Abstract: Introduction. Blast phase (BP) is the terminal and most incurable phase of myelofibrosis (MF) and occurs in a not negligible fraction of patients (pts). In the pre-ruxolitinib (RUX) era, peripheral blasts, thrombocytopenia, unfavorable cytogenetics, and high risk category were identified as predictors of BP. RUX is the standard of care for symptomatic MF; however, information on clinical/laboratory correlates of BP in RUX-treated pts is not available. Aims. The primary objective of the study is to assess real-world data on incidence, risk factors and outcome of BP in RUX-treated MF pts. Methods. A multicentre observational retrospective study on RUX-treated MF pts was conducted in 20 European Hematology Centers. Data were extracted from an electronic database that included consecutive pts treated with RUX from June 2011. Data cut-off was June 2019. Risk category was assessed at RUX start according to the Dynamic International Prognostic Score System (DIPSS) or the Myelofibrosis Secondary to PV and ET Collaboration Prognostic Model (MYSEC-PM) in pts with post-Polycythemia Vera (PV)/post-Essential Thrombocythemia (ET) MF (secondary MF, SMF). A time-to-event (BP) analysis was conducted with Fine & Gray model with death/time of stem cell transplant as competing risks. Variables tested for association with BP were: age≥65yr, sex, transfusion-dependency, PLT 〈 150x109/l, peripheral blasts ≥3%, marrow fibrosis grade, CALR-unmutated genotype, unfavorable karyotype, spleen length (≥10 cm), total symptoms score (≥20), previous hydroxyurea (HU), alkylating agents, and interferon (IFN) use, time from MF diagnosis to RUX start, and PV/ET duration. Cumulative Incidence Function among risk categories for DIPSS and MYSEC-PM was calculated applying the Gray's model. Results . Overall, 589 MF pts were included and observed for 1833 pt-yrs from RUX start (median, 35.4 mos). Diagnosis was PMF in 304 pts (51.6%), PPV-MF in 164 pts (27.8%) or PET-MF in 121 (20.6%); 58.4% males. Molecular status was: JAK2V617F (82.5%), CALR (11.3%) and MPLW515K/L (1.1%); 5.1% were triple negatives. Overall, 368 (62.5%) pts received ≥1 cytoreductive therapy before RUX, specifically: HU, n. 357; alkylating agents, n. 47; anagrelide, n. 33; and IFN, n. 29. Median time from MF diagnosis to RUX start was 1.3 yrs. DIPSS for the whole cohort was: INT-1 (52.9%), INT-2 (40.1%), and HIGH (7%). DIPSS distribution in PMF pts was: INT-1 (47.8%), INT-2 (45.7%), and HIGH (6.5%), while SMF pts were categorized at LOW (11.1%), INT-1 (43.1%), INT-2 (31.2%) and HIGH (14.6%) risk according to the MYSEC-PM. Overall, 65 (11%) developed BP. In 61 pts, BP caused RUX withdrawal after a median time of 1.2 yrs (0.7-6.2); in 4 pts BP occurred after RUX stop (median time: 2.4 yrs). BP incidence rate was 3.6 x100 pt-yrs and was comparable in PMF and SMF (p=0.1). In univariate analysis, the probability of BP evolution for the PMF cohort was significantly reduced by previous IFN use (p=0.001). In SMF, predictors for BP in univariate analysis were PLT 〈 150 x109/l (p=0.001), blasts ≥3% (p=0.002), grade 3 marrow fibrosis (p=0.03) and PV/ET duration ≥ 10 yrs (p=0.02); previous IFN significantly reduced the risk of BP (p=0.02). In multivariable analysis, PLT 〈 150 x109/l (HR 2.4, 95% CI 1.1-5.4, p=0.03), blasts ≥3% (HR 3.3, 95% CI 1.4-7.5, p=0.004) and previous IFN (HR 0.1, 95% CI 0.02-0.8, p=0.04) remained significant. High DIPSS risk significantly predicted BP in PMF (p=0.04, HR [95% CI]: 2.6 [1.1-6.5] ) but not in SMF (p=0.40). In this latter cohort, only the MYSEC-PM was associated with BP (p=0.02, HR 1.7 [95% CI]: [1.1-2.8] ) (Fig.1). Estimated HRs, in reference to the lower score category, were: 1.10 for INT-1, 1.82 for INT-2, and 4.04 for HIGH risk. HR for HIGH risk, comparing to all lower risk groups, was 3.53 (95% CI: 1.53-8.11). Overall, 54 (81.8%) BP pts died and median survival was 2.8 mos. Survival after BP was not influenced by type of MF, previous response to RUX, and type of salvage treatment. Conclusions. Thrombocytopenia and peripheral blasts at RUX start identified pts at higher risk of BP in SMF, while previous IFN use was associated with reduced BP evolution in both PMF and SMF, suggesting a possible disease-modifying action of this agent. Also, this analysis supports the ability of MYSEC-PM in predicting BP in pts with SMF. Despite RUX use, outcome after BP remained dismal, confirming the need for newer treatment strategies. Disclosures Palandri: Novartis: Consultancy, Honoraria. Breccia:Incyte: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Tiribelli:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Benevolo:Novartis Pharmaceuticals: Consultancy. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Iurlo:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Sgherza:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Isidori:Janssen: Honoraria; Novartis: Honoraria; Gilead: Honoraria. Heidel:Novartis: Consultancy, Research Funding; Celgene: Consultancy; CTI: Consultancy. Latagliata:Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Trawinska:Novartis: Consultancy, Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Cuneo:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo:takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria. Palumbo:Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Hospira: Honoraria; Teva: Honoraria.

Abstract: Introduction: Hydroxyurea (HU) is the recommended treatment in patients (pts) with polycythemia vera (PV) at high thrombotic risk. In 2013, European LeukemiaNet (ELN) guidelines defined criteria for response to HU including hematology and clinical parameters (Barosi G, Blood 2013). Yet, estimates of ELN response rates and of their influence on clinical outcomes are lacking. Methods: The "PV-NET" is a European multicentre observational clinical study including now 530 cases of PV followed in 16 European Hematology Centers. Inclusion criteria are: 2016 WHO diagnosis of PV; availability of clinical/laboratory data at diagnosis and during follow-up; age≥18 yrs. Data cut-off was June 2019. A time-to-event (thrombosis, hemorrhage, evolution into blast phase [BP] or myelofibrosis [MF] ) analysis was calculated from HU start with Fine & Gray model with death as competing risk. Overall survival (OS) was calculated from HU start to last contact/death (log-rank p). Response to HU was defined per ELN criteria: Complete (CR): Hematocrit (Hct) 〈 45% without phlebotomies (PHL) & PLT ≤400×109/L & WBC ≤10×109/L & normal spleen size & no PV-related symptoms; Partial (PR): Hct 〈 45% without PHL or response in 3/4 criteria. Results: Overall, 438 required HU and were observed for 3069 pt-yrs. Characteristics at diagnosis were: median age: 62.3 yrs (22.3-89.5); males: 52.5%; median (range) WBC/PLT count, x109/l: 10.8 (1.1-33)/490 (143-1070); median hemoglobin (g/dl)/Hct (%): 18.6/56 (males); 17.6/54.7 (females); 56 (12.8%) and 30 (6.9%) pts had a thrombosis prior to or at diagnosis, respectively. Overall, 327 (74.7%) pts reported at least one PV-related symptom and 166 pts (37.9%) had a palpable spleen (≥10 cm: 8.4%). Median time from diagnosis to HU start was 2.9 (0.07-238) mos. At HU start, 350 (79.9%) pts were at high thrombotic risk. HU was used first-line in 426 (97.3%) pts and second-line in 12 pts (10 pts after interferon). Median HU dose was 0.5 g/d (0.25-2); 21.7% of pts received ≥ 1 g/d. After HU start, 36 pts presented 50 all-grades thromboses (arterial: 50%; grade ≥3: 51.1%), for an incidence rate of 1.6 per 100 pt-yrs (grade ≥3: 0.7). Thromboses were: deep/superficial vein thrombosis (32%/10%), acute myocardial infarction (12%), stroke (10%), transient ischemic attack (12%), spleen infarction (12%), retinal artery occlusion (4%), pulmonary embolisms (6%), and one splanchnic vein thrombosis. Thirteen bleedings (gastrointestinal: 61.5%; mucocutaneous: 30.8%; one hemothorax) occurred in 11 pts, for an incidence rate of 0.5 (grade ≥3: 69.2%). Overall, 12 progressions to BP and 29 MF evolutions were recorded (incidence rates: 0.5 and 1.3 X 100 pt-yr); 31 pts died. At the time of best response to HU, 62.3% of pts had at least one elevated hematology value; 231 (52.7%) pts continued PHL during HU (median PHL per yr: 2.5 [1-4]) (Fig.1). Per ELN criteria, 125 pts (28.6%) and 228 (52%) achieved a CR and PR, respectively, while 85 (19.4%) had no response (NR). The type of ELN response to HU (CR vs PR vs NR) did not affect the probability of thrombosis (p=0.56), hemorrhages (p=0.70), evolution to BP (p=0.60) or MF (p=0.14), and OS (p=0.37). After a median follow-up from HU start of 4.2 yrs, 95 (21.7%) patients discontinued HU. The percentage of pts who discontinued HU was 8.4%, 16.2% and 19.4% at 5, 10 and 15 yrs and was significantly lower in CR pts compared to pts with PR and NR (p=0.02). The overall HU discontinuation rate was 4.1 per 100 pt-yr. Reasons for HU discontinuations were: failure to control hct and/or leucocytosis and/or thrombocytosis (16.9%), failure to reduce splenomegaly and/or symptoms (7.4%), MF (12.6%) or BP (4.2%) evolution, second neoplasia (4.2%). A total of 52 pts (54.7%) discontinued due to HU-related toxicity, specifically: skin lesions (46.3%), oral aftosis (14.6%), gastrointestinal disorders (12.2%), fever (9.8%), thrombocytopenia (9.8%), and anemia (7.3%). Survival was not influenced by HU discontinuation (p=0.50). Conclusions: ELN-defined CR was rarely achieved by HU-treated pts, mainly due to low HU doses and PHL requirement, and did not influence outcome parameters. These data outline the relatively low utility in the current clinical practice of ELN criteria for the evaluation of HU treatment; their implementation would be relevant to base therapy changes on prognostic considerations. Finally, around 20% of pts discontinued HU, confirming that there is room for improvement in PV treatment strategy. Disclosures Palandri: Novartis: Consultancy, Honoraria. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Benevolo:Novartis Pharmaceuticals: Consultancy. Tiribelli:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Palumbo:Novartis: Honoraria; Teva: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Hospira: Honoraria. Heidel:Novartis: Consultancy, Research Funding; Celgene: Consultancy; CTI: Consultancy. Crugnola:Incyte: Honoraria; Novartis: Honoraria. Cuneo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Breccia:Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cavo:sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latagliata:Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Novartis: Honoraria.

Abstract: Introduction . The 2016 WHO criteria identified early primary myelofibrosis (early-PMF) as an individual entity with different clinical/laboratory presentations and a significantly better outcome compared to overt PMF. No information is available on the therapeutic effects of ruxolitinib (RUX) in the context of each disease separately. Aims . To report the differences between early and overt PMF patients (pts) treated with RUX in terms of baseline clinical/laboratory characteristics, response to treatment and toxicity. Methods . A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. Hematologic toxicity and infections were graded according to the WHO scale. Overall survival (OS) and progression-free survival (PFS) were estimated from diagnosis using the Cox proportional hazards regression model, with adjustment for the dynamic international prognostic score system (DIPSS) and left-truncation. Results . A total of 199 pts had a diagnosis of early (n. 59, 29.7%) or overt (n. 140, 70.3%) PMF confirmed by bone marrow biopsy at RUX start and were included in this analysis. At RUX start, median age was 68.4 yrs (26.5-88.9) and 66.3% of pts had a spleen palpable at ≥10 cm below the left costal margin (LCM) (median spleen length: 12 cm). Median hemoglobin value and total symptoms score (TSS) were 10.5 g/dL and 20 (0-80), respectively. DIPSS distribution was: intermediate-1 (50.5%), intermediate-2 (42.1%), high (7.4%). Molecular status was: JAK2V617F 72.3%, CALR 13.7%, MPLW515K/L 3.1%, triple-negative 5%. Median time from diagnosis to RUX start was 22.4 mos (0.1-394). Compared to overt PMF pts, pts with early PMF started RUX with higher hemoglobin levels (median, 11.6 vs 10.4 g/dl, p=0.01) and lower circulating blast counts (p 〈 0.001), and were more frequently at intermediate-1 DIPSS risk (69.6% vs 42.5%, p 〈 0.001). RUX starting and 12-weeks titrated doses were comparable in the two groups. At 3 and 6 months, 43.1% and 48.9% of early-PMF pts achieved a SR, compared to 27.9% and 31.3% of overt-MF pts (p=0.04 and p=0.04, respectively). The rate of SyR was also higher in early-PMF pts at 3 months (82.5% vs 68.8%, p=0.05) and at 6 months (90.0 vs 73.7, p=0.02). In the first 12 months from RUX start, anemia/thrombocytopenia of all grades occurred in 75.6%/43.1% and 86.3%/60.0% of early and overt PMF pts, respectively (p=0.11 and p=0.03). At 3 months, anemia was more frequent in overt PMF pts (94.7% vs 80.0%, p=0.01), with 32.6% of pts having a grade 3-4 anemia compared to 17.8% in early PMF (p=0.02). The incidence of thrombocytopenia was also higher in overt PMF at 3 (51.5% vs 36.2%, p=0.05) and 6 (52.9% vs 35.8%, p=0.04) months, with only 2.2% and 2.5% of pts having a grade 3-4 thrombocytopenia, respectively. Seventy-five pts had at least one grade ≥2 infectious episode during RUX therapy. Considering death as competing risk, the cumulative risk of infections grade ≥2 was comparable in the two cohorts (p=0.4). Overall, 108 pts discontinued RUX (52.5% and 55.0% of early and overt PMF pts, p=0.7). Evolution into acute leukemia (AL) occurred in 21 pts. After a median follow-up of 23 months, 69 pts died (19 early), specifically because of progression of myelofibrosis (38%), AL (16.9%), infections (11.3%), hemorrhage/thrombosis (12.6%), second neoplasias (8.5%) or transplant-associated toxicity (2.8%), other causes (9.9%). OS (p=0.88) and PFS (p=0.86) were comparable in early and overt PMF pts. Conclusions . This study indicates for the first time that early PMF represents a category of pts that is projected to have better responses and lower toxicities from RUX treatmemt. In the setting of RUX therapy, a WHO-defined diagnosis may contribute to better identify pts who may deserve a strict monitoring during treatment. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palumbo: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. Abruzzese:BMS: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Foà:INCYTE: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Vitolo:Takeda: Speakers Bureau; Janssen: 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, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Sandoz: Speakers Bureau. Aversa:Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: 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, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria.

Abstract: Introduction Hydroxyurea (HU) is worldwide used in the current clinical practice as first line treatment in high risk patients with Polycythemia Vera (PV). However, its efficacy has been seldom evaluated in the real-life setting. Aims The present study aims to address the role of Complete Peripheral Recovery (CPR) as useful response criteria in PV patients treated with HU in a large cohort of unselected patients. Methods After IRB approval, data of 846 PV patients, revised according to WHO2008/2016 and followed in 21 European Hematology Centers, were retrospectively collected. Definition of CPR during HU treatment included all the following criteria: hematocrit (Ht) level ≤45% (≤3 phlebotomies per year allowed), white blood cells (WBC) count ≤10 x109/l, platelets (PLT) count ≤ 400 x109/l. Spleen size and symptoms were not considered in the definition of CPR. Event-free survival (EFS), considering as event evolution into blast phase (BP) or myelofibrosis (MF) and death from any cause, was calculated from HU start to last contact/event by Cox analysis with age≥70y. Overall survival (OS) was calculated from the start of HU to last contact/death (log-rank p). Results Among the 846 patients of the entire cohort, 724 (85.5%) were treated with HU after a median time from PV diagnosis of 2.6 months [interquartile range (IQR) 0.5 - 19.6]: the main clinical features of these 724 patients at diagnosis are reported in the Table 1. Starting doses of HU, available in 709 patients, were & lt;500 mg/day in 42 (5.9%), 500 mg/day in 371 (52.3%), 750 mg/day in 39 (5.5%), 1000 mg/day in 219 (30.9%) and & gt;1000 mg/day in 38 (5.4%). Twenty-five patients were not evaluable for response to HU. Among the remaining 699 patients, 426 (60.9%) achieved a CPR after a median time from HU start of 4.9 months (IQR 2.1 - 15.7) while 273 (39.1%) never achieved a CPR. Among the 426 patients who achieved CPR, 115 (26.9%) needed a treatment period & gt;12 months before obtaining the CPR. The main baseline clinical features of patients achieving or not CPR are reported in the Table 1: female sex, older age at diagnosis and at HU start, lower WBC count, no phlebotomies need and no palpable spleen were all associated in univariate analysis with CPR achievement. During HU treatment, a thrombotic episode occurred in 36 patients achieving CPR (8.4%) compared to 16 patients without CPR (5.8%) (p=0.162). Among 426 patients achieving CPR, 20 (4.6%) evolved in MF and 10 (2.3%) evolved in BP: among 273 patients without CPR, 20 (7.3%) evolved in MF and 9 (3.3%) evolved in BF (p=0.134 and 0.451, respectively). Ten-year EFS was 79.2% [95%Confidence Interval (CI) 72.1 - 84.8] in patients achieving CPR compared to 67.3% (95%CI 56.9 - 75.7) in patients without CPR (p=0.001) (Fig. 1). Ten-year OS was 80.5% (95%CI 73.9 - 87.1) in patients achieving CPR compared to 74.4% (95%CI 65.6 - 83.2) in patients without CPR (p=0.116). Conclusions In the current clinical practice, HU is effective in inducing CPR in about two thirds of patients with PV treated front-line. CPR is more frequently achieved by patients with lower disease burden, including lower WBC count, and less frequent PHL need and palpable spleen. Notably, & gt;25% of responding patients achieved CPR after & gt;12 months from HU start, suggesting the need for a long period of HU therapy before efficacy evaluation. The clinical importance of CPR is highlighted by a significantly longer EFS in patients achieving this type of response. Disclosures Breccia: Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Heidel:Novartis: Consultancy, Honoraria, Research Funding. Crugnola:Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria. Pane:AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: 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, Speakers Bureau. Cuneo:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Semenzato:Abbvie: Honoraria; Roche: Honoraria; Takeda: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri:Novartis: Consultancy, Honoraria.

Abstract: Introduction . Ruxolitinib (RUX) is the only targeted therapy available for the treatment of myelofibrosis (MF)-related splenomegaly and symptoms. Significant clinical responses may be achieved in around 50% of patients (pts). However, half of responding pts lose the response over time. Aims . To report the outcome of a large cohort of MF pts after RUX failure, in terms of disease status, treatment strategies and survival. Methods . A clinical database was created in 23 European Hematology Centers including retrospective data of 537 MF pts treated with RUX from Jan 2011 to July 2018. Updated information at the date of July 15th 2018 was available in 442 pts who were included in the present analysis. Spleen and symptoms response (SR & SyR) to RUX were evaluated according to the 2013 IWG-MRT criteria. RUX-related toxicity and infections were graded according to the WHO scale. Overall (OS) was estimated from the date of RUX discontinuation to the date of death or last contact, using the Kaplan-Meyer method (log-rank test). Results . After a median follow-up of 30.5 months (1.7-84.3), 214 out of 442 evaluable (48.4%) pts had discontinued RUX. 43 (20.1%) died while on therapy because of: MF progression (34.9%), infections (25.6%), heart disease (16.3%), second neoplasia (7%), hemorrhages (7%), other (9.2%). The median follow-up after RUX discontinuation for the remaining 171 pts was 11.3 months (0.5-66.7). Causes of RUX discontinuation were: drug-related toxicity (28.6%), loss/lack of response (23.4%), MF progression (12.3%), acute leukemia (AL) (13.4%), allogeneic stem cell transplantation (ASCT) (11.1%), second solid neoplasia (4.1%), other unrelated causes (i.e. pts decision; 7.1%). After stopping RUX, 68 pts received 1 line of therapy, 21 received 2 lines and 9 received 〉 2 treatments; 73 pts did not receive any therapy. Treatments received after RUX discontinuation, alone or in combination, included hydroxyurea (HU) (n. 61, 62.2%), ASCT (n. 20, 20.4%), second-generation JAK2 inhibitors (momelotinib/fedratinib/pacritinib) (n. 11, 11.2%), splenectomy (n. 7, 7.1%), azacytidine/decitabine (n. 5, 5.1%), chemotherapy (n. 4, 4.1%), investigational agents (imetelstat/PRM151: n. 4), danazole (n. 4), erythropoietin-stimulating agents (ESA) (n. 4). A total of 95 pts (55.6%) died after RUX discontinuation, because of: MF progression (30.5%), AL (25.4%), infections (14.7%), second neoplasia (9.5%), hemorrhages (4.2%), heart disease (4.2%), ASCT (4.2%), thrombosis (2.1%), other (5.2). Median survival time from RUX stop of the 171 evaluable pts was 22.6 mos (95% CI, 13.2-30.7). Among baseline features, survival after discontinuation was significantly influenced by the dynamic international prognostic score (DIPSS) category (p 〈 0.001), transfusion dependency (p 〈 0.001) and driver mutation status (with triple-negative pts having the worst survival compared to JAK2V617F and CALR-mutated pts, p=0.01). During therapy, 45 out of 153 (29.4%) and 123 out of 161 (76.4%) evaluable pts achieved a SR and a SyR at any time. Survival was not affected by the previous response to RUX at any time-point. Conversely, survival significantly differed according to the reason for stopping RUX, with pts discontinuing because of AL evolution/second solid neoplasia having the worst outcome (Figure 1a, p 〈 0.001). In pts who discontinued RUX in chronic phase, the use of second generation TKIs and other investigational agents tended to prolong survival compared to the administration of conventional medical treatments (i.e. HU, danazole, ESA) (Figure 1b, p=0.07) Discussion . After RUX failure, very limited therapeutic options are available and the prognosis of MF pts is dismal, particularly for those pts starting RUX with advanced stage disease (i.e. high DIPSS category and transfusion dependency). Also, disease evolution into AL and occurrence of a second solid neoplasia significantly reduced life expectancy. In chronic phase pts, survival probability may be improved by the use of medical therapies that are still in the experimental phase. Novel investigational agents are needed. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: 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, Research Funding, Speakers Bureau. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; NOVARTIS: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau. Di Raimondo:Celgene: Honoraria; Takeda: Honoraria, Research Funding. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo: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.

Abstract: Background: Comorbidities and body mass index (BMI) are significantly associated with outcome in patients (pts) who receive continue treatment with tyrosine kinase inhibitors (TKIs), such as in Ph+ leukemias. Ruxolitinib (RUX) is the first JAK1/2 inhibitor that may induce spleen/symptom responses and improve quality of life in pts with myelofibrosis (MF). Up-to-date, no data are available on the impact of comorbidities and BMI on pts treated with RUX. Aims: To evaluate the impact of comorbidities and BMI on responses, overall survival (OS) and maintenance of RUX dose in a large cohort of pts. Methods: Data were extracted from an electronic database that included retrospective data on pts treated before January 2015 in 16 Italian Hematology centers. Response to RUX was evaluated according to IWG-MRT criteria. BMI was calculated at the time of start of RUX and classified according to WHO criteria. Comorbidities were recorded at the time of start of RUX and classified according to the Charlson Comorbidity Index (CCI). Overall survival (OS) was calculated from the date of RUX start to the time of death or to last follow-up, whichever came first. Results: Between June 2011 and Apr 2016, 289 pts with PMF (52.6%), or PET-MF (17%) or PPV-MF (30.4%) were treated with RUX in participating Centers. At RUX start, median age was 68.4 years (range 39-89) with a male prevalence (56.4%); International Prognostic Score System (IPSS) was intermediate (intm)-1 (15.6%), intm-2 (45.3%), high (39.1%). Transfusion dependence and spleen enlargement were present in 26.6% and 96.9% of pts, respectively (69.6% with spleen≥ 10 cm). Median total symptom score (TSS) was 20 (range 0-70). JAK2V617F was present in 80.3% of 234 evaluable pts. Median follow-up from MF diagnosis was 3.8 yr (range 0.3-29.6) and median RUX exposure was 20 months (3-56.2). Overall, comorbidities were evaluable in 275 pts. CCI stratification showed the absence of comorbidities in 100 pts (36.4%), one comorbidity in 63 pts (22.9%) and two or more in 112 pts (40.7%). Compared to pts with CCI 〈 2, pts with CCI ≥2 were more frequently: male (66.1% vs 49.1%, p=0.005), ≥65y (74.1% vs 54%, p=0.001), at intm2/high IPSS risk (90.2% vs 81%, p=0.03) and transfusion-dependent (36.6% vs 20.2%, p=0.003). Notably, the percentage of pts starting RUX 〉 2y from MF diagnosis was lower if CCI≥2 (33.9% vs 54%, p=0.001). Higher CCI did not correlate with lower spleen response (achieved by 45.2% vs 34.7%, p=0.09), TSS response (90.1% vs 83.2%, p=0.11), and higher incidence of RUX-induced anemia (Hb 〈 10 g/dl in pts with baseline Hb ≥10 g/dl) (48% vs 41%, p=0.33). RUX starting and titrated doses at 12-wks were similar in the two groups (p=0.44 and p=0.81, respectively). OS was significantly higher in pts with CCI 〈 2 (96.7% vs 87.8% at 2 yr, p 〈 0.001). After stratification according to CCI (below or above 2) and the achievement of a spleen response, both factors remained significantly associated with survival. Indeed, in pts with CCI 〈 2 OS at 2 yr was 92.7% and 79.1%, depending on the achievement of a spleen response (SR) or not (NR), respectively (p=0.034). Analogously, in pts with CCI≥2 the achievement of a spleen response significantly increased survival (79.2% vs 55.3% in pts without spleen response, p=0.011). Notably, OS was comparable in pts with lower CCI /no spleen response and in pts with higher CCI/spleen response (79.1% vs 79.2%) (Figure 1). BMI was evaluable in 269 pts: 169 pts (62.8%) were classified as under-weight/normal for a BMI 〈 25, whereas 100 pts were overweight/obese (BMI ≥25). Pts with BMI≥25 were more frequently male (71% vs 47.3%, p 〈 0.001) and with a lower incidence of anemia (30% vs 42%, p=0.049). BMI stratification did not correlate with differences in spleen response (p=0.83) and TSS (p=0.18) or onset of anemia/infections during treatment (p=0.49 and p=0.28). Starting and median doses, as well as percentage of pts reducing RUX dose over time, were similar in the two groups. Summary: In MF pts treated with RUX, BMI and comorbidities did not influence the achievement of spleen/symptom responses, maintenance of RUX dose or onset of drug-related anemia. Although CCI stratification correlated with survival, as in Ph+ leukemias treated with TKIs, the achievement of a spleen response was able to counterbalance the negative prognostic effect of a higher CCI. Consequently, higher BMI and CCI should not be regarded as contraindication to RUX therapy. Figure Figure. Disclosures Breccia: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding. Cimino:Bristol-Mayer: Honoraria; Celgene: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Abstract: Introduction: Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by excessive red cell production and release of pro-inflammatory cytokines resulting in increased thrombotic risk, presence of systemic symptoms and reduced overall survival (OS). Abnormal body mass index (BMI) and comorbidities, as categorized by the Charlson Comorbidity Index (CCI), were found to influence treatment success and survival in several hematological malignancies, including myelofibrosis (MF). We evaluated the impact of CCI and BMI on the outcome of PV pts on the basis of real-world data. Methods: A network called "PV-NET" started in January 2019 including clinical/laboratory data of 2016 WHO-defined PV pts diagnosed and followed in 16 European Hematology Centers. Data cut-off was June 2019. OS was calculated from PV diagnosis to last contact or death (log-rank p). Cumulative incidences of events (thromboses, hemorrhages, infections, second neoplasia, and evolution into blast phase [BP] or MF) were conducted with Fine & Gray model with death as competing risk. Therapies were treated as time-to-event variables. Results: A total of 530 PV pts were collected. Median follow-up was 5.4 yrs (0.5-34) (total observation: 3633 pt-yrs). Main characteristics at diagnosis were: median age: 62.4 yrs (18.3-89.5); males: 53.4%; median (range) leukocyte/platelet count, x109/l: 9.8 (1.1-33)/448 (143-1386); median hemoglobin (g/dl)/hematocrit (%): 18.6/56 (males); 17.6/54.4 (females). Sixty-four (12.1%) and 34 (6.4%) pts had a thrombosis prior to or at diagnosis, respectively. At least one cardiovascular risk factor (CVRF) among smoke, diabetes, and hypertension was present in 343 pts (64.7%). Age-adjusted CCI was 0 (15.9%), 1 (18.9%), 2 (23.8%), and ≥3 (41.5%). Median BMI was 24 (17.4-37.3); 3.3%, 51.2%, 35.9% and 9.6% were underweight (BMI 〈 18.5), normal weight (18.5-24.9), overweight (BMI≥25) or obese (BMI≥30), respectively. Baseline features were comparable across BMI and CCI categories, but male pts were significantly more likely to have a BMI≥25 than female (p 〈 0.001). During follow-up, 64 all-grades thromboses (arterial, 56.3%), 29 bleedings, 56 infections and 66 second neoplasia were recorded. Overall, 13 pts progressed to BP and 32 to MF. Thirty-three pts died, because of BP (27.3%), second neoplasia (24.2%), MF (15.2%), old age (9.1%), thrombosis (6.1%) or other causes (18.1%). Incidence rates per 100 pt-yrs of all-grades events were: 1.5 (thromboses), 0.7 (bleedings), 1.4 (infections), 1.6 (second neoplasia), 0.4 (BP) and 0.9 (MF). Pts with CCI≥2 had a significantly higher rate of second neoplasia (p=0.01) and infections (p=0.03) over time and a worse OS (p 〈 0.001) compared to pts with CCI 〈 2. A BMI 〈 25 was associated with a higher probability of MF progression (p=0.02) and with reduced OS (p=0.04) (Fig.1). Notably, thrombotic risk was not influenced by CCI (p=0.16) and BMI (p=0.43). Pts received phlebotomies (PHL) (92.1%), hydroxyurea (HU) (82.6%), interferon (IFN) (7.9%), busulfan (2.6%), and ruxolitinib (RUX) (10.9%). Pts with CCI≥2 were significantly less treated with IFN (p 〈 0.001) and received more frequently HU (p 〈 0.001); notably, CCI did not influence the decision to start RUX (p=0.41). All pts treated with IFN but two had a BMI 〉 18.5; both underweight pts discontinued IFN due to intolerance. Overall, 0.8%, 19.4%, and 38.1% of pts had grade≥2 toxicity and/or stopped therapy because of intolerance during PHL, HU, and IFN, respectively. IFN intolerance tended to be more frequent in pts with CCI≥2 (p=0.06). Conclusions: CCI and BMI are rarely assessed in PV but may influence treatment strategy and survival. Particularly, CCI/BMI oriented the choice of IFN, but not RUX. Overweight PV pts had an improved survival, mimicking the "obesity paradox" observed in non-malignant CV diseases (Elagizi, et al. 2018). However, BMI may not be a reliable measure of adiposity. In cancer pts, an under/normal-weight may mask a hypercatabolic state with lean mass loss caused by a more aggressive disease, as supported by a higher rate of MF evolutions in pts with BMI 〈 25. Quantified body composition and careful control of comorbid conditions can improve PV management, prognostication and outcome. Disclosures Benevolo: Novartis Pharmaceuticals: Consultancy. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Latagliata:Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Pfizer: Honoraria. Tiribelli:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Heidel:Celgene: Consultancy; CTI: Consultancy; Novartis: Consultancy, Research Funding. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Bonifacio:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; BMS: Honoraria. Crugnola:Incyte: Honoraria; Novartis: Honoraria. Cuneo:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Cavo:amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria. Breccia:Celgene: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Palumbo:Hospira: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Teva: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Palandri:Novartis: Consultancy, Honoraria.