Harrison, Claire

Abstract Introduction: Myelofibrosis (MF) is a life-threatening hematologic malignancy characterized by splenomegaly and debilitating symptoms including fatigue, abdominal pain, night sweats, bone pain, pruritus, and unintentional weight loss. The myeloproliferative neoplasm symptom assessment form (MPN-SAF) is a PRO tool designed to measure MF-related symptom burden and was developed and validated at Mayo Clinic. It was modified (MPN-SAF total symptom score [TSS] and TSS 2.0) for use in the PERSIST-1 and PERSIST-2 phase 3 trials. For PERSIST-1, when examining the 6 common symptoms in both TSS versions (tiredness, night sweats, early satiety, itchiness, bone pain, and abdominal pain), pacritinib-treated patients (pts) had significant improvements in TSS overall and in individual symptoms vs BAT; Pt Global Impression of Change (PGIC) was also significantly improved for pts receiving pacritinib. Improvements in EORTC-QLQ-C30 scales were noted in the pacritinib arm (Mesa, EHA 2015). The proportion of pts achieving spleen volume reduction (SVR) ≥35% at Week 24 was significantly greater with pacritinib vs BAT (ITT: 19.1% vs 4.7%, p=0.0003; evaluable at baseline and Week 24: 25.0% vs 5.9%; p=0.0001). This analysis examines relationships between TSS improvement and changes in splenomegaly and HRQoL outcomes. Methods: Pts who received no prior JAK inhibitor therapy were randomized 2:1 to oral pacritinib 400 mg once daily or BAT. Pts were stratified by DIPSS risk (Int-1/Int-2 vs High) and platelet count (<50,000/μL vs 50,000/μL to <100,000/μL vs ≥100,000/μL). Pts must have had a baseline total TSS ≥13 using MPN-SAF TSS 2.0. Each symptom is rated on a scale from 0 (absent) to 10 (worst imaginable) using MPN-SAF TSS and TSS 2.0. Results for the 6 symptoms common to both TSS versions are reported. Additional PROs used for assessment of HRQoL included EORTC QLQ-C30 and EQ-5D-5L. In multivariate logistic regressions, odds of TSS reduction ≥50% at Week 24 were modeled as a function of Week 24 SVR ≥35%, spleen length reduction (SLR) ≥ 50%, PGIC, improvement in each EORTC scale, and improvement in EQ-5D-5L Overall Health State (OHS) and in each dimension individually while adjusting for treatment (pacritinib vs BAT). Correlations were examined in all pts and by baseline platelet counts (<50,000/μL, <100,000/μL, and ≥100,000/μL). Results: A total of 327 pts were enrolled (PAC: 220, BAT: 107). 62% of pts had primary MF, 32% had baseline platelets <100,000/μL, and 16% had baseline platelets <50,000/μL. TSS reduction ≥50% was found to be associated with SVR ≥35% and improvement in splenomegaly (SLR ≥50%). In the total pt population, there was a significant association between TSS reduction and SVR (odds ratio [OR]=2.60, p=0.016). In all pts, there was a significant association between TSS reduction and improvements in OHS as measured by EQ-5D-5L (OR=2.30, p=0.013). TSS reductions were also marginally associated with improvements in the QLQ-C30 Global Health Scale (GHS)/QoL Scale (OR=1.92, p=0.050) and, though not statistically significant, there was a trend of improvement in perceived overall health as measured by PGIC (OR=2.16, p=0.118). TSS reductions were further examined in pts grouped by baseline platelet count. Improvement in EQ-5D-5L OHS was marginally associated with TSS reductions in pts with platelets <50,000/μL (OR=6.03, p=0.057). For pts with platelets <100,000/μL, reductions in TSS were significantly associated with reductions in splenomegaly (SLR ≥50%; OR=9.53, p=0.004), and improvements in the QLQ-C30 GHS/QoL domain (OR=4.03, p=0.022) as well as the EQ-5D-5L OHS (OR=5.49, p=0.008). A significant association between TSS reductions and SVR ≥35% was observed in pts with platelets ≥100,000/μL (OR=3.99, p=0.005). In all pts, improvements in Fatigue as measured by QLQ-C30 were significantly associated with TSS reductions (OR=2.20, p=0.019) as well as in pts with baseline platelets <50,000/μL (OR=17.88, p=0.008) and <100,000/μL (OR=10.18, p<0.001). Conclusions: In the total pt population, TSS reduction was associated with improvements in spleen response and perceived overall health. This trend was also observed in pts with low baseline platelet counts. Additionally, TSS reduction was significantly associated with improvements in fatigue, a major contributor to poor HRQoL in pts with MF. This reinforces the clinical relevance of measuring TSS using a validated instrument as an endpoint in MF trials. Disclosures Mesa: NS Pharma: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Genentech: Research Funding; Promedior: Research Funding. Off Label Use: This abstract discusses off-label use of pacritinib. Harrison:Shire: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Dean:CTI Biopharma: Employment, Equity Ownership. Wang:CTI Biopharma: Employment, Equity Ownership. Yang:Baxalta: Employment, Other: Stock. Vannucchi:Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: There are few effective treatment options available for patients (pts) with myelofibrosis (MF). Pts with thrombocytopenia, a risk factor for shorter overall survival, have poorer prognosis (Gangat, J Clin Oncol 2010). Pacritinib is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFSR1 and has demonstrated minimal myelosuppression in clinical trials (Hart, Leukemia 2011; Komrokji, Blood 2015; Mesa, ASCO 2015). In the phase III open-label PERSIST-1 trial, a significantly greater proportion of pts treated with pacritinib achieved spleen volume reductions (SVR) ≥35% vs BAT (ITT: 19.1% vs 4.7%, p=0.0003; pts evaluable at baseline and Week 24: 25.0% vs 5.9%, p=0.0001; Mesa, ASCO 2015). This analysis examines pt responses across subgroups. Methods: Pts naive to treatment with JAK inhibitors were randomized 2:1 to receive oral pacritinib 400 mg once daily or BAT. Stratification factors included DIPSS risk status and baseline platelet count. Pts were eligible who had DIPSS Intermediate (Int)-1, Int-2, or High risk disease; absolute neutrophil count >500/µL; palpable splenomegaly ≥5 cm; and baseline Total Symptom Score (TSS) ≥13 using the Modified MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS and TSS 2.0). There was no restriction on baseline platelets or hemoglobin (Hgb) levels. The primary endpoint was the proportion of pts achieving SVR ≥35% at Week 24 by centrally-reviewed MRI or CT and the secondary endpoint was the proportion of pts achieving ≥50% reduction in TSS from baseline at Week 24 using 6 symptoms from the MPN-SAF TSS. Pt responses were analyzed by baseline risk factors for MF including platelet counts (<50,000/µL vs ≥ 50,000/µL and <100,000/µL vs ≥100,000/µL), sex, age (≥65 y vs <65 y), JAK2V617F mutation status (positive vs negative), baseline MF diagnosis (primary MF [PMF] vs secondary MF), reticulin and collagen fibrosis staging (> 1 vs ≤1), TSS (≥20 vs <20), white blood cell count (>25×109/L vs ≤25×109/L), peripheral blasts (≥5% vs <5%), Hgb (<10 g/dL vs ≥10 g/dL), transfusion dependency by Gale criteria (Y vs N), time from diagnosis (<12 mos vs ≥12 mos), ECOG PS (2-3 vs 0-1), and bone pain (>3 vs ≤3). In multivariate logistic regressions, the odds of SVR ≥35% and TSS reduction ≥50% at Week 24 were modeled as a function of prognostic factors for MF and adjusted for treatment (pacritinib vs BAT). Results for the 6 symptoms common to both TSS versions are reported. Results: 327 pts were enrolled and randomized (pacritinib: 220, BAT: 107). Overall, 62% of pts had PMF; 32% had baseline platelets <100,000/µL and 16% had <50,000/µL; 75% were positive for JAK2V617F. After a median follow-up of 8.4 months, treatment with pacritinib resulted in consistent rates of SVR across subgroups (Figure 1). When comparing vs BAT, the greatest differences in SVR ≥35% rates between treatment arms were observed in pts with baseline platelets <50,000/μL (+22.9% vs BAT), JAK2V617F-negative pts (+23.0% vs BAT) and those aged <65 y (+21.2% vs BAT). Improvements in TSS (TSS and TSS 2.0 reduction ≥50%) were also consistent for pts receiving pacritinib (Figure 2). By multivariate analysis, SVR ≥35% was significantly correlated only with ECOG PS ≥2 (odds ratio [OR]=2.97, p=0.030) and TSS reduction ≥50% was significantly correlated only with bone pain >3 (OR=0.35, p=0.004). Conclusions: Treatment with pacritinib resulted in consistent rates of SVR ≥35% and TSS reduction ≥50% irrespective of baseline characteristics. Comparisons vs BAT were favorable for all patient subpopulations examined for both endpoints. These results support the use of pacritinib across all intermediate- or high risk MF pt subgroups analyzed. Figure 1. Proportion of Patients Receiving PAC who Achieved ≥35% SVR from baseline to Week 24 (95% CI) Figure 1. Proportion of Patients Receiving PAC who Achieved ≥35% SVR from baseline to Week 24 (95% CI) Figure 2. Proportion of Patients Receiving PAC who Achieved ≥50% TSS reduction (6 common symptoms in MPN-SAF TSS and MPN-SAF TSS 2.0) from baseline to Week 24 (95% CI) Figure 2. Proportion of Patients Receiving PAC who Achieved ≥50% TSS reduction (6 common symptoms in MPN-SAF TSS and MPN-SAF TSS 2.0) from baseline to Week 24 (95% CI) Disclosures Vannucchi: Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This abstract discusses off-label use of pacritinib. Mesa:Gilead: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Promedior: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Prasad:BIOGEN IDEC: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Elinder:Celgene: Consultancy. Recher:Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Chugai: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. te Boekhorst:CTI Biopharma: Consultancy; Novartis: Consultancy. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dean:CTI Biopharma: Employment, Equity Ownership. Harrison:Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Abstract Background Symptom burden among MPN patients is severe compared to age-matched controlled and other individuals with cancer. MPN-Related Fatigue (MRF) is among one of the most frequent and debilitating of symptoms among MPN patients and contributes greatly to the loss of quality of life. To date, little is known regarding the breadth and efficacy of strategies to reduce or palliate MRF. Methods A 17-item internet-based survey was hosted on the MPN Forum website during February of 2013. The survey included data on demographics, type of fatigue (chronic, sporadic, or both), strategies to reduce fatigue, and symptom burden using the MPN-SAF TSS. The MPN-SAF TSS also included a validated 1-item measure to assess worst fatigue in the last 24 hours (scored on a 0 (absent/as good as it can be) to 10 (worst-imaginable/as bad as it can be) scale). Results 879 MPN patients responded to the online survey. The majority of patients had been diagnosed with their MPN for more than one year (5.8% less than one year, 34.4% one to five years, 30.3% five to ten years, and 27.6% more than 10 years). Mean age of MPN diagnosis was 49.3 (range 12-84). A near equal mix was seen of chronic (35.3%), sporadic (29.9%) and both chronic and sporadic fatigue (28.8%). Average symptom burden was very severe (mean MPN-SAF TSS =31.9), with an average worst 24-hr fatigue rated as 5.9/10. Many strategies to reduce MPN-related fatigue were mentioned via open and categorical responses (Table 1). Exercise was the most commonly mentioned fatigue reduction strategy, followed by diet and social interaction. Diet strategies included the consumption of fruits and vegetables and using foods to combat specific nutrient deficiencies (e.g., iron). Interventions to increase rest included obtaining >8 hours of sleep at night, taking frequent naps if needed, and strategically timing naps (e.g., sleeping prior to activity). Timing strategies were implemented to maximize energy levels, including scheduling activities at time periods during the day when patients felt most awake. Stress-reduction strategies included massages, meditation and yoga. Some respondents felt work was both source of energy and motivation, although others mentioned cutting back work hours or obligations in order to reduce fatigue. New activities such as gardening and enjoying the outdoors were also mentioned. Use of non-prescription supplementation, including caffeine and over-the counter energy supplementation, was common. Prescription energy stimulants included MPN-specific treatments (e.g., ruxolitinib, hydroxurea, ASA, interferon), steroids, noradrenergic stimulants (e.g., methyphenidate, modafinil), prescription vitamin supplements (e.g., vitamin B12 injections), erythropoietin analogues, and blood thinners. Conclusions Overall patients were very symptomatic of disease (previously reported MPN-SAF TSS scores 18.7 ET, 21.8 PV, and 25.3 MF) and worst 24-hr fatigue (previously reported as 4.0 ET, 4.4 PV, and 5.0 MF) than previously published MPN cohorts (JCO 2012 20;30(36):4590). Many intervention strategies are utilized to reduce MRF. Future trials investigating pharmacologic, psychosocial, and activity-related interventions to reduce MRF are needed. Disclosures: 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; Sbio: 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.

Abstract Abstract 1731 Background: Symptom burden in primary, post-ET and post-PV myelofibrosis (MF) is frequently severe and correlates with a poor prognosis. However, symptom manifestations are heterogeneous with variable presence of specific symptoms, splenomegaly and cytopenias. We sought to identify the spectrum and features of MF symptomatic phenotypes by cluster analysis of prospectively gathered information on MF symptoms and disease features. Methods: Data was collected among an international cohort of subjects with MF. Data included demographics, disease features and completion of the Brief Fatigue Inventory (BFI) and Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) (Blood 2011; 118:401–408). Surveyed symptoms addressed key disease features on a 0 (absent) to 10 (worst-imaginable) scale. Cluster development was based on consideration of r-squared in hierarchical clustering using Ward's linkage. Final cluster assignment was based on the nonhierarchical k-means method. Comparisons between symptom clusters were based on ANOVA and chi-squared tests. Results: Subject Demographic and Disease Characteristics: Data from 329 prospectively enrolled persons with MF was collected (Chinese 102, French 54, German 19, Italian 22, Dutch 45, English 51, Spanish 29, Swedish 7) including 223 PMF, 67 post-ET MF and 39 post-PV MF patients. Participants were of typical age (mean 59) and gender (47% F). Among all participants, four natural symptom clusters were identified (Figure 1). Among clusters, disease features including leukopenia, thrombocytopenia, and enlarged spleen varied significantly between clusters (P<0.05). Cluster 1: The “Fatigue Dominant with Few Lab Abnormalities” Profile (n=150 (46%; 69% PMF, 20% post-ET MF, 11% post-PV MF)). Cluster 1, the largest, is characterized by fatigue-dominant complaints in the setting of the lowest overall MPN-SAF TSS and highest proportion of males (59%). Individuals among this group have the lowest prevalence of laboratory abnormalities (65% total; anemia, 67%; thrombocytopenia, 20%) or clinical deficiencies including enlarged spleen (average 6.0 cm below costal margin), prior thrombosis (9%), prior hemorrhage (5%) or prior RBC-transfusions (20.4%). Interestingly, individuals in this group are most likely to have had prior splenectomy (5.8%). Cluster 2: The “Cognitive Complaints with Enlarged Spleen” Cluster (n=105 (32%; 65% PMF, 20% post-ET MF, 15% post-PV MF)). Cluster 2 is the 2nd largest cluster. Subjects have relatively few abnormal lab values (67% vs 65%–77%) but have high severity of fatigue, sexual difficulties, insomnia, inactivity and reduced QOL. These individuals have the largest spleen size (8.7cm below costal margin). Cluster 3: The “Nighttime and Cognitive Complaints” Group (n=53 (16%; 64% PMF, 25% post-ET MF, 11% post-PV MF)). Cluster 3 is the smallest cluster. Subjects have many cognitive and nighttime-related complaints including sexual difficulties, night sweats, insomnia, and concentration problems. Subjects with post-ET MF are predominant. This cluster also has the 2ndsmallest spleen size (7 cm) or history of prior thrombosis (9.6%), hemorrhage (7.8%) or requirement for transfusions (21.2%). Cluster 4: The “Severe Fatigue with Few End-organ Complaints” Cluster (n=21 (6%; 81% PMF, 14% post-ET MF, 5% post-PV MF)). Cluster 4 is the most symptomatic cohort with the highest proportion of subjects with PM. There is a lower frequency of end-organ complaints including abdominal pain, cough, and headaches. Symptoms including sexual difficulties, sad mood and insomnia are predominant. No subjects had prior splenectomy. Subjects also have the highest prevalence of prior thrombosis (29%), hemorrhage (14%), and transfusions (43%). Additionally, this cohort has the largest prevalence of lab abnormalities (77%) with thrombocytopenia (71%), leukopenia (41%) and anemia (41%). Conclusion: This analysis will allow us to examine a new framework for evaluating persons with MF using symptom profiles and is the 1st cluster evaluation of MF. Lab and physical findings contrast significantly between symptom clusters indicating these phenotypic symptoms likely result from etiological factors present in specific disease phenotypes. Future studies should evaluate whether there is a correlation between cluster profiles, prognosis and genotype. Disclosures: Kiladjian: Celgene: Research Funding; Novartis: Honoraria, Research Funding; Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm driven by JAK/STAT activation and is associated with erythrocytosis and a broad symptom burden that may negatively impact patient quality of life (QoL). Hydroxyurea (HU) is often used as first-line therapy for high-risk patients but may not effectively control or reduce symptom burden. RESPONSE is a phase III trial comparing ruxolitinib (RUX) with best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU according to modified European LeukemiaNet (ELN) criteria. The primary study endpoint (a composite of hematocrit control and ≥35% spleen volume reduction at Week 32) was achieved by 21% of patients in the RUX arm vs 1% in the BAT arm (P<0.0001); 77% of patients in the RUX arm achieved at least one component of the primary endpoint. The current analysis was conducted to evaluate the effect of RUX on PV-related symptoms and QoL measures in the RESPONSE trial. Methods : Patients with PV aged ≥18 years, resistant to or intolerant of HU (modified ELN criteria) with splenomegaly, and who required phlebotomy for hematocrit control were randomized 1:1 to receive open-label RUX 10 mg twice daily (BID) or BAT (administered based on investigator judgment). Dose adjustments were permitted (RUX, 5-mg BID increments [25 mg BID max]; BAT was adjusted per investigator judgment). Objectives of this analysis included assessment of improvement in symptom burden as assessed by patient-reported outcomes using the 14-item modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), the Pruritus Symptom Impact Scale (PSIS), the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the Patient Global Impression of Change. The 14-item MPN-SAF (graded from 0 [absent] to 10 [worst imaginable]) comprised symptoms related to cytokines (tiredness, itching, muscle ache, night sweats, and sweats while awake), hyperviscosity (vision problems, dizziness, concentration problems, headache, numbness/tingling, ringing in ears, and skin redness), and splenomegaly (abdominal discomfort and early satiety). Changes in total symptom score (TSS; maximum score = 140) and individual symptom scores from baseline to Week 32 were summarized by treatment group. For the EORTC QLQ-C30 Global Health Status/QOL score, the percentage of patients with a minimally important difference (MID) from baseline (10-point change) at Week 32 was summarized. Results : Overall, 222 patients were randomized (RUX, 110; BAT, 112). Median age (range) was similar between arms (RUX, 62.0 [34.0–90.0]; BAT, 60.0 [33.0–84.0]); the RUX and BAT arms were 60% and 71% male, respectively. At Week 32, a higher proportion of patients in the RUX vs the BAT arms had a ≥50% improvement in MPN-SAF TSS (49% vs 5%, respectively) and MPN-SAF symptom cluster scores (cytokine, 64% vs 11%; hyperviscosity, 37% vs 13%; splenomegaly, 62% vs 17%). Median percentage changes in individual symptom scores are presented in the Table. Mean changes from baseline at Week 32 on the 5 items of the PSIS indicated that the severity of pruritus and its interference on daily life improved with RUX (range, −1.5 to −2.2) and was unchanged/worsened with BAT (range, −0.1 to 0.3). Treatment with RUX vs BAT was associated with improved mean changes from baseline at Week 32 on EORTC QLQ-C30 symptom subscales, functional subscales, and Global Health Status/QOL (Table); 46% of RUX patients versus 10% of BAT patients achieved an MID in Global Health Status/QOL (Figure). At Week 32, RUX patients were more likely to rate their global impression of symptom changes as “very much improved” or “much improved” (67%) vs BAT patients (13%). Conclusion : In patients with PV who were resistant to or intolerant of HU, treatment with RUX was associated with greater and clinically meaningful improvements in PV-related symptom burden and QoL measures compared with BAT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures 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. 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. Verstovsek:Incyte Corporation: Research Funding. Kiladjian: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. He:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Côté:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Abstract 2847 Background and Purpose: Myelofibrosis (MF) is a progressive Philadelphia-negative myeloproliferative neoplasm characterized by debilitating symptoms, massive splenomegaly, and anemia, which severely impairs quality of life. When medical therapy is not effective or tolerated, splenectomy may be required to ease symptoms in patients with symptomatic portal hypertension, massive splenomegaly, and/or frequent red blood cell transfusions (Barbui et al. J Clin Oncol. 2011;29:761–770). In a recent study (Tefferi et al. Mayo Clin Proc. 2012;87:25–33) up to 27% of patients diagnosed with MF eventually underwent splenectomy. However, splenectomy is associated with limited duration of symptom response, high rates of perioperative morbidity and mortality, and acceleration of hepatomegaly. Clinical studies in patients with MF have demonstrated that ruxolitinib, an oral JAK1/JAK2 inhibitor, provides significant and durable reductions in splenomegaly, the burden of MF-associated symptoms, and also improved quality of life. In this post hoc analysis of pooled data from these studies, we determined the incidence of splenectomy in patients treated with ruxolitinib and those who received placebo or best available therapy (BAT) to evaluate whether ruxolitinib therapy may affect the need for splenectomy. Methods: This analysis included patients who participated in the ruxolitinib phase I/II trial (N=153; Verstovsek et al. N Engl J Med. 2010;363:1117–1127); COMFORT-I, a phase III, 24-month placebo-controlled trial of ruxolitinib (N=309; Verstovsek et al. N Engl J Med. 2012;366:799–807); and COMFORT-II, a phase III, 48-month randomized trial comparing the effects of ruxolitinib and BAT (N=219; Harrison et al. N Engl J Med. 2012;366:787–798). Incidence of splenectomy while on treatment or during the protocol-specified follow-up period, adjusted for differences in the duration of follow up, was calculated for patients on ruxolitinib, placebo, or BAT. Results: As a result of the crossover rules and a higher discontinuation rate on the comparator arms in the phase III studies, mean follow-up duration for placebo (0.67 years) or BAT (0.95 years) overall was substantially shorter than mean follow-up duration for ruxolitinib (1.78 years). Baseline characteristics of the 14 patients who underwent splenectomy were as follows: median age=63 years; median time since initial diagnosis=7.8 years; median spleen length (n=13): 17.0 cm (range: 0–28.0 cm); median spleen volume (in those with measurement, n=11)=2924 cm3 (range: 1203–6807 cm3); IPSS high risk=50%, intermediate-2 risk=43%, intermediate-1=7%. Among patients originally randomized and treated with ruxolitinib, the incidence of splenectomy was 1.1 events per 100 patient years (Table). For patients treated with placebo or BAT in the phase III studies, the incidence of splenectomy was approximately three times higher at 2.9 events per 100 patient years, despite the fact that patients on placebo or BAT were allowed to crossover to ruxolitinib if they had worsening symptomatic splenomegaly. Conclusions: Although limited by small numbers, results of this analysis suggest that ruxolitinib reduces the need for splenectomy in patients with MF. Because of crossover to ruxolitinib and higher discontinuation rates in placebo and BAT, follow-up duration was shorter in these treatment arms compared with ruxolitinib. Further, ruxolitinib treatment in crossover patients may have prevented progression of symptomatic splenomegaly in some patients who may have otherwise become candidates for splenectomy. Our analysis may underestimate the true incidence of splenectomy among patients not receiving ruxolitinib therapy and therefore, the relative reduction in splenectomy rate in patients receiving this therapy. Longer-term follow up will better define the splenectomy rate in ruxolitinib-treated patients. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Gotlib:Incyte Corporation: Consultancy, Honoraria, Support for travel to meeting for the study or other purposes from Incyte Other. Kantarjian:Incyte: grant support Other. Sirulnik:Novartis: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sandor:Incyte Corporation: An employee of Incyte and receiving stock options as part of his compensation Other, Employment. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding.

Abstract Abstract 2852 Background: The 18-item Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF, Scherber et al Blood 2011) given in conjunction with the 9-item Brief Fatigue Inventory (BFI, Mendoza et al Cancer 1999) is a patient-completed questionnaire for assessing symptoms in persons with MPNs. The MPN-SAF has been translated and validated in 9 languages to date. The Total Symptom Score (TSS) is computed from 10 of the most pertinent MPN-SAF items to assess symptom burden in MPN patients and to evaluate response to therapy. Psychometric properties of the TSS have been previously reported (Emanuel et al Blood 2012). The purpose of this analysis is to compare MPN-SAF symptoms and psychometric properties of the TSS across 9 languages in an international sample. Methods: Data were collected in an international cohort of subjects with MPNs. Surveyed symptoms included fatigue, early satiety, abdominal pain and discomfort, inactivity, headaches, concentration, dizziness, extremity tingling, insomnia, sexual problems, mood changes, cough, night sweats, pruritus, bone pain and fever on a 0 (absent) to 10 (worst imaginable) scale. TSS was computed using the published scoring algorithm on a 0 (all symptoms absent) to 100 (all symptoms worst imaginable) scale. Demographic and disease-related data including disease type, gender, and age had to be present to be included in analysis. Demographics were compared across languages groups using ANOVA and chi-squared tests. Symptoms and TSS were compared across language groups using a general linear model adjusting for disease type, age, and gender with post-hoc Tukey pairwise comparisons. Internal consistency and factor structure of the TSS were investigated overall and within language groups using Cronbach's alpha and principal-axis factoring analysis. Results: Subject Demographics and Disease Type: 1,851 subjects with polycythemia vera (PV N=655), essential thrombocythemia (ET N=769) and myelofibrosis (MF N=427; 286 primary MF, 61 PV-MF, 80 ET-MF) were prospectively enrolled and administered the MPN-SAF and BFI in 1 of 9 languages: English [UK] 55, English [US] 102, Italian 186, Swedish 114, German 112, French 457, Spanish 192, Dutch 236, and Chinese 397. Age (median 61, range, 15–94) and gender (55% F) were typical. Disease type and age varied across language groups (both p <0.001). MPN-SAF Symptoms and TSS: Symptom frequencies ranged from 19% (fever) to 88% (fatigue) overall with mean severities ranging from 0.4 (SD=1.3, fever) to 4.3 (SD=2.3, fatigue). Fatigue had the highest mean severity among all symptoms within each language group. Overall, mean TSS was 21.5 (SD=16.7) with the Swedish (mean=18.1, SD=15.2) and Dutch (mean=27.6, SD=17.1) cohorts reporting the lowest and highest unadjusted TSS means, respectively. When comparing symptom items across languages (adjusting for disease type, age, and gender), concentration and sexual problems had the most statistically significant pairwise differences (11 and 10, respectively, out of a possible 36) followed by dizziness and overall quality of life (9 each, out of a possible 36). No statistically significant pairwise differences were observed for abdominal discomfort, headache, extremity tingling, or insomnia. For the TSS, the Dutch cohort appeared to statistically significantly differ (all p <0.05) with all other languages except the English cohorts. All other TSS pairwise comparisons were not statistically significant. TSS Internal Consistency and Factor Structure: The TSS had excellent internal consistency overall (Cronbach's alpha 0.83) as well as within language groups (Cronbach's alpha 0.81–0.86). Overall factor analysis identified a single underlying construct among the 10 TSS items. Factor loadings ranged from 0.41 for fever to 0.73 for inactivity. A single factor solution was appropriate for each language group with factor loadings ranging from 0.18 to 0.85. Conclusion: This analysis suggests that the available translations of the MPN-SAF are generally acceptable for use in a broad context. The TSS demonstrated acceptable internal consistency and similar factor structure across all language groups. Most symptom and TSS comparisons between languages were not statistically significant, but for the few which differed, further studies are needed to evaluate whether these variances are due to disease-related factors or due to linguistic or cultural influences present in the cohorts. Disclosures: Kiladjian: Novartis: Honoraria, Research Funding; Celgene: Research Funding; Shire: Honoraria. Griesshammer:Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract Abstract 1726 Background: We previously reported that symptom burden among persons with ET and PV can be severe and adversely affect QOL. The presence of severe symptoms is linked to poor prognosis. There is considerable inter-subject heterogeneity regarding which symptoms are present in which subjects. No studies have empirically evaluated whether disease characteristics can be grouped in related symptom clusters. Using our previously validated 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408) given in conjunction with the 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196), we sought to evaluate symptom burden by means of cluster analysis. Methods: Data was collected from an international cohort of subjects with MPNs including demographics, disease features and the completed BFI and MPN-SAF instruments. Surveyed symptoms included fatigue, early satiety, abdominal pain and discomfort, inactivity, headaches, concentration, dizziness, extremity tingling, insomnia, sexual difficulties, mood changes, cough, night sweats, pruritus, bone pain and fever on a 0 (absent) to 10 (worst-imaginable) scale. Development of symptom clusters was based on consideration of r-squared in hierarchical clustering using Ward linkage. Final cluster assignment was based on the nonhierarchical k-means method. Comparisons between symptom clusters were based on ANOVA and chi-squared tests. Results: Subject Demographic and Disease Characteristics: Data from 1,141 subjects with PV (N=519) and ET (N=622) was prospectively collected (Chinese 236, French 305, German 45, Italian 114, Dutch 191, English 56, Spanish 109, Swedish 85. Age (mean 59, range, 26–87) and gender (54% F) were typical. Five clusters were selected (Figure 1). Frequencies of prior bleeding, spleen size, anemia, presence of any lab abnormality, language, gender, and MPN type varied significantly between clusters (P<0.05). Cluster 1: The “Reduced Symptom” Profile (n=421 (37%; 60% ET, 40% PV) The largest cluster, subjects had increased complaints of sexual difficulties and fatigue. There was a slightly higher proportion of subjects with ET (60%) versus PV. There were fewer lab abnormalities (28% prevalence) and less prior bleeding (3%) compared to other clusters. Spleen size was smallest of the cluster (1 cm below costal margin). Cluster 2: The “Fatigue-dominant” Group (n=286 (25%; 56% ET, 44% PV)). Subjects in this cluster were predominantly female and had relatively few laboratory abnormalities (19%) than other cohorts. They are characterized by high severity of fatigue compared to end-organ symptoms. Symptom profiles emphasize fatigue, QOL and insomnia with some end-organ complaints. The cohor 63% of the cohort. Cluster 3: The “End-Organ Complaints” Group (n=210 (18%; 49% ET, 51% PV)). Male predominant (56%), subjects had mainly macro-vascular symptom complaints including sexual difficulties, insomnia, and overall QOL, with few microvascular related symptoms (low itching/night sweats). Cluster 4: “Cognitive Complaints” Cluster (n=110 (10%; 53% ET, 47% PV)). The smallest cluster and female predominant (64%), main complaints include fatigue, insomnia, loss of concentration, numbness, and sad mood. Cluster 5: The “Highly Symptomatic” Cluster (n=114 (10%; 44% ET, 56% PV)). Subjects had many cognitive complaints and symptoms correlated with severe micro-vascular abnormalities (pruritus) and or splenomegaly. This cluster had the largest spleen sizes (mean 3 cm), the highest prevalence of prior thrombosis (29%), and highest frequency of lab abnormalities (43%). Cognitive and end-organ complaints were rated as most severe. Conclusion: This analysis offers new means of evaluating persons with PV and ET utilizing symptom clusters. Laboratory and physical abnormalities differed significantly between symptom clusters indicating that our groupings likely result from biological alterations present in specific disease phenotypes. Future studies should investigate correlations between clusters and prognosis and genotype. Disclosures: Kiladjian: Celgene: Research Funding; Novartis: Honoraria, Research Funding; Shire: Honoraria. Roy:Novartis, BMS: Speakers Bureau. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.

Abstract BACKGROUND: The presence of constitutional symptoms has been associated with increased mortality risk in myelofibrosis (MF) (Blood 2010;115(9):1703-8). New therapies exist which alleviate the severe symptom burden profile observed in MF patients but are only approved for use in those with intermediate-2 or high risk disease (N Engl J Med 2012;366:787-798). However, it has been proposed that there are patients who may benefit from symptom based treatment regardless of prognostic score (Am Soc Hematol Educ Program 2014;2014:277-286). We have recently characterized symptom score cutoffs at which patients would statistically benefit from treatment based on symptom scores alone (Scherber et. al. EHA 2016: a2250). These treatment thresholds included aMyeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) total score of greater than or equal to 20, a worst individual item score of greater than 5, or a combined criteria of those with both an MPN-10 total score of greater than or equal to 20 and a worst individual item score greater than 5. This abstract represents an additional analysis of our MF cohort to better characterize the profile of patients who meet criteria for symptom-based therapy. METHODS: Patient demographics, symptom burden via the MPN-10 score (JCO 2012;30(33)4098-103), and disease traits were collected from MF patients and their physicians at a single time point during therapy. Previously we identified MPN-10 cutoffs via AkaikeÕs Information Criterion (AIC) analysis (Ecology 2014;95: 631-6), which represented the optimal model among all models specified for the data at hand to determine which patients would most benefit from symptom-directed therapy. RESULTS: Demographics. 695 MF patients without previousruxolitinib therapy were included in this analysis. Overall, of 455 patients (65.4%) fit a cutoff of having a single worst symptom item of greater than 5/10. 401 patients (57.7%) had a MPN-10 score of equal to or greater than 20. A total of 381 (54.8%) patients fit both of these criteria. A distribution of worse MPN-10 individual scores is shown in Table 1. Mean TSS score was 26.4 (SD=17.7). Symptom Criteria Associations. Demographics and disease traits: Neither mean age or age greater than 60 was significantly associated with meeting any of the symptom score cutoff criteria. Females were significantly more likely to meet any of the symptom score cutoffs (for all criteria, p=0.0003 or less). Patients with splenomegaly, particularly spleen size of greater than 15cm below the LCM, were significantly more likely than those with a normal sized spleen to meet any of the three criteria (spleen enlargement of any size p=0.014 or less; spleen greater than 15cm p=0.0114 or less). Patients who met any of the three symptom criteria tended to have a longer MPN duration, although this trend did not meet significance. A prior history of thrombosis was not associated with achieving any cutoff criterions. Symptom burden: Individuals who met the any symptom criteria were significantly more likely to have higher DIPSS prognostic risk score (for all p=0.0002 or less). Laboratory values: For those meeting criteria for a worst symptom greater than 5, mean WBC was 11.7 vs 9.1 x 109/L (p=0.025) and platelet count was 238.7 versus 329.1 (p=0.023). For those meeting criteria for a TSS greater than or equal to 20, mean WBC was 11.8 vs 9.5 x 109/L (p=0.04). For individuals meeting both criteria, mean WBC was 11.9 vs 9.5 x 109/L (p=0.034). The presence of peripheral blasts were significantly more common in patients with an individual worst symptom score greater than 5 (p=0.0364). Hemoglobin level was not significantly associated with symptom criteria for any cutoffs. CONCLUSION: Our analysis indicates that patients who would be treated based on symptom criteria are similar to patients who would be treated based on high risk features such as high DIPSS prognostic score, concerning blood count abnormalities (i.e., leukocytosis, thrombocytopenia, presence of peripheral blasts), and splenomegaly (particularly massive splenomegaly). Thrombosis history and age were not associated with criterion cutoff assignment, and it is notable that elderly age nor history of thrombosis alone would likely alter treatment choice other than anticoagulation. This data supports that JAK2 inhibitor treatment be strongly considered in patients meeting symptom based criteria. Disclosures Dueck: Bayer: Honoraria. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Etienne:ARIAD: Speakers Bureau; Pfizer: Speakers Bureau; novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau. Harrison:Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Radia:Novartis: Honoraria; Pfizer: Honoraria. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. 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 Abstract 1736 Background: Histone deacetylase inhibition (HDACi) has shown a potent inhibitory activity on the autonomous proliferation of hematopoietic cells of PV and ET patients carrying the JAK2V617F mutation (Leukemia. 2008;22(4):740–7). Hematological responses have been recorded during treatment with the HDACi givinostat in patients with PV and myelofibrosis (Blood. 2011; 118:a1748). Additionally, combinational use of givinostat and hydroxyurea (HU) have shown encouraging clinical response in PV (Br J Haematol. 2010;150:446–55). Recent laboratory studies of vorinstat-treated JAK2V617F knock-in mice have observed normalization of peripheral blood counts, markedly reduced splenomegaly and decreased mutant allele burden (Blood 2012; 119, 3779–89). Despite this evidence of hematologic response, to date no studies have evaluated specific changes in symptom burden among PV and ET patients treated with HDACi. METHODS ET and PV patients from the UK were enrolled in a non-randomized, open-label phase II multicenter study of the HDACi vorinostat (Haematologica 2011;96(s2):a1023). Patients were asked to complete the 18 item Myeloproliferative Neoplasm Assessment Form (MPN-SAF) (Blood 2011;118:401–408), 9 item Brief Fatigue Inventory (BFI) (Cancer 1999;85:1186–1196) and 30 item EORTC QLQ-C30 (J Natl Cancer Inst 1993; 85(5):365-76) at enrollment, week 12, week 24, and week 36. From weeks 1 through 24, participants were given 400mg of vorinostat daily and were observed from weeks 24 to 36. RESULTS Participant Demographics and Mutational Status: 15 PV and 10 ET patients were enrolled in the study. Median age of participants was 65 and 48% of participants were female. JAK2 mutations were present in 5/10 (50%) of ET and 14/15 (93%) of PV patients. Change in Symptom Severity with Vorinostat: Although most symptom severity changes did not reach statistical significance likely due to the small sample size, individual symptoms of headache (mean 1.6 baseline to 0.5 wk 36, mean maximum improvement 0.5 from baseline), dizziness (mean 1.6 baseline to 0.9 wk 36, mean maximum improvement 0.6 from baseline), sad mood (mean 2.6 baseline to 1.9 wk 36, mean max improvement 0.2 from baseline), and bone pain (mean 2.7 baseline to 0.8 wk 36, mean max improvement 0.7 from baseline) indicated consistent reductions in severity. Change in Symptom Incidence with Vorinostat: Non-sustained reductions in symptom incidence were seen with initiation of therapy for items of dizziness (50% baseline, 43% wk12, 55% wk 24, and 38% wk 36), numbness (65% baseline, 38% wk 12, 36% wk 24, 63% wk 36), sad mood (55% baseline, 47% wk 12, 40% wk 24, 50% wk 36), and itching (65% baseline, 50% wk 12, 40% wk 24, 75% wk 36). Change in MPN-SAF TSS Score with Vorinostat: Overall, MPN-SAF TSS did not vary significantly for the cohort over the course of the study (score change −.4 week 12, −0.5 week 24, −1.2 week 36, Figure 1). However, 9/17 participants who had a TSS of at least 6 at baseline had an overall improvement of at least 6 points (a moderate improvement) on at least one assessment after baseline. Of these, 5 of those 9 participants had an improvement of at least 10 points, which constitutes a large improvement in symptom burden based on a distributional definition of clinical significance using the standard deviation from a previous cohort. CONCLUSION This study represents the first analysis of symptom burden among PV and ET patients receiving vorinostat to date. In addition to previously identified changes in clinical and hematologic response, reductions in symptom burden including QOL and fatigue were observed in patients receiving vorinostat therapy which was most noticeable in patients with high baseline burden. The toxicity profile of vorinostat also suggests that better results might have observed if individualized assessment of clinicohematological responses including an integrated a marker for response into daily clinical practice and tailoring pharmacotherapy based on side effect profile (Leukemia. 2012;26(5):1148–9). Although further investigation among larger cohorts is needed, preliminary data is encouraging for successful therapeutic use of vorinostat in a clinical setting and with possible combinational therapy to reduce symptom burden among PV and ET patients. Disclosures: Harrison: Novartis: Honoraria, Research Funding, Speakers Bureau; YM Bioscience: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Shire: Honoraria, Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; Sanofi: Research Funding; NS Pharma: Research Funding; YM Bioscience: Research Funding.