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In 816 patients with 2016 World Health Organization-defined polycythemia vera (PV) enrolled in a multicenter retrospective study, we investigated the predictive value of Charlson comorbidity index (CCI) and body mass index (BMI) on thrombosis, progression to post-PV myelofibrosis (PPV-MF) and survival. Patients were subgrouped according to CCI=0 (58.1%, no comorbidities) or CCI≥1 (41.9%) and according to normal/underweight (BMI&nbsp

Comorbidities defined by the Charlson comorbidity index (CCI) and body mass index (BMI) are significantly associated with outcome in patients who receive continuous treatment with tyrosine kinase inhibitors. We evaluated the impact of CCI and BMI on responses, drug-related toxicities, and outcome in a cohort of 402 patients with myelofibrosis (MF) treated with ruxolitinib in 23 European Hematology Centers. Comorbidities were evaluable in all 402 patients. A higher (≥ 3) CCI did not correlate with a lower spleen reduction at any time (p = 0.68) or symptoms' response (p = 0.11), but influenced the onset of anemia during the first 3months of treatment and later (p = 0.02 and p = 0.03, respectively) in patients without anemia baseline. BMI was evaluable in 380 patients and did not correlate with differences in spleen and symptoms response (p = 0.57 and p = 0.49, respectively). A higher CCI and a lower BMI correlated also with a reduced overall survival (p

BACKGROUND: After ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities. METHODS: The authors performed a subanalysis of an observational, retrospective study (RUX-MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival. RESULTS: A total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX-again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX-stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX-again patients (P =.004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P 10 mg twice daily predicted better spleen (P =.05) and symptom improvements (P =.02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX-again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX-again patients (P =.004). CONCLUSIONS: Ruxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.

ObjectivesThis study compared the burden of fatigue between treatment-naïve patients with newly diagnosed acute myeloid leukaemia (AML) and the general population and investigated patient factors associated with fatigue severity.MethodsPretreatment patient-reported fatigue was assessed with the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire in a sample of 463 newly diagnosed patients with AML who were enrolled in a clinical trial. Multivariable linear regression models were used to estimate the adjusted mean differences in fatigue between patients with AML and adults from the general population (n=847) by AML disease risk categories. A clinically meaningful difference in fatigue was defined as ≥3 points. Univariable and multivariable linear regression models were used to identify sociodemographic, clinical and molecular correlates of worse fatigue in patients with AML.ResultsPatients with AML reported adjusted mean fatigue scores that were 7.5 points worse than the general population (95% CI −8.6 to −6.4, pConclusionsPatients with newly diagnosed AML reported worse fatigue than the general population, and mean differences exceeded twice the threshold for clinical significance. Our findings may help to identify patients with AML most likely to benefit from supportive care interventions to reduce fatigue.

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The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow-up from ruxolitinib start of 3 years (range 0.1-7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient-years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate-1 risk patients (2.3 vs 5.6 per 100 patient-years in intermediate-2/high-risk patients, P

Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22–4·60, P=0·01] and thrombocytosis>400×109/l at RUX start (HR:1·98, 95%CI: 1·10–4·60, P=0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24–7·92, P=0·02) and duration of hydroxycarbamide and RUX therapy>5years (HR: 3·20, 95%CI: 1·17–8·75, P=0·02 and HR: 2·93, 95%CI: 1·39–6·17, P=0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11–5·25, P=0·03), platelet>400×109/l (HR: 3·30, 95%CI: 1·67–6·50, P=0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48–8·14, P=0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.

Introduction: Ruxolitinib (Rux) has been recently approved as second-line therapy in patients (pts) with Polycythemia Vera (PV) resistant/intolerant to hydroxyurea (HU). Median age of PV pts enrolled in the pivotal Response trials was around 60 yrs; at present, no data is reported on the use of Rux in elderly pts. Aims: In a real-world cohort of PV pts treated with Rux, we investigated whether the efficacy and safety of Rux were comparable in pts who initiated therapy when aged ≥75 years compared with younger pts. Methods: After IRB approval, clinical/laboratory data of 934 WHO2016-defined PV pts followed in 29 Hematology Centers were retrospectively collected. Of them, 168 (17.9%) were considered resistant/intolerant to HU at any time during follow-up by responsible physician and shifted to Rux as second-line therapy. Results: Among the 168 pts treated with Rux, 42 (25%, median age 78.2 years) were aged ≥75 yrs at Rux start, 74 (44%, median age 67.7) were aged 60-74 and 52 (31%, median age 53) were No significant differences were observed between the 3 groups, apart from a lower need for phlebotomies in pts aged ≥75 yrs and lower presence of palpable spleen in older pts (age ≥60), that more frequently switched to Rux due to HU intolerance (Table 1). Median duration of HU treatment was 41.0 months (IQR 14.6 - 85.8), with a trend for a longer median treatment duration in pts aged ≥75 [61.0 months (IQR 21.5 - 89.6) vs 35.9 months (IQR 13.4 - 79.6), p=0.04]. Rux starting dose was similar across age groups; however, more elderly pts underwent Rux dose reductions during follow-up (45.2% in pts aged ≥75 vs 28.6% in younger pts, p=0.04). Responses during Rux therapy are reported in Table 2, with no significant differences between the 3 groups at any time. In the overall cohort, response on PV-related symptoms at 6 and 12 months was significantly higher in pts who switched to Rux because of HU intolerance; however, this difference was not observed in pts aged ≥75 yrs. As to the most common hematologic Rux-related toxicities, grade 3-4 anemia and thrombocytopenia were observed in only 2 (1.2%) and 5 (3%) pts, with no difference across age groups (p=0.45 and p=0.18). However, any grade anemia and thrombocytopenia during Rux were more frequently observed in pts aged ≥75 (68.3% vs 51.7% of anemia, p=0.06 and 12.2% vs 3.5% of thrombocytopenia in younger pts, p=0.04). Nineteen and 4 pts experienced infectious and thrombotic complications during Rux with incidence rates of 0.59 and 0.12 per 100 patient-months, respectively, comparably in younger and older (≥75) pts (p=0.75 and p=0.29, respectively). Notably, 6 infections were herpes simplex/zoster virus, comparably distributed between the 3 groups (p=0.60). Permanent Rux discontinuation was needed in 14 pts (8.3%) after a median Rux exposure of 7.8 months (IQR 4.6 - 17.6) (incidence: 0.41 per 100 pts/months). Discontinuation was comparable between age groups, with Rux stop in 4 pts aged ≥75 yrs and 10 younger pts (2.4% vs 5.2% at 8 months, log-rank p=0.75). At last follow-up, 2 pts had died (1 from 2 nd neoplasia after 19.1 months from Rux start and 1 from acute leukemia after 3.3 years), both pts aged 60-74 yrs. Conclusions. In this real-world analysis, use of Rux in HU resistant/intolerant elderly PV pts was effective and safe despite the more frequent need for dose reductions. Older age should not discourage Rux therapy, but stricter hematological monitoring may be suggested. Figure 1 Figure 1. Disclosures Latagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria. Bonifacio: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: 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; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; 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, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Background: The presence of peripheral blasts (PB) is a negative prognostic factor in patients (pts) with primary and secondary myelofibrosis (PMF/SMF) and PB ≥4% was associated with a particularly unfavorable prognosis (Masarova L et al, Cancer 2020). Ruxolitinib (RUX) is the JAK1/2 inhibitor most used for treatment of MF-related splenomegaly and symptoms. Its role has not been assessed in correlation with PB. Aims: To evaluate the impact of PB percentage on RUX efficacy and prognosis Methods: After IRB approval, the "RUX-MF" retrospective study collected 804 RUX-treated chronic-phase (CP, defined as PB Comparisons of quantitative variables between the 3 groups were carried out by Kruskal-Wallis and Dunn's tests while association between categorical variables was tested by the χ2 test. Variables significantly associated to RUX stop/leukemic transformation (LT)/overall survival (OS) in univariate analysis (Log-rank test) were considered for multivariable analyses, carried out using the Cox regression model, with evaluation of the model's performance in terms of goodness of fit. Results: Pts were categorized according to PB at RUX start: PB-0 (no PB; n. 487, 61.3%), PB-5 (PB 1-5%; n. 283, 35.8%), and PB-9 (PB 6-9%; n. 24, 2.9%). Pts characteristics at RUX start were: median age 68.1y (24-89); males 58.1%; PMF 52.5%; JAK2, CALR and MPL mutated: 80.5%, 13.1% and 2% (4.4% triple negative), high DIPSS: 7.6%; PLT25 x10 9/l: 10.8%/16.4%; spleen length ≥10 cm: 47.8%, TSS ≥20: 60.6%; ≥1/≥2 high-risk mutation (HMR): 69/18 out of 167 evaluable (41.3%/10.8%); fibrosis grade ≥2: 77.9%; starting/cumulative RUX dose ≥15 mg BID: 61.4%/52.6%. Higher PB count was associated to high DIPSS risk (PB-0: 1.9%, PB-5: 16.2%, PB-9: 21.7%, p At 3 and 6 mos, 26.9% and 30.4% of evaluable pts achieved a SR, while 59.7% and 68.1% were in SyR, respectively. At 3 mos, SR (PB-0: 31.8%, PB-5: 20.6%, PB-9: 10%, p=0.001) and SyR (PB-0: 62.9%, PB-5: 55.5%, PB-9: 36.8%, p=0.02) were less frequently achieved by PB-5 and PB-9 pts compared to PB-0 pts. This association remained significant for SR at 6 mos (PB-0: 35%, PB-5: 23.9%, PB-9: 14.3%, p=0.006) and for both SR (p=0.003) and SyR (p=0.01) at any time. After a median RUX exposure of 1.5 y (0.1-8.9), 491 (61.8%) pts stopped RUX, 110 (13.9%) had a LT and 365 (46%) died. In univariate analysis, at 2y PB-9 pts had higher rates of RUX stop (73.9% vs 40.8% and 34.3% in PB-5 and PB-0 pts, log-rank p In multivariable analysis, PB-9 pts confirmed their association with: 1) RUX stop (HR 3.74, 95%CI 1.51-3.70, p20 (HR 1.66, 95%CI 1.05-2.61, p=0.03), and HMR≥2 (HR 2.69, 95%CI 1.26-4.47, p=0.007); 2) LT (HR 3.71, 95%CI 1.71-8.04, p Conclusions: CP-MF pts with PB>5% have a worse response to RUX and a worse outcome. Personalized approaches beyond RUX monotherapy may be useful in this context. Further clinical trials evaluating combination strategies and new drugs are required. Figure 1 Figure 1. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy. Abruzzese: Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Iurlo: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Bonifacio: Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Cuneo: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau. Lemoli: Celgene: Other: Support for attending meetings and/or travel; Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau. Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, 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, EXPENSES, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: 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. Breccia: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria.

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Introduction: Hydroxyurea (HU) is the most used cytoreductive therapy (tx) for patients (pts) with polycythemia vera (PV). However, many pts may have suboptimal responses (SubOR) and/or toxicity (TOX) to HU. After HU, Ruxolitinib (RUX) may achieve hematocrit (HCT) and spleen reductions, but other tx are also available, mainly busulfan (BUS) and interferons (IFN). Aims: In a large cohort of PV pts, we investigated if: 1) type of SubOR to HU influenced subsequent tx strategy; 2) differential tx had an impact on overall survival (OS). Methods: After IRB approval, clinical/laboratory data of 2016 WHO-defined PV pts from 21 European Hematology Centers were retrospectively collected. SubOR included ≥1 of the following criteria after ≥3 mos of HU: WBC/PLT count >10/400 x109/l, need for phlebotomies (PHL); splenomegaly and/or symptoms persistence/occurrence (Barosi G et al, Blood 2009). Only pts with stable SubOR were included in this analysis. Since a complete response was never achieved, the index date (ID) was set at 3 mos from HU start in all pts (Barosi G et al, BJH 2009). OS was calculated from the ID by Cox analysis with age>80, adjusted with left truncation from PV diagnosis. Results: At data cut-off date (June 2020), 808 PV pts were collected; 688 received HU. Among the 452 (65.7%) pts who presented a stable SubOR to HU, 41 did not receive any tx for PV due to early death or progression to BP/MF and were excluded from this analysis. Baseline characteristics of the 411 evaluable pts were: median age: 65 yrs (21- 87); males: 54%; median (range) WBC/PLT count, x109/l: 10 (1.1-38)/465 (139-1209); median Hb (g/dl)/HCT (%): 18.6/56 (males); 17.6/54 (females); palpable splenomegaly: 38%; symptoms: 80.5%; pruritus: 42%. A previous thrombosis occurred in 104 (25.3%) pts. At least one cardiovascular risk factor (CVRF: smoke, diabetes, hypertension, dyslipidemia and overweight) was present in 325 pts (79.1%). After a median follow-up of 4.8 yrs (0.5-27.6) from HU start, 104 (25.3%) switched to RUX (HU-RUX), 18 (4.4%) switched to another agent (HU-other, including IFN, BUS, PHL only), and 289 (70.3%) continued HU (HU-alone). Pts with baseline palpable spleen (p While 331 (80.5%) pts had a stable SubOR without TOX, 80 (19.5%) had also TOX. Notably, pts with only SubOR more frequently continued HU (p In 45.5% of pts, the SubOR was related only to uncontrolled WBC/PLT/HCT, while 16.1% of pts had an optimal hematological control but presented spleen/symptoms; the remaining 38.4% of pts had both uncontrolled myeloproliferation and spleen/symptoms. The presence of both uncontrolled myeloproliferation and spleen/symptoms significantly predicted RUX switch (p Investigating the SubOR criteria individually among the HU-alone/other and the HU-RUX groups, we found that uncontrolled leukocytosis and/or thrombocytosis (p After the ID, 31 pts died. HU-RUX pts presented increased OS compared to HU-alone/other pts (p=0.03). Conclusions. This study revealed a high rate of SubOR to HU, possibly also affected by low HU doses, and a lack of urgency to change the tx in these pts, with >70% of pts continuing HU despite the stable SubOR. Particularly, good tolerance to HU, absence of splenomegaly and pruritus, and older age were the main factors against a tx change. Notably, despite HCT>45% is associated with worse outcome (Marchioli R, NEJM 2013), PHL need did not significantly trigger tx change. The better OS in the HU-RUX group is presumably multifactorial and requires further confirmation. Overall, this analysis points out the need to improve HU management and response evaluations, weighing appropriate tx strategies in case of SubOR. Disclosures Palandri: Novartis: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Breccia:Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Abbvie: Consultancy; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Heidel:Celgene: Consultancy; CTI: Consultancy; Novartis: Consultancy, Research Funding. Crugnola:BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Pane:Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Cuneo:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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. 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:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Lemoli:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Palumbo:Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: The outcome of patients (pts) with myelofibrosis (MF) who discontinue ruxolitinib (RUX) is poor with scarce therapeutic possibilities (Palandri et al, 2020). However, some evidences suggest that pts may respond to a rechallenge of RUX after drug stop (Gerds et al, 2018). Aims: To investigate in a real-world context: 1) frequency and reasons for rechallenge; 2) therapeutic effects of rechallenge; 3) impact of rechallenge on overall survival (OS) Methods: After IRB approval, a clinical database was created in 20 European Hematology Centers including now retrospective data of 703 MF pts who started RUX from Jan 2011 to Nov 2019. Only chronic phase (CP) pts who stopped RUX for ≥14 days and survived ≥30 days after discontinuation were included. A specific survey collected clinical/laboratory data at RUX stop and at rechallenge, reasons for discontinuation and treatments before rechallenge. OS was estimated from the date of the first/only RUX discontinuation to last contact (log-rank test). Results: A total of 219 CP pts was evaluable for this study. In 60 (27.4%) pts, RUX was re-challenged for ≥14 days after the first discontinuation (RUX-again), while 159 (72.6%) pts discontinued RUX permanently (RUX-stop). The median time from RUX start to stop was of 16.5 and 12.3 mos for RUX-again and RUX-stop pts, respectively (p=0.41). At RUX start, characteristics of RUX-again were: median age 67y (24-88); males 61.7%; PMF 53.3%; median Hb 10.2 g/dl; median PLT/WBC: 249/12.6 x109/l; median RUX starting dose: 15mg BID. Baseline characteristics of RUX-again and RUX-stop pts were comparable. In the 60 RUX-again pts, reasons for discontinuation included loss of/inadequate response (18 pts, 30%) and toxicity (42 pts, 70%). Toxicity included G3-4 thrombocytopenia (38.1%), anemia (26.2%), infections (21.4%), other (14.3%). Conversely, RUX-stop pts discontinued RUX mainly due to loss of/inadequate response (75 pts, 47.2%), while intolerable toxicity occurred in 69 pts (43.4%) (p=0.004) and other causes in 9.4%. At first RUX discontinuation, 35.7% of RUX-again pts presented with large (>10 cm) splenomegaly; median Total Symptoms Score (TSS) was 10 (TSS>20 in 30.4% of pts). The median duration of temporary RUX discontinuation was 2 mos (range 0.5-71.1). During RUX stop, 65% of RUX-again pts did not receive any therapy, 15% received only palliation (steroids, hydroxyurea), while 11.7% switched to investigational agents, 3.3% underwent splenectomy and 5% allogeneic transplantation. Compared to disease status at first RUX stop, at RUX restart there was a significant increase of pts with large splenomegaly and high TSS, while the PLT count was higher and RUX dose significantly lower (Table 1). The median duration of RUX rechallenge was 7.5 mos (0.5-72.7). During the rechallenge, 44.6% and 48.3% pts improved spleen and symptoms, and there was a significant increase in pts with TSS reduction (p=0.01); 8 pts (13.3%) continued RUX with stable/worsening spleen size and improvement in TSS. Conversely, 26.8% and 20% of pts had increase in spleen size and in symptoms, respectively. While Hb levels remained stable, PLT count significantly decreased during rechallenge (p The reasons for temporary discontinuation had no impact on the reduction of spleen/symptoms during rechallenge and on OS. However, comparing RUX-again and RUX-stop pts, RUX-again pts showed a better OS, with a median survival of 41.1 mos and 23.7, respectively in the 2 cohorts (Fig. 1). Conclusions: This real-world study highlights that RUX rechallenge is quite common in CP-MF pts, involving almost 30% of treated pts, particularly when the discontinuation is due to toxicity. The temporary discontinuation, while improving PLT count, generally caused a significant increase in disease burden. After rechallenge, almost 50% of pts achieved clinical responses regardless of reason of first discontinuation. This residual disease control activity, that correlated with improved OS, should be weighed up also given the new therapeutic possibilities available in these pts. Disclosures Palandri: Novartis: Consultancy, Honoraria. Breccia:Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Cavazzini:Incyte: Honoraria; Pfize: Honoraria; Novartis: Honoraria. Crugnola:Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Heidel:CTI: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Research Funding. Pane:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; 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; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Cuneo:janssen: 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. 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:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding. 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; Celgene: 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.

Ruxolitinib is a JAK1/2 inhibitor that may control myelofibrosis (MF)-related splenomegaly and symptoms and can be prescribed regardless of age. While aging is known to correlate with worse prognosis, no specific analysis is available to confirm that ruxolitinib is suitable for use in older populations. A clinical database was created in 23 European Haematology Centres and retrospective data on 291 MF patients treated with ruxolitinib when aged ≥65 years were analysed in order to assess the impact of age and molecular genotype on responses, toxicities and survival. Additional mutations were evaluated by a next generation sequencing (NGS) approach in 69 patients with available peripheral blood samples at the start of ruxolitinib treatment. Compared to older (age 65-74 years) patients, elderly (≥75 years) showed comparable responses to ruxolitinib, but higher rates of drug-induced anaemia and thrombocytopenia and worse survival. Nonetheless, the ruxolitinib discontinuation rate was comparable in the two age groups. Number and types of molecular abnormalities were comparable across age groups. However, the presence of high molecular risk (HMR) mutations significantly affected survival, counterbalancing the effect of aging. Indeed, elderly patients with

Although infectious complications represent a relevant cause of morbidity and mortality in patients with myelofibrosis (MF), little is known about their incidence, outcome and risk factors. We retrospectively evaluated a cohort of 507 MF patients, diagnosed between 1980 and 2014 in five Italian hematology centers, to define the epidemiology of infections and describe the impact of ruxolitinib (RUX) treatment. Overall, 112 patients (22%) experienced 160 infectious events (grade 3-4, 45%) for an incidence rate of 3.9% per patient-year. Infections were mainly bacterial (78%) and involving the respiratory tract (52% of cases). Also, viral (11%) and fungal infections (2%) were recorded. Overall, infections were fatal in 9% of the cases. Among baseline features, high/intermediate-2 IPSS category (HR 1.8, 95%CI:1.2-2.7; p=0.02) and spleen length ≥10 cm below left costal margin (HR 1.6, 95%CI:1.1-2.5; p=0.04) were associated with higher infectious risk in multivariate analysis. Overall, the rate of infections was higher in the cohort of 128 RUX-treated patients (44% vs. 20%, p

Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.

Introduction Malignancy can be heralded by unprovoked venous thromboembolism (VTE) but also by arterial thrombosis. To date it is unknown whether this association is present also in myeloproliferative neoplasms (MPN), in which arterial thrombosis is more frequent that venous thrombosis and solid tumors are reported with an increased frequency. The MPN-K nested case-control study addressed the impact of cytoreductive drugs on the risk of developing second cancer in MPN patients (Barbui T et al, Leukemia 2019); here we re-examined the study database to evaluate the frequency and type of vascular complications in MPN patients with second cancer excluding leukemia and to establish whether arterial and venous thrombosis during follow-up after diagnosis of MPN could predict the occurrence of a second cancer. Patients and methods Cases were patients with second cancer diagnosed concurrently or subsequent to the diagnosis of MPN. Controls were MPN patients without second cancer. For each case with second cancer, up to 3 cancer-free controls were matched by each center for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. Each set consisting of one case and their matched-controls had a similar observational period (from MPN diagnosis until the index date of diagnosis for the second cancer). The study included 647 cases with second cancer (carcinoma, non-melanoma-skin cancers, hematological secondary cancer and melanoma). The most frequent category was carcinoma (n=426, 65.8%). Cases were comparable with the 1,234 matched controls for demographics, type of MPN, and exposure to potential confounders such as mutational profile, abnormal karyotype and cardiovascular risk factors. The thrombotic events of interest were ischemic stroke, transient ischemic attacks, acute coronary syndromes, peripheral arterial thrombosis, deep venous thrombosis (including thrombosis of cerebral and splanchnic veins) and pulmonary embolism. Thrombosis had to be concurrent with or in the 2 years before MPN diagnosis or occurring after MPN diagnosis. The cumulative incidence of either arterial or venous thrombosis from MPN diagnosis was estimated by the Kaplan-Meier method and was compared between cases and controls using the log-rank test. A conditional logistic regression model estimated the Odds Ratio (OR) with 95% Confidence Interval (CI) of second cancer associated with the occurrence of thrombosis before/at diagnosis of MPN and during follow-up. Other covariates were patient age, cardiovascular risk factors, the JAK2V617F mutation, and treatment during follow-up. Results Approximately 20% of either MPN cases or controls had thrombosis before MPN or at diagnosis (19.8% vs. 21.1%, respectively, p=0.462). After a median observation time from diagnosis of MPN to an index date of 4.5 years (interquartile range 1.5-8.2) in cases and 3.7 years (interquartile range 1.5-7.5) in controls, cases showed a percentage of thrombosis higher than in controls (75/647, 11.6% vs. 100/1234, 8.1%, respectively, p=0.013). Approximately one-third of thrombosis preceding cancer occurred in the 12 months before the diagnosis of second cancer (22/75, 29.3%). The excess of thrombosis in cases was due to a higher frequency of arterial thrombosis (6.2% vs. 3.7%, p=0.015), whereas no significant difference was found for venous thrombosis (5.4% vs. 4.3%, p=0.277). While the cumulative incidence of venous thrombosis over time was similar among cases and controls (p=0.864), the cumulative incidence of arterial thrombosis was higher in cases with second cancer (p=0.006) (Figure 1). The excess of arterial thrombosis after MPN diagnosis was limited to cases with carcinoma (6.8% vs 3.9%, p=0.027). In a multivariable model, arterial thrombosis during the follow-up was confirmed to be an independent predictor factor for carcinoma, with an odds ratio of 1.97 (95%CI 1.14-3.41, p=0.015). Conclusions. These findings reveal an association of arterial thrombosis with subsequent second cancer (namely carcinoma) in MPN patients. A possible biological plausibility for this link may be related to an underlying common pathogenic mechanism such as an aberrant inflammatory response consistently found in MPN. This observation may have practical implications and suggests careful clinical surveillance for early diagnosis of second cancer in MPN patients with arterial thrombosis during the follow-up. Disclosures Palandri: Novartis: Consultancy, Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Bonifacio:Incyte: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Rumi:novartis: Honoraria, Research Funding. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Lunghi:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Benevolo:Novartis Pharmaceuticals: Consultancy. McMullin:Italopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Daiko Sanyo: Membership on an entity's Board of Directors or advisory committees. Griesshammer:Novartis: Consultancy, Honoraria, Speakers Bureau. Vannucchi:CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: 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; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

We designed a trial in which postremission therapy of young patients with de novo acute myeloid leukemia (AML) was decided combining cytogenetics/genetics and postconsolidation levels of minimal residual disease (MRD). After induction and consolidation, favorable-risk patients (FR) were to receive autologous stem cell transplant (AuSCT) and poor-risk patients (PR) allogeneic stem cell transplant (AlloSCT). Intermediate-risk patients (IR) were to receive AuSCT or AlloSCT depending on the postconsolidation levels of MRD. Three hundred sixty-one of 500 patients (72%) achieved a complete remission, 342/361 completed the consolidation phase and were treatment allocated: 165 (48%) to AlloSCT (122 PR, 43 IR MRD-positive) plus 23 rescued after salvage therapy, for a total of 188 candidates; 150 (44%) to AuSCT (115 FR, 35 IR MRD-negative) plus 27 IR patients (8%) with no leukemia-associated phenotype, for a total of 177 candidates. Overall, 110/177 (62%) and 130/188 (71%) AuSCT or AlloSCT candidates received it, respectively. Two-year overall (OS) and disease-free survival (DFS) of the whole series was 56% and 54%, respectively. Two-year OS and DFS were 74% and 61% in the FR category, 42% and 45% in the PR category, 79% and 61% in the IR MRD-negative category, and 70% and 67% in the IR MRD-positive category. In conclusion, AuSCT may still have a role in FR and IR MRD-negative categories. In the IR MRD-positive category, AlloSCT prolongs OS and DFS to equal those of the FR category. Using all the available sources of stem cells, AlloSCT was delivered to 71% of the candidates.This trial was registered at www.clinicaltrials.gov as #NCT01452646 and EudraCT as #2010-023809-36.

We conducted a large international nested case-control study including 1881 patients with Philadelphia-negative myeloproliferative neoplasms (MPN). Cases (n = 647) were patients with second cancer (SC: carcinoma, non-melanoma skin cancer, hematological second cancer, and melanoma) and controls (n = 1234) were patients without SC, matched with cases for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. The aim was to evaluate the risk of SC after exposure to cytoreductive drugs. Patients exposed to hydroxyurea (HU) (median: 3 years) had a risk of SC similar to unexposed patients (OR = 1.06, 95% CI 0.82-1.38). In contrast, in cancer-specific stratified multivariable analysis, HU had two-fold higher risk of non-melanoma (NM) skin cancer (OR = 2.28, 95% CI 1.15-4.51). A significantly higher risk of NM-skin cancer was also documented for pipobroman (OR = 3.74, 95% CI 1.00-14.01), ruxolitinib (OR = 3.87, 95% CI 1.18-12.75), and for drug combination (OR = 3.47, 95% CI 1.55-7.75). These three drugs did not show excess risk of carcinoma and hematological second cancer compared with unexposed patients. Exposure to interferon, busulfan, and anagrelide did not increase the risk. In summary, while it is reassuring that no excess of carcinoma was documented, a careful dermatologic active surveillance before and during the course of treatments is recommended.

The 2016 WHO criteria identified early primary myelofibrosis (PMF) as an individual entity with milder clinical features and better outcome compared with overt PMF. Here, we compared early and overt PMF patients treated with ruxolitinib in terms of baseline clinical/laboratory characteristics, response, and toxicity to treatment. We observed that early-PMF patients achieve better and more stable spleen and symptoms responses, with significantly lower rates of hematological toxicities. No differences in overall and leukemia-free survival were detected between the two cohorts. The application of 2016 WHO criteria is crucial to identify those PMF patients who deserve a stricter monitoring during treatment.

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 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 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 (p18.5; 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 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.

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 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 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.

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) 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.

We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.

An accurate histological diagnosis may distinguish essential thrombocythaemia (ET) from early primary myelofibrosis (early-PMF), which is associated with worse outcome. Outcome of ET is also negatively affected by the presence of the JAK2V617F mutation. To investigate the impact of JAK2V617F mutation burden and histology on outcome, we collected 475 WHO-diagnosed ET (69.2%) or early-PMF JAK2V617F-positive patients followed in 4 Italian haematology centers. JAK2V617F allele burden was ≤50% in 90% and 87% of ET and early-PMF patients, respectively (P = .34). During follow-up, 32 (9.7%) ET and 18 (12.3%) early-PMF patients experienced 59 thrombotic events, and 27 patients (5.6%) and 6 (1.2%) patients evolved to myelofibrosis and acute leukemia, respectively. At last contact, 28 (5.8%) patients had died. In early-PMF compared to ET, the 10-year mortality rates (6.7% and 4.3%, P = .73), leukemic transformation rates (1.4% and 1.2%, P = .45), and thrombosis rates (16.7% and 12.2%, P = .12) were comparable. Only progression to overt myelofibrosis at 10 years was significantly worse (11.4% and 1.5%, P = .004). In multivariate analysis, a higher (>50%) JAK2V617F burden was significantly correlated with fibrotic progression and histology. Considering JAK2V617F-positive disease, a higher (>50%) JAK2V617F burden and histological classification are independent prognostic risk factors for disease progression. These findings reinforce the need for standardized detection of this mutation.

Recently, the myelofibrosis secondary to PV and ET prognostic model (MYSEC-PM) was introduced to assess prognosis in myelofibrosis (MF) secondary to polycythemia vera and essential thrombocythemia (post-PV and post-ET MF), replacing the International Prognostic Scoring System (IPSS) and/or Dynamic IPSS (DIPSS) that was applied for primary MF (PMF). In a cohort of 421 ruxolitinib (RUX)-treated patients (post-PV and post-ET MF: 44.2%), we evaluated the following: (1) disease phenotype, responses, and toxicity to RUX; and (2) performance of the MYSEC-PM in post-PV or post-ET ME. While the IPSS failed to correctly stratify post-PV or post-ET MF patients at diagnosis, the MYSEC-PM identified 4 risk categories projected at significantly different survival probability (P < .001). Additionally, the MYSEC-PM maintained a prognostic value in post-PV and post-ET MF also when used over time, at RUX start. Notably, the MYSEC-PM reclassified 41.8% and 13.6% of patients into a lower and higher risk category, respectively. Finally, patients at intermediate-1 risk had significantly higher spleen responses and lower hematological toxicities compared to higher risk patients. Compared to PMF, post-PV and post-ET MF presented a more hyperproliferative disease, with higher leukocyte and/or platelet count and hemoglobin levels both at diagnosis and at RUX start. Despite comparable response rates, post-PV and post-ET MF had lower rate of RUX-induced anemia and thrombocytopenia at 3 and 6 months. The study validates MYSEC-PM in post-PV and post-ET MF prognostication. Post-PV or post-ET MF represents a separate entity compared to PMF in terms of clinical manifestations and toxicity to RUX. (C) 2018 Elsevier Inc. All rights reserved.

In this prospective observational single-center study, 55 patients with essential thrombocythemia who were candidates for second line treatment with anagrelide (ANA) received a preliminary cardiovascular (CV) clinical, instrumental and biochemical evaluation (CV history and symptoms, CV risk factors, blood pressure, heart rate, ECG and ECHO-cardio parameters, Troponin I, NT-proBNP). After this in-depth CV screening, 54 out of 55 patients were deemed to be fit for ANA treatment. Thirty-eight of the 55 patients received ANA treatment for a median of 36 months (range 3-48), and were monitored using the same CV evaluation. Fourteen of these 38 patients manifested CV adverse events (10 palpitation, 4 edema, 2 arterial hypertension, 2 acute myocardial infarction) that were not predicted by the in-depth CV evaluation, and that led to ANA withdrawal in only one case (non-cardiac refractory edema). In conclusion, the planned in-depth CV evaluation did not appear to be necessary in ET patients to evaluate their suitability for ANA treatment, and, moreover, was not able to predict the occurrence of CV adverse events during ANA treatment. Nevertheless, the CV adverse events (mostly palpitations and edema) were easily managed by the hematologists, and required the cardiologist involvement in very few selected cases.

none 18 no We investigated the influence of molecular status on disease characteristics and clinical outcome in young patients (⩽ 40 years) with World Health Organization (WHO)-defined essential thrombocythemia (ET) or early/prefibrotic primary myelofibrosis (early-PMF). Overall, 217 patients with ET (number 197) and early-PMF (number 20) were included in the analysis. Median follow-up time was 10.2 years. The cumulative incidence of thrombosis, hemorrhages and disease evolution into myelofibrosis/acute leukemia were 16.6%, 8.6% and 3% at 15 years, respectively. No differences were detectable between ET and early-PMF patients, although the latter cohort showed a trend for worse combined-event free survival (EFS). Mutation frequency were 61% for JAK2V617F, 25% for CALR and 1% for MPLW515K, and were comparable across WHO diagnosis; however, JAK2V617F allele burden was higher in the early-PMF group. Compared with JAK2V617F-positive patients, CALR-mutated patients displayed higher platelet count and lower hemoglobin level. CALR mutations significantly correlated with lower thrombotic risk (9.1% versus 21.7%, P = 0.04), longer survival (100% versus 96%, P = 0.05) and better combined-EFS (86% versus 71%, P = 0.02). However, non-type 1/type 2 CALR mutations ('minor' mutations) and abnormal karyotype were found to correlate with increased risk of disease evolution. At last contact, six patients had died; in five cases, the causes of death were related to the hematological disease and occurred at a median age of 64 years (range: 53-68 years). Twenty-eight patients (13%) were unmutated for JAK2, CALR and MPL: no event was registered in these 'triple-negative' patients. Palandri, F; Latagliata, R.; Polverelli, N.; Tieghi, A.; Crugnola, M.; Martino, B.; Perricone, M.; Breccia, M.; Ottaviani, E.; Testoni, N.; Merli, F.; Aversa, F.; Alimena, G.; Cavo, M.; Martinelli, G.; Catani, L.; Baccarani, M.; Vianelli, N. Palandri, F; Latagliata, R.; Polverelli, N.; Tieghi, A.; Crugnola, M.; Martino, B.; Perricone, M.; Breccia, M.; Ottaviani, E.; Testoni, N.; Merli, F.; Aversa, F.; Alimena, G.; Cavo, M.; Martinelli, G.; Catani, L.; Baccarani, M.; Vianelli, N.

// Francesca Palandri 1 , Giuseppe Alberto Palumbo 2 , Massimiliano Bonifacio 3 , Mario Tiribelli 4 , Giulia Benevolo 5 , Bruno Martino 6 , Elisabetta Abruzzese 7 , Mariella D’Adda 8 , Nicola Polverelli 9 , Micaela Bergamaschi 10 , Alessia Tieghi 11 , Francesco Cavazzini 12 , Adalberto Ibatici 13 , Monica Crugnola 14 , Costanza Bosi 15 , Roberto Latagliata 16 , Ambra Di Veroli 17 , Luigi Scaffidi 3 , Federico de Marchi 4 , Elisa Cerqui 8 , Barbara Anaclerico 18 , Giovanna De Matteis 19 , Marco Spinsanti 1 , Elena Sabattini 1 , Lucia Catani 1 , Franco Aversa 14 , Francesco Di Raimondo 2 , Umberto Vitolo 5 , Roberto Massimo Lemoli 10 , Renato Fanin 4 , Francesco Merli 11 , Domenico Russo 9 , Antonio Cuneo 12 , Maria Letizia Bacchi Reggiani 20 , Michele Cavo 1 , Nicola Vianelli 1 and Massimo Breccia 16 1 Institute of Hematology “L. and A. Seragnoli”, Sant'Orsola-Malpighi University Hospital, Bologna, Italy 2 Division of Hematology, AOU 'Policlinico-V.Emanuele', Catania, Italy 3 Department of Hematology, University of Verona, Verona, Italy 4 Division of Hematology and BMT, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy 5 Division of Hematology, Citta della Salute e della Scienza Hospital, Torino, Italy 6 Division of Hematology, Azienda Ospedaliera 'Bianchi Melacrino Morelli', Reggio Calabria, Italy 7 Division of Hematology, Ospedale S. Eugenio, Roma, Italy 8 Division of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy 9 Unit of Blood Diseases and Stem Cell Transplantation, ASST Spedali Civili di Brescia, Brescia, Italy 10 Division of Hematology, IRCCS AOU San Martino-IST, Genova, Italy 11 Department of Hematology, A.O. Arcispedale Santa Maria Nuova – IRCCS, Reggio Emilia, Italy 12 Division of Hematology, University of Ferrara, Ferrara, Italy 13 Division of Hematology and Bone Marrow Transplant, IRCCS San Martino-IST, Genova, Italy 14 Division of Hematology, AOU of Parma, Parma, Italy 15 Department of Hematology and Bone Marrow Transplantation, A.O. of Piacenza, Italy 16 Division of Cellular Biotechnologies and Hematology, University Sapienza, Roma, Italy 17 Division of Hematology, Policlinico Tor Vergata, Roma, Italy 18 Division of Hematology, Ospedale S. Giovanni, Roma, Italy 19 Department of Life and Reproduction Sciences, Section of Clinical Biochemistry, University of Verona, Verona, Italy 20 Division of Cardiology, University of Bologna, Bologna, Italy Correspondence to: Francesca Palandri, email: francesca.palandri@unibo.it Keywords: myelofibrosis, splenomegaly, response, ruxolitinib, predictive factors Received: March 29, 2017 Accepted: May 15, 2017 Published: June 27, 2017 ABSTRACT In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk ( p =0.024), large splenomegaly ( p =0.017), transfusion dependency ( p =0.022), platelet count 2 years ( p =0.048). Also, patients treated with higher (≥10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates ( p =0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response ( p

In patients who do not meet the World Health Organization (WHO) criteria for overt polycythaemia vera (PV), a diagnosis of masked PV (mPV) can be determined. A fraction of mPV patients may display thrombocytosis, thus mimicking essential thrombocythaemia (ET). No previous studies have examined clinical outcomes of mPV among young JAK2-mutated patients. We analysed a retrospective cohort of 538 JAK2-mutated patients younger than 40 years, after a re-assessment of the diagnosis according to the haemoglobin threshold for mPV. In this cohort of patients, 97 (18%) met the WHO criteria for PV, 66 patients (12%) were classified as mPV and 375 (70%) as JAK2-mutated ET. Surprisingly, a significant difference in the incidence of thrombosis was found when comparing mPV versus overt PV patients (P = 0·04). In multivariate analysis, the only factor accounting for the difference in the risk of thrombosis was the less frequent use of phlebotomies and cytoreduction in mPV patients compared to those with overt PV. Thus, we emphasize the need for the identification of mPV in young JAK2-mutated patients in order to optimize their treatments. © 2014 John Wiley & Sons Ltd

To investigate the characteristics and clinical course of cerebral vein thrombosis (CVT) in patients with myeloproliferative neoplasms (MPN) we compared 48 patients with MPN and CVT (group MPN-CVT) to 87 with MPN and other venous thrombosis (group MPN-VT) and 178 with MPN and no thrombosis (group MPN-NoT) matched by sex, age at diagnosis of MPN (±5 years) and type of MPN. The study population was identified among 5,500 patients with MPN, from January 1982 to June 2013. Thrombophilia abnormalities were significantly more prevalent in the MPN-CVT and MPN-VT than in MPN-NoT group (P = 0.015), as well as the JAK2 V617F mutation in patients with essential thrombocythemia (P = 0.059). Compared to MPN-VT, MPN-CVT patients had a higher rate of recurrent thrombosis (42% vs. 25%, P = 0.049) despite a shorter median follow-up period (6.1 vs. 10.3 years, P = 0.019), a higher long-term antithrombotic (94% vs. 84%, P = 0.099) and a similar cytoreductive treatment (79% vs. 70%, P = 0.311). The incidence of recurrent thrombosis was double in MPN-CVT than in MPN-VT group (8.8% and 4.2% patient-years, P = 0.022), and CVT and unprovoked event were the only predictive variables in a multivariate model including also sex, blood count, thrombophilia, cytoreductive, and antithrombotic treatment (HR 1.97, 95%CI 1.05-3.72 and 2.09, 1.09-4.00, respectively).

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 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.

Background Myelofibrosis (MF) is featured by an inflammatory condition that can also drive the progression of disease. Ruxolitinib (RUX) is the-first-in-class Jak1/2 inhibitor approved for treatment for MF. Clinical benefits of RUX are presumably derived from reduction of inflammatory cytokines even if the exact mechanism remains unclear. Recent reports have identified the ratio between absolute neutrophils count (ANC) and absolute lymphocyte count (ALC), called NLR, as a simple parameter that mirrors the inflammatory status and the myeloid associated immune suppression. In various malignancies NLR has been indicated as predictor of progression free survival (PFS) and overall survival (OS). Our preliminary work in a single-center experience showed that patients with NLR>6 before RUX start had a lower chance to obtain > 50% spleen reduction in the first 12 weeks or a complete resolution of splenomegaly at 24 weeks. Objective : We proposed to test NLR=6 as bio-marker in MF to apply into clinical practice as a possible predictor of response to RUX. Methods We used two separate cohorts to validate NLR (as a continuous variable and as a cut off 6) as predictor of response to RUX bases on our preliminary data from healthy volunteers (data not shown). Cohort (#1) including 111 MF patients from MD Anderson Cancer Center treated with RUX on phase 1/2 clinical trial from 2007 to 2010; and cohort (#2) including 367 patients treated at 18 Italian centers between years 2012 - 2018. Spleen responses to RUX treatment, PFS and OS were independently validated in cohorts #1 and 2. As cohort 1 included patients treated on clinical trial, spleen was assessed by MRI before and after 24 weeks of RUX therapy, and by physical examination at week 12. In cohort #2, spleen size was assessed by physical examination before, after 12 and 24 weeks of RUX continuous treatment in a real-life setting. NLR was calculated using data obtained from the complete blood count before RUX start and correlated with driver mutations, early spleen reduction, progression free survival (PFS), defined as time from RUX start to last follow-up or progressive disease (including progression to acute myeloid leukemia, ≥20% blasts in peripheral blood or bone marrow, AML) or death for any reason; and overall survival (OS). Results : Clinical and demographics characteristics of patients in each cohort are summarized in Table 1. In cohort #1 we found that NLR was lower in patients with lower bone marrow fibrosis (grade 0-1: 6.2±0.8 versus grade 2-3: 7.3±0.8, p=0.03). Similarly, in cohort #2, patients with grade 0-1 bone marrow fibrosis had lower NLR than those carrying grade 2-3 bone marrow fibrosis (7.7±0.7 versus 10.6±1.3, p=0.04). NLR was higher in patients carrying JAK2 (V617F) mutation (mean +/- SD, 6.4±0.6 vs 5.3±0.5, p=0.02 in cohort 1 and 9.1±0.6 vs 5.0±0.5, p=0.002 in cohort 2). While in cohort 1 NLR appeared lower in CALR (exon 9 indel) mutated patients, the difference was statistically significant in cohort 2 (5.4±0.8 vs 8.9±0.6, p=0.03). In both cohorts, there were no differences in NLR in either triple negative or MPL (exon 10) patients. In cohort 1, the mean percentage change from baseline in palpable spleen length was −47.7% at week 12 and −53.4% at week 24. NLR=6 was able to identify at baseline early response to RUX with 66.9% sensitivity and 72.3% specificity (HR 1.68, p=0.01). Patients with NLR>6 before RUX start had a lower chance to obtain a complete resolution of splenomegaly at 24 weeks (p=0.001). These observations were confirmed in cohort 2 where NLR > 6 was able to identify at baseline early response to RUX with 50.3% sensitivity and 67.7% specificity (HR 1.56, p=0.01). The mean percentage change from baseline in palpable spleen length was −60.3% at week 12 and −66.7% at week 24. Patients with NLR>6 before RUX start had a lower chance to obtain a complete resolution of splenomegaly at 24 weeks (p At the time of this analysis, 84/111 (75.6%) patients in cohort 1 and 122/367 (33.2%) in cohort 2 had died (p 6 was not a predictor of PFS or OS. Conclusions : NLR before RUX start could serve as a useful, simple and early predictor of spleen response in MF patients; and it positively correlates with JAK2 mutation and higher fibrosis grade. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vitolo:Sandoz: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. 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. Aversa:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria. Cavo: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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: 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; Takeda: 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. 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. Di Raimondo:Takeda: Honoraria, Research Funding; Celgene: Honoraria. Verstovsek:Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION The incidence of secondary cancer (SC) in patients with myeloproliferative neoplasms (MPN) is high and comparable to that of thrombosis. However, the identification of patient subgroups that might be at increased susceptibility of developing SC has not been systematically addressed. We report here the results of an international case-control study (MPN-K) aimed at comparing the frequency of exposure to possible causes of SC in patients with classical MPN, polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). METHODS This European Leukaemia Network (ELN) study reports MPN patients from 28 sites of 5 European countries and Israel, diagnosed in the period from 2000 to 2016. Cases were MPN patients with concomitant diagnosis of a non-myeloid SC (n=15) or its presentation during the course of the disease (n=412). Controls were MPN patients cancer-free, matched to the paired case for sex, age (±5 years), date of MPN diagnosis (±5 years), and MPN disease duration (±6 years). A multivariable conditional logistic regression model was used to estimate the effect of selected variables on total SC risk and in different types of SC. RESULTS Among 1,259 MPN patients, there were 427 cases and 832 matched controls. Cases presented melanoma (n=20; 4.7%), non-melanoma skin cancer (n=69; 16.2% - basal/squamous cell carcinoma), non-skin solid cancer (n=290; 67.9%) including breast, ovary/uterus, colorectal, upper gastrointestinal, liver/pancreas, lung, prostate/urinary, other and lymphoproliferative diseases (n=48; 11.2%) including multiple myeloma, chronic lymphocytic leukemia, low and high grade B- and T-lymphoma. At diagnosis, there were slightly more patients with PV among SC cases (n= 152; 35.6%) than controls (n=256; 30.8%), while conversely there were slightly less ET patients among cases (n=196; 45.9%) than controls (n=426; 51.2%). Cases and controls presented similar proportion of MF diagnosis (n=79 cases, 18.5% and 150 controls, 18.0%). Driver mutations (JAK2 V617, EXON-12, CALR, MPL), non-driver mutations and abnormal karyotype were equally represented in cases and controls. Other variables such as cardiovascular risk factors, exposure to cancerogens, family history of cancer and chronic inflammatory diseases were reported with similar frequency in cases and controls. After MPN diagnosis, exposure to first and other lines of treatments until the index event, with Phlebotomy (n=193; 15.3%), Hydroxyurea (n=814; 64.7%), Anagrelide (n=14; 1.1%), Interferon (n=30; 2.4%), Pipobroman (n=8; 0.6%), Busulphan (n=13; 1.0%), Ruxolitinib (n=11; 0.9%), was similar in the two groups except for aspirin that was used less frequently (p=0.043) in cases (n=320; 74.9%) compared to controls (n=664; 79.9%). In particular, the lower use of aspirin was circumscribed to non-skin solid tumors. A multivariable analysis was carried out in all patients and stratified by different type of tumors (Table). In non-skin solid cancers, the time to exposure of the MPN disease > 5 years (OR=2.95; 95% CI 1.54-5.66, p=0.001) and the PV phenotype (OR=2.40, 95% CI 1.15-5.01, p=0.020) were more burdened by the incidence of events than the reference ET group. No difference in SC risk was found for MF patients compared to patients with ET. Interestingly, the independent protective role of aspirin retained its statistical significance only in non-skin SC. In non-melanoma skin cancer, multivariable analysis revealed that the presence of JAK2 mutation was less associated with SC (OR=0.32, 95% CI 0.13-0.81, p=0.016) and confirmed that exposure to HU and other cytotoxic agents was associated with a significantly higher risk of SC (OR=6.00, 95% CI 1.23-29.28, p=0.027 and OR=9.80, 95% CI 1.24-77.78, p=0.031, respectively). This finding was not seen in non-skin SC and in lymphoma. CONCLUSION The considered clinical and biological features, at MPN diagnosis, were not different in cases with SC and controls. During the course of the disease, three factors significantly and independently affected the risk of SC in these MPN patients: 1) patients with PV had a 77% higher risk than those with ET, 2) patients with MPN duration of more than 5 years had a twice higher risk than those with lower duration, 3) for the first time, we documented that in non-skin solid cancers, aspirin treatment reduced SC risk of 38%. Exposure to HU and other cytoreductive drugs was confirmed as a risk factor for non-melanoma skin cancer. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Marchetti:Gilead: Consultancy; takeda: Speakers Bureau; amgen: Speakers Bureau; janssen: Speakers Bureau. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background. Ruxolitinib (RUX) is the first commercially available JAK1/2 inhibitor that may control splenomegaly and systemic symptoms related to myelofibrosis (MF). Despite MF occur frequently in elderly patients (pts), no data are yet available on RUX efficacy and safety in this particularly frail population. Methods We report on 100 pts [M/F 57/43, median age at diagnosis 75.7 years, interquartile range (IQR) 72.3 - 78.0, median age at baseline of RUX treatment 77.7 years, IQR 76.2 - 80.3] with WHO-defined MF treated with RUX when aged ≥ 75 years. Data were extracted from the whole cohort of 408 pts of any age collected in a database involving 22 Italian Centers. Comorbidities were recorded at the time of diagnosis and classified according to the Charlson Comorbidity Index (CCI). Response to RUX was evaluated according to IWG-MRT criteria. Results Main clinical features after stratification according to age at RUX start are reported in Table 1. Compared to younger pts, elderly pts carried a higher number of co-morbidities and had lower hemoglobin and platelet values, thus starting RUX with lower doses. Time from diagnosis to RUX start was comparable among the two cohorts (median 15.5 months, IQR 4.6 - 66.7, vs 20.8 months, IQR 4.1 - 66.0, p=0.74). According to IWG criteria, a spleen response was achieved by 37 out of 90 (41.1%) evaluable elderly pts compared to 115 out of 272 (42.2%) pts Drug-related anemia (Hb Evolution into acute leukemia occurred in 8 (8.0%) elderly pts and in 22 (7.1%) younger pts, respectively (p=0.78), with a similar evolution-free survival from RUX initiation (p=0.35). As expected, 43 (43.0%) elderly pts and 53 (17.3%) younger pts died (p The 4-year cumulative Event-Free Survival (taking into account: RUX discontinuation, blastic evolution and death for any cause) was 30.1% (95% CI: 16.2 - 44.0) in elderly pts and 46.1% (95% CI 37.3 - 54.9) in younger subjects, respectively (p=0.002). Conclusions. Despite the elderly carried a higher number of comorbidities and were treated with lower starting and titrated doses of RUX,RUX was feasible and effective in this setting, achieving clinical responses similar to younger subjects, with comparable toxicity rates. Thus, the study do not support to restrain the use of RUX based on older age and comorbidities. Figure Figure. Disclosures Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Tiribelli:Novartis: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. Cavo:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria, Research Funding. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

Background: Response to ruxolitinib (RUX), the only JAK1/2 inhibitor commercially available for the treatment of Myelofibrosis (MF) may vary among patients (pts) and is largely unpredictable at therapy start. Therefore, pts' selection is based only on clinical needs. Aims: To evaluate the impact of pre-treatment clinical/laboratory factors, as well as RUX dose, on response to RUX in a cohort of "real-life" MF pts. Methods: A multicenter observational study on WHO-defined MF was conducted in 18 Italian Hematology Centers. Data were extracted from a database that included retrospective data on pts treated before January 2015. Subsequently, data were prospectively collected and updated at a 6-month interval.Response to RUX was evaluated according to IWG-MRT criteria. Results: Between June 2011 and Apr 2016, 408 pts with PMF (54.4%), or postET (27.7%) / post-PV (17.9%) were treated with RUX. At RUX start, baseline characteristics were (median): age, 68.5 y (range, 26.5-89); ≥65 y, 63.5%; male, 56.4%; hemoglobin (Hb), 10.7 g/dL (7-16.7); transfusion-dependence 27.9%; PLT, 256×109/L (50-1887); PLT Molecular data were available for 332 pts (81.4%) and was positive in 81% (JAK2V617F), 6.3% (CALR), 1% (MPLW515K/L); 2.7% (triple negative). 30 pts (9%) were JAK2V617Fnegative but did not receive further molecular evaluation. Karyotype was abnormal in 55 (26%) out of 210 evaluable pts (unfavorable: 8.1%). Median follow-up from MF diagnosis was 3.8 yr (0.3-29.6) and median RUX exposure was 20 mos (3-56.2). Overall, 152 out of 365 (42%) pts with spleen ≥5cm achieved a spleen response at any time during RUX therapy. At 3 and 6 mos, the response was achieved by 26.6% and 34.4% of evaluable pts, respectively. In univariate analysis, pre-treatment factors negatively correlating with spleen response were: transfusion dependence, platelet count ≤200x109/l, spleen palpable ≥10 cm below costal margin, grade 3 marrow fibrosis, intm-2/high IPSS risk and interval between MF diagnosis and RUX start ≥2y. Three variables remained significant in multivariate regression logistic analysis: large splenomegaly (HR: 2.05, 95%CI: 1.1-3.7; p=0.02), time-interval ≥2y (HR: 1.78, 95%CI:1.0-3.1; p=0.04) and transfusion dependency (HR: 1.95, 95%CI:1.0-3.7; p=0.04). Spleen response significantly correlated with the average RUX dose in the first 12 wks, with pts treated with doses ≥10 mg BID having better response rates (47.3% vs 26.6% if dose 360 pts had a TSS >10 at RUX start and 319 (88.6%) achieved a symptom response. In multivariate analysis, factors associated with worse responses were: transfusion dependency (HR: 3.15, 95%CI 1.5-6.4, p=0.001) and a baseline TSS >20 (HR: 6.7, 95%CI 3.2-13.8, p Drug-related anemia (acquisition of transfusion dependency or Hb 80 (19.6%) pts discontinued RUX because of: lack/loss of response (28.8%); drug-related toxicity (27.5%, specifically: thrombocytopenia, 16.2%; infection, 6.3%; anemia, 5%); disease progression with/without acute evolution (8.8%); death (13.8%); allogeneic transplant (8.8%); 2ndneoplasia (3.8%); other unrelated causes (8.5%). Summary/Conclusion: In a real-life setting, IWG-MRT-defined spleen and symptoms response rates were observed in 42% and 88.6% of evaluable pts, respectively. Disease severity (in terms of transfusion dependency and large splenomegaly) and a delay in RUX start ≥2yr from diagnosis identified pts with lower spleen response rates. Titrated doses Disclosures Palumbo: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Bonifacio:Novartis: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy. Tiribelli:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Fanin:Novartis: Speakers Bureau. Merli:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Breccia:Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

In patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), the anti-thrombotic and/or cytoreductive treatment in the follow-up may affect the evaluation of the pro-thrombotic weight of the clinical and biological characteristics at diagnosis. In order to avoid this potential confounding effect, we investigated the relationship between prior thrombosis (PrTh: thrombosis occurred before diagnosis and before treatment) and the characteristics at diagnosis in 977 thrombocythemic patients with MPN, reclassified according to the WHO 2008 criteria. PrTh occurred in 194 (19.9%) patients, with similar rates in the different MPNs. In multivariate analysis, PrTh rate was significantly related to minor thrombocytosis (platelets ≤700 × 109/L), leukocytosis (leukocytes >10 × 109/L), higher hematocrit (HCT >45%), JAK2 V617F mutation, older age, and cardiovascular risk factors (CVRFs). The highest PrTh rate (33.9%) was associated with the coexistence of minor thrombocytosis and leukocytosis. Of note, the inverse relationship between PrTh rate and platelet count is consistent with the hemostatic paradox of thrombocytosis. In conclusion, this analysis in MPN patients disclosed the unbiased characteristics at diagnosis with a pro-thrombotic effect. Moreover, it suggests that the optimal control of blood cells counts, and CVRFs might be of utmost importance in the prevention of thrombosis during the follow-up.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Prior thrombosis is a well-established risk factor for re-thrombosis in polycythemia vera and essential thrombocythemia but scarce data are available on the rate of re-thrombosis and the optimal strategy for prevention of recurrence.We retrospectively estimated the rate of recurrence in a multicenter cohort of 494 patients (poly-cythemia vera/essential thrombocythemia 235/259) with previous arterial (67.6%) or venous thrombosis (31%) or both (1.4%). First thrombosis was cerebrovascular disease in 191 cases, acute coronary syndrome in 106, peripheral arterial thrombosis in 44, and venous thromboembolism in 160. Microcirculatory events were not computed.Thrombosis recurred in 166 patients (33.6%), with an incidence of 7.6% patient-years. Sex, diagnosis (polycythemia vera or essential thrombocythemia), and presence of vascular risk factors did not predict recurrence, whereas age60 years did (multivariable hazard ratio [HR], 1.67; 95% confidence interval [CI] 1.19-2.32). Increased leukocyte count at the time of the first thrombosis was a risk factor for recurrence in patients60 years old (HR 3.55; 95% CI 1.02-12.25). Cytoreduction halved the risk in the overall cohort (HR 0.53; 95% CI 0.38-0.73) and the combination with antiplatelet agents or oral anticoagulants was more effective than administration of single drugs. Significant prevention of rethrombosis was independently achieved in patients with venous thromboembolism by both oral anticoagulants (HR 0.32; 95% CI 0.15-0.64) and antiplatelet agents (HR 0.42; 95% CI 0.22-0.77), in those with acute coronary syndrome by cytoreduction (HR 0.30; 95% CI 0.13-0.68), and in those with cerebrovascular disease by antiplatelet agents (HR 0.33; 95% CI 0.16-0.66). The overall incidence of major bleeding was 0.9% patient-years and rose to 2.8% in patients receiving both antiplatelet and anti-vitamin K agents.In patients with polycythemia vera and essential thrombocythemia, cytoreduction protects against recurrent thrombosis, particularly after acute coronary syndrome. The contemporary use of oral anticoagulants (after venous thromboembolism) or antiplatelet agents (after cerebrovascular disease or venous thromboembolism) further improves the protective effect. Such findings call for prospective studies aimed at investigating whether strategies tailored according to the type of first thrombosis could improve prevention of recurrences.

Purpose The risk of recurrent venous thromboembolism (VTE) in patients with polycythemia vera and essential thrombocythemia has been scarcely addressed, and whether long-term oral anticoagulant treatment or acetylsalicylic acid should be recommended after first occurrence of deep venous thrombosis (DVT) is unknown. This multicenter cohort study was aimed to assess the rate of recurrent VTE in patients with polycythemia vera or essential thrombocythemia in comparison with a control group of individuals with previous VTE and without neoplastic diseases. Patients and Methods We retrospectively estimated the rate of recurrence in 79 patients with myeloproliferative disorders (MPDs; polycythemia vera/essential thrombocythemia, 45/34) and with a previous proximal DVT. Patients were divided into 2 groups. The first comprised 41 patients who received acetylsalicylic acid after 6 months of oral anticoagulant treatment. The second group was composed of 38 patients given long-term oral anticoagulant treatment without acetylsalicylic acid. The majority of patients were treated with cytotoxic drugs. The results were compared with the recurrences seen in 176 patients without cancer with previous proximal DVT given short-term oral anticoagulant treatment. Results In the patients with polycythemia vera and essential thrombocythemia, the rate of recurrent DVT was higher in the group receiving acetylsalicylic acid (32%) compared with the group on oral anticoagulant treatment (16%), although not statistically significant. The rate of recurrent DVT in MPD cases receiving acetylsalicylic acid was quite similar to that of patients without cancer (33%). The cumulative probability of recurrent VTE indicated a trend of fewer events in the MPD cases on long-term oral anticoagulant treatment. In the patients with MPDs, the incidence of major bleeding during oral anticoagulant treatment or acetylsalicylic acid was 1% and 0.5% patient-years (years of observation), respectively. Conclusion This retrospective analysis would suggest a long-term oral anticoagulant treatment after a first DVT in patients with polycythemia vera and essential thrombocythemia. However, this indication should be weighed against the risk of major hemorrhagic events that seems lower during long-term prophylaxis with acetylsalicylic acid. Therefore, a prospective clinical trial comparing acetylsalicylic acid in patients with polycythemia vera and essential thrombocythemia with oral anticoagulant treatment in the prevention of recurrent VTE is warranted.

Cytogenetic and fluorescence in situ hybridization studies were successfully performed in 217 chronic lymphocytic leukemia (CLL). In all, 13 patients with 6q21 deletion were identified and characterized in comparison with 92 patients with 'favourable' karyotype (normal or 13q-), 69 cases with 'intermediate risk' (1-2 anomalies) and 43 cases with 'unfavourable' karyotype (complex, 11q- or 17p-). Six out of 13 cases with 6q- showed an excess of atypical lymphocytes, a finding confirmed at the histologic level;20% CD38+ cells were seen in 5/6 cases. IGVH mutational status revealed98% homology to the germline sequence in 4/10 cases. When compared with the 'favourable' group, patients with 6q- showed a higher white blood cell (WBC) count, frequent splenomegaly, atypical morphology, CD38+ and short time from diagnosis to first treatment and short survival. A higher median WBC count was found in the 6q- group vs the intermediate-risk group; survival was shorter in the unfavourable group. To ascertain if the 6q- anomaly was an independent factor predicting for an inferior outcome among those patients with 'favourable' cytogenetics, we performed an analysis of prognostic factors in 105 patients (92 'favourable' plus 13 with 6q-), showing that the 6q- chromosome maintained its prognostic significance at multivariate analysis (P=0.02) along with stage (P=0.01). We conclude that CLL with 6q- is characterized by a high incidence of atypical morphology, classical immunophenotype with CD38 positivity and intermediate incidence of IGVH somatic hypermutation. Clinicobiological features and outcome show that this cytogenetic subset of CLL should be allocated in an intermediate-risk category.

The urokinase-type plasminogen activator (uPA) system, which consists of a proteinase (uPA), a receptor (uPAR or CD87) and inhibitors, is involved in proteolysis, cell migration, tissue remodelling, angiogenesis and cell adhesion. Recent findings suggest that malignant plasma cells express uPA and uPAR. The expression of these factors could represent a process by which myeloma plasma cells interact with the bone marrow (BM) environment and influence important biological events such as bone matrix degradation, plasma cell invasion and homing and, possibly, clinical evolution. We evaluated uPAR (CD87) and its soluble form (suPAR) in 49 multiple myeloma (MM) patients and correlated their expression and levels with clinico-biological characteristics of the disease. Flow cytometric analysis demonstrated that CD87 was expressed in all MM patients. High CD87 expression was associated with higher intensity of expression of CD56 (P = 0.038), CD38 (P = 0.058) and CD138 (P = 0.054) and CD45bright positivity (P = 0.014). suPAR levels correlated positively with soluble serum CD138 (P = 0.001), creatinine (P = 0.001), beta2-microglobulin (P < 0.001), disease stage (P = 0.017) and extra-BM involvement (P = 0.002). In the 46 evaluable patients, multivariate analysis showed that high levels of suPAR (P = 0.0214) and disease stage (P = 0.0064) were predictive of extra-BM involvement. In multivariate Cox analysis, 13q deletion (P = 0.0278), high soluble serum CD138 (P = 0.0201) and high suPAR (P = 0.0229) were the only parameters that independently affected survival. We conclude that CD87 is expressed on myeloma plasma cells and that suPAR, which predicts extra-BM involvement and poor prognosis, possibly represents a molecule with a relevant role in the biology of MM.

Background. The therapeutic approach in thrombocythemic patients with Philadelphia negative chronic myeloproliferative neoplasms (Ph- MPN), in order to result cost-effective (primum non nocere), is commonly driven by the risk factors considered in the gradually updated guidelines. However, no studies were addressed to evaluate if and how the real-life therapeutic approach changed in the last decades. Objective. To evaluate, in a large series of thrombocythemic patients with Ph- MPN, the impact of clinical and biological characteristics at diagnosis on the therapeutic approach adopted before and after the publication of the Italian guidelines for essential thrombocythemia therapy [1]. Methods. The analysis considered, in the patients of the Registro Italiano Trombocitemie (RIT), the clinical and biological characteristics at diagnosis, and the treatment ongoing after 3, 6, 12, and >12 months from diagnosis (antiplatelet alone [AntiPLT]; cytoreductive alone [CYT]; CYT+AntiPLT). Results. The analyzed patients were 2418, 914 (38%) males and 1504 (62%) females, with a diagnosis (PVSG or WHO criteria) performed before and after 2005 in 51% and 49% of cases, respectively. The rate of ongoing treatment with AntiPLT, CYT, and CYT+AntiPLT increased as follows: at 3rd month 16%, 12%, and 31%; at 12th month 17%, 14%, and 39%; after 12 months 19%, 16%, and 55%, respectively. Patients treated with CYT or CYT+AntiPLT did not significantly differ in their characteristics at diagnosis. The analysis of data at the 3rd month (initial phase) showed that: 1) CYT±AntiPLT treatment, ongoing in 43% of patients, was significantly related, in univariate analysis, to male gender, older age, prior thrombosis, higher thrombocytosis, leukocytosis, higher HCT level, CVRFs, comorbidities, symptoms, splenomegaly, hepatomegaly, and bone marrow fibrosis grade >0 (no relationship with JAK2 V617F mutation, and prior hemorrhage); in multivariate analysis, it was significantly related to age >60 y, age 40-60 y, prior thrombosis, PLT >1000 x109/L, PLT 700-1000 x109/L, symptoms, and comorbidities. 2) patients with standard high risk (age >60 y, and/or prior thrombosis, and/or PLT >1500 x109/L ) were receiving CYT±AntiPLT (59%), AntiPLT (7%), and no treatment (34%). 3) patients with standard low risk were receiving CYT±AntiPLT (22%), AntiPLT (27%), and no treatment (51%). Low risk patients receiving CYT±AntiPLT had age 40-60 y (73%), CVRFs (59%), symptoms (53%), comorbidities (42%), PLT 1000-1500 x109/L (35%), PLT 700-1000 x109/L (42%), JAK2 V617F mutation (30%), WBC >10 x109/L (22%). 4) in patients receiving CYT±AntiPLT, the initial cytoreductive drug and the median age were: hydroxycarbamide (80%, 68 y), anagrelide (6%, 49 y), interferon alpha (9%, 42 y), pipobroman (2%, 72 y), busulfan (3%, 70 y). The AntiPLT drug mostly used was low dose ASA (86-90% of cases, at any age). 5) Patients diagnosed after 2005, compared with those diagnosed before, showed a higher rate of CYT±AntiPLT treatment when at standard high risk ( 64% vs 53 % p Conclusion. The initial (within the 3rd month) therapeutic approach in the thrombocythemic Ph- MPN patients of the RIT was after 2005 relatively compliant with the 2004 Italian guidelines. In fact, the rate of CYT±AntiPLT treatment in patients with standard high risk was higher than before (64% vs 53%, p [1] Barbui T et al. Haematologica 2004; [2] Harrison C et al. NEJM 2005; [3] Gisslinger H et al. NEJM 2013; [4] Passamonti F et al. Blood 2012; [5] Barbui T et al. Blood 2012 *The RIT is a project of the GIMEMA Foundation Disclosures Gugliotta: Shire : Honoraria.

Background: the Registro Italiano Trombocitemie (RIT) was activated mainly to evaluate the diagnosis and therapy appropriateness in the thrombocythemic patients with Ph-negative myeloproliferative neoplasm (MPN) observed in the adhering centers. Objective: to evaluate how the diagnostic and therapeutic approach changed in the RIT patients diagnosed with thrombocythemic MPN in the last two decades. Methods: the RIT centers registered by a web-based system during the years 2005-2014 their thrombocythemic MPN patients, and semesterly updated their follow-up data. For patients diagnosed before 2005, the data on diagnosis and prior follow-up were retrospectively collected. The diagnostic process and the initial treatment (started into the first year after diagnosis) were comparatively analyzed in the patients diagnosed before and after 2005. Results: the RIT centers registered 2629 patients. 2388 of them, object of this analysis, were diagnosed between1995 and 2014: 1098 (46%) in the decade 1995-2004 (Group I), and 1290 (54%) in the decade 2005-2014 (Group II). The diagnostic process in the patients of Group II and Group I included bone marrow biopsy (BMB, performed into 1 year and before any cytoreduction): 85% vs 80%, p The patients of Group II, as compared with those of Group I, showed a similar gender distribution (M/F ratio 0.61 vs 0.65, p 0.452), and had at diagnosis: a higher age (median 60 vs 57 years, p 60 years in 50% vs 45% of cases, p Moreover, they had: a lower platelet (PLT) count (median 737 vs 775 x 109/L, p 10 x 109/L in 28% vs 26% cases); a similar median levels of hematocrit (HCT %, in females 41.4 vs 41.0; in males 44.7 vs 44.6) and hemoglobin (Hb g/dL, in females 13.8 vs 13.6; in males 15.0 vs 14.9). The BMB, revised according to the WHO 2008 criteria, showed a not different distribution (p 0.21) of ET (64% vs 61%), ep-PMF (16% vs 17%), PMF (3% vs 2%), PV (4% vs 4%), and U-MPN (13% vs 16%. The JAK2 V617F mutation in patients of Group II (at diagnosis) and of Group I (after diagnosis) was found in 62% and in 58% of tested cases (p 0.054), respectively. The patients at high standard thrombotic risk were 58% vs 52%, p 0.004. In the patients of Group II and Group I the distribution of the treatment started into the first year was significantly different (p The treatment CYT ± AntiPLT was started in the patients at high standard thrombotic risk with a rate of 81% vs 80%, respectively, and in the patients at low standard thrombotic risk in 37% vs 43% of cases, respectively. The initial treatment CYT±AntiPLT was related, in multivariate analysis, both in patients of Group II and Group I, with older age (>60 and 40-60 vs 1000 and 700-1000 vs Conclusion: in the studied thrombocythemic MPN patients the real-life diagnostic approach was improved after 2005 not only due to the routine use of JAK2 tests, but also due to the higher rate of BMB done (85% vs 80%). The appropriateness of the cytoreductive treatment (CYT±AntiPLT started into one year from diagnosis) remained high in patients at high standard thrombotic risk (over 80% of cases were treated). Concomitantly, the inappropriate use of the cytoreductive drugs in patients at low standard thrombotic risk appreciably decreased (from 43% to 37% of cases). Moreover, it has to be remarked that the therapeutic approach was significantly influenced not only by older age and prior thrombosis, but also by thrombocytosis (PLT count >700 x 109/L), disease-related symptoms, and inconstantly by leukocytosis and CVRFs. Table Table. Disclosures Gugliotta: SHIRE Co.: Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Abstract 4 Introduction Current treatment recommendations in polycythemia vera (PV) have emphasized to maintain the hematocrit (HCT) values Aim In a large scale randomized clinical trial (Cyto-PV) we prospectively determined the efficacy and safety of maintaining the recommended HCT target versus HCT levels in the range of 0.45–0.50 to prevent thrombotic events in PV patients. Methods Patients were eligible if they met WHO-2008 diagnostic criteria for PV. Both cases with newly diagnosed disease and previous treatment were centrally randomized to Arm A (HCT Results Arm A and Arm B included 182 and 183 patients respectively. At randomization, there were no significant differences between the two groups with respect to age, gender, years from diagnosis to recruitment, previous history of major thrombosis, bleeding, concomitant cardiovascular risk factors, and hematological presentation. Treatments were equally distributed with regard to phlebotomy, antiplatelet drugs, warfarin and hydroxyurea or their combination. After randomization, median HCT levels in arm A and Arm B during follow-up (median 31.0 months) were 0.44 and 0.48 respectively. A quarter of patients of arm A and Arm B failed to maintain the assigned HCT levels during the study period. Noticeable was that leukocyte levels remained higher in arm B than Arm A while no difference was revealed concerning the platelet count. Additionally, no difference in the safety profile was recognizable. As compared with arm B, the more intensive treatment aimed at maintaining the HCT Conclusion In this randomized clinical trial, the incidence of major cardiovascular events was 4 fold higher in patients who maintained HCT levels >0.45. Therefore, an HCT level Disclosures: No relevant conflicts of interest to declare.

Background. In patients with Ph-negative chronic myeloproliferative neoplasm (MPN) the molecular pattern, beside other characteristics at diagnosis, has been related to the disease prognosis. Aim. To compare clinical and biological features at diagnosis and during the follow-up in gender/age-matched MPN patients showing different molecular pattern. Material and methods. The Registro Italiano Trombocitemie (RIT) is a web-based registry that includes thrombocythemic MPN patients diagnosed according to PVSG or WHO criteria, registered after 2005, and then prospectically followed. The JAK2 V617F mutation (JAK2+) was reported in 941 (58.4%) out of 1610 tested patients. On the basis of subsequent tests, performed in part of the JAK2 WT (JAK2-) subjects, 103 patients were JAK2-/CALR+ (CALR+), 14 patients were JAK2-/CALR-/MPL+ (MPL+), and 46 were JAK2-/CALR-/MPL- (3NEG). The 103 CALR+ patients were compared with 309 (103 x 3) JAK2+ patients matched for gender, age, and revised diagnosis (WHO 2008 criteria). A similar comparison was done between 46 3NEG patients and other 138 (46 x 3) JAK2+ matched patients. Results. CALR+ and matched JAK2+ patients had, as expected, the same gender distribution (males 41%), the same median age (51 years), and no significant difference (p 0.42) in the WHO diagnosis distribution. CALR+ patients, as compared with JAK2+ patients, showed at diagnosis: higher median platelet (PLT) count (839 vs 718 x109/L, p CARL+ and JAK2+ patients had the same rate of antiplatelet and cytoreductive treatment (96% vs 96%, and 86% vs 84%, respectively). During the follow-up the incidence of thrombotic and hemorrhagic events was not significantly different (1.3 vs 1.1/100 pt-years, and 1.0 vs 0.6/100 pt-years, respectively). Moreover, no significant difference was observed in the incidence of evolution to overt primary myelofibrosis (PMF, 0.76 vs 0.61/100 pt-years), polycythemia vera (PV, 0 vs 0.24/100 pt-years), and AL/MDS (0.08 vs 0.10/100 pt-years). Finally, the same overall survival was found after 5, 10. 15, and 20 years (99, 97, 94, 93%, respectively). 3NEG patients, as compared with JAK2+ matched patients, showed at diagnosis: lower median WBC count (7.9 vs 10.9 x 109/L, p 0.03); lower Hb and/or HCT level (p 0.006); lower rate of splenomegaly (7% vs 28%, p 0.003); lower rate of symptoms (35% vs 51%, p 0.049). No significant difference was found in: median PLT count (700 vs 720 x 109/L, p 0.61); PrTh (7% vs 16%, p 0.11); prior hemorrhage (4.7% vs 7.5%, p 0.52); high/intermediate thrombotic risk (IPSET, 36 vs 48%, p 0.37). Moreover, no significant difference was observed during the follow-up in: antiplatelet and cytoreductive treatment; thrombosis and hemorrhage rate; PMF, PV, and AL/MDS evolution; overall survival. Conclusion. CALR+ patients, as compared with JAK2+ matched patients, although showed a lower thrombotic risk (lower WBC and HCT levels, lower PrTh rate), received the same antiplatelet and cytoreductive treatment, had the same incidence of adverse events during the follow-up (vascular complications and disease evolution/transformation), and had the same overall survival. 3NEG patients, as compared with JAK2+ matched patients, showed results similar to those observed by comparing CALR+ and JAK2+ matched patients. To better define the role of the precise definition of molecular pattern in Ph-MPN patients, new prospective controlled studies seem necessary. Disclosures De Stefano: Janssen Cilag: Research Funding; Roche: Research Funding; Novartis: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Bruno Farmaceutici: Research Funding; Celgene: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Shire: Speakers Bureau. Passamonti:Novartis: Consultancy, Honoraria, Speakers Bureau.

Background In patients with Ph-negative MPN, a prior thrombosis (PrTh) occurs in around 1/5 of cases, with variable platelet (PLT) count and variable distance from diagnosis. Objective To investigate the influence of PLT count at PrTh on diagnostic and therapeutic approach in MPN patients. Material and methods We evaluated 129 MPN patients from RIT, reclassified according to WHO 2008 criteria as ET (n70), initial-primary myelofibrosis (n29), early-PV (n10), and unclassifiable-MPN (n20). Results Patients, 60 males and 69 females, showed following PrTh: 91(71%) major arterial (37 AMI, 4 angina, 24 stroke, and 26 TIA); 12(9%) minor arterial; 22(17%) major venous (8 DVT, 7 splanchnic, 4 cerebral sinus, 3 pulmonary embolism); and 4(3%) minor venous events. PrTh occurred at a median distance of 4.1 months (range 0.1-118) from MPN diagnosis. This distance was >24 months in 21(16%) patients. At occurrence of PrTh, median age was 58 years. PLT count (x109/L) had a median value of 661 (range 150-2200), and was ≤450, 451-600, 601-700, 701-1000, and >1000 in 15(12%), 35(27%), 26(20%), 43(33%), and 10(8%) patients, respectively. Median white blood cell (WBC) count was 9.0 x 109/L and median hematocrit (HCT) value was 46% in males, and 41% in females. Median time (months) from PrTh to diagnosis of MPN was higher (p0.004) in patients with lower PLT count (x 109/L): ≤450 (50.2), 451-600 (11.7), 601-700 (2.7), 701-1000 (1.8), and >1000 (1.4). After occurrence of PrTh, all patients received conventional anti-thrombotic treatment, but in 7(5.4%) patients 9 recurrent thrombosis were reported before MPN diagnosis (11/100 pt-years). At MPN diagnosis, clonality was documented in 101(78%) patients (JAK2 V617F mutation in 96 cases, 74%). The age was >60 years in 61(47%) patients. PLT count (x109/L) had a median value of 720 (166-2440), and was ≤450 (n 7, 5%), 451-600 (n 21, 16%), 601-700 (n 28, 22%), 701-1000 (n 58, 45%), >1000 (n15, 12%). WBC count (109/L) had a median value of 8.9, and was >10 in 40 (31%) cases. Median HCT level (%) was 45.6 in males and 42.1 in females. Cardiovascular risk factors (CVRF), comorbidities and symptoms were documented in 103(80%), 97(75%), and 57(44%) cases, respectively. Thrombotic risk (IPSET-Th) was high in 97.5%, and intermediate in 2.5% of cases. All 129 patients received anti-thrombotic drugs (low dose aspirin in 95% of cases) and, immediately after the diagnosis, they started a cytoreductive treatment (hydroxycarbamide 89%, anagrelide 8%, interferon-alpha 3%). Patients with a PLT count (x109/L) at PrTh ≤600(n 50), as compared with those with a PLT count >600(n 79), showed a longer median time to the MPN diagnosis (16.7 vs 2.0 months, p60 years (52% vs 44%, p0.39); CVRF (82%vs79%, p0.63); WBC >10 x109/L (23% vs 39%, p0.07); HCT high level [>47% in males, >44% in females](28% vs 36%, p0.37), and high thrombotic risk [IPSET-Th] (96%vs99%, p0.56). During follow-up (median 7.9 years) they showed a higher incidence of thrombosis recurrence (30%vs15%, p0.04; 4.5 vs 1.7/100 pt-y, p Conclusion Time to MPN diagnosis was significantly longer in patients with PLT count (x109/L) at PrTh ≤600 vs >600, and this time to diagnosis was characterized by a not negligible thrombosis recurrence. Moreover, during follow-up they showed a higher incidence of thrombosis recurrence. This analysis strongly suggests that a PLT count Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees.