Vannucchi, Alessandro M.

Introduction: Approximately two-thirds of patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis (MF) have anemia, many of whom require red blood cell (RBC) transfusions. In this heavily transfused population there are severely limited treatment options; effective treatment for anemia in MF is a critically unmet medical need. Luspatercept is a first-in-class erythroid maturation agent which binds to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. Here we report the interim results of the ongoing open-label, phase 2 trial evaluating luspatercept in patients with MF and anemia. Methods: Seventy-four patients with MF and anemia were enrolled, including 41 not receiving concomitant ruxolitinib at study entry who received either no RBC transfusions (n = 20; Cohort 1) or 2-4 RBC U/28 d in the 12 wks prior to treatment (n = 21; Cohort 2). Thirty-three enrolled patients were receiving a stable dose of ruxolitinib for at least 16 wks, of which 14 were not receiving RBC transfusions (Cohort 3A) and 19 were (Cohort 3B). Patients in Cohorts 3A and 3B received a median dose of ruxolitinib of 20 mg/d (range, 5-50 mg/d) for a median of 41 and 43 wks, respectively. Patients received luspatercept every 21 d at a starting dose of 1.0 mg/kg in doses escalating up to 1.75 mg/kg. The primary endpoint in patients not receiving transfusions was a hemoglobin (Hb) increase ≥ 1.5 g/L at every assessment from baseline for ≥ 12 consecutive wks, within the first 24 wks on study. In patients receiving RBC transfusions, the primary endpoint was RBC transfusion-independence (RBC-TI) for ≥ 12 consecutive wks, within the first 24 wks on study. Additional endpoints included proportion of patients achieving mean Hb increase ≥ 1.5 g/dL in Cohorts 1 and 3A, and ≥ 50% decrease in RBC transfusions (minimum 4 RBC U decrease from baseline) in Cohorts 2 and 3B, with both responses lasting ≥ 12 consecutive wks, within 24 wks of study entry. Intent-to-treat (ITT) data were analyzed as of May 10, 2019. Results: Median age was 71 y (range, 50-88 y) and 42 (57%) were male. Median interval from MF diagnosis to study entry was 3.3 y (range, 19 d-13.5 y). Seven patients were Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, 58 were intermediate-2, and 8 were high risk. Median Hb concentration at study entry was 8.8 g/dL (range, 6.7-9.8 g/dL) for Cohort 1 and 8.6 g/dL (range, 6.7-9.1 g/dL) for Cohort 3A. Patients in Cohort 2 received a median of 2.7 RBC U/28 d (range, 1-5 U/28 d) and patients in Cohort 3B received a median of 2.3 RBC U/28 d (range, 2-4 U/28 d). Patients received a median of 8 cycles of luspatercept (range, 1-24 cycles). Efficacy data are displayed in the Table, per ITT data. Two of twenty (10%) and 3/14 (21%) patients in Cohorts 1 and 3A, respectively, achieved an absolute Hb increase ≥ 1.5 g/dL at every measurement from baseline over any consecutive 12 wks. Two of twenty-one (10%) and 6/19 (32%) patients in Cohorts 2 and 3B, respectively, achieved RBC-TI over any consecutive 12 wks. Median duration of Hb response was 20 wks (range, 12-27 wks) in Cohort 1 and 12 wks (range, 12-13 wks) in Cohort 3A. Median duration of RBC-TI was 23 wks (range, 16-31 wks) in Cohort 2 and 32 wks (range, 12-65 wks) in Cohort 3B. Three (15%) and 8 (57%) patients in Cohorts 1 and 3A, respectively, achieved a mean Hb increase of ≥ 1.5 g/dL. Eight (38%) and 10 (53%) patients in Cohorts 2 and 3B, respectively, achieved a ≥ 50% reduction in RBC transfusion burden from baseline. Ruxolitinib exposure remained stable throughout the 24-wk treatment period in both Cohorts 3A and 3B. There was no difference in spleen size between responders and non-responders. Four (5%) patients had grade 3-4 treatment-related adverse events (AEs). There were no treatment-related deaths. Treatment-related AEs occurring in ≥ 3% of patients were hypertension (11%), bone pain (8%), and diarrhea (4%). Seven (9%) patients had ≥ 1 AE resulting in treatment discontinuation; 23 (31%) remain on study. Conclusions: The initial results from this ongoing study suggest clinically significant activity of luspatercept in patients with MF-associated anemia, including those receiving concomitant ruxolitinib. A minority of AEs were grade 3-4 in severity, consistent with previous studies in MDS and beta-thalassemia. Disclosures Gerds: CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding. Vannucchi:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Gotlib:Celgene Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Promedior: Consultancy, Research Funding; Kartos: Consultancy, Honoraria, Research Funding; CTI Biopharma: Research Funding. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees. Mead:Celgene: Consultancy, Research Funding; CTI: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy; Pfizer: Consultancy. Harrison:Sierra Oncology: Honoraria; Gilead: Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Promedior: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau. Mesa:Shire: Honoraria; Promedior: Research Funding; Genotech: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; LaJolla: Consultancy; AbbVie: Research Funding; NS Pharma: Research Funding; CTI: Research Funding; Gilead Sciences: Research Funding; Samus: Research Funding; Baxalta: Consultancy; Galena Biopharma: Consultancy; Celgene Corporation: Research Funding; Sierra Oncology: Consultancy; PharmaEssentia: Research Funding; Genentech: Consultancy; Pfizer: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Incyte: Other: travel, accommodations, expenses, Research Funding. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. Gale:Celgene Corporation: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Pariseau:Celgene Corporation: Employment. Gerike:Celgene Corporation: Employment. Zhang:Celgene Corporation: Employment, Equity Ownership. Linde:Abbott Laboratories, Inc.: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. Verstovsek:Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Roche: Research Funding; Incyte: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Summary Survival prediction in essential thrombocythaemia (ET) and polycythaemia vera (PV) is currently based on clinically‐derived variables; we examined the possibility of integrating genetic information for predicting survival. To this end, 906 molecularly‐annotated patients (416 Mayo Clinic; 490 University of Florence, Italy), including 502 ET and 404 PV, were recruited. Multivariable analysis identified spliceosome mutations to adversely affect overall ( SF3B1 , SRSF2 in ET and SRSF2 in PV) and myelofibrosis‐free ( U2AF1 , SF3B1 in ET) survival; TP53 mutations predicted leukaemic transformation in ET; “adverse” mutations occurred in 51 (10%) ET and 8 (2%) PV patients. We confirmed the independent survival effect of adverse mutations [hazard ratio (HR) 2·4, 95% CI 1·6–3·5], age >60 years (6·6, 4·6–9·7), male sex (1·8, 1·3–2·4) and leukocytosis ≥11 × 10 9 /l (1·6, 1·1–2·2), in ET, and adverse mutations (7·8, 3·1–17·0), age >67 years (5·4, 3·6–8·1), leukocytosis ≥15 × 10 9 /l (2·8, 1·8–4·2) and thrombosis history (2·0, 1·4–2·9), in PV. HR‐based risk point allocation allowed development of three‐tiered mutation‐enhanced international prognostic systems (MIPSS) which were validated in both cohorts and performance was shown to be superior to conventional scoring systems. Spliceosome mutations enhance survival prediction in ET and PV and identify patients at risk for fibrotic progression. TP53 mutations predict leukaemic transformation in ET.

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis and overactive JAK/STAT activity. The RESPONSE trial compared ruxolitinib (RUX), a JAK1/JAK2 inhibitor, with best available therapy (BAT) in patients (pts) with PV intolerant of or resistant to hydroxyurea according to modified European LeukemiaNet criteria. RUX was superior to BAT in achieving the primary endpoint (21% vs 1%; P<0.0001), and 60% of pts randomized to RUX achieved protocol-defined hematocrit (HCT) control through Wk 32 vs 20% of pts randomized to BAT (J Clin Oncol32:5s, 2014; suppl, abstract 7026). However, the actual phlebotomy rate between Wks 8−32 was only 20% in pts randomized to RUX compared with 62% in pts randomized to BAT, and 85% of pts in the RUX arm continued to receive treatment at the median 81-wk follow-up, suggesting most pts derived some benefit from RUX. Therefore, an analysis was conducted to evaluate the clinical efficacy of RUX in pts who did and did not achieve protocol-defined HCT control. Methods: Phlebotomy-dependent PV pts with splenomegaly, aged ≥18 years, and resistant to or intolerant of HU were enrolled. Pts were required to have HCT between 40%−45% 14 days prior to randomization; those who did not could enter a phlebotomy control period to achieve a HCT in this range within 14 days of randomization. Eligible pts were randomized 1:1 to RUX or BAT. BAT pts could cross over to receive RUX from Wk 32 if they had not met the primary endpoint, or after Wk 32 due to protocol-defined disease progression. The primary composite endpoint comprised HCT control and a ≥35% reduction from baseline in spleen volume (SV) at Wk 32. HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In pts who were HCT control non-responders (HCT-N) as defined by protocol, time to second phlebotomy eligibility was evaluated. For this analysis, pts without phlebotomy eligibility were excluded and phlebotomies in the first 8 wks were not considered. Patient-reported outcomes were evaluated in both HCT control responders (HCT-R) and HCT-N, including the 14-item modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the Patient Global Impression of Change (PGIC). Results: Of 222 randomized pts (RUX, n=110; BAT, n=112), most were male (RUX, 60%; BAT, 71%) and the median age (range) was similar between treatment arms (RUX, 62.0 [34.0–90.0]; BAT, 60.0 [33.0–84.0]). Although pts had a HCT between 40% and 45% within 14 days prior to randomization (with or without phlebotomy), 24% of pts had a HCT >45% on Day 1 (similar between treatment arms) illustrating that many pts have poor HCT control over short intervals of observation. RUX treatment resulted in long-term benefits on HCT levels, even in pts who did not achieve protocol-defined HCT control through Wk 32. Among the RUX HCT-R group, the probability of maintaining HCT response was 97% at 48 wks and 87% at 80 wks. Most BAT pts crossed over to receive RUX immediately after the Wk 32 visit (84% between Wks 32 and 48). In the RUX HCT-N pts, the median time to subsequent phlebotomy eligibility was 52 wks, compared with 21 wks for BAT HCT-N pts (Figure). Compared with the entire BAT group, more RUX-R and RUX-N pts had a ≥50% improvement in the MPN-SAF total symptom score at Wk 32 (RUX-N, 38%; RUX-R, 40%; BAT, 4%). Median changes from baseline at Wk 32 in key symptoms such as tiredness (RUX-N; −50%; RUX-R, −49%; BAT, −4%), itching (RUX-N, −88%; RUX-R, −97%; BAT, −2%), and night sweats (RUX-N, −100%; RUX-R, −97%; BAT, 4%) were also greater among RUX-R and RUX-N pts than BAT pts. RUX-N and RUX-R pts were also more likely to consider their symptoms to be “much improved” or “very much improved” on the PGIC compared with BAT pts (RUX-N, 57%; RUX-R, 74%; BAT, 13%). Conclusion: Among pts receiving RUX who did not achieve protocol-defined HCT control, the median time to subsequent phlebotomy eligibility was 1 year. In contrast, pts on BAT had a median time to subsequent phlebotomy eligibility of 21 wks. Furthermore, pts in the RUX arm achieved meaningful improvements in PV-related symptoms, regardless of meeting the endpoint of HCT control, while pts treated with BAT showed worsening or no improvement. Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: 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. Kiladjian: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. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), Myelofibrosis (Primary [PMF] and secondary to PV and ET [PPV-, PET-MF] and unclassified MPN (U-MPN), are associated with an increased risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT). SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites,hepatic failure and biliopathy. According to a meta-analysis MPN is the underlying cause of portal vein thrombosis (PVT) in 31.5% and Budd Chiari syndrome (BCS) in 40.9% of cases (Smalberg, 2012); a more in-depth analysis of clinical characteristics and evolution of MPN-associated SVT has been hampered by heterogeneity of cohorts comprising small number of cases. We conducted a retrospective multicenter study in patients (pts) with SVT associated with WHO2008-diagnosed MPN, with the aim to describe patient characteristics, disease course and prognostic factors with potential implications for clinical practice. Data were collected from 16 international hematologic centers in the framework of the Italian AGIMM and the IWG-MRT groups. We collected 519 cases of pts with PVT, splenic or mesenteric vein thrombosis (75.1%) and BCS (24.9%) associated with MPN. We used as comparator a cohort of 1686 controls (Ctr) represented by MPN without (w/o) SVT: 741 ET (43.9%), 684 PV (39.7%), 261 PMF (15.5%). Frequency of MPN associated with SVT was 37.8% ET (n=196), 36.8% PV (n=191), 15.4% MF (n=80), 10% U-MPN (n=52). Median follow-up was 89.9 months (mo) (range 0.5-430). For SVT vs Ctr group females were 54.5% vs 44.4% in PV (P=0.001), 68.4 vs 63.5% (p=0.13) in ET, 63.7% vs 29.1% in PMF (p<0.0001); median age at MPN diagnosis (dg) was 43.5 yr (range 12-90) vs 60.6 yr (range 12-93) (p<0.0001). Age at SVT dg was 44 yr (range 15-85). In 240 cases (46.7%) MPN and SVT dg were coincident, in 121 (23.6%) SVT occurred before MPN dg (median 26 mo, range 4-307) and in 153 (29.8%) during MPN follow up (median 68 mo, range 4-362). JAK2V617F mutation was found in 94% PV vs 94% in Ctr, 84% vs 61% ET (p<0.0001), 88.1% vs 68% PMF (p=0.006) and in 93% U-MPN. Erythropoietin-independent colonies (EEC) were evaluated in 111 SVT pts and found in 80 (72%), accounting for 38/48 PV (79%), 31/44 ET (70.5%), 9/12 PMF (75%) and 2/7 U-MPN (28.6%). At dg, SVT PV pts had lower hemoglobin levels than Ctr: median was 17.4 g/dL vs 18.5 g/dL (p<0.0001) in male, 16.9 g/dL vs 17.7 g/dL (p=0.0006) in female. A co-existing thrombophilic status was found in 38.5% SVT vs 11.8% of Ctr (p<0.0001). Recurrent SVT occurred in 12.2% of pts with a rate of 1.6% person/year (CI 1.2-2.1); risk of venous thrombosis other than SVT was increased in SVT group vs Ctr (p=0.02), with no difference for arterial thrombosis. Hemorrhage was more frequent in SVT group (32%) vs Ctr (7.2%)(p<0.0001), mainly related to esophageal varices, which were present in 66.9% of SVT pts. There was no difference in evolution to MF and acute leukemia (AL) for PV and ET pts with and w/o SVT, while risk of AL was lower in MF with SVT (p<0.00001). Overall survival was shorter in ET pts with SVT vs Ctr (p<0.0001). In PMF survival was better in SVT group (p<0.00001) and was associated with a higher proportion of SVT pts in lowest risk categories: IPSS low 65%, intermediate-1 20%, intermediate-2 10% and high 5% compared with 15%, 34%, 25% and 26% in Ctr group. At last FU, 79/519 pts (15.2%) had died; causes of death were evolution to AL (15.4%), other cancers (13.8%), disease progression without AL (10.8%), SVT (10.8%), hepatic failure and venous thrombosis other than SVT (7.7% each), heart failure and arterial thrombosis (6.2% each), hemorrhage (5.5%), renal failure and infection (4.6% each). Therapy after SVT included anticoagulation in 77%, antiaggregant in 21.2% and combination in 1.8%; 70% received cytotoxic drugs; 12.4% were treated with transjugular porto-systemic shunt. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) MPN associated with SVT correlated with younger age and female sex and might antedate the clinical phenotype in a quarter of the patients. MPN-associated SVT equally affected PV and ET, was more likely to occur in the presence of JAK2V617F or underlying thrombophilia and predicted recurrent venous but not arterial thrombosis. The apparent association of SVT with better or worse prognosis in PMF and ET, respectively, requires further investigation. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Thrombotic and hemorrhagic complications are commonly encountered in uncontrolled essential thrombocythemia (ET). Both anagrelide and hydroxyurea (HU) have proven efficacious in cytoreduction as well as reducing these events and remain first line therapy for most high-risk ET patients. Independent of their role in risk-reduction, little is known about how these therapies impact patient symptomatology or quality of life. In this study, we compared the clinical and symptomatic profiles of ET patients receiving HU or anagrelide against patients with no previous experience with these agents. Methods: Data was assessed from a prospectively collected international database of ET patients in which demographics, disease features, and ET symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. ET risk scores were calculated using the IPSET scoring algorithm (Passamonti 2012). Thrombocytopenia was defined as a platelet count <100 x 10(9)/L, anemia was defined as hemoglobin<10 g/dL and leukopenia was defined as a white blood cell count <4.0 x 10(9)/L. Associations between the MPN-SAF individual symptoms were investigated using chi-square test for categorical data and ANOVA F-test for continuous variables. Results Hydroxyurea vs. HU Naive A total of 402 ET patients with active HU use were compared to 392 ET patients with no history of HU use. Patients using HU were older (63.5 years vs. 52.3 years, p<0.001) and had a greater concentration of both high risk (24.9% vs. 11.4%, p=0.001) and intermediate risk (53.9% vs 38.4%, p<0.001) patients. They also had a higher rate of prior thrombosis (29.8% vs 11.3%, p<0.001) and leukopenia (10.1% vs. 3.0%, p<0.001). No differences were noted between gender, a history of prior hemorrhage, red blood cell transfusion requirements, or the presence of anemia/thrombocytopenia. In comparing symptom profiles, no significant differences were noted between TSS or individual symptoms with the exception of slightly more severe cough in HU patients (1.5 vs. 1.1, p=0.02, Figure 1). Anagrelide vs. Anagrelide Naive A total of 49 ET patients with active anagrelide use were compared to 794 ET patients with no history of anagrelide use. Patients using anagrelide had a longer mean disease duration (8.1 years vs. 5.8 years) and were more anemic (9.1% vs. 1.2%, p<0.001). No differences were noted between age, gender, risk scores, the presence of leukopenia/thrombocytopenia, a history of prior thrombosis or hemorrhage complications or red blood cell transfusion requirements. Additionally, there were no significant differences between TSS or individual symptom items (Figure 1). HU vs. Anagrelide A total of 402 patients currently using HU were compared to 39 patients currently using anagrelide. Overall, HU users were slightly older (63.5 years vs. 55.1 years, p<0.001) with a greater population of patients meeting high risk criteria (24.9% vs. 2.8%, p=0.002) and having a history of prior thrombosis (29.8% vs. 12.8%, p=0.02). Patients receiving anagrelide had a slightly longer disease duration (8.2 years vs. 6.0 years, p=0.0446). In comparing symptom profiles, no differences were noted in TSS or individual symptom items between cohorts. Discussion In this retrospective analysis, it does not appear cytoreduction with either HU and/or anagrelide has a significant impact on ET symptom burden despite reducing vascular events. Importantly, the higher risk scores in HU patients did not translate directly into greater patient symptomatology supporting previous studies demonstrating a poor association between these two items. Prospective trials measuring ET symptom change, in the setting of randomized trials will better quantify impact of cytoreduction on symptom burden as well as quantify impact of newer agents such as interferon or jak inhibition. Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Figure 1. Symptom Comparisons Between HU, Anagrelide and Other Therapy Disclosures Kiladjian: Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. te Boekhorst:Novartis: Consultancy; CTI Biopharma: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Background Interferons are recognized as active agents in the treatment of patients with high risk essential thrombocythemia (ET) or polycythemia vera (PV), both in the upfront setting as well as beyond. Several trials have shown high rates of hematologic and molecular responses with the use of interferons, however, data on direct comparison of interferon activity in patients with early disease in comparison to patients refractory or resistant to prior therapies, such as hydroxyurea (HU) are lacking. We conducted a controlled analysis of the activity of pegylated interferon alfa-2a (PEG) in two prospective parallel clinical trials conducted in these two unique patient populations. Methods The MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 open-label clinical trial that evaluated PEG therapy in patients with high risk PV and high-risk ET who were either refractory or intolerant (R/I) to HU by modified ELN criteria. The MPD-RC 112 trial (NCT01258856) enrolled patients with high risk ET/PV who were treatment-naïve (TN) (HU <3 months) and randomized them (1:1) to PEG or HU. All patients randomized to PEG were included in this analysis. Both protocols were conducted concurrently at the MPD-RC member institutions and utilized a similar primary endpoint of overall response rate (complete and partial response rates) by ELN Criteria at 12 months confirmed by the same blinded central review committee. Both studies utilized the same PEG starting dose of 45 mcg weekly and was titrated for response to a maximum of 180 mcg weekly. Secondary endpoints included safety information, impact on disease biomarkers, bone marrow (BM) response, and quality of life data. Results Patients ET: 39 TN and 65 R/I ET patients were available for this analysis. Median disease duration was 2.9 months in TN and 37.3 months in R/I patients. Baseline characteristics and demographics were similar in the two cohorts except lower baseline hemoglobin level in RI patients. (Table1A) PV: 43 TN and 50 R/I PV patients were included. Median disease duration was 2.5 months in TN and 54.8 months in R/I patients. Baseline characteristics only differed by lower frequency of phlebotomy rate in R/I patients. (Table1B) Baseline symptoms scores and quality of life were similar in TN and RI groups (Table 2) Response ET: CR/PR/ORR at 12 months were observed in 43.1%/26.2%/69.2% in R/I ET patients and in 43.6%/25.6%/69.2% in TN ET patients (p=0.99 for ORR). (Table 3, Figure 1) PV: CR/PR/ORR at 12 months were observed in 22%/38%/60% in R/I PV patients, and in 27.9%/58.1%/86% in TN PV patients (p=0.005 for ORR). (Table 3, Figure 1) Safety PEG was equally well tolerated throughout both treatment groups with treatment discontinuation due to adverse events occurring in 14.6% in TN patients and 13.9% in R/I patients. The mean (SD) dose of PEG was 102.7 (52.3) mcg in R/I ET patients and 128.7mcg (46.4) in R/I PV patients. For TN patients, mean dose was 85.7mcg (59.7) in ET and 93.5 mcg (44.0) in PV. Adverse events were consistent with historic reports of PEG use and the distribution of events was similar in R/I and TN patients. (Table 4) Conclusion This intention to treat response analysis included TN and R/I ET and PV patients with balanced baseline characteristics who received prospective therapy with PEG. Patients with ET had a higher overall response rate at 12 months that was equivalent in patients who were treatment-naïve and in patients who were intolerant or refractory to HU. By contrast, patients with PV who were treatment-naïve had a higher ORR than patients those intolerant or refractory to HU. We conclude that treatment with PEG is an effective therapeutic option both treatment naïve PV and ET as well as those previously treated with HU, however PEG as a second line agent is especially effective in ET patients. Disclosures Yacoub: Hylapharm: Equity Ownership; Agios: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Equity Ownership; Cara: Equity Ownership; Dynavax: Equity Ownership. Mascarenhas:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Consultancy, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding. Mesa:AbbVie: Research Funding; Samus: Research Funding; Incyte: Research Funding; Sierra Onc: Consultancy; Genotech: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; CTI Biopharma: Research Funding; La Jolla Pharma: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. McMullin:Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Italopharma: Membership on an entity's Board of Directors or advisory committees. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Mead:Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; CTI: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy. De Stefano:Alexion: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Baer:Astellas: Research Funding; Al Therapeutics: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Forma: Research Funding; Kite: Research Funding; Takeda: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Hexner:novartis: Research Funding. Rambaldi:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: 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, Other: travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support. Ritchie:Genentech: Other: Advisory board; Tolero: Other: Advisory board; agios: Other: Advisory board; Pfizer: Other: Advisory board, travel support; Celgene: Other: Advisory board; Jazz Pharmaceuticals: Research Funding; Celgene, Novartis: Other: travel support; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; Celgene, Incyte, Novartis, Pfizer: Consultancy. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy. Harrison:Promedior: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hoffman:Merus: Research Funding. OffLabel Disclosure: Pegylated Interferon Alfa-2a for in Patients with Polycythemia Vera or Essential Thrombocythemia

AbstractMyeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG‐MRT), and AIRC‐Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN‐SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN‐SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient‐years. Vitamin K‐antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN‐SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN‐SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN‐U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to‐date largest, contemporary cohort of MPN‐SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.

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. Treatments include pharmacologic approaches, phlebotomy, and bone marrow transplant. Outcome studies have historically focused on hematologic improvement and survival benefit. Few prospective studies have evaluated patient-reported symptoms and quality of life outcomes after standard therapy. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard treatments. Here we provide updated results for the prospective MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: The MEASURE trial is a prospective international cohort study evaluating responsiveness of the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) in an anticipated 480 ET, PV, and MF patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF TSS (JCO 2012) for seven consecutive days at enrollment then again for seven days between 90 days and six months later. Patients also complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. Physicians report demographic, laboratory, and clinical data. Results: Demographics To date, 340 patients have enrolled and 270 have completed both study visits. Participants include ET (60%), PV (29%), and MF (12%; including 68% primary MF, 12% post-ET, 20% post-PV) patients. Enrolled patients are 51% male. The most common therapies received prior to enrollment were aspirin (34%), phlebotomy (15%), hydroxyurea (14%), and warfarin/clopidogrel/anticoagulation (6%). The most common current MPN therapies were hydroxyurea (67%), aspirin (24%), phlebotomy (9%), and ruxolitinib (8%). Information on mutational analysis was also collected; 77% of patients have a known JAK2 V617F mutation, 3% have an MPL W515 mutation. Symptom Measures On the MPN-SAF TSS, the majority of individual symptoms assessed did not change significantly between the two assessment time points while on standard therapy. Notable exceptions were a significant decrease in weight loss (mean 2.0 vs. 1.7 on a 0=absent to 10=worst imaginable scale, p=0.005) and a significant worsening in quality of life (mean 3.6 vs. 3.8 on a 0=as good as it can be to 10=as bad as it can be scale, p=0.04). No changes were seen in other symptoms including early satiety, abdominal discomfort, night sweats, fatigue, inactivity, poor concentration, bone pain, itching, or fever. Similarly, the cumulative MPN-SAF TSS score remained stable at a mean of 24.4 over the treatment period. These findings were congruent with those observed using the EORTC QLQ-C30 instrument, with no significant changes seen in emotional, physical, role, cognitive, or social functioning. Finally, the MDASI also revealed a lack of change in either symptom severity (mean 2.7) or symptom distress (mean 3.0) scores, which remained stable over the study period. Discussion: Myeloproliferative neoplasms are associated with burdensome symptoms that significantly compromise quality of life. To date, no studies have quantified symptomatic response to standard-of-care treatments. Overall, results from the MEASURE study suggest that standard treatments have limited systematic impact on patient symptomatology over time, with no improvements in overall quality of life. However, we note the relatively low proportion of patients in this cohort treated with ruxolitinib, which has been shown previously to improve symptom burden, and this may have impacted the symptom responses seen in the group as whole; detailed responses by treatment and MPN subtype will be presented. Figure. Figure. Disclosures Dueck: Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Tam:Janssen: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding. Radia:Novartis: Speakers Bureau; Blueprint: Consultancy. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; NS Pharma: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy.

Abstract Background : Survival prediction in essential thrombocythemia (ET) and polycythemia vera (PV) is currently based on clinically-derived risk variables, including age, thrombosis history and leukocyte count (Blood. 2012;120:1197; Leukemia. 2013;27:1874). We have previously reported on the prognostic contribution of mutations, in both ET and PV (Blood Adv. 2016;1:21). The current study examines the possibility of integrating genetic and clinical information for predicting overall (OS), leukemia-free (LFS) and myelofibrosis-free (MFFS) survival in ET and PV. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA and the University of Florence, Florence, Italy, based on availability of next-generation sequencing (NGS)-derived mutation information. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). NGS-detected coding region variants were filtered through the Exome Aggregation Consortium (ExAC) database and annotated by the Catalogue of Somatic Mutations in Cancer (COSMIC) database as mutants or variants of uncertain significance (VUS). Conventional statistics was employed for outcome analysis and assessment of model performance. Results: 906 molecularly-annotated patients (416 from Mayo and 490 from Florence), including 502 ET and 404 PV cases, were included in the current study. The Mayo/Florence cohorts included 270/232 ET (median age 57/54 years, 60%/59% females) and 146/258 PV (median age 63/58 years, 52%/44% females) patients; median follow-up was 9.9/12.9 years for ET and 10.7/12.4 years for PV; during this time 39%/38% deaths and 4.4%/6.5% leukemic and 16%/33% fibrotic progressions were documented for ET, with the corresponding figures for PV being 50%/26%, 4.8%/3% and 13%/36%. Cytogenetic information was available in 84%/63% ET and 80%/49% PV cases in the Mayo/Florence cohorts. In both Mayo and Florence cohorts, multivariable analysis of mutations identified primarily spliceosome mutations to adversely affect OS (SF3B1 and SRSF2 in ET and SRSF2 in PV) and MFFS (U2AF1 and SF3B1 in ET); in addition, TP53 mutations was associated with leukemic transformation in ET, in both patient cohorts. Other mutations with independently significant contribution, validated in one but not both cohorts, included EZH2 (OS and LFS in ET), IDH2 (OS and LFS in PV) and RUNX1 (LFS in PV and ET). For the purposes of the current study, mutations considered "adverse" for subsequent analysis and development of prognostic models required validation in both Mayo and Florence cohorts. Age-adjusted, all-inclusive multivariable analysis of genetic and clinical variables identified the following as independent risk factors for OS, in both Mayo and Florence cohorts: ET ─ SRSF2/SF3B1 mutations, age >60 years and male sex; PV ─ SRSF2 mutations, age >67 years and leukocyte count ≥11 x 109/l. In addition, multivariable analysis flagged leukocytosis in ET (Florence cohort only) and abnormal karyotype in PV (Mayo cohort only) as additional factors. Development of mutation-enhanced international prognostic systems for ET and PV In order to optimize the number of informative cases, the two Mayo and Florence databases were subsequently combined and subjected to multivariable analysis that confirmed the independent survival effect, in ET, of SRSF2/SF3B1 mutations (HR 2.8, 95% CI 1.8-4.3), age >60 years (HR 6.7, 95% CI 4.8-9.4) and male sex (HR 1.8, 95% CI 1.4-2.4) and, in PV, of SRSF2 mutations (HR 7.0, 95% CI 2.3-17.4), age >60 years (HR 5.7, 95% CI 3.3-10.1), and leukocyte count ≥11 x 109/l (HR 2.4, 95% CI 1.5-3.9); the combined analysis also flagged independent prognostic contribution from abnormal karyotype in PV (HR 2.1, 95% CI 1.1-3.6). HR-weighted risk point allocation resulted in new, mutation-enhanced 4-tiered risk models for ET (MIPSS-ET based on mutations, age and sex; figure 1a) and PV (MIPSS-PV based on mutations, karyotype, leukocyte count and age; figure 1b). Both models displayed high predictive accuracy and were internally validated by bootstrapping. The combined analysis also confirmed the impact of TP53 mutations on LFS (figure 1c) and U2AF1/SF3B1 mutations on MFFS (figure 1d), in ET. Conclusions: Spliceosome mutation information enhances survival prediction in ET and PV and identifies those at risk for fibrotic progression. TP53 mutations predict leukemic transformation in ET. Disclosures No relevant conflicts of interest to declare.