Abstract: 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.

Abstract: Patients with Philadelphia-negative myeloproliferative neoplasms (MPN) can develop venous thrombosis and MPN are the leading cause of splanchnic vein thrombosis. Cerebral vein thrombosis (CVT) is a rare life-threatening disease that in approximately 3% of cases encounters MPN among risk factors and tends to recur in 2-4% of patients as CVT and in 4-7% as venous thrombosis at other sites. Little or no information is available on patients with MPN who develop CVT. Objective and design To investigate the characteristics and clinical course of CVT in patients with MPN we carried out a multicenter (n=11), observational, retrospective cohort study. Patients Centers were asked to provide information on index patients with MPN who developed CVT (group MPN-CVT). For each of them, 2 patients with MPN and venous thrombosis other than CVT (group MPN-VT) and 4 patients with MPN and no venous thrombosis (group MPN-NoVT) were provided, matched by sex, age at diagnosis of MPN (+/-5 years) and type of MPN (polycytemia vera, essential thrombocytemia, myelofibrosis) with index patients. Results From January 1982 to June 2013, 48 MPN-CVT, 87 MPN-VT and 178 MPN-NoVT patients were identified in a population of 5,500 patients with MPN. Diagnosis of MPN and thrombosis coincided in 46% of MPN-CVT and 29% of MPN-VT patients (p=0.046). Compared to MPN-NoVT, MPN-CVT and MPN-VT patients had a higher prevalence of thrombophilia abnormalities (40% and 35% vs 21%, p=0.015) and, among those with essential thrombocytemia, of the JAK2 V617F mutation (76% and 78% vs 55%, p=0.059). Compared to MPN-VT, MPN-CVT patients had a higher rate of recurrent thrombosis (42% vs 25%, p=0.049) that in two-third of patients in both groups was venous, with a similar site distribution. This difference occurred despite a shorter median follow-up period (6.1 vs 10.3 years, p=0.019), a higher proportion of patients on long-term antithrombotic treatment (94% vs 84%, p=0.099) and a similar proportion of patients on cytoreductive treatment (75% vs 72%, p=0.745) among MPN-CVT than MPN-VT patients. The incidence of recurrent thrombosis was 8.8% patients/year in MPN-CVT and 4.2% patients/year in MPN-VT patients (log-rank test, p=0.022) and CVT was the only variable in a multivariate model including blood counts, thrombophilia, cytoreductive and antithrombotic treatment, that was predictive of recurrent thrombosis (HR 1.86, 95%CI 1.00-3.58). Conclusions Patients with MPN develop recurrent thrombosis in a much higher proportion than those without, particularly if they had a CVT. Patients with MPN and CVT have an approximately 2-fold increased probability to develop recurrent thrombosis than those with MPN and venous thrombosis at other sites, independently of other risk factors. Disclosures: No relevant conflicts of interest to declare.

Abstract: 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.

Abstract: Abstract 4 Introduction Current treatment recommendations in polycythemia vera (PV) have emphasized to maintain the hematocrit (HCT) values 〈 0.45 based on hemorrheological notions, results of a few small observational retrospective studies and consensus of experts. However, post-hoc analysis of two large randomized clinical trials (namely PVSG-1 and ECLAP) failed to show a different incidence of major thrombosis when HCT levels were kept in the range between 0.40 and 0.50. So far, no randomized clinical trial has provided evidence-based data assessing the usefulness of tight HCT control in reducing thrombosis. Thus, uncertainty of the optimal HCT target exists in clinical practice. 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 〈 0.45) ) or to Arm B (HCT 0.45–0.50). The composite primary end points from randomization were major thrombosis (stroke, acute coronary syndrome, transient ischemic cerebral attack, peripheral arterial thrombosis, pulmonary embolism, abdominal thrombosis, deep vein thrombosis), and cardiovascular death. Secondary end points were the incidences of hematological transformation to myelofibrosis and acute leukemia. From February 2008 to May 2012, 21 Italian hematological centers enrolled 365 patients. The trial was closed in May 2012 because the research network had reached its maximal recruitment potential and the effect of the two treatment strategies were evaluated as to efficacy and safety. 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 〈 45% reduced the risk of the primary combined endpoint ( 1.1% versus 4.4% /patients per year; HR =3.90, p=0.007). Seven patients developed overt myelofibrosis (6 in Arm A and 1 in Arm B; p=0.10). There was no difference concerning frequencies of acute leukemia that occurred in 3 and 1 patients of Arm A and B respectively. 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 〈 0.45 is significantly associated with a prevention of thrombotic complications and is confirmed to be the target of therapy in PV. Disclosures: No relevant conflicts of interest to declare.

Abstract: Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative diseases characterized by frequent episodes of deep venous thrombosis (DVT), arterial thromboembolism (AT) and by hemorrhagic complications. Surgical procedures could represent a risk factor for thrombosis and bleeding, but no data on the real frequency of these complications are available. To estimate the frequency of thrombosis and haemorrhages after surgical procedures and their outcomes, a multicenters retrospective analysis was performed. Data from 105 PV and 150 ET patients (128 males, 127 females, median age at diagnosis 60, were analyzed, for a total of 311 surgical interventions. At least one risk factor for arterial thrombosis (diabetes mellitus, hypercholesterolemia, arterial hypertension, previous AT, smoke) was present in 128/255 (50.1%), more frequently in PV than in ET patients (58.5 vs. 46.8%, p=0.02). An excess of male and older patients in PV than in ET explained this finding (multivariate analysis). Previous DVT was present in 9/255 patients (3.5%). After diagnosis, antiplatelet drugs were given to 211/255 patients (82.7%); cytoreductive treatments to 188/255 (74%), warfarin to 16/255 (6.2%); all PV patients were phlebotomized. In 25/311 surgeries (8.0%), an emergency procedure was performed; 195 surgeries were done under general anaesthesia; 21/91 abdominal interventions (23%) were performed under laparoscopy. Major surgeries were 160/311 (51.4%). Data about antithrombotic prophylaxis were available for 292/311 surgeries: in 126 (43.2%) low molecular heparin, in 38 (13%) unfractioned heparin, in 5 (1.7%) warfarin and in 123 no anticoagulant therapy was administered. In 45/123 (36.6%) patients without antithrombotic prophylaxis, antiplatelet therapy was administered before surgery. 189/255 (74%) were on cytoreductive therapy before surgery; for 9 surgical procedures, a short cycle of chemotherapy was administered before surgery. Clinical outcomes after surgery were recorded with a 3 months follow-up. No event was observed in 259/311 procedures (83.2%); there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages and 5 deaths. AT were more frequent in ET patients (5.3 vs. 1.5%, p=0.08) while venous events were more frequent in PV patients (7.7 vs. 1.1%, p=0.002). There was a strong risk gradient for AT associated with the presence of one or more arterial risk factors (OR for 4 or more risk factors: 40.9, p=0.003). Platelet count and hematocrit at surgery (median 477 x 109 /l and 42.6%, respectively) were not associated with either venous or arterial thrombosis. There was no correlation between bleeding episodes and type of diagnosis, use of antithrombotic prophylaxis and type of surgery. In conclusion, despite an active approach (cytoreduction and antithrombotic prophylaxis in the majority of the cases) a high proportion of PV and ET surgeries was complicated by DVT and AT (7.7%) but also by major hemorrhages (7.3%), requiring more investigation on the optimal prophylaxis in these patients.

Abstract: 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.

Abstract: Abstract 1748 Introduction: Polycythemia vera (PV) is a chronic myeloproliferative neoplasms characterized by erythrocytosis, vasomotor disturbances, pruritus, risk of disease progression into acute myeloid leukemia or myelofibrosis and cardiovascular events, the last representing the main cause of morbidity and mortality. Since 2005 the V617F point mutation in Janus Kinase 2 (JAK2) gene gained a dominant role in determining the molecular basis and the diagnosis of PV. We compared the clinical epidemiology of the 1638 patients included in the ECLAP trial in the years 1997 to 2001, with that of a “modern” cohort of 365 PV, JAK2-positive patients included in the Italian CYTO-PV randomized clinical trial and followed from the year 2008 to 2012. Methods: Patients were eligible in CYTO-PV trial and in ECLAP study if they met WHO-2008 diagnostic criteria and the criteria established by the PVSG or Pearson/Messinezy respectively. Clinical characteristics have been compared. The incidence of major cardiovascular events (CV death plus major thrombosis [stroke, acute coronary syndrome, transient ischemic cerebral attack, peripheral arterial thrombosis, pulmonary embolism, abdominal thrombosis, deep vein thrombosis) and total CV events incidence has been evaluated. The median follow up was 31.0 months (range 0– 48.13 months) and 33.1 months (range 0–63.6) for patients included CYTO-PV and in ECLAP respectively. Results: In CYTO-PV 49.3% patients with recent PV diagnosis were included (within 2 years prior inclusion) while in ECLAP the proportion was 35.5%. Mean age at recruitment was similar for patients in CYTO-PV (64.5 yrs) and ECLAP (65.4 yrs). History of thrombosis was reported in 28.9 % vs 38.6% patients in the CYTO-PV and in ECLAP, respectively (p 〈 0.05). Consistently higher proportions of arterial and venous thrombotic events were found in ECLAP as compared to CYTO-PV. History of major bleeding was reported in 1.7% vs 4.8% of the patients in CYTO and ECLAP, respectively. Medical treatment at recruitment was more intensive in CYTO-PV vs. ECLAP: phlebotomy 72.3% vs 63.5% (ns), hydroxyurea (HU) 54.2 vs 48.4, antiplatelet drugs 84.9% vs 58.3% (p 〈 0.05), aspirin 77.0% vs 50.2% (p 〈 0.05), anti-hypertensive and hypocholesterolemic medications were administered respectively in 48.5% and 13% of CYTO–PV patients vs. 39% and 3.5% of ECLAP population (p 〈 0.05) As compared with ECLAP, the incidence of risk of major thombosis in CYTO-PV was 2.7 vs 4.4 and of total CV events was 3.4 vs 5.5 per 100 person/years, respectively. The incidence of total CV events in CYTO-PV for the subgroups of patients with age 〈 65 and no previous thrombosis (PT), age 〉 65 and no PT, age 〈 65 and PT, age 〉 65 and PT at randomization was 2.2, 4.8, 3.5 and 3.4 per 100 person/years, respectively. Conclusions: The comparison of these two cohorts of PV patients followed 10 years apart suggests that JAK-2 PV patients are currently better managed for the control of classical CV risk factors, are more frequently administered aspirin, and HU with better control of their disease, and eventually have a risk of thrombosis approximately half than in the past. Disclosures: No relevant conflicts of interest to declare.

Abstract: 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.