Vannucchi, Alessandro M.

Abstract Abstract 1729 Background: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm whose survival at diagnosis is predicted by the International Prognostic Scoring System (IPSS), which is based on the presence of the following five risk factors: age greater than 65 years, presence of constitutional symptoms, hemoglobin level below 10 g/dL, leukocyte count greater than 25 ×109/L, and circulating blast cells 1% or greater (Cervantes et al, Blood 2009). To allow dynamic prognostication at any time during follow up, we further developed the Dynamic International Prognostic Scoring System (DIPSS), based on the same IPSS-factors, but with different score values (one point for each risk factor, two points for acquisition of anemia) and with a distinct score model (low risk, LR, 0 points; intermediate-1 risk, Int-1R, 1–2 points; intermediate-2 risk, Int-2R, 3–4 points; high risk, HR, 5–6 points) (Passamonti et al, Blood 2010). The DIPSS model was also efficient in the prediction of acute myeloid leukemia (AML) evolution (Passamonti et al, Blood 2010) and in the assessment of survival and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (Scott et al, Blood 2012). Aim: The aim of the present study is to update outcome data of PMF patients included in the original series used to generate the DIPSS model and to assess the DIPSS prediction of survival in PMF patients with a longer follow up. The Institutional Review Board approved the study, and the procedures followed were in accordance with the Declaration of Helsinki. Patients and methods: This study was performed on 520 of 525 regularly followed DIPSS-PMF patients, as five patients have been lost to follow up after the original publication. Results: Updated median follow up was of 4.1 years (range, 0.1–30.1). At the time of analysis 326 (63%) patients died, of whom 194 due to known causes: 69 AML, 16 non-AML disease progression, 21 bleeding, 17 thrombosis, 33 infections, 38 other. Median survival was 6 years (95% CI: 5.1–6.7). DIPSS stratification allowed different survivals in PMF patients even with a longer follow-up (Figure 1). Hence, to assess the time to DIPSS-category progression, we evaluated the median time spent within each risk group. This estimate revealed that the median time spent in each risk category was: 4.9 years in LR (range, 0–26.7), 2.1 years in Int-1R (range, 0–18.7), 1.7 years in Int-2R (range, 0–13.4), and 0.74 years in HR (range, 0–13.7). To investigate the prognostic role of the DIPSS score on survival, we analyzed the score as a categorical time-dependent covariate in a Cox survival regression model: the hazard ratio of shifting category from LR to Int-1R was 5.0 (95% CI: 2.4–10.6; P <0.001), it was 3.6 when shifting from Int-1R to Int-2R (95% CI: 2.6–4.9; P <0.001), and 2.7 (95% CI: 2.0–3.6; P <0.001) from Int-2R to HR. Conclusion: The updated analysis shows that the DIPSS model continues to predict survival in patients with PMF. Disclosures: No relevant conflicts of interest to declare.

Abstract BACKGROUND: Symptom burden in essential thrombocythemia (ET) and polycythemia vera (PV) is severe even among individuals with low risk disease (Blood 2012. 12;123(24):3803-10). New therapies exist which alleviate the severe symptom burden and reduce splenomegaly in ET and PV patients (N Engl J Med 2015; 372:426-435). This analysis is the first to date to evaluate thresholds at which symptom-based treatment can be considered for ET and PV patients who are intolerant or resistant to hydroxyurea (HU). METHODS: Patient demographics, symptom burden, and disease traits were collected from ET and PV patients at a single time point during therapy. The MPN-10 total symptom score (TSS, JCO 2012;30(33)4098-103) was utilized to assess symptom burden. Symptom criteria models were determined as previously described among a population of MF patients (Scherber et. al. EHA 2016: a2250). Cutoffs were then evaluated in a cohort of ET and PV patients to assess for utility as a symptom model among this population. RESULTS: Demographics and symptom burden: 838 PV and 867 ET patients with previous hydroxyurea therapy were included in this analysis. Patients were of mean age (54.9 years ET, 64.0 years PV) and gender (69.2% female ET, 55.7% female). Mean disease duration was 6.0 years for ET and 7.3 years for PV.Among ET and PV patients, 15.0% and 24.2% had prior thrombosis respectively. In evaluating prognostic risk, ET patients tended to be low (45.5%) or intermediate risk (42.9%) with only a minority of patient meeting criteria forhigh risk disease (11.6%). Laboratory findings: ET patients had a mean platelet value of 598.7x 109/L(SD=283.4). Among PV patients, mean hematocrit was 45.8% (SD=8.1) and 42.6% of patients had a hematocrit of greater than 45%. White blood cell count was normal between the two groups (ET mean 8.3 x 109/L, PV mean 9.0 x 109/L). Symptoms: Mean worst symptom severity was 6.4 out of 10 (SD=2.7). Among ET patients, worst symptom was most frequently fatigue (32.7%, mean 5.0/10, SD=3.1, overall prevalence 88%) followed by night sweats (13.6%, mean 2.0/10, SD=3.0, overall prevalence 53%) and concentration difficulties (8.6%, mean 3.1/10, SD=3.0, overall prevalence 68%). For PV, worst individual symptom items were most frequently fatigue (29.2%, mean 5.2/10, SD=3.0, overall prevalence 91%), pruritus (14.1%, mean 3.2/10, SD=3.2, overall prevalence 69%), and night sweats (12.8%, mean 2.5/10, SD=3.0, overall prevalence 57%). Cutoff Scoring: 47.0% of ET patients fit criteria for TSSgreater than to equal to 20; 59.0%% had a single itemgreater than 5; and 45.7% had both a TSS greater than or equal to 20 and a single item greater than 5. Among PV participants, 54.5% had aTSS greater than to equal to 20; 66.1% had a single itemgreater than 5; and 51.5% had both a TSS greater than or equal to 20 and a single item greater than 5. Each scoring method was significantly associated with individual item scores (Table 1). Prognostic scoring was not significantly associated with any of the symptom cutoffs evaluated. Correlations: Among ET patients, a prior history of thrombosis was significantly associated with having a worst symptom item greater than 5 (p=0.043). ET patients with lower hemoglobin were significantly more likely to meet criteria for a MPN-10 score greater than or equal to 20 or to meet combined criteria for a MPN-10 greater than or equal to 20 and single worst item greater than 5 (for both p=0.01 or less). For PV, lower hematocrit levels were significantly associated with having an individual worst symptom score of greater than 5 (44.9% versus 46.7%, p=0.0376). CONCLUSION: Assessment of ET and PV symptoms, now measurable through standardized and practical instruments such as the MPN-10, is an integral part of determining therapeutic impact of newer therapies in both clinical practice and trial settings. In our modeling, patients with severe symptom burden profiles are well represented by utilizing cutoff criteria including aworst individual symptom item of greater than 5 out of 10, an MPN-10 score of greater than or equal to 20, or combined criteria of both cutoffs. These cutoffs can be considered when determiningwhich HU intolerant or resistant patients would most benefit fromsymptom orientedtreatment. Disclosures Kiladjian: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding. Schouten:Novartis: Consultancy; Sanofi: Consultancy. Etienne:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Pfizer: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Radia:Pfizer: Honoraria; Novartis: Honoraria. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

Abstract Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Few studies have evaluated patient-reported outcomes during treatment with non-experimental pharmacological regimens. Aims: The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify MPN symptom severity, frequency and quality of life at baseline and throughout treatment with non-experimental therapies utilizing the Myeloproliferative Neoplasm Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS; JCO 2012). In this abstract, we provide updated results for the prospective international cohort trial currently in active enrollment: the MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: This study aims to recruit 180 international ET, PV, and MF (including primary MF and post-ET or post-PV MF) patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the European Organisation for Research and Treatment of Cancer (EORTC) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. At visits, physicians acquired demographic, laboratory, physical examination, and radiographic data. Descriptive statistics were used to summarize data. Results: Clinical Data The MEASURE trial opened for enrollment in 2012 and remains in recruitment phase with 15 participating international sites. To date, 39 patients have been enrolled and 25 have completed both study visits. Participants include ET (28%), PV (24%), and MF (48%; 50% primary MF, 8% post-ET, 42% post-PV) patients. The majority of patients are male (64%) and of expected age (mean 69.3, range 39-89) for the disorders. Seventeen percent had prior thrombosis, 9% required red blood cell transfusion, and none reported prior splenectomy or hemorrhage. Mean hematologic measures included hemoglobin 13.2 g/dL, WBC count 11.4 x109/L, ANC 8.5 x109/L, and platelets 514 x109/L. Therapies received prior to enrollment included aspirin (n=16), hydroxyurea (n=11), phlebotomy (n=8), warfarin/clopidogrel/anticoagulation (n=8), erythropoietin (n=2), and interferon (n=1). The most common current MPN therapies were hydroxyurea (n=9), aspirin (n=9), interferon (n=4), and phlebotomy (n=2). Symptom Assessment In comparing MPN-SAF TSS mean symptom scores, all symptoms except bony pain improved between the first and second visits, including fatigue, early satiety, abdominal discomfort, inactivity, concentration, night sweats, itching, fever, weight loss, and overall quality of life (Figure1). Total MPN-SAF TSS scores improved from a mean of 32.3 to 25.9. On the EORTC, mean scores for physical, role, emotional, and social functioning improved from the first to the second visit (Figure 2). Cognitive functioning showed a slight decline. Global health status measure improved from 60.2 to 72.9. On the MDASI, symptom severity scores decreased from 3.6 to 2.8 from the first to second visit (Figure 3). Symptom distress measure decreased from 4.1 to 3.0. Discussion: Interim results from the MEASURE trial demonstrate that standard, non-experimental treatment regimens offer improvement in quality of life-related symptoms on multiple patient-reported survey instruments including the MPN-SAF TSS, EORTC QLQ-C30, and MDASI. Updated data including symptom correlations and mutational analysis to be presented at the 2016 ASH conference. Disclosures Ross: Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Radia:Novartis: Honoraria; Pfizer: Honoraria. McMullin:Novartis: Honoraria, Speakers Bureau. Cargo:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Sekhar:Novartis: Research Funding. Mesa:Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy; Ariad: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Promedior: Research Funding.

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by erythrocytosis, and in many cases leukocytosis and thrombocytosis. PV is driven by activating mutations in the JAK/STAT pathway, primarily JAK2V617F. For high-risk patients, a commonly used first-line therapy is hydroxyurea (HU); however, a subgroup of patients become intolerant of or resistant to HU. The phase 3 RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU (modified European LeukemiaNet criteria). Patients randomized in the BAT arm were permitted to cross over to receive RUX from Week 32 of the study. The results of the primary analysis comparing RUX to BAT prior to crossover have been reported, in which RUX was superior to BAT in achieving hematocrit control, reductions in spleen volume, and improvements in PV-related symptoms. This current analysis was conducted to evaluate the efficacy of RUX treatment in patients who crossed over from BAT relative to their original BAT treatment and relative to those originally randomized to RUX. Methods : Enrollment criteria included PV diagnosis, age ≥18 years, resistance to or intolerance of HU, splenomegaly, and phlebotomy requirement to control hematocrit. Patients were randomized 1:1 to receive open-label RUX 10 mg BID or BAT administered based on investigator judgment. BAT may have included HU, interferon/pegylated interferon, pipobroman, anagrelide, immunomodulators (eg, lenalidomide or thalidomide), or no medication. The protocol allowed for dose modifications (RUX, 5-mg BID increments [25 mg BID max]; BAT was adjusted per investigator judgment). Patients in the BAT group could cross over to RUX from Week 32 if they had not met the primary endpoint, or after Week 32 due to protocol-defined disease progression. The primary study endpoint was a composite of hematocrit control and a ≥35% reduction in spleen size at Week 32. Hematocrit was assessed at screening, every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32, and 2, 4, 6, 8, 16, 24, and 32 weeks following crossover. Spleen volume was assessed by magnetic resonance imaging at screening and study Weeks 16, 32, 48, 64, 80 and every 32 weeks thereafter. The number of phlebotomy procedures was evaluated over time in each group. Results : A total of 110 patients were randomized to RUX and 112 to BAT; study discontinuation by Week 32 (before crossover was permitted) was 11% in both groups. However, most patients in the BAT arm crossed over to receive RUX treatment immediately after the Week 32 visit (84% between Weeks 32 and 48); only 3% of patients remained in the BAT arm compared with 85% in the RUX arm at the time of the data analysis (median 81-week follow-up). With up to 32 weeks on BAT therapy, 25% of patients in this group did not require a phlebotomy; in contrast, with up to 32 weeks on RUX, 79% of patients after crossover and 74% of patients initially randomized to RUX did not require phlebotomy. The number of phlebotomy procedures adjusted for 100 patient-years during BAT therapy was 196.8 vs 38.5 after crossover to RUX and 34.1 on randomized RUX treatment. Reduction in spleen volume from baseline at any visit occurred in 49% of patients receiving BAT, vs 73% of patients after crossover to RUX and 88% of patients initially randomized to RUX. The proportion of patients achieving at least a 35% reduction in spleen volume (best percentage change) was 1.8% during BAT treatment vs 38.5% after crossover to RUX and 60.0% during randomized RUX treatment. Conclusion : Treatment with RUX after crossover from BAT resulted in improved clinical outcomes compared with original BAT treatment. These findings support the primary RESPONSE results and further validate the efficacy of RUX in this patient population. Disclosures Kiladjian: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Durrant:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals : Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Verstovsek:Incyte Corporation: Research Funding.

Abstract Background We have previously reported on the high prevalence and severity of challenges with intimacy and sexuality amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between issues of intimacy (sexual desire and function), their relationships to MPN disease features, individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF included the patient’s perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Specifically, the MPN-SAF sexuality item asked about “problems with sexual desire or function”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF sexuality item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the sexuality item with the final multivariate model selected using forward regression. Results Demographics A total of 1908 MPN patients (essential thrombocythemia=799, polycythemia vera=671, myelofibrosis=432, missing=6) completed the sexuality item. Participants were of typical age (median=60, range 15-94) and gender (female=53%). Overall, 1218 subjects described sexuality related complaints (score >0) with an overall mean symptom score of 3.5 (median=2.0, SD=3.7, range 0-10); 725/1908 (38%) patients had severe sexuality related complaints (score >4). Univariate Analysis Among the QLQ-C30 functioning scales, all domains had similar statistically significant correlations (r=-.26 to -.32, all p<0.001). Among QLQ-C30 symptom scales, all QLQ-C30 symptoms displayed correlations ranging between .08 and .29 (all p<0.001). Among MPN-SAF items, the MPN-SAF sexuality item correlated most significantly with the TSS (r=.41, p<0.001), along with MPN-SAF symptoms (r=.16 to .39; all p<0.001). MPN-SAF sexuality measure significantly differed by anemia (means: absent 3.3, present 4.5; p<0.001), leukopenia (means: absent 3.4, present 4.4; p=0.01), thrombocytopenia (means: absent 3.3, present 4.5; p<0.001), red cell transfusion (means: no 3.5, yes 5.0; p<0.001), MPN subtype (ET mean 3.1, PV mean=3.6, MF mean=4.4; p<0.001) and language (means ranged from 2.4 [Swedish] to 4.6 [Chinese]; p<0.001). MPN-SAF sexuality did not significantly differ by age, gender, prior thrombosis or prior hemorrhage. Multivariate Analysis In a multivariate model of MPN-SAF sexuality containing all QLQ-C30 functioning scales, physical (p=0.001), emotional (p=0.01), cognitive (p=0.005) and social (p=0.002) functioning were all statistically significant. Numerous symptoms were also significant in a multivariate model of MPN-SAF sexuality containing all other MPN-SAF symptoms (all p<0.05; abdominal pain, inactivity, dizziness/vertigo/lightheadedness, insomnia, depression/sad mood, cough, night sweats and overall QOL). The final multivariate model based on forward regression starting with all demographics, clinical variables, and patient-reported QLQ-C30 scales and MPN-SAF items found age, language, QLQ-C30 role functioning and MPN-SAF items (insomnia, depression/sad mood, night sweats and QOL) to be significant (p<0.05). Conclusions Sexuality related complaints have been linked to both physiologic and psychologic origins and are highly prevalent within the MPN population. The results of this study congruently identified close associations between sexuality and function within emotional, cognitive and social domains. Additionally, the correlations of sexuality issues with MPN symptoms and disease features further suggest this item is a key correlate of overall functionality and quality of life. Future investigations into the causative factors and biological correlates of this complaint may assist in addressing this ongoing challenge. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria. 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.

Abstract Background:The Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib has been evaluated for patients with MF in the phase 3 COMFORT studies. In both trials, ruxolitinib prolonged OS, reduced splenomegaly, and improved MF-related symptoms and quality of life compared with controls. Here, we report the results of an exploratory pooled analysis of OS in the COMFORT studies at 5 years of follow-up. Methods: The double-blind COMFORT-I trial and the open-label COMFORT-II trial were randomized phase 3 studies that evaluated the safety and efficacy of ruxolitinib in patients with intermediate-2 (int-2) or high-risk primary MF (PMF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF). The comparator was placebo in COMFORT-I and best available therapy (BAT) in COMFORT-II. The ruxolitinib starting dose was 15 or 20 mg twice daily based on baseline platelet counts (100-200 and >200 × 109/L, respectively); dose modifications were permitted for safety and efficacy. Patients were allowed to cross over to ruxolitinib from the control arm for progressive splenomegaly, defined as a ≥25% increase in spleen volume from baseline (COMFORT-I) or study nadir (COMFORT-II), or select protocol-defined progression events; crossover was mandatory following treatment unblinding in COMFORT-I. OS was a secondary endpoint in both studies and was evaluated in an intent-to-treat (ITT) analysis using a Cox proportional hazard model that estimated the treatment effect stratified by clinical trial and International Prognostic Scoring System (IPSS) risk. The crossover-corrected treatment effect was estimated using a rank-preserving structural failure time (RPSFT) method. Results: Overall, 528 patients were randomized: 301 to ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 to placebo (n=154) or BAT (n=73). All ongoing patients in the control arms crossed over to ruxolitinib by the 3-year follow-up. Patient populations were similar between the two trials and their details were previously published. In the combined ruxolitinib group, 162 patients (53.8%) had high-risk MF and 139 (46.2%) had int-2 risk MF based on IPSS criteria. At the 5-year ITT analysis, 128 patients (42.5%) died in the ruxolitinib group compared with 117 (51.5%) in the control group. The risk of death was reduced by 30% with ruxolitinib compared with control (median OS: ruxolitinib, 63.5 mo; control, 45.9 mo; HR, 0.70; 95% CI, 0.54-0.91; P=0.0065; Figure A). After correcting for crossover using RPSFT, OS advantage was more pronounced for patients originally randomized to ruxolitinib (median OS: ruxolitinib, 63.5 mo; control, 27 mo; HR, 0.35; 95% CI, 0.23-0.59; Figure B). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged survival compared with control (median OS: ruxolitinib, 63.5 mo; control, 28.3 mo; HR, 0.53; 95% CI, 0.36−0.78; P=0.0013; Figure C). Among all patients treated with ruxolitinib, those with lower-risk disease had longer survival compared with those with high-risk disease (median OS: int-2, not reached [estimated, 102 mo]; high-risk, 50 mo; HR, 2.86; 95% CI, 1.95-4.20; P<0.0001; Figure D). In a subgroup analysis, OS favored ruxolitinib compared with placebo for patients with int-2 or high-risk MF (data not shown). At 5 years, median OS appeared to favor patients with int-2 (n=58) or high-risk (n=89) PMF who were originally randomized to ruxolitinib compared with historical (Cervantes et al; J Clin Oncol 30:2981-2987) controls (int-2 PMF, not reached [estimated, 70 mo] vs 48 mo; high-risk PMF, 34 vs 27 mo); OS was longer among patients with int-2 vs high-risk PMF (P=0.0003). Subgroup analyses showed that ruxolitinib provided an OS advantage regardless of age (>65 or ≤65 y), sex, disease type (PMF, PPV-MF, PET-MF), risk status (int-2 or high), JAK2V617F mutation status, baseline spleen volume (>10 or ≤10 cm), anemia, white blood cell count (>25 or ≤25 × 109L), or platelet count (>200 or ≤200 × 109/L). Conclusion: Long-term treatment with ruxolitinib up to 5 years prolonged survival in patients with MF compared with BAT or placebo. Corrections for patients who crossed over to ruxolitinib suggested that the separation between ruxolitinib and control OS curves was primarily caused by a delay in ruxolitinib treatment. The results suggest that earlier treatment with ruxolitinib may provide a greater survival advantage for patients with MF. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mesa:Incyte: Research Funding; Ariad: Consultancy; Novartis: Consultancy; Celgene: Research Funding; CTI: Research Funding; Promedior: Research Funding; Galena: Consultancy; Gilead: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Dong:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau.

Abstract Background: Cytoreductive therapy with hydroxyurea (HU) has been considered first line therapy for patients with high risk polycythemia vera (PV) and essential thrombocythemia (ET) since the results of the PVSG-08 trial demonstrated thrombotic risk reduction (Fruchtman SM et al 1997) for PV and PT1 for ET (Harrison CN et al 2005). Although HU is well tolerated by most patients and has been shown to reduce thrombotic risk in this setting, concern regarding the leukemogenic potential of this oral ribonucleotide reductase inhibitor balanced by the observation of molecular responses with interferon-α (IFN-α) led us to compare the clinical response and tolerability of pegIFN-α (PEG) and HU in a global, randomized, phase III trial. Methods : MPD-RC 112 trial (NCT01258856) enrolled patients with high risk (age >60 years, history of thrombosis, extreme thrombocytosis, symptomatic splenomegaly, uncontrolled cardiovascular risk factors), newly diagnosed (<5 years), WHO defined ET/PV that were treatment naïve (HU <3 months) and randomized (1:1) to PEG or HU. The primary endpoint was complete hematologic response (CHR) rate by European LeukemiaNet (ELN) criteria between the arms after 12 months of therapy. A planned interim analysis based on intent-to-treat with testing boundaries for efficacy and futility was conducted after 75 patients were on study for 12 months. Response assessment by ELN criteria were conducted by blinded review by 4 investigators (JM, RAM, AY, RH). Intent-to-treat analysis was conducted for efficacy endpoints (HU n=39; PEG n=36). Safety analysis included all patients who received treatment (HU n=36; PEG n=36). Results: Patients: The MPD-RC 112 trial involved 24 centers in 6 countries; enrollment began 09/2011 and concluded 7/2016 prior to full accrual due to study drug availability with 168 patients enrolled (Table 1 for 75 patients in the interim analysis). There was no imbalance between arms with respect to history of thrombosis, erythromelalgia, diabetes, hypertension, but age was significantly older on HU. This remained true when analyzing by ET/PV disease strata with the exception of diabetes which was slightly imbalanced within the PV cohort (HU 5/23, 22%; PEG 0/21, 0%; p<0.05). Response: CHR and PHR were observed in 13 (33%) and 14 (36%) patients for an overall response rate (ORR) of 69% (27/39) for HU, and 10 (28%) and 19 (53%) for an ORR of 81% (29/36) for PEG (CHR comparison p=0.60 based on z-test which did not cross either testing boundary). 10 patients randomized to HU were not evaluable for 12-month response due to never initiating treatment (n=3) or early study discontinuation for AEs (n=1), patient withdrawal (n=5), or treatment non-compliance (n=1). 3 patients were not evaluable for response on PEG due to early study discontinuation for AEs (n=1), physician decision (n=1), or patient withdrawal (n=1). Excluding patients who never initiated treatment did not impact the primary endpoint comparison (HU 13/36, 36%; PEG 10/36, 28%; p=0.45). For ET, CHR and PHR were observed in 7 (44%) and 4 (25%) patient on HU, and 6 (40%) and 6 (40%) for PEG (CHR comparison p=0.83). For PV, CHR and PHR were observed in 6 (26%) and 10 (44%) patients on HU, and 4 (19%) and 13 (62%) for PEG (CHR comparison p=0.58). Normalization of spleen by palpation at 12 months was seen in 2/7 (29%) and 5/7 (71%) of the HU and PEG treated patients with palpable spleen at baseline, respectively. Among 38 PV patients, rate of phlebotomy use at 12 months was 0/18 (0%) vs 5/20 (20%) on HU and PEG (p=0.02). From baseline to best score through 12 months, 9/28 (32%) and 12/34 (35%) patients with data on HU and PEG, respectively, had a ≥50% reduction in MPN-SAF Total Symptom Score (p=0.79). Toxicity: No Grade 4 AEs occurred in either treatment arm. Overall, Grade 3 AEs occurred in 5/36 (14%) HU patients and 16/36 (44%) PEG patients (Grade 3 hematologic: 4/36 [11%] HU vs 8/36 [22%] PEG; Grade 3 non-hematologic: 5/36 [14%] HU vs 16/36 [44%] PEG). See Table 2 for Grade 3 AEs regardless of attribution occurring in >10% of patients in either arm. Conclusions: This interim analysis does not show a clear difference in primary endpoint of CHR between HU and PEG. A comparative analysis of the quality of life and symptom burden will provide further insight into the tolerability of these agents (Mesa et al ASH 2016). The final results of this pivotal trial will provide necessary data required to firmly establish the optimal first line therapy for patients with high risk ET/PV. Disclosures Mascarenhas: CTI Biopharma: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Roche: Research Funding; Novartis: Other: DSMB , Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding. Mesa:Celgene: Research Funding; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Harrison:Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: 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. Vannucchi:Novartis: 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:Incyte: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

Abstract Background We have previously reported on the high prevalence and severity of insomnia amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between insomnia and the MPN disease features (in particular splenomegaly, status of blood counts), individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF included the patient’s perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Specifically, the MPN-SAF insomnia item asked about “difficulty sleeping”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF insomnia item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the insomnia item with the final multivariate model selected using forward regression. Results Demographics A total of 1992 MPN patients (essential thrombocythemia=834, polycythemia vera=703, myelofibrosis=449, unknown=6) completed the insomnia item. Participants were of typical age (median=61, range-15-94) and gender (female=54%). Overall, 1307 subjects endorsed the MPN insomnia item (score >0) with an overall mean symptom score of 3.0 (median=2.0, SD=3.1. range=0-10); 603/1992 (30%) of patients had severe insomnia related complaints (score >4). Univariate Analysis Among QLQ-C30 functioning scales, emotional functioning most highly correlated with the MPN-SAF insomnia item (r=-.47, p<0.001) with all other domains also having statistically significant but slightly weaker correlation (all p<0.001). Among QLQ-C30 symptom scales, insomnia (r=.79, p<0.001) and fatigue (r=.45, p<0.001) most highly correlated with the MPN-SAF insomnia item with all other QLQ-C30 symptoms having correlations between .13 and .37 (all p<.001). Among MPN-SAF items, the MPN-SAF insomnia item correlated with all MPN-SAF items (all p<0.001) including the TSS (r=0.55, p<0.001) and most highly with depression (r=.52, p<0.001), concentration problems (r=.43, p<0.001), overall QOL (r=.41, p<0.001), night sweats (r=.41, p<0.001), and extremity tingling (r=.40, p<0.001). MPN-SAF insomnia significantly differed by gender (means: M 2.4, F 3.4; p<0.001), language (means ranged from 2.6 [Italian] to 3.6 [German]; p=0.01), anemia (means: absent 2.8, present 3.5; p<0.001), prior hemorrhage (means: no 2.9, yes 3.7; p=0.01), and requiring red blood cell transfusion (means: no 2.9, yes 3.6; p=0.03), with a trend for a difference by MPN type (ET mean=2.7, PV mean=3.0, MF mean=3.2; p=0.06). Multivariate Analysis In a multivariate model of MPN-SAF insomnia containing all QLQ-C30 functioning scales, physical, emotional, and cognitive functioning along with global health status/QOL were all significant (all p<0.001). Numerous symptoms were also significant in a multivariate model of MPN-SAF insomnia containing all other MPN-SAF symptoms (all p<0.05: headaches, extremity tingling, depression, sexual problems, night sweats, pruritus, fever, and QOL). The final multivariate model based on forward regression starting with all demographics, clinical variables, and patient-reported QLQ-C30 scales and MPN-SAF items found age, gender, QLQ-C30 emotional functioning and MPN-SAF items to be significant. Conclusions Insomnia is highly prevalent and severe in MPN patients and closely correlates with most other MPN-related symptoms and functional domains bearing a multi-faceted impact on overall quality of life. Correlations between insomnia and emotional, cognitive, and physical complaints including depression/sad mood, concentration problems, night sweats, and numbness/tingling in the extremities suggest that the cause of MPN-related sleep complaints is likely complex. Future studies should evaluate the impact of interventions on MPN associated insomnia as well as its biological underpinnings. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria.

Abstract Background: The majority of pts with MF present with a mutation in exon 14 of the JAK2 gene (JAK2V617F). Studies have suggested that in pts with MF and this mutation, a lower AB is associated with a myelodepletive phenotype and shortened survival (Tefferi, Leukemia 2008; Guglielmelli Blood 2009; reviewed in Vannucchi, Ther Adv Hematol 2011). For example, in a Cox proportional hazard model for factors predictive of overall survival (OS) in pts with primary MF, a JAK2V617F AB of <25% was associated with a shortened OS (p=0.002; Guglielmelli, Blood 2009). In the phase III trials of ruxolitinib (RUX) therapy in JAK inhibitor-naïve MF, RUX-treated pts had a median decrease in AB of 16% (maximal) in COMFORT-I followed up to 216 weeks and 7% in COMFORT-II at 48 weeks. The median AB at the start of therapy was not reported for COMFORT-I and in COMFORT-II was 84.5% (Cervantes, Blood 2013; Deininger, Blood2015). Methods: In this communication, we report on clinical correlates of quantitative baseline JAK2 mutational status and the effect of treatment on JAK2V617Fmutational burden in the PERSIST-1 trial. This trial enrolled JAK inhibitor-naïve pts with primary or secondary MF without restrictions on baseline platelet counts, randomized 2:1 between PAC and BAT (excluding JAK2 inhibitors) arms. Stratifications included Dynamic International Prognostic Scoring System (DIPSS) risk category, and baseline platelet counts (<50,000/μL, 50,000-100,000/μL, >100,000/μL). Following the 24-week primary analysis, crossover was allowed by physician/pt choice and 90/107 BAT-treated pts (84%) crossed over to receive PAC. Baseline characteristics have been previously reported (Mesa, ASCO 2016) and included 203/327 (62%) pts with Primary MF, 42 (13%) with post-essential thrombocythemia MF and 81 (25%) with post-polycythemia vera MF. 320 of 327 pts had informative PCR testing for JAK2V617F. We report the baseline characteristics of pts with high (≥50%) AB of JAK2V617F, low (<50%) AB of JAK2V617Fand those without a detectable mutation at baseline (<0.1%), as well as the effect of PAC and BAT on AB and correlation with outcome measures. Results: 131 (40.9%) had AB >50% (high AB), 115 (35.9%) had an AB ≥0.1% and ≤50% (low AB), and 74 (23.1%) had AB <0.1% (wild-type JAK2). Median AB values were 80.3% for the high AB group and 30.3% for the low AB group. Baseline characteristics that were significantly different between high and low AB pts are shown in the Table. No differences were noted in the DIPSS risk category or baseline percentage of blasts between pts with low or high AB. There were a higher percentage of pts with a lower AB in the PAC arm (64% vs. 48%; p=0.01). PAC therapy resulted in a median decrement in AB at Week 24 of −15.8% vs −7.9% for pts in the BAT arm (Figure). The median greatest reduction from baseline in AB in PAC-treated pts was −31.6%. Decrease in AB was strongly correlated with spleen volume reduction (p=0.003) and trended towards correlation with improvement in total symptom score (p=0.07) in PAC-treated, but not in BAT-treated pts. Overall survival was shorter in PAC-treated pts with a minimal AB reduction vs pts with greater decreases in AB. Conclusions: In the PERSIST-1 trial, pts with a JAK2V617FAB of <50% had substantially different disease and demographic characteristics when compared with those pts with a >50% AB despite similar distribution of DIPSS scores. In this trial, reduction in AB associated with PAC, but not BAT correlated with clinical benefit. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Mead:Baxalta: Consultancy, Honoraria. Perkins:Novartis Oncology: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Mayer:CTI BioPharma Corp.: Other: Travel, Accommodations, Expenses, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Farber:Alexion: Equity Ownership; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Seattle Genetics: Speakers Bureau; Pharmacyclics: Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Consultancy, Research Funding. Nangalia:Novartis: Consultancy, Other: Travel, Accommodations, Expenses. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Zhou:CTI BioPharma Corp.: Employment, Equity Ownership. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau.

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis, thrombocytosis, and/or leukocytosis and a broad range of disease-related symptoms. In high-risk patients, the most common first-line treatment is hydroxyurea (HU). The open-label RESPONSE trial demonstrated that ruxolitinib (RUX), a JAK1/JAK2 inhibitor, provided superior efficacy compared with best available therapy in patients with PV who were resistant to or intolerant of HU according to modified European LeukemiaNet (ELN) criteria. This study (RELIEF) was conducted in patients receiving a stable dose of HU and who were generally well controlled but reporting disease-associated symptoms, comparing the change in PV-related symptom burden in patients continuing their HU therapy with those switching to RUX treatment. Methods: RELIEF was a randomized, multicenter, double-blind, double-dummy, phase 3b study of patients with PV aged ≥18 years on a stable dose of HU monotherapy and reporting PV-related symptoms. Patients were required to be receiving HU for ≥12 weeks prior to enrollment and on the same dose level for the last 4 weeks, and have a score ≥8 on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) cytokine total symptom score (TSS-C). The TSS-C comprised symptoms of itching, tiredness, muscle ache, night sweats, and sweats while awake; each symptom was rated on a scale of 0=absent to 10=worst imaginable, with a maximum TSS-C score of 50. Patients also had to meet one of the following: ≤1 phlebotomy in the previous 6 months or no palpable splenomegaly. Those eligible were randomized 1:1 to receive RUX 10 mg BID and HU-placebo, or HU at the same dose/schedule and RUX-placebo. Dose adjustments were permitted for safety and efficacy. After Week 16, patients could receive open-label RUX until Week 48. The primary endpoint was the proportion of patients with a ≥50% reduction in TSS-C at Week 16; secondary endpoints included proportion of patients with a ≥50% reduction in individual TSS-C symptoms and safety. Results: Overall, 54 and 56 patients were randomized to RUX and HU, respectively; 87.0% and 89.3% remained on treatment through Week 16. At baseline, the median age (range) was 64 (36-87) in the RUX group and 66 (19-85) in the HU group; 44% and 61% were men. The majority of patients in the RUX and HU groups did not have baseline platelet counts or WBC above ELN thresholds: platelets >400 and ≤600 x 109/L (RUX 31.5%, HU 28.6%), >600 x 109/L (3.7%, 8.9%); WBC >10 and ≤15 x 109/L (16.7%, 16.1%), >15 x 109/L (11.1%, 14.3%). In the RUX and HU groups, the mean TSS-C at screening (22.4, 23.1) was higher than that at baseline (16.7, 18.0); the ratio of screening to baseline TSS-C was 1.7 and 1.6. The proportion of patients achieving a ≥50% reduction from baseline in TSS-C at Week 16 (primary endpoint) was 43.4% in the RUX group and 29.6% in the HU group (P=0.139; OR, 1.82; 95% CI, 0.82-4.04). The proportions of patients in the RUX vs HU groups achieving a ≥50% reduction in scores for itching and tiredness at Week 16 were 40.0% vs 26.4% and 54.2% vs 32.0%, respectively. Median percentage changes in individual TSS-C symptoms are shown in Table 1. Additional analyses found no correlation between individual changes in HU dose from baseline to Weeks 13-16 and percentage change in TSS-C in the HU arm (r2=0.030). Even patients maintaining the same HU dose from prior to study entry through Week 16 reported symptom improvement: 12/35 (34.3%) with no dose change, 4/12 (33.3%) with a dose increase, and 0/9 (0%) with a dose decrease had a ≥50% reduction in TSS-C. The most common nonhematologic adverse events in the RUX arm on randomized treatment were fatigue (20.4% RUX vs 10.7% HU), headache (16.7% vs 5.4%), and dizziness (13.0% vs 8.9%). The most common adverse events on HU were diarrhea (9.3% RUX vs 19.6% HU) and constipation (7.4% vs 12.5%); most events were grade 1 or 2. Grade 3 or 4 anemia or thrombocytopenia (lab values) were not reported in the RUX group; two patients in the RUX group had grade 3 or 4 neutropenia. Conclusion: In generally well controlled PV patients receiving a stable dose of HU, there was a positive trend in symptom improvement for patients switched to RUX therapy versus those continuing on HU therapy, although this was not statistically significant. The 34% response rate among patients who continued to receive a stable HU dose suggests a placebo effect that led to an underpowered study. Further analyses are required to better interpret these findings. Disclosures Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yacoub:Alexion Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees. Koschmieder:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne:Novartis Pharmaceuticals: Honoraria. Verstovsek:Incyte Corporation: Research Funding. Hunter:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Morozov:Novartis Pharmaceuticals: Employment, Equity Ownership.