ALBERT

Description: Introduction: Ruxolitinib has been shown in two randomized clinical trials (RCTs) to be effective in alleviating systemic symptoms and effecting a reduction in spleen size in patients with myelofibrosis (MF). However, JAK2 allele burden is not significantly impacted by this drug and there is no consistent salutary effect on marrow fibrosis or definite improvement in overall survival. Currently, the goals of Ruxolitinib treatment remain palliative. We sought to determine the efficacy and tolerability of Ruxolitinib in a cohort of unselected patients with MF treated in routine clinical practice. Methods: MF patients treated with Ruxolitinib for at least 3 months in 13 participating centers that are members of the Israel Myeloproliferative Neoplasm (MPN) Working Group were identified. The following demographic and clinical data were analyzed: the form of MF [primary (PMF), post polycythemic myelofibrosis (PPVMF), post essential thrombocytosis myelofibrosis (PETMF)], duration of MPN, indication for treatment, initial dose, dose reduction, hematologic toxicity, response to therapy and withdrawal of treatment. Results: One hundred and two patients from 13 centers that began Ruxolitinib between January 2012 and April 2014 were identified. Ninety three patients who were treated for more than 3 months were included in the analysis. Median age at diagnosis was 59 years (range 25-84), 57 % were males. PMF was the diagnosis in 44 patients (47.3%), PPVMF in 29 (31.2%) and PETMF in 17 (18.3%). The median duration of disease was 5 years (range 3 months-35 years) for the entire cohort. Median age at Ruxolitinib initiation was 67 years (range 32-84). Seventy two (78.3%) patients received cytoreductive therapies for MF prior to Ruxolitinib. Indications for treatment were constitutional symptoms only in 14 patients (15%), symptomatic splenomegaly only in 6 patients (6%) and both in 71 patients(76%). Two patients received Ruxolitinib for other indications (non-constitutional symptoms and refractory thrombocytosis). The median initial dose of Ruxolitinib was 30 mg per day (range 10-40mg). Median duration of Ruxolitinib therapy was 11 months (range 3-31 months). Eighty two patients (88.2%) responded to therapy, 76 (84.4%) patients had improvement in constitutional symptoms and 60 patients (70.6%) had reduction in spleen length. While on Ruxolitinib, 60 patients (64%) had a nadir hemoglobin level of less than 10g/dL, 43 patients (46%) had a nadir platelet count of less than 100 x 109/µL and in 12 of them (12.9%) a platelet nadir was less than 50 x 109/µL. Twenty one patients (22.6%) needed packed red blood cell (PRBC) transfusion in the 2 months preceding Ruxolitinib initiation and they received a median of 2.5 units (range 1-8), while 27 patients (29.1%) needed PRBC transfusion in the first 2 months after starting treatment and they received a median of 4 units (range 1-8). Thirty five patients required dose reduction of Ruxolitinib and 14 (15.2%) discontinued their therapy. Univariate analysis revealed that response to Ruxolitinib occurred in patients with a lower white blood cell (WBC) count (median 9.7 x 103/µL vs 21.5 x 103/µL; P=0.033), a greater degree of splenomegaly (median 12 vs 4 cm below costal margin; P=0.001) and hepatomegaly (median 4 vs 0 cm below costal margin; P=0.011). In multivariate analysis, the degree of splenomegaly was found to be predictive of response to treatment (odds ratio=1.263, p=0.03 and 95% CI=1.08-1.476) while there was a trend to improved response in patients with a lower WBC (p=0.074). Conclusions: The present analysis of a cohort of MF patients treated with Ruxolitinib in routine clinical practice has demonstrated the efficacy and tolerability of this drug outside of a highly monitored RCT setting. Data of this sort are currently sparse, and emanate mainly from single-center reports. Our study performed in 13 academic and community hospitals provides real-life evaluation of the utility of Ruxolitinib and factors associated with response to treatment. Disclosures No relevant conflicts of interest to declare.

Description: INTRODUCTION Recent large randomized controlled trials (RCTs) have shown non-vitamin K antagonist oral anticoagulants (NOACs) are at least as effective as vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation (AF) and are associated with similar or lower rates of bleeding. The results for bleeding seen in Phase 3 trials might not be applicable to real world practice. We performed a large population-based study to determine the incidence of bleeding in patients with AF beginning treatment with dabigatran, rivaroxaban or a VKA. METHODS From the computerized database of the 4.5 million member Israeli Clalit Health Services health care provider, consecutive patients initiating a VKA or NOAC for AF between January 1, 2011 and December 31, 2013 were studied. For prevention of embolism in AF, dabigatran had regulatory approval for 36 months and rivaroxaban for 24 months. Bleeding patients who required hospitalization were identified and key clinical and laboratory data were recorded. Because patients received different anticoagulants for different durations, time-to-event analyses were performed and bleeding incidences were calculated and reported as rates per 100 patient-years of treatment. Bleeding sites and all-cause mortality within 30 days were recorded and case fatality rates were calculated as the proportions of bleeding patients who died within 30 days. RESULTS (Table1) 18249 patients initiated anticoagulants for AF: 9564 received VKA, 4170 received dabigatran 110 mg bid , 1806 received dabigatran 150 mg bid and 2709 received rivaroxaban. The bleeding rates per 100 patient-years were 3.9 in VKA-treated patients, 2.8 in dabigatran 150 mg patients, 4.6 in dabigatran 110 mg patients and 4.3 in rivaroxaban patients. The intracranial hemorrhage (ICH) rates per 100 patient-years were 0.70 in VKA-treated patients, 0.37 in dabigatran 150 mg patients, 0.49 in dabigatran 110 mg patients and 0.27 in rivaroxaban patients. The gastrointestinal (GI) hemorrhage rates per 100 patient-years were 1.88 in VKA-treated patients, 1.85 in dabigatran 150 mg patients, 3.36 in dabigatran 110 mg patients and 2.39 in rivaroxaban patients. The case fatality rate for any bleed was 21%; for ICH 28.8%, and for GI bleeds it was 11.1%. Multivariate analysis revealed that increased age and increased serum creatinine were risk factors for bleeding in NOAC-treated patients. CONCLUSIONS The results of our population-based non-randomized study of AF patients are consistent with the RCTs in showing similar rates of overall bleeding, an increase in GI bleeding associated with dabigatran and a reduction in ICH seen with both dabigatran and rivaroxaban. Table 1: Clinical profile of patient cohort VKA Dabigatran 150 mg Dabigatran 110 mg Rivaroxaban Overall Number of patients 9564 1806 4170 2709 18249 Age in years) Median (Range) 79 (27-99) 78 (52-89) 82 (55-95) 82 (58-91) 80 (27-99) Women % 43.8 45.1 47 38.6 43.7 Serum creatinine mg/dL Median (Range) 1.2 (0.3-11.6) 1.0 (0.5-4.4) 1.2 (0.4-4.1) 1.3 (0.5-3.5) 1.2 (0.3-11.6) CHADS2 score Median (Range) 3 (0-6) 3 (1-6) 4 (1-6) 4 (2-6) 3 (0-6) Anti aggregant use (%) 52 50 35 55 48 Bleeds per 100 patient years (N) 3.9 (372) 2.8 (50) 4.6 (191) 4.3 (116) (729) Fatalities within 1 month of hemorrhage N 44 8 15 3 70 Intracranial hemorrhage N 67 4 16 3 90 Gastrointestinal hemorrhage N 178 20 108 26 332 Disclosures Ellis: Boehringer Ingelheim: Honoraria. Eikelboom:Bayer: Honoraria, Research Funding; Bristol Meyers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding.

Description: Introduction: Philadeliphia chromosome negative myeloproliferative neoplasms (MPNs) [polycythemia vera (PV), essential thrombocytosis (ET) and myelofibrosis (MF)] are characterized by an increased risk of venous thromboembolism (VTE). In PV the VTE incidence has been reported to be 7.4% before or at diagnosis and 9% after diagnosis (Tefferi A et al, 2013). In general, the first VTE event provoked by a reversible risk factor warrants 3-6 months of anticoagulation, while VTE associated with active cancer is usually treated until remission. There are no controlled studies evaluating the optimal duration of anticoagulant therapy in MPN patients (pts). A consensus statement regarding prophylaxis and management of VTE in MPN patients (Hernández-Boluda et al, 2015) has recommended permanent anticoagulation only in pts with very high thrombotic risk [recurrent VTE, Budd Chiari Syndrome (BCS), major thrombophilia]. This retrospective study aims to identify characteristics of MPN pts receiving long-term anticoagulant therapy after VTE and to determine the VTE recurrence rate in pts on long-term versus short-term anticoagulation after an initial VTE. Methods: Pts with MPN diagnosed according to World Health Organization criteria, with a history of VTE [cerebral sinus, deep vein thrombosis (DVT), pulmonary embolism (PE), BCS, spleno-portal or mesenteric vein thrombosis] within 2 years prior to MPN diagnosis or at any time thereafter were identified in 8 centers that are members of the Israel MPN Working Group. VTE was diagnosed at least 1 year before data collection. Clinical characteristics and treatment data were recorded. Long-term anticoagulation was defined as therapy for 〉1 year with any anticoagulant. Results: Ninety one MPN pts [31 (34%) - PV, 35 (38%) - ET, 18 (20%) - MF, 7 (8%) - MPN unclassified] with VTE fulfilling study criteria, were included in the analysis. Eighty two percent were JAK2V617F positive (PV-97%, ET-81%, MF-71%, MPN-unclassified-57%). Forty nine pts underwent thrombophilia testing, of whom 21 (43%) had coexistent thrombophilia. Twenty six pts (28.6%) were treated with anticoagulants for less than a year (Group 1), while 65 (71.4%) pts received long-term anticoagulation (Group 2). At time of VTE diagnosis, there were no differences between the groups regarding age, gender, type of MPN, JAK2 V617F mutational status or blood counts.VTE types were the same in both groups, apart from BCS, which was found in Group 2 only (0 vs 16.9%, p=0.029). Thrombophilia testing was done in 66% of pts from Group2 and in 32% of pts from Group 1. Long-term anticoagulation was used in 86% of pts with coexisting thrombophilia and in83% of pts without thrombophilia. Reasons for anticoagulation cessation were: bleeding (n=1), hematologic control (n=8), a transient additional risk for thrombosis at time of VTE (n=3), other reasons such as poor compliance (n=9) and unknown (n=5). At a median follow-up of 6.7 years, there were no differences in recurrent VTE rates and mortality rates between Group 1 and Group 2 (12.5% vs 14.5%, respectively, p=1 and 11.5% vs 13.8%, respectively, p=1). When comparing pts with recurrent VTE vs those without recurrent VTE, there were no differences regarding MPN type, JAK2 V617F mutational status, type of VTE or coexisting thrombophilia. None of the pts who stopped anticoagulation after achieving disease control had VTE recurrence. Conclusions: Most MPN pts with VTE received long-term anticoagulant therapy (71.4%). There were no differences in clinical characteristics between those who were treated with long-term anticoagulation versus those who were not apart from BCS patients who were treated indefinitely. We found no difference in the rates of VTE recurrence between patients receiving short- vs long-term anticoagulation however confounding variables such as hematologic control of the MPN may account for this finding, therefore, anticoagulation therapy until attainment of hematologic control may be considered. Prospective clinical trials are needed to evaluate the optimal duration of anticoagulation for prevention of recurrent VTE in MPN pts. Disclosures Leader: Novartis: Research Funding.

Description: Introduction Vitamin K antagonist (VKA) drugs require immediate reversal in VKA-treated patients with major bleeding or requiring urgent surgery. 4-factor prothrombin complex concentrates (PCCs)are approved for urgent VKA reversalbecause they reverse the international normalized ratio (INR) more rapidly than fresh frozen plasma (FFP). Studies comparing the clinical benefits of PCC and FFP have focused on VKA reversal prior to urgent surgery. Few data comparing laboratory and clinical outcomes of patients receiving PCC or FFP for major hemorrhage have been published, and these pertain to intracranial hemorrhage (ICH) only. Given the complexity of performing randomized studies in this setting, observational studies are relevant to inform on this issue. AIMS To compare the effects of PCC versus FFP on patient outcomes in VKA-associated major hemorrhage. The primary outcomes were the rate of INR reversal and blood product utilization. The secondary outcome was duration of intensive care and total hospital admission. Methods We performed a retrospective, single-center study of consecutive unselected patients receiving a 4-factor PCC for VKA reversal because of hemorrhage between January 2012 and April 2015 compared to consecutive unselected patients treated with FFP for the same indication from January 2010-December 2011, a period prior to introduction of PCC at the Meir Medical Center. Patients were identified by review of clinical and blood bank electronic medical records. We analyzed patient demographics, indication for VKA, underlying illnesses, aspirin use, site and severity of hemorrhage, INR pre- and post reversal, rate of INR reversal, transfusion requirements and duration of hospitalization, treatment. Results 56 patients received PCC and were compared to 56 patients treated with FFP. In the PCC group 17 patients had ICH and 25 had gastrointestinal hemorrhage compared to 17 and 31 patients respectively in the FFP group. Patients were adjusted for age, sex, presence of renal failure, active cancer, aspirin use, site of hemorrhage, pre-treatment INR and hemoglobin concentration and hemorrhagic shock at presentation. Outcomes: Median time to INR of ≤1.3 was 0.5 (range 0.5-1.5) vs 15.5 (range 5-96) hours for PCC vs FFP respectively, P

Description: INTRODUCTION Recent large randomized controlled trials have shown that direct oral anticoagulants (DOACs) are at least as effective as vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation (AF) and are associated with similar or lower rates of bleeding. The results for bleeding seen in Phase 3 trials might not be applicable to real world practice. Population-based studies suggest that the bleeding risk for DOACs and VKA is similar however neither the risk of bleeding associated with different doses of DOACs nor that associated with apixaban in routine clinical practice is well established. We performed a large population-based study to determine the incidence of bleeding in patients with AF beginning treatment with different doses of dabigatran, rivaroxaban, apixaban or a VKA. METHODS From the computerized database of the 4.5 million member Israeli Clalit Health Services health care provider, consecutive patients initiating a VKA or DOAC for AF between January 1, 2011 and December 31, 2014 were studied. Bleeding patients who required hospitalization were identified and key clinical and laboratory data were recorded. Incidence of bleeding was calculated during the first 20 months of treatment which was the minimum duration of treatment for all of the drugs. Adjusted hazard ratios for overall bleeding, intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding and all-cause mortality within 30 days were recorded and case fatality rates were calculated as the proportions of bleeding patients who died within 30 days. RESULTS 26184 patients initiated anticoagulants for AF: 14258 received VKA, 214 -received dabigatran 75 mg, 3563 received dabigatran 110 mg , 1410 received dabigatran 150 mg, 2570 received rivaroxaban 15 mg, 2140 received rivaroxaban 20 mg, 1227 received apixaban 2.5 mg and 802 received apixaban 5 mg. Key patient demographics and the overall and site-specific bleeding rates are shown in table 1. Hazard ratios for any bleeding, ICH and GI bleeding adjusted for age, renal failure, CHADS2 score, aspirin use and Charlson comorbidity score favored dabigatran 150 mg versus VKA (P

Description: Background: Hydroxyurea (HU) is an effective and common therapy for high-risk Polycythemia Vera (PV). Some patients may demonstrate resistance or intolerance to HU, but the consequences of these warrant further studies. Objective: Evaluate the clinical and economic implications of HU resistance/intolerance, in routine clinical practice in Israel. Methods: A retrospective analysis of Maccabi Health Services' (MHS) database was performed. MHS is a Non-for-Profit healthcare insurer and provider in Israel, with over 2.2 million members. Patients were included in the study if they had a recorded PV diagnosis or complete blood count indicative of PV, and had purchased HU for at least 3 months between 2000-2015. Enrolled patients were divided into 3 groups: A) Resistant to HU (patients prescribed 2g/day of HU); B) Intolerant of HU (patients who stopped HU, transitioned to another line of therapy or who developed HU related cytopenias); C) Stable on HU. A mid-time point was added to "Stable" to compensate for the time required for transition in the "Intolerant" group. Only patients who developed Intolerance within 5 years were included. Collected data pertained to demographics, clinical outcomes, resource utilization and expenditure data. Results: A total of 830 patients were identified. Only 3 met criteria for Resistance and were disregarded for further analysis, while 318 (38%) were defined as "Intolerant" and 509 (61%) as "Stable". At baseline, there were no significant differences between "Intolerant" and "Stable" groups, apart from platelet counts (431 vs. 495, respectively) and red cell distribution width (RDW) (18.4 vs. 17.6, respectively). Intolerance was determined based on HU-related cytopenias (n=144, 45% of Intolerant), transition to other treatment line (n=52, 16%) or stopping HU (n=122, 38%). These results indicate some patients continue HU treatment despite lack of disease control. "Intolerant" patients who had transitioned by 5 years from first HU purchase (N=173) and "Stable" patients who met the mid-point of time to transition (N=487) were eligible for comparison. Median follow up time was 4.9 and 5.5 years for "Intolerant" and "Stable" groups, respectively. Thrombotic events occurred in 8% of the "Intolerant" group compared with 3% of "Stable" (p=0.003) and event rate per 100 patient-years was 1.6 versus 0.5 (p

Description: Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory syndrome which may occur in adults with hematologic malignancies (HM). The diagnosis of HLH in this context (HM-HLH) is hindered by a number of factors. First, the currently used HLH 2004 diagnostic criteria are derived from pediatric patients commonly with HLH-associated genetic lesions, a very different population than adults with cancer. Second, most parameters used for diagnosis of HLH are directly impacted by the underlying HM and may reflect the presence of the malignant clone itself rather than an inflammatory process. Finally, appropriate diagnostic cutoff values for laboratory abnormalities in HM-HLH have not been defined. In this study we determine the diagnostic value of the laboratory components of the HLH 2004 diagnostic criteria and establish optimal cutoffs for the diagnosis of HM-HLH in HM patients. Methods: This is a multicenter, retrospective study of adult patients with a hematologic malignancy in whom sCD25 was measured because of clinically suspected HM-HLH or as part of routine screening of patients with a newly diagnosed hematologic malignancy, between January 2012 and March 2020. We considered patients fulfilling the five of eight of the HLH 2004 diagnostic criteria to have HM-HLH. Patients fulfilling fewer than five criteria were assigned to the HM group. These cohorts were well balanced in terms of disease distribution. We established the optimal cutoffs for laboratory parameters used for the diagnosis of HM-HLH using receiver operating curves (ROC) in a discovery cohort and tested their performance in a validation cohort. In order to improve the results obtained using the individual ROC, we then created a combined ROC using parameters demonstrating the highest individual performance (highest area under the curve (AUC)), in order to develop a diagnostic index. Finally, we examined the performance of each parameter in each cohort by using a contingency table and Chi-square and Fisher's exact test to determine the positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and likelihood ratio (LR) of disease for each parameter. Results: 212 adults with HM with or without HLH in whom testing for HLH was performed were included in the study. HMs were: B cell lymphoma (41%), T cell lymphoma (26%), Hodgkin lymphoma (9%), acute myeloid leukemia (8%), myelodysplastic syndrome (8%), myeloproliferative neoplasms (5%) and chronic lymphocytic leukemia (4%). 99 (47%) patients had HM-HLH. Despite considerable overlap in laboratory values between the patient groups, all parameters apart from fibrinogen were able to distinguish HM-HLH from HM alone, with ferritin and sCD25 having the greatest discriminatory power. ROC analysis revealed an optimal cutoff value of 〉5,600 U/mL for sCD25 (sensitivity/specificity 76%/78%, AUC=0.83) and 〉1,300 ng/ml for ferritin (sensitivity/specificity 76%/76%, AUC=0.83). Combining the two markers to create a novel inflammatory index (HM-INFL) yielded superior diagnostic ability (AUC =0.86). Using HLH 2004 cutoff levels the HM-INFL index had a sensitivity of 94% and NPV of 94% and when using the optimal cutoff levels, it had a specificity of 92% and PPV of 90% (Table 1). Conclusions: HM-INFL is an index comprising only ferritin and sCD25. Using the original HLH 2004 cutoffs the index is an effective screening tool. Using our newly defined cutoff levels obtained by ROC analysis it is highly specific and can be used as a confirmatory test for the diagnosis of HLH in HM patients. These findings also support the hypothesis that HLH in the context of HM is an inflammatory condition associated with immune dysregulation. Disclosures Miller: Foundation Medicines, Inc.: Consultancy. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jordan:Sobi: Consultancy.