although it is associated with older age, leukocytosis and unfavorable karyotype. The latter associations account for the inferior survival seen in patients with monocytosis. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from disease related events linked to risk of vascular events, splenomegaly, progression to myelofibrosis/acute leukemia, and disease related symptoms arising from both elevated cytokines and issues of vascular flow. Impact of front line therapy on ET/PV symptoms has not been reported in a systematic fashion. Methods: MPD-RC 112 trial (NCT01258856) enrolled cytoreductive therapy naïve (hydroxyurea [HU] <3 mo) pts with high risk ET or PV within 3 years of diagnosis. Pts were randomized (1:1, stratified by ET vs PV) to either response adjusted pegylated interferon alpha 2a (PEG) or HU. MPN symptoms, treatment toxicities, and quality of life (QoL) were measured by the MPN-SAF and EORTC QLQ-C30 at baseline and 3, 6, 9, and 12 mo. PEG related toxicities were assessed with 5 questions on PEG arm only. European Leukemia Net (ELN) complete hematological responses (CHR) at 12 mo were determined by central blinded review. Individual time point and longitudinal group comparisons were based on mixed models adjusting for age. T-tests were used to compare change scores at 12 mo between pts with and without CHR. Results: Patients: MPD-RC 112 enrolled 168 pts from 9/2011 to 7/2016, with 75 pts included in the interim analysis. 73 (97%; HU 37, 95%; PEG 36, 100%) completed surveys at baseline of which 66 (90%; HU 30, 81%; PEG 36, 100%) completed at least 1 survey during treatment. Median age was 60 (range 19-84) with 32 (44%) females; 30 (41%) / 43 (59%) with ET / PV; 19 (26%) had a history of thrombosis; and 16 (22%) had palpable spleen. Baseline characteristics where balanced between arms with the exception of age (median age: HU 66, PEG 54; p<0.001). Baseline Symptom Burden/QoL: Mean MPN-SAF Total Symptom Score (TSS, scale 0 [absent]-100 [worst imaginable]) was 15.4 (SD 12.5; range 0-52.2) with means of 12.6 (SD 11.7) / 17.3 (SD 12.7) for ET / PV which were somewhat better than reported means of a previous cohort receiving any line of treatment (ET mean 18.7, SD 15.3; PV mean 21.8, SD 16.3; Emanuel RM, JCO 2012). Symptoms (scale 0 [absent]-10 [worst imaginable]) with the highest prevalence (score >0) included fatigue (65/73, 89%) and insomnia (47/73, 64%). The symptom with the lowest prevalence was fever (8/72, 11%). Mean QLQ-C30 global health status/QoL (GHS/QoL) was 73.3 (SD 19.1) which is comparable to a general healthy population (mean 71.2, SD 22.4) and better than a general cancer population (mean 61.3, SD 24.2; QLQ-C30 Reference Manual 2008). TSS, symptoms, and QoL did not differ between arms. Impact of Therapy on Symptom Burden/QoL: On HU, pts initially experienced worsening of TSS, fatigue, early satiety, itching, bone pain, and fever (all p<0.05) with some symptoms returning to baseline after 6 mo (Table 1). On PEG, pts experienced improved abdominal pain and discomfort, but worsening of headache, cough, injection site irritation, blurry vision, and vision change (all p<0.05). Sad mood did not worsen on PEG, although this may be confounded by concurrent use of mood stabilizers. Concentration problems on PEG were significantly worse at 9 mo (p=0.04). Both arms experienced worsened QoL (MPN-SAF single item: HU p=0.009, PEG p=0.003). In comparing between arms, TSS significantly differed (p=0.009) with higher symptoms on HU vs PEG at 3 and 6 mo, but lower symptoms at 9 and 12 mo (Figure 1). Similar descriptive profiles were observed for most individual symptoms; however, the only symptom profiles which significantly differed between arms was early satiety (p=0.03). ELN Response and Symptom Burden/QoL: Among 62 pts with symptom and response data at 12 mo, CHR rate was 37% (23/62). Change in sad mood and sexuality were the only significant differences between pts with and without CHR regardless of arm though in the unanticipated direction (sad mood: mean change 1.5 vs -0.8, p<0.001; sexuality: mean change 2.33 vs 0.3, p=0.03). Conclusions: PEG was associated with an initial decrease in MPN symptom burden when compared to HU. However, with longer duration of therapy, this superiority dissipated. Patient-reported PEG toxicities worsened over time. On both arms, symptom worsening was observed in pts achieving an ELN CHR, possibly leading to the observed negative impact on mood and sexuality. Future research on the impact of PEG on disease progression and molecular features will be important to assess whether increased side effects with PEG are justified. Disclosures Mesa: CTI: Research Funding; Celgene: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. McMullin:Novartis: Honoraria, Speakers Bureau. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Kessler:Pfizer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Ritchie:Pfizer: Honoraria; Novartis: Honoraria; Arian: Speakers Bureau; Celgene: Speakers Bureau; Incyte: Speakers Bureau. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding. Mascarenhas:Promedior: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Novartis: Other: DSMB , Research Funding; Roche: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding.

Abstract Background and purpose of the study: Several reports have documented that histone deacetylase inhibitors induce neoplastic cells to undergo growth arrest, differentiation and/or apoptotic cell death. Among these agents, Givinostat inhibits proliferation of cells bearing the JAK2V617F mutation and has shown clinical significant activity with good tolerability in patients with chronic myeloproliferative neoplasms, including polycythemia vera (PV). In two phase II studies [Rambaldi et al. Br J Haematol 2010;150:446, Finazzi et al. Br J Haematol 2013;161:688] the maximum administered dose (150 mg/day) was generally well tolerated. Assuming a linear relationship between dose and efficacy, greater clinical efficacy could be expected with increased doses of Givinostat. Methods: This is a two-part, multicenter, open label, non-randomized, phase Ib/II study to assess the safety and tolerability, maximum tolerated dose (MTD) and preliminary efficacy of Givinostat in patients with JAK2V617F positive PV. Part A (i.e. phase Ib) is the dose escalation portion of the study, while Part B assesses the preliminary clinical efficacy of Givinostat at the MTD defined in Part A. Eligible patients for this study include JAK2V617F positive PV patients, who have active and/or uncontrolled disease, defined as: (i) Hematocrit (HCT) ≥ 45% or HCT <45% normalized by phlebotomy, and (ii) PLT > 400 x109/L, and (iii) WBC > 10 x109/L. Study therapy is administered in 28 day cycles (cycle is defined as 4 weeks of treatment). Disease response has been evaluated according to the clinico-haematological European LeukemiaNet (ELN) criteria [Barosi et al. Blood 2009;113:4829] at Cycles 3 and 6. Disease-related symptoms have been reported directly by the patients who completed the MPN-SAF QoL form. The study lasts up to a maximum of 24 weeks of treatment. However, after completion of the trial, all patients achieving clinical benefit are allowed to continue treatment with Givinostat in a long-term study (ClinicalTrials.gov ID: NCT01761968). In Part A, the Cycle 1 has been used to define the MTD of Givinostat. Only dose limiting toxicities (DLTs) experienced during Cycle 1 were considered for dose escalation decisions. Part B is the cohort expansion part of the study to assess the preliminary clinical efficacy of Givinostat at the MTD in evaluable patients Results: In Part A, 12 patients with active and/or uncontrolled disease, were treated with Givinostat, 6 patients at DL1 (100 mg b.i.d.), 3 patient at DL6 (150 mg/die) and 3 patients at DL0 (50 mg b.i.d.). Only one DLT .(grade 3 dyspepsia) was observed in the 6 patients treated at DL1 during the Cycle 1. Givinostat treatment was generally well tolerated: one patient developed grade 4 and two patients grade 3 thrombocytopenias at DL1 after the Cycle 1. Complete/partial response was observed in 100% of evaluable patients at Cycle 3 (Figure). At that time, an important reduction of WBC and PLT count (about 50% in both cases), an HCT control without phlebotomy, a net decrease of MPN-SAF total score and JAK2V617F allele burden (about 50% and 30%, respectively) have been noted and generally maintained at Cycle 6. One out of 3 (33%) patients with splenomegaly at baseline normalized the spleen at Cycle 6. PK/PD evaluations are currently under analysis. Part B started on December 2015 and is currently recruiting patients. At the time of ASH Meeting, a presentation of the preliminary results of the interim analysis (IA) is planned. The objective of this IA is to evaluate the response rate of the first 12 treated and evaluable patients. Conclusions: Taking into account the continuous schedule of the drug as prescribed in this current study, the daily dosage of 200 mg has been identified as the MTD of Givinostat in PV patients. Givinostat treatment is generally well tolerated and shows preliminary clinical efficacy in PV patients with an active/uncontrolled disease. Response rate of patients in Part A C3D28 = Cycle 3 Day 28, or three months of treatment. C6D28 = Cycle 6 Day 28, or six months of treatment. Two patients dropped-out the study Part A, due to Informed Consent Form withdrawal, while 1 patient left the study for AE (i.e. grade 3 dyspepsia, DLT). At C3D28, 1 Complete Response (CR) and 8 Partial Response (PR) have been observed. At C6D28, 1 Complete Response (CR), 7 Partial Response (PR) and 1 No Response (NR) have been observed Figure Figure. Disclosures McMullin: Novartis: Honoraria, Speakers Bureau. Vannucchi:Novartis: Honoraria, Speakers Bureau. Mesa:Ariad: Consultancy; CTI: Research Funding; Galena: Consultancy; Celgene: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Gilead: Research Funding. Tibes:Italfarmaco S.p.A.: Consultancy, Honoraria. Bettica:Italfarmaco S.p.A.: Employment. DI Tollo:Italfarmaco S.p.A.: Employment.

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: Post polycythemia vera (PV) and essential thrombocytosis (ET) myelofibrosis (MF), like primary MF (PMF), are heralded by splenomegaly, cytopenias, heavy symptom burden, and decreased overall survival. Risk prognostication tools, including the dynamic international prognostic scoring system (DIPSS) and the Passamonti risk score for post-PV MF (Passamonti et al. Blood 2010, 2008), are helpful to estimate survival and guide therapeutic decision-making. For Post-PV/ET MF, it is unknown if DIPSS correlates with the Passamonti risk score. Here we evaluate the correlation between the two available risk prognostication tools in post-PV/ET MF. Methods: Retrospective chart review conducted for patients with post-PV/ET MF seen between 2000-2012. Descriptive statistics were used to describe patient demographic and clinical variables in post PV/ET patients. DIPSS Score: calculated at time of last follow up: 1 point for age >65, 2 points for hemoglobin <10g/dL, 1 point for leukocytes >25 x 109, 1 point for circulating blasts 1% and 1 point for constitutional symptoms. Risk group was assigned: low-risk (0 adverse points), intermediate-1 risk (1 adverse point), intermediate-2 risk (2-3 adverse points) and high-risk (4-6 adverse points). Passamonti Risk Scores: calculated at time of last follow up: with 1 point assigned for hemoglobin level less than 100 g/L (10 g/dL), platelet count less than 100 x10 (9)/L, and/or leukocyte count more than 30x10(9)/L. Cross-tabulation of DIPSS score versus Passamonti risk score at time of last follow-up was conducted and the percent agreement was described. Spearman correlation coefficient between DIPSS score at follow-up with Passamonti score was conducted. Results: Patients: Sixty-one (58%) post-ET and 44 (42%) post-PV patients were identified, total N=105. Male to Female ratio was 1:1. Median age was 65 (range 25-87). JAK2 V617Fpresent in 68 (65.4%). Median hemoglobin was 10.9 g/dL (range 5.3-17.0), median platelet count 287 x 109 (range 20-1864), and median WBC was 11.1x 109 (range 1.1-165). Risk prognostication: When DIPSS risk scores were applied 11 patients were low, 48 patients were Intermediate-1, 31 patients were Intermediate-2, and 10 patients were high. When Passamonti risk scores were applied 57 patients received score of 0, 31 patients scored 1, 9 patients scored 2, and 3 patients scored 3. DIPSS and Passamonti risk score agreement: The overall agreement between DIPSS and Passamonti risk scores was low, with 24% of cases in agreement. Spearman correlation: Rho=0.451; p<0.001. See Table #1 with agreement seen in highlighted cells. Table 1. DIPSS and Passamonti Agreement Passamonti Risk Score DIPSS 0 1 2 3 Total Low 9 (75%) 3 (25%) 0 0 12 Int-1 31 (77.5%) 8 (20%) 1 (2.5%) 0 40 Int-2 17 (43.6%) 14 (35.9%) 6 (15.4%) 2 (5.1%) 39 High 0 6 (75%) 1 (12.5%) 1 (12.5%) 8 Total 57 (57.6%) 31 (31.3%) 8 (8%) 3 (3%) 100 Conclusion: Post PV/ET MF represents a unique clinical entity and risk prognostication schemes developed for PMF, such as DIPSS, may not represent accurate prognosis estimation in this subgroup of MF. When DIPSS and Passamonti risk scores were applied to same post PV/ET group, agreement was poor at 24%. Additionally, DIPSS was more likely to assign patients to high-risk category than Passamonti. Further studies are needed to evaluate the DIPSS and Passamonti prognostic risk score application to the post PV/ET MF population. Disclosures Mesa: Incyte Corporation: Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; CTI Biopharma: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; NS Pharma: Research Funding.

Abstract Background: Patients with polycythemia vera (PV) can have a pronounced symptom burden that negatively impacts their quality of life (QoL). Traditional treatment options such as phlebotomy, hydroxyurea, and interferon provide clinical benefit but frequently do not alleviate symptoms. The ongoing REVEAL study is being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the US. This preliminary analysis describes the burden of PV based on patient-reported outcomes (PROs), including health-related QoL and work productivity. Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study. Eligible patients are ≥18 years of age with a PV diagnosis and currently under active management by a physician in the US. PROs are being collected at study enrollment and every 3 months thereafter. Each of the 10 items on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) are graded from 0 (absent) to 10 (worst imaginable), with individual symptom scores ≥7 considered severe; total symptom score (TSS) ranges from 0-100. Raw scores for items on the 30-item European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) are standardized by linear transformation to 0-100. Higher scores on the EORTC QLQ-C30 indicate better functioning for global health status/QoL and functional subscales and worse severity for symptom subscales. Outcomes with the 6-item Work Productivity and Activity Impairment Specific Health Problem questionnaire (WPAI-SHP) are presented as a proportion from 0% (minimal/no impairment) to 100% (maximal impairment/productivity loss). Analyses of these preliminary data were descriptive. Results: At the time of data cutoff (June 9, 2015), REVEAL had enrolled 865 patients (total planned enrollment, n=2000), the majority were male (55.5%) and white (89.5%), with a median age of 67 (range, 22-95) years. 782 patients had completed the PRO questionnaires at the enrollment visit. A majority of patients reported ≥1 PV-related symptom. Mean (SD) MPN-SAF symptom scores were highest for fatigue (3.5 [2.7]), early satiety (2.7 [2.8]), inactivity (2.7 [2.9]), itching (2.6 [3.1]), and concentration problems (2.1 [2.6]). The mean (SD) MPN-SAF TSS (sum of 10 symptom scores) was 19.6 (16.1). The most frequently reported severe symptoms were fatigue, itching, inactivity, early satiety, night sweats, concentration problems, and bone pain (Table 1). Mean (SD) global health status/QoL reported on the EORTC QLQ-C30 was 72.8 (23.4); functional subscales were as follows: cognitive functioning, 80.3 (24.5); emotional functioning, 80.7 (24.0); physical functioning, 83.1 (20.6); role functioning, 84.3 (26.1); and social functioning, 85.0 (25.0). The most severe mean (SD) symptom subscale scores were fatigue (30.7 [28.5]), insomnia (29.5 [34.5]), pain (20.9 [29.3]), and dyspnea (17.3 [28.6]). Among patients who were employed at baseline (n=273), mean (SD) PV-related WPAI-SHP scores were as follows: absenteeism (ie, work time missed), 2.9% (10.6%); presenteeism (ie, impairment at work/reduced on-the-job effectiveness), 10.7% (20.4%); work productivity loss (ie, absenteeism plus presenteeism), 12.0% (22.2%); and activity impairment, 21.0% (28.0%). Conclusion: Preliminary descriptive data from patients currently enrolled in REVEAL suggest that patients with PV have notable impairment in QoL because of their disease; patient-reported scores on the MPN-SAF and EORTC QLQ-C30 were similar to those reported previously for patient populations with MPNs. Similarly, PV is associated with marked work productivity loss among patients who are currently employed. Subsequent analyses from REVEAL will evaluate changes over time in PROs and investigate correlations with disease progression and treatment. REVEAL can provide novel insights into questions related to the contemporary real-world QoL burden and its impact on PV-related symptoms and work productivity. Disclosures Mesa: Pfizer: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding. Boccia:Incyte Corporation: Honoraria. Moliterno:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Naim:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Stein:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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.