ALBERT

Description: Introduction: Chronic liver disease (CLD) results in thrombocytopenia [1]. Depression of thrombopoietin (TPO) levels in CLD leads to thrombocytopenia. Thrombocytopenia increases the risk of bleeding in patients undergoing invasive diagnostic or therapeutic procedures [2]. TPO agonists have been depicted to be safe and efficacious in the treatment of thrombocytopenia due to idiopathic immune thrombocytopenia and aplastic anemia. Several studies have evaluated the use of TPO agonist versus placebo for pre-procedural treatment of thrombocytopenic patients with chronic liver disease. These studies were of limited sample sizes. We conducted a meta-analysis to determine if TPO agonists reduce the need of platelet transfusions before procedures in chronic liver disease patients. Methods: We performed a computerized search of Medline, Cochrane and Google Scholar databases through March 2019 for studies evaluating the efficacy of thrombopoietin (TPO) agonists versus placebo in the treatment of thrombocytopenia of chronic liver disease patients undergoing procedures. We screened 295 studies and only 5 of them met our inclusion and exclusion criteria. Inclusion criteria were studies with adults 〉18 years old, English literature, randomized controlled trials utilizing a TPO agonists in chronic liver disease patients. Exclusion criteria were studies with patients

Description: Introduction Venous thromboembolism (VTE), is the second leading cause of death in patients with cancer. The risk of VTE in patients with cancer is 4 to 7-fold, when compared to the general population. Even during anticoagulant treatment, the cumulative incidence of recurrent VTE is 3.5 times higher in patients with cancer than in cancer-free patients. Low-molecular-weight heparin has been the "gold standard" for the of treatment for VTE in cancer associated thrombosis, following the landmark trial by Lee et al. Methods We conducted a meta-analysis to evaluate the safety and efficacy of direct oral anticoagulants in patients with cancer. We systematically searched Medline for randomized-control clinical trials and post-hoc analyses. For each study, data on recurrent VTE, major or clinically relevant non-major bleeding (CRNMB), and major bleeding (MB) were extracted. We included randomized control trials (RCT's) where interventions consisted of direct oral anticoagulants (DOA) versus vitamin K antagonists (VKA) or low molecular weight heparins (LMWH), in which all or a part of the study population had active cancer. We excluded studies that were not comparing DOA versus VKA/LMWH or did not have a subset of active cancer patients. Results Seven studies met our eligibility criteria. Data for recurrent VTE was extractable from all 7 RCT's. There were 2178 enrolled participants total. The pooled results show evidence for a lower incidence of recurrent VTE with the use of DOA versus VKA/LMWH. The pooled risk ratio for recurrent VTE was 0.68 (95% confidence interval 0.50 to 0.93; P = 0.01). There was negligible heterogeneity among the trials (I2 = 0%; P = 0.99). Data for major bleeds was extractable from 6 RCT's, including 1952 enrolled participants total. The pooled results show no evidence for a difference in frequency of major bleeds with the use of DOA versus VKA/LMWH. The pooled risk ratio was 1 (95% CI 0.53 to 1.87; P= 0.99). There was moderate heterogeneity among trials (I2 = 40%; P = 0.17) Data for clinically relevant bleeding was extractable from 6 RCT's, including 1952 enrolled participants total. The pooled results show no evidence for a difference in frequency of nonmajor but clinically relevant bleeds with the use of DOA versus VKA/LMWH. The pooled risk ratio was 1.06 (95% CI 0.80 to 1.42; P= 0.68). There was negligible heterogeneity among trials (I2 = 27%; P = 0.24). Data for all bleeds (major or nonmajor) was extractable from all 7 RCT's. There were 2178 enrolled participants total. The pooled results show no evidence for a difference in frequency of bleeds with the use of DOA versus VKA/LMWH. The pooled risk ratio was 0.95 (95% CI 0.68 to 1.32; P= 0.74). There was substantial heterogeneity among trials (I2 = 65%; P = 0.02). Conclusions Our results suggest that DOACs might reduce the incidence of VTE recurrence in patients with cancer without putting them at high risk for major bleeds or clinically relevant nonmajor bleeds. Table. Table. Disclosures No relevant conflicts of interest to declare.

Description: INTRODUCTION: Both solid and hematologic malignancies are associated with an increased risk of thromboembolic events, according to previous studies. One of the most common risk scoring systems was developed based on type of non-hematologic cancer, body mass index (BMI), WBC, hemoglobin, and platelet counts. However, compared to other solid tumors, acute leukemia patients commonly present with pancytopenia at the time of diagnosis and the Khorana Risk Score (KRS) has not been validated in patients with acute myeloid leukemia (AML). The goal of our study was to validate the KRS in AML patients. METHODS: Using Total Cancer Care (TCC), we retrospectively identified histologically confirmed AML patients from 2000 to 2018. Clinical and laboratory variables including age, gender, previous cancer history, use of growth factors, underlying coagulopathy, white blood cell counts, hemoglobin, and platelet counts were characterized at the time of AML diagnosis and annotated using descriptive statistics. The thrombotic event rate was estimated with the Kaplan-Meier method and compared using log-rank test. All statistical analyses were performed using SPSS v24.0 and GraphPad Prism 7. RESULTS: A total of 867 AML patients were included in this study. The median age at AML diagnosis was 75 (51-96) years and male patients were 65% (n=565). A total of 28% (n=241) patients had prior cancer history (hematologic malignancies, n=34; solid tumor, n=207). A total of 12% (n=101), 7% (n=58), and 1% (n=8) patients had EPO, G-CSF, GM-CSF treatment prior to AML diagnosis and 84% (n=728) patient were treated with any typed of growth factors after AML diagnosis. The median BMI was 27.1 (14.8-103) and 5% (n=47) patients had BMI higher than 35. A total of 26% (n=229) patients had WBC ≥11 x109/L (median 3.165 (0.08-413.74) x109/L), 67% (n=584) patients had hemoglobin 350 x109/L (median 46 (1-800) x109/L). A total of 22% (n=191) patients had Khorana score 0, 51% (n=445) patients had score 1, 24% (n=207) patients had score 2, and 3% (n=24) patients had score 3, respectively. A total of 42 thrombotic events were observed in the median follow up of 3 (0.1-307) months. Among these, a total of 3% (n=6/191), 5% (n=23/445), 6.3% (n=13/207), and 0% (n=0/24) thrombotic events occurred in patients with Khorana sore 0, 1, 2, and 3, respectively. Log-rank (Mantel-Cox) test showed no statistical difference between individual subgroup (p=0.1949). CONCLUSIONS: In AML patients, there was a higher incidence of thrombotic events in patients with higher Khorana score though the difference was not statistically significant. The proportion of patients with Khorana score ≥3 was relatively low, which could be due to pancytopenia, a common presentation in AML patients. These results suggest that the development of better thrombotic risk scoring system is warranted in patients with AML. Disclosures Komrokji: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Description: Introduction: Hemophilia A is a rare blood disorder caused by an F8 variant resulting in insufficient Factor VIII (FVIII) activity. Updated results and follow-up of an ongoing gene therapy study in patients with severe hemophilia A are presented. Methods: The Alta study is a dose-ranging, single-dose study of SB-525 gene therapy, a recombinant adeno-associated virus (rAAV6) vector encoding an F8 gene. SB-525 was injected into 11 patients in 4 cohorts of 2 patients each across 4 ascending doses (9e11, 2e12, 1e13 and 3e13 vg/kg) with expansion of the high dose cohort by 3 additional patients. Endpoints included: safety events, changes in circulating FVIII activity, FVIII antigen, FVIII usage, and frequency and severity of bleeding. Results: In the third cohort (1e13 vg/kg), a single infusion of SB-525 resulted in stable and clinically relevant increases in FVIII activity. Patients in the fourth cohort (high dose, 3e13 vg/kg) achieved FVIII levels within the normal range (Table 1), with no bleeding events reported up to 24 weeks post-injection. Patients treated at 3e13 vg/kg did not require FVIII replacement therapy following the initial prophylactic period of up to approximately 3 weeks post-SB-525 administration. No bleeding events were observed in any of the patients treated at the 3e13 vg/kg dose. One patient had a treatment-related serious adverse event of hypotension and fever, with symptoms of headache and tachycardia, which occurred ~6 hours after completion of the vector infusion and resolved with treatment within 24 hours. In the three first cohorts, no ALT elevation requiring more than 7 days of corticosteroid treatment was observed. Of the 5 patients treated to date in the high dose cohort, 3 followed for at least 8 weeks showed transient and mild (grade 1) ALT elevations. All responded to corticosteroids within one week. At the time of abstract submission, all patients were off corticosteroids. FVIII antigen was assessed by ELISA, and preliminary results from the high dose cohort showed a good correlation by chromogenic assay between the specific activity of SB-525 derived FVIII and Xyntha, a recombinant B-domain deleted protein control. Dosing in the fourth cohort is ongoing, and additional analyses of the trial data including FVIII levels, bleeding rate and factor usage will be presented as available. Four- to 11-month follow-up data on all patients in the fourth dose cohort will also be presented. Conclusions: To date, treatment with a single infusion of SB-525 gene therapy resulted in dose-dependent and sustained increases in FVIII levels, with a substantial decrease in FVIII usage, and no bleeding episodes recorded in the highest dose cohort. Patients treated in the highest dose cohort achieved FVIII activity in the normal range. No ALT elevations persisting longer than 7 days were observed in the first three dose cohorts. The study is ongoing, and the results support further development of SB-525 for the treatment of severe Hemophilia A. Disclosures Giermasz: uniQure: Consultancy, Other: Research; Sangamo: Other: Research; Bioverativ/Sanofi: Consultancy, Speakers Bureau; BioMarin: Consultancy, Other: Research; Genentech/Roche: Consultancy, Other: Research, Speakers Bureau. Arkin:Pfizer: Employment, Equity Ownership. Di Russo:Pfizer: Employment, Equity Ownership. Snyder:Sangamo Therapeutics: Employment. Woolfson:Sangamo Therapeutics: Employment, Equity Ownership. Rouy:Sangamo Therapeutics: Employment, Equity Ownership.

Description: BACKGROUND: Venous thromboembolism is a well-known complication of malignancy. The Khorana Risk Score (KRS) utilizes the type of cancer, blood counts, and body mass index to predict risk of thrombosis in cancer patients. Patients with a KRS of greater than 3 are considered high risk for developing blood clots and may benefit from prophylactic anticoagulation. We wanted to determine if the use of the KRS would have led to prophylactic anticoagulation (AC) in these cancer patients prior to their thrombotic events. METHODS: This study utilized a group of 286 patients treated at Moffitt Cancer Center between May 1, 2010 and June 30, 2015 with a wide variety of cancer diagnoses with known venous thromboembolic events (VTE) (pulmonary embolism or deep venous thrombosis). We aimed to validate the KRS by retrospective analysis to determine if the KRS would have predicted VTE in these patients on the day of their venous thromboembolic event. The demographics are summarized using descriptive statistics. Wilcoxon rank-sum test is used for testing the difference in continuous variables. Fisher exact test is used for testing the difference in categorical variables. RESULTS: We found that the majority of these cancer patients with known VTE (89%) would have been classified as low risk of having VTE. Only 11% would have been classified as high risk to where prophylactic anticoagulation might have been indicated. CONCLUSIONS: We found that in a diverse group of cancer patients who had thrombotic events, the KRS did not appropriately stratify patients at the highest risk of VTE. The majority of patients with VTE were actually found to be low risk which would not have led to improved awareness or medication prophylaxis. Improved risk stratification methods are needed for cancer patients to implement an effective prophylactic strategy. Table Table. Disclosures No relevant conflicts of interest to declare.

Description: INTRODUCTION Thrombotic episodes represent significant morbidity and mortality in patients with hematologic malignancies and may be influenced by several risk factors. Current predictive and prognostic models do not take into account several risk factors. Furthermore, prophylactic and therapeutic management of thrombosis remains to be standardized for patients with AML. Few studies report the impact of catheters to the likelihood of thrombosis. We comprehensively report our institution's experience with thrombosis in AML patients. METHODS The Total Cancer Care (TCC) database was used to retrospectively chart review patients with histologically confirmed AML from 2000 to 2018. Several parameters were extracted including but not limited to history of thrombosis and recurrences, chemotherapy regimens, and laboratory values for significant events. All statistical analyses were performed using SPSS v24.0 and GraphPad Prism 7. RESULTS: A total of 1101 patients were diagnosed with either de novo (516, 46.87%) or secondary (584, 53.04%) AML. The median age of diagnosis was 75 years (52, 95) and men were the majority, 726 (65.94%). In terms of cytogenetics, 25 (2.27%) had good/favorable, 616 (55.95%) had intermediate, and 334 (41.75%) had poor cytogenetics. At the time of diagnosis, CBC revealed median WBC of 3 (0, 420), ANC 1 (0, 132), Plt 52 (1, 996), and hgb 9 (1, 15). Median ECOG score was 1. 159, 14.4% patients had a history of thrombosis prior to AML diagnosis; with a median of 1 episode of thrombosis (1, 4). After AML diagnosis 70 patients had one episode of thrombosis, 9 had two episodes, and 2 patients had three recurrent episodes. As far as the first-line induction therapy, 247 (22.43%) patients received 7+3, 12 (1.08%) received CLAG, 36 (3.27%) received hypomethylating agents, and the remaining 227 (2.06%) received other therapies such as clinical trials or off-label drugs. Repeat cycles of therapies were also recorded. In terms of growth factor use after AML diagnosis, 132 (11.99%) used EPO, 209 (18.98%) G-CSF, 32 (2.90%) GM-CSF, and 778 (70.66%) used any other growth factor not mentioned. Out of the 139 episodes of thrombosis, 81 (58.3%) were venous, and 58 (41.7%) were arterial. Among the venous, 45 (55.6%) were lower extremities, 21 (25.9%) were upper extremities, and 10 (12.3%) were pulmonary embolus. Among the arterial thrombosis, 27 (46.6) were coronary events, 23 (39.7%) were cerebral events. Only 15 patients had catheter-associated thrombosis events, 11 (73.3%) were PICC, and 2 (13.3%) were Port lines or central lines. In terms of management, 39 patients were on temporary anticoagulation, 60 patients were on indefinite anticoagulation, and 522 were not on any anticoagulation. In terms of complications, 3 patients had minor bleeding, 1 had major bleeding, 2 had HIT and the large majority of 419 had no complications of anticoagulation. CONCLUSIONS: Thrombosis both venous and arterial events manifest during treatment for leukemias. PICCs lines are associated with more catheter associated thrombosis events than ports. Further prospective studies are needed to evaluate the risk of both arterial and venous thrombosis in patients with acute leukemia. Further risk mitigation strategies are needed. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau.

Description: Background: Etranacogene dezaparvovec is an investigational gene therapy for hemophilia B (HB) comprising an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) gene with a liver specific promoter. In a Phase 2b study, a single dose of etranacogene dezaparvovec provided mean FIX activity of 41.0% sustained at 1yr post-dose in 3 participants (pts). Although most gene therapy clinical studies exclude pts with pre-existing neutralizing antibodies (NAbs) to the capsid serotype, early clinical studies and nonhuman primate data suggest that generally prevalent titers of anti-AAV5 NAbs may not preclude successful transduction with etranacogene dezaparvovec. Aims: A Phase 3, Health Outcomes with Padua gene; Evaluation in Hemophilia B (HOPE-B; NCT03569891) was established to further assess efficacy and safety of etranacogene dezaparvovec in adults with HB with a wide range of pre-existing NAbs to AAV5. Here we report outcomes at 26 weeks (wks). Methods: HOPE-B is a Phase 3, open-label, single-dose, single-arm, multi-national trial in adult males with severe or moderate-severe HB (FIX≤2%). All pts received routine FIX prophylaxis prior to study. Pts were not excluded based on pre-existing NAbs to AAV5. Pts entered a prospective lead-in period of at least 6 months during which bleeding/factor use was monitored, then received a single intravenous dose of etranacogene dezaparvovec (2x1013 gc/kg). Pts will be followed for 5yrs. Primary endpoints comprised FIX activity (one stage) at 26 and 52wks after dosing and 52wk annualized bleeding rate. For pts with no clean post-treatment FIX samples (≥10d post exogenous FIX), factor activity was imputed as baseline value based on historic disease severity. Secondary endpoints include factor replacement use, adverse events (AEs), and reactive use of corticosteroids. Results: 75 pts were screened, of whom 67 entered lead-in. 54 pts were dosed (44 severe, 10 moderately severe HB) and completed 26wks of follow-up. Mean age (±SD) was 41.5 (15.8) yrs. 38/54 pts (70.4%) had bleeds (n=123) during the lead-in despite prophylaxis, and 23/54 (42.6%) had NAbs to AAV5 at baseline (max titer: 3212.3). Following treatment, FIX activity increased rapidly to a mean (SD; min,max) of 37.2% (±19.6; 1.0, 97.1) at wk26, representing a mean (SD; min,max) change from baseline of 36.0% (±19.7; 0, 96.1 p

Description: Direct oral anticoagulants (DOACs) may be good alternatives to low molecular weight heparin (LMWH) or vitamin K antagonists (VKA) for treatment of cancer associated thrombosis (CAT). We conducted a meta-analysis of ten randomized clinical trials to evaluate the efficacy and safety of DOACs in patients with CAT. All had study populations composed in entirety or in part of patients with CAT. The primary outcome (efficacy) was recurrent VTE and the secondary outcomes (safety outcomes) included major bleeding, clinically relevant non-major bleeding (CRNMB), and all bleeding (major bleeding + CRNMB). Participants treated with DOACs had lower risk of recurrent VTE, overall (RR 0.63; 95% CI 0.51–0.79; p 

Description: Introduction: Hemophilia A is a rare bleeding disorder caused by pathogenic variants in the F8 gene, resulting in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)-mediated gene transfer enables the delivery of a modified functional F8 gene to hepatocytes that subsequently synthesize FVIII at levels that may prevent bleeding events in the absence of exogenous FVIII. Updated results and follow-up from the Alta study, an ongoing gene therapy study in patients with severe hemophilia A, are presented. Methods: The Alta study is a phase 1/2 dose-ranging, single-dose study of giroctocogene fitelparvovec (also known as SB-525 and PF-07055480), a recombinant AAV serotype 6 (rAAV6) vector encoding a modified F8 gene. Adults aged ≥18 years with severe hemophilia A were eligible for inclusion. Giroctocogene fitelparvovec was infused into patients in 4 cohorts of 2 patients each across 4 ascending doses (9e11, 2e12, 1e13, and 3e13 vg/kg). The 3e13 vg/kg dose cohort was expanded with 3 additional patients. Key end points included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. Presented data are from the ongoing Alta study (NCT#03061201; data cutoff date, 26 May 2020; database not locked; data reflect those at time of data cutoff, have not undergone standard quality checks, and may be subject to change). Results: Eleven male patients participated in the study (mean [SD] age, 30.3 [7.8] years; white, 81.8%). As of the cutoff date, patients have been followed for 35 to 144 weeks; one patient in the 1e13 vg/kg cohort discontinued from the study. Overall, the most commonly reported adverse events (AEs; n) included increased alanine aminotransferase (ALT; 8 [72.7%]), increased aspartate aminotransferase (AST; 5 [45.5%]), upper respiratory tract infection (4 [36.4%]), and pyrexia (4 [36.4%]). Treatment-related serious AEs were reported in 1 patient (in the 3e13 vg/kg cohort) who experienced hypotension and fever ≈6 hours after giroctocogene fitelparvovec infusion; the events fully resolved with treatment and did not delay post-infusion discharge. In the 3 lower-dose cohorts, no ALT elevation requiring more than 7 days of corticosteroid treatment was observed. Of the 5 patients in the 3e13 vg/kg cohort, 4 had elevations in ALT that were managed with a tapering course of corticosteroids (ranging from 10-134 days) without loss of clinically relevant FVIII activity through 40 weeks, as evidenced by a lack of bleeding events before and after treatment with corticosteroids. Increases in FVIII activity from baseline were generally dose-dependent. Patients in the 3e13 vg/kg cohort achieved a mean normal-range of FVIII activity within 5 weeks post-infusion, with mean FVIII activity maintained through week 40, which is the last time point with data for all 5 patients in this cohort (Table). Following the initial prophylactic period of up to ≈3 weeks after giroctocogene fitelparvovec administration, no bleeding events occurred in any patient treated in the 3e13 vg/kg cohort. Use of FVIII replacement therapy ≥3 weeks after giroctocogene fitelparvovec administration was reported in 5/6 patients in the lower-dose cohorts (range: 9-115 infusions); none of the patients in the 3e13 vg/kg cohort required FVIII replacement beyond initial use of prophylactic factor for up to ≈3 weeks (prophylactic coverage stopped 3 weeks and 2 days after giroctocogene fitelparvovec administration in 1 patient in the 3e13 vg/kg cohort). Conclusions: To date, a single infusion of giroctocogene fitelparvovec gene therapy in patients with severe hemophilia A resulted in dose-dependent and sustained increases in FVIII levels without administration of exogenous FVIII, bleeding episodes or sustained adverse events in the highest-dose cohort (3e13 vg/kg). Additionally, patients treated in the highest-dose cohort achieved a mean FVIII activity in the normal range within 5 weeks, which was maintained through week 40. Data on all patients with more than 1 year of follow-up will also be presented. The study is ongoing, and these interim results support further development of giroctocogene fitelparvovec for the treatment of patients with severe hemophilia A. Disclosures Leavitt: BioMarin: Membership on an entity's Board of Directors or advisory committees. Konkle:Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; BioMarin: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sigilon: Consultancy, Research Funding; Roche: Consultancy. Stine:Biomarin: Consultancy; Applied Stem Cell Therapeutics: Consultancy. Visweshwar:Biogen Idec: Membership on an entity's Board of Directors or advisory committees. Giermasz:uniQure: Consultancy, Research Funding; Sangamo Therapeutics: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau. Arkin:Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company. Fang:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Plonski:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Smith:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Tseng:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Di Russo:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Cockroft:Sangamo Therapeutics: Current Employment, Other: Shareholder of Sangamo Therapeutics. Rupon:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Rouy:Sangamo Therapeutics: Current Employment, Other: Shareholder of Sangamo Therapeutics.