Risk of Venous Thromboembolism in Acute Leukemias: A Meta-Analysis

Abstract Background: Venous thromboembolism (VTE) is an important cause of morbidity and mortality in cancer patients (pts). The risk of VTE, however, differs according to cancer type. Pts with hematologic malignancies are at an increased risk of VTE events, either due to the underlying disease biology or related to treatment. This risk exists even in acute leukemia (AL), which is characterized by profound thrombocytopenia and coagulopathies that present treatment challenges. Advances in anti-leukemic therapies and improved supportive care over the last several decades may have impacted the extent to which an average patient is at risk for VTE We performed a meta-analysis of published literature on VTE rates in AL pts and evaluated trends in VTE incidence in relation to the reported study time period. Methods: This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed, EMBASE, Medline, Scopus and Cochran databases to identify relevant studies published between January 1980 and June 2018. All studies including randomized controlled, retrospective or observational studies in AL pts which investigated VTE as an endpoint were included. Abstracts, posters, review articles, and case reports were excluded. Articles were excluded if they did not provide disease-level data. The search terms included "venous thromboembolism", "deep venous thrombosis", "pulmonary embolism", and "leukemia". Furthermore, citations were supplemented by cross checking the reference lists of eligible studies and relevant reviews to identify additional published data. We collected study period, study design, study publication date, AL subtype, total patients, and rates of VTE. When reported, we collected information on VTE prophylaxis and presence of central lines. Meta-analysis of VTE rates was performed using an established Bayesian logistic random effects model. The model assumes that the log odds of VTE is exchangeable across studies with Gaussian distribution and random hierarchical mean and standard deviation. For both analyses, the hierarchical mean assumed a Gaussian prior with mean 0 and variance = 200. The inter-study standard deviation was assumed uniform (0,10). Given treatment and patient heterogeneity among distinct subtypes of AL, analyses were undertaken separately for each AL subtype. Results for individual studies and the combined inter-study mean VTE rate are described by the resultant posterior medians and 95% highest posterior density (HPD) intervals. Results: From the initial search, 2527 articles were identified. Among these, 938 were duplicate publications, 1408 did not meet content inclusion criteria, 150 were review articles or case reports, 2 studies lacked disease level data, thus, leaving 31 studies for analysis. A total of 29 studies focused on ALL, 11 on AML, 11 on APL, and some studies included multiple disease populations. The inter-study mean incidence of VTE for ALL was 8.67% (95% HPD 6.01%-11.58%), fig 1a, for AML was 7.25% (95% HPD 4.12%-11.09%), fig 1b, and for APL was 12.94% (95% HPD 7.04%-20.67%), fig 1c. .. Our graphical analysis indicates an increase in risk of VTE with time for ALL (fig 2a), AML (fig 2b), and APL (fig 2c). Conclusion: In the present meta-analysis, we determined that the overall incidence of VTE in AL pts ranged from 7-13%. Among AL subtypes, APL pts had the highest rate of VTE. We observed an increased risk of VTE over time. We postulate this is multifactorial and may be related to an increase in case findings from increased screening, aging sedentary population, and increased use of prothombotic agents. Notable strengths of this study include the largest review of association of VTE with AL and evolving risk of VTE with time. These findings need to be considered in light of several limitations - lack of comparator group limiting ability to generate pooled relative risks for VTE, heterogeneity in study populations and reporting and scare data on VTE prophylaxis. Further data are required to determine the mechanism for the increase in risk. Given the VTE risk and its known impact on morbidity, mortality and associated health care costs, prospective studies are warranted in AL pts to facilitate establishment of guidelines for prophylaxis and management of thrombotic complications. Disclosures Carraway: Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Speakers Bureau. Advani:Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy; Pfizer: Honoraria, Research Funding. Nazha:MEI: Consultancy. Gerds:Apexx Oncology: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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No Increased Risk of Secondary Neoplasms in Patients Treated with Rituximab for Non-Hodgkin’s Lymphoma : A Meta-Analysis of 9 Trials

Blood ◽

10.1182/blood.v124.21.1659.1659 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1659-1659

Author(s):

Isabelle Fleury ◽

Sylvie Chevret ◽

Michael Pfreundschuh ◽

Gilles Salles ◽

Bertrand Coiffier ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Odds Ratio ◽

Research Funding ◽

Meta Analysis ◽

Advisory Committees ◽

Secondary Neoplasms ◽

Increased Risk ◽

American Society

Abstract Background. Rituximab improved outcomes of all CD20+ non-Hodgkin lymphoma (NHL) subtypes. Rituximab induces a transient B-cell depletion and a dose-dependent T-cell inactivation (Stroopinsky et al., Cancer Immunol Immunother 2012) predisposing to T-cell dependent infections and to a potential impaired T-cell immunosurveillance. Secondary neoplasms (SN) is infrequent in trials including rituximab and the SN risk associated to rituximab across multiple trials has not been reported. We performed a systematic review of published trials comparing chemotherapy with or without rituximab to evaluate SN occurrence. Methods. Our primary endpoint was SN risk in patients with NHL treated with rituximab. We searched PubMed and Embase databases for randomised controlled trials on rituximab and lymphoma where rituximab constituted the only difference between treatment arms and where SN incidence or SN related death were reported. Authors were contacted for SN related rituximab exposure if not detailed. Chronic lymphocytic leukemia and HIV-related lymphomas were excluded due to increased risk of SN. Updated follow-up of eligible trials presented at annual meetings of the American Society of Clinical Oncology and American Society of Hematology were retrieved. Data were extracted independently by two authors. A random effects DerSimonian-Laird meta-analysis was performed to estimate the summary effect of rituximab on the hazard of SN. Statistical heterogeneity was tested using Woolf test. Results. We identified nine trials cumulating 4621 patients with 2312 exposed to rituximab and 2309 not exposed. These nine trials are known with the following names: PRIMA (1), GELA LNH98.5 (2), MINT (3), CORAL (4), IELSG-19 (5), EORTC20981 (6), OSHO#39 (7), SAKK 35/98 (8), RICOVER60 (9). Histology were diffuse large B cell (n=4), follicular (n=4) and marginal zone (n=1) lymphomas. Median age was 58.1 years. Sex distribution was available for seven trials with 1650 (47.6%) women and 1814 (52.4%) men. In all these trials but one (SAKK 35/98), rituximab was used associated with chemotherapy: CHOP, CHOEP, FCM, MCP, DHAP, ICE, or chlorambucil. At a median follow-up of 73 months [interquartile range: 72-84], a total of 334 SN was observed, including 169 SN in patients randomised to rituximab as compared to 165 SN in patients not randomised to rituximab (OR= 0.88; 95%CI: 0.66-1.19) (Figure 1). No evidence of significant heterogeneity was noticed across trials (p = 0.93). Notably, the proportion of females, histology subtypes, use of rituximab in first line, and use of rituximab over prolonged periods in maintenance did not influence SN risk (p = 0.94, p = 0.80, p = 0.87, p = 0.87 respectively). The SN risk was not increased in protocols administrating rituximab over periods of 8 months to 12 months (CORAL , OSHO#39) as opposed to periods of 24 months (PRIMA, EORTC20981) (p=0.86). Conclusions. This meta-analysis of nine trials randomising rituximab in NHL patients suggests no SN predisposition at a median follow-up of 6 years. SN risk associated with the combination of rituximab and new targeted therapies warrants prospective monitoring. Figure 1. Standard meta-analysis plot of the odds ratio of SN prevalence in the rituximab arm compared to the control arm Figure 1. Standard meta-analysis plot of the odds ratio of SN prevalence in the rituximab arm compared to the control arm Disclosures Fleury: Lundbeck: Membership on an entity's Board of Directors or advisory committees, Preceptorship Other. Pfreundschuh:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Spectrum: Research Funding. Salles:Roche: Honoraria, Research Funding. van Oers:Roche: Consultancy. Gisselbrecht:Roche: Research Funding. Zucca:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: 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. Herold:Roche Pharma AG/Germany: Honoraria, Research Funding. Ghielmini:Roche: Research Funding, Speakers Bureau.

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Perioperative Heparin Bridging in Patients Receiving Oral Anticoagulation: Meta-Analysis of Bleeding and Thromboembolic Rates

Blood ◽

10.1182/blood.v118.21.545.545 ◽

2011 ◽

Vol 118 (21) ◽

pp. 545-545 ◽

Cited By ~ 1

Author(s):

Jovana Yudin ◽

Deborah Siegal ◽

Wendy Lim ◽

Scott Kaatz ◽

James Douketis ◽

...

Keyword(s):

Board Of Directors ◽

Oral Anticoagulation ◽

Health Research ◽

Research Funding ◽

Clinical Decision Making ◽

Controlled Trial ◽

Meta Analysis ◽

Advisory Committees ◽

Methodologic Quality ◽

Increased Risk

Abstract Abstract 545 Background: Periprocedural bridging using unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in patients receiving chronic oral anticoagulation (OAC) is often utilized with the view to reduce the risk of thromboembolic (TE) events. Optimal perioperative anticoagulant methods have not been established. Methods: Systematic review and meta-analysis of published English-language studies from 2001 to 2010 examining bleeding and TE events in patients receiving bridging therapy during temporary OAC interruption for elective procedures. Results: A search of MEDLINE, EMBASE and Cochrane Collaboration databases yielded 32 studies on 6760 bridged patients. Studies were reviewed by 2 independent data collectors (k=0.869). Study quality was generally poor with risk of bias. Thirty-one studies were observational with 1 randomized controlled trial. Low TE risk and/or non-OAC patient groups were used for comparison in 12 observational studies. Major (22/32, 68.8%) and non-major (27/32, 84.4%) procedures were represented. TE events occurred in 67 of 6760 bridged (0.87%; 95% CI 0.40%–1.35%) and 29 of 4897 non-bridged (0.77%; 95% CI 0.24%–1.30%) patients. Using a random effects model, there was no difference in the risk of TE events in bridged versus non-bridged patients (OR 1.02, 95% CI 0.53–1.95). Bridged patients had a significantly increased risk of overall bleeding (OR 5.47, 95% CI 3.89–7.70) and major bleeding (OR 3.43, 95% CI 1.13–10.4) compared to non-bridged patients. There was no difference in TE events (OR 2.44, 95% CI 0.34–17.4) or overall bleeding (OR 2.40 95% CI 0.72–8.05) in patients receiving full versus intermediate/low dose LMWH. Summary: Patients receiving heparin bridging during OAC interruption appear to be at increased risk of bleeding and similar risk of TE events compared to non-bridged patients. Studies of high methodologic quality are needed to develop an optimal anticoagulation strategy and inform clinical decision-making. Disclosures: Lim: Leo Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy; Pfizer: Honoraria. Kaatz:Boehringer-Ingelheim: Consultancy, Research Funding, Speakers Bureau; Bristol Myer Squibb: Consultancy, Research Funding; Bayer: Research Funding; National Institute of Health: Research Funding; Canadian Institute of Health Research: Research Funding; Pfizer: Consultancy; Johnson and Johnson: Consultancy; Ortho-McNeil: Consultancy; GlaxoSmithKline: Speakers Bureau; AC Forum: Membership on an entity's Board of Directors or advisory committees; National Certification Board of Anticoagulation Providers: Membership on an entity's Board of Directors or advisory committees; National Blood Clot Alliance: Membership on an entity's Board of Directors or advisory committees.

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Anticoagulation Prophylaxis with Weight-Adjusted Enoxaparin Reduces Rates of Venous Thromboembolism in Patients with Acute Lymphoblastic Leukemia Receiving Asparaginase-Based Intensification Therapy

Blood ◽

10.1182/blood-2018-99-119984 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3974-3974 ◽

Cited By ~ 3

Author(s):

Hassan Sibai ◽

Ruiqi Chen ◽

Xing Liu ◽

Aaron D Schimmer ◽

Andre Schuh ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Committees ◽

Historical Cohort ◽

Vte Prophylaxis ◽

Patient Cohort ◽

The Mean ◽

Prophylactic Anticoagulation

Abstract Background Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASNase)-based intensification chemotherapy for acute lymphoblastic leukemia (ALL). The optimal preventative strategy is unclear. We previously reported high thrombosis rates during intensification without VTE prophylaxis. Our objective is to determine the effects of weight-adjusted enoxaparin as primary VTE prophylaxis in ambulatory adults receiving ASNase-based intensification chemotherapy for ALL. Methods Patients who achieved complete remission following induction from 2011-2017 went on to receive ASNase-based intensification on the Dana Farber Cancer Institute (DFCI) 91-01 protocol. Patients already on therapeutic anticoagulation for prior VTE were excluded. VTE prophylaxis commenced on day 1, cycle 1 of intensification until the completion of the entire 21-30 week. From 2011 to 2014 patients received enoxaparin subcutaneously once daily, at a dose of 40 mg for patients weighing less than 80 kg, and 60 mg for those 80 kg and over for the first 3 years. Due to continuing occurrence of VTE from 2014-2017 patients received an escalated dose aiming at 1mg/kg daily (rounded to the nearest 20 mg). Results were compared to an historical patient cohort that received the same regimen without VTE prophylaxis prior to 2011. Result: In our historical cohort of adult ALL that did not receive prophylactic anticoagulation (n=99), the rate of VTE was 27%. 124 patients received one of the above prophylactic anticoagulation schedules. The treated and control groups did not differ with respect to median age, gender, weight and number of ASNase treatment cycles per patient. 16 of 124 patients (12.9 %) in the prophylaxis groups developed symptomatic VTE. Sites of VTE in the prophylaxis group included lower extremity (10), sagittal sinus (2), subclavian line related (3), and pulmonary embolism (4). There were no major bleeding complications observed in the prophylaxis group. In the first patient cohort (n=42), receiving fixed enoxaparin doses of 40 or 60 mg, dosing ranged from 0.39-0.69 mg/kg. The mean enoxaparin dose administered was 0.57 mg/kg. Seven (16.6 %) developed a symptomatic VTE, which was not significantly different from the historical non-prophylaxis cohort. In the second patient cohort (n=82), all patients received weight-adjusted enoxaparin > 0.7 mg/kg of enoxaparin. The mean enoxaparin dose administered was 0.88 mg/kg. Nine of 82 patients (10.9 %)) in this cohort had a symptomatic VTE, which was lower than the historical cohort (OR = 0.33 {95% CI, 0.15-0.77} and P< 0.01). Conclusions: Weight-adjusted enoxaparin prophylaxis targeting 1 mg/kg/day reduced the incidence of symptomatic VTE in adult ALL patients receiving intensification chemotherapy with ASNase. This treatment is a viable VTE prevention option with no documented major bleeding. Disclosures Schimmer: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Consultancy; Medivir AB: Research Funding; Jazz Pharmaceuticals: Consultancy. Schuh:Teva: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Amgen Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Shire: Consultancy; Otsuka: Consultancy. Maze:Novartis: Consultancy, Honoraria. Yee:Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding. Gupta:Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Brandwein:Pfizer: Consultancy; Celgene: Consultancy; Lundbeck: Consultancy; Novartis: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding.

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Association of Bleeding Severity with Mortality with in-Hospital and Extended Thromboprophylaxis in the Medically Ill in the Magellan Trial

Blood ◽

10.1182/blood-2019-122930 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2441-2441

Author(s):

Alex C. Spyropoulos ◽

Gary E. Raskob ◽

Alexander T Cohen ◽

Walter Ageno ◽

Jeffrey I. Weitz ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Events ◽

Employment Equity ◽

Advisory Committees ◽

Increased Risk ◽

Bayer Healthcare ◽

Equity Ownership

Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MAGELLAN study (NCT00571649) evaluated whether rivaroxaban (10 mg QD for 35±4 days) compared with enoxaparin (40 mg QD for 10±4 days) followed by placebo could prevent asymptomatic deep vein thrombosis, symptomatic VTE, and VTE-related death. Through Day 35, rivaroxaban was superior to enoxaparin/placebo in the modified intent-to-treat population (4.4% vs 5.7%, RR 0.77, 95%CI, 0.62 to 0.96, p=0.02), but there was an increase in clinically relevant bleeding, the composite of major and non-major clinically relevant (NMCR) bleeding (4.1% vs 1,7%, RR 2.5, 95%CI 1.85-3.25, p<0.001). Although major bleeding has been associated with increased mortality, the relationship between NMCR bleeding and all-cause mortality (ACM) is not established. We hypothesized that subjects in the MAGELLAN trial with major bleeding but not those with NMCR bleeding, would be at an increased risk of ACM irrespective of treatment group. Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 90 visit in 3 mutually exclusive groups: (1) subjects with no major or NMCR bleeding; (2) subjects whose first event was NMCR bleeding; and (3) subjects whose first event was major bleeding. Subjects only developing minimal or trivial bleeding were grouped with those who had no clinically relevant bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates significantly associated with ACM at p<0.05 (age, BMI, history of cancer, history of anemia, inflammatory disease, acute ischemic stroke, and acute respiratory insufficiency), we compared the risk of ACM in subjects with and without bleeding events. Results: The incidence of ACM for subjects who had NMCR bleeding was numerically higher but not significantly increased compared with subjects with no bleeding (20/176, 11.4% vs 468/7763, 6.0%, HR 1.41 95%CI 0.88, 2.25, p=0.151), while subjects with major bleeding were at a significantly increased risk of death (28/59, 47.5% vs 468/7763, 6.0%, HR 7.74 95%CI 5.16, 11.59, p<0.0001). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and may have been underpowered to detect differences in ACM associated with NMCR bleeding. Conclusion: Major bleeding was associated with a significantly increased risk of ACM but NMCR bleeding was not. This suggests that a modest increase in NMCR bleeding associated with extended thromboprophylaxis with rivaroxaban may be acceptable to prevent VTE. Strategies to better select patients at lower risk of bleeding may improve the benefit risk profile of extended thromboprophylaxis with rivaroxaban. Disclosures Spyropoulos: Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Portola: Consultancy; Bayer Healthcare: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Janssen R&D, LLC: Consultancy. Raskob:Janssen R&D, LLC: Consultancy, Honoraria; Novartis: Consultancy; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy; Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Eli Lilly: Consultancy. Cohen:Boston Scientific: Consultancy; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Speakers Bureau; GLG: Consultancy; AbbVie: Consultancy; ACI Clinical: Consultancy; Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Ageno:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Weitz:Janssen R&D, LLC: Consultancy; Bayer Healthcare: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. It is currently under review by FDA for approval as thromboprophylaxis in acutely ill medical patients at risk for venous thromboembolism.

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Impact of Venous Thromboembolism during High Intensity Chemotherapy for Acute Leukemia Patients on Duration of Hospital Stay

Blood ◽

10.1182/blood-2018-99-115257 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4806-4806 ◽

Cited By ~ 1

Author(s):

Madeline Waldron ◽

Caitlin Siebenaller ◽

Marc Earl ◽

Xuefei Jia ◽

Hetty E. Carraway ◽

...

Keyword(s):

Venous Thromboembolism ◽

Length Of Stay ◽

Acute Leukemia ◽

Board Of Directors ◽

High Intensity ◽

Research Funding ◽

Advisory Committees ◽

Icu Admission ◽

Duration Of Hospital Stay ◽

Increased Risk

Abstract Background: Patients (pts) with hematologic malignancies have an increased risk of venous thromboembolism (VTE) events, driven by both the underlying cancer and cancer treatment. This risk exists even in acute leukemia (AL) in the setting of profound thrombocytopenia and coagulopathies, which can delay VTE diagnosis and complicate management. We evaluated the incidence of VTE in AL pts during an admission for chemotherapy and determined its effect on the duration of hospital stay and likelihood of intensive care unit (ICU) admission. Methods: All pts admitted to the Cleveland Clinic inpatient leukemia service with a diagnosis of acute myeloid (AML), lymphoblastic (ALL), or promyelocytic leukemia (APL) between January 1, 2013 and March 31, 2018 and treated with high-intensity chemotherapy were included. High intensity regimens for AML and APL included infusional cytarabine and an anthracycline with the addition of ATRA for latter and for ALL included Hyper-CVAD and CALBG regimens. Pts were excluded if they were admitted directly to the ICU or were transferred after initiating chemotherapy from another institution. Cases with VTE were defined using specific ICD-9-CM codes [451.1x, 451.2; 451.81, 453.1, 453.2, 453.8, 453.9, 415.1x; and, in addition, 997.2 or 997.3 when coupled with a secondary diagnosis of VTE]. All VTE cases identified through this strategy via an electronic medical record query were additionally validated on subsequent chart review. Pts with a diagnosis of VTE were matched 1:3 based on age, sex, race, and leukemia subtype to pts who did not experience VTE during the incident admission. Pts were also assessed for administration of prothrombotic agents, including: PEG-asparaginase, oral contraceptives, and tyrosine kinase inhibitors. The length of stay for the incident hospitalization and incidence of ICU admission were compared between pts who did and who did not experience VTE. Results: Of the 400 AL pts admitted to the inpatient leukemia service during the study period to receive high-intensity chemotherapy, 10 (2.5%) had a documented VTE during the admission. Baseline characteristics of the 1:3 matched cohorts (AL with and without VTE) are shown in Table 3. The median age of the AL pts who developed VTE was 54.5 years (range, 20-78 yrs), 60% were females, median platelet count at the time of VTE diagnosis was 117,900/mL [(range, 29-476,000/mL); 4 pts had platelet (plt) counts below 50,000/mL, 8 pts had plt below 100,000/mL; 2 pts had normal plt counts], and four pts had bloodstream infections within 7 days of VTE occurrence. By disease breakdown, four had AML, 3 had APL and 3 had ALL. By treatment course, 9 pts were receiving initial chemotherapy 1 pt was receiving salvage therapy. By VTE site, 8 patients had line associated VTE and 2 patients had pulmonary embolism. Five VTE pts were treated with either unfractionated or low molecular weight heparin, 2 underwent IVC filter placement and 3 were untreated. Pts in the VTE group experienced a longer duration of hospitalization compared to those who did not have a VTE event (29.81 vs 23.13 days, respectively, P=.027), and were more likely to be admitted to the ICU compared to those who did not experience VTE (66.7% vs 14.8%, respectively, P=.010). VTE risk was not associated with use of prothrombotic agents (p=.430). Summary and Conclusion: While the incidence of VTE in our patient population was lower than what has been previously reported, it was associated with a prolonged hospitalization and increased risk of ICU admission. The incidence of VTE was not associated with use of thrombotic agents and VTE events occurred in patients with normal plt counts and even in the setting of moderate or severe thrombocytopenia. While it is unclear if early intervention after the diagnosis of VTE affects clinical outcome, the association with increased length of stay and ICU admission can increase healthcare-associated costs in the current environment with increasing focus on value. Further studies are warranted to characterize the risk factors for VTE in AL population. Disclosures Carraway: Novartis: Speakers Bureau; FibroGen: Consultancy; Jazz: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau; Balaxa: 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. Advani:Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy; Pfizer: Honoraria, Research Funding. Nazha:MEI: Consultancy. Gerds:Incyte: Consultancy; CTI Biopharma: Consultancy; Apexx Oncology: Consultancy; Celgene: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

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A Retrospective Study of Venous Thromboembolism in Acute Leukemia Patients during Prolonged Hospital Stay. the Princess Margaret Cancer Centre Experience

Blood ◽

10.1182/blood.v128.22.2615.2615 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2615-2615

Author(s):

Hassan Sibai ◽

Umberto Falcone ◽

Arjun Datt Law ◽

Ali Hosni ◽

Carmen Tan ◽

...

Keyword(s):

Acute Leukemia ◽

Hospital Stay ◽

Board Of Directors ◽

Research Funding ◽

Prolonged Hospital Stay ◽

Advisory Committees ◽

Vte Prophylaxis ◽

Cancer Centre ◽

Increased Risk ◽

Prolonged Hospital

Abstract Background The role of thromboprophylaxis in solid organ malignancies is well established. Hematologic malignancies can also be associated with a considerable risk of thromboembolic complications. The incidence of these events is variable and is influenced by multiple factors. Limited data are available regarding the incidence of venous thromboembolism (VTE) in hospitalized acute leukemia (AL) patients. The management of symptomatic VTE in patients with AL can be challenging due to the increased risk of thrombocytopenia-related bleeding. Methods The Discharge summary Database (DAD) was used to extract post-admitted PE and DVT volumes in AL patients admitted to Princess Margaret Cancer Centre from 2007-2016. ICD-10-CA diagnosis codes for acute leukemia, and both PE and DVT events, were used. Only patients diagnosed with VTE at least 48 hours post-admission were included to restrict the cohort to patients that developed VTE during their admission. Results We analyzed a total of 10,041 patients that were admitted to Princess Margaret Cancer Centre during the 2007-2016 period. (Table 1) Of these, 7759 had a solid tumor diagnosis (271 VTE events, 3.4%) and 2282 patients had AL (1675 AML, 464 ALL, 144 APL). The AL patients (AML, ALL, APL) admitted to our Centre for chemotherapy or for the management of complications were further evaluated to determine VTE incidence and to evaluate its management in this setting. As of September 2012, patients with solid tumors treated at our Centre received standard thromboprophylaxis as part of an institutional in-patient (VTE) prophylaxis policy (IPP) that reduced the incidence of VTE from 4.8% (219/4520) to 1.6% (3239/52) before and after the policy was initiated, respectively. AL patients are not given prophylactic anticoagulation. 37 AL patients (22 AML, 10 ALL, and 5 APL; overall incidence 1.6%) developed symptomatic VTE (DVT only 23, PE only 8, DVT + PE 6). VTE was reported as central venous catheter related in 12/37 patients (32.4%). PE was detected in all cases by CT-PE. Median age of VTE patients was 53 years (range 32-77), with a median hospital stay of 35 days (range 2-144). Chemotherapy was given to 26 of the 37 patients that developed VTE, with 20 receiving initial induction chemotherapy. 17/37 (46%) patients had PLT<50.000/mm3 at VTE diagnosis. Full dose low molecular weight heparin with platelet transfusion support was used to treat 35/37 patients with acute VTE during the first month of treatment. 2/37 did not receive anticoagulation due to ongoing active bleeding. None of the treated patients experienced major bleeding. Conclusions In our experience, the incidence of VTE in AL patients during prolonged hospital stay is relatively low, raising questions about the need for routine VTE prophylaxis in this group. The relatively increased risk of VTE in AL patients receiving chemotherapy (particularly, induction chemotherapy), should prompt particular scrutiny in symptomatic patients. Disclosures Schuh: Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schimmer:Novartis: Honoraria.

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Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽

10.1182/blood-2020-140743 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Rita V Masese ◽

Dominique Bulgin ◽

Liliana Preiss ◽

Mitchell Knisely ◽

Eleanor Stevenson ◽

...

Keyword(s):

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Transfusion Requirement ◽

The United States ◽

Acute Chest Syndrome ◽

Maternal Outcomes ◽

Maternal Complications ◽

Advisory Committees ◽

Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

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Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽

10.1182/blood-2019-127270 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2409-2409

Author(s):

Tiffany Lin Lucas ◽

Shveta Gupta ◽

Joanna A. Davis ◽

Fernando F. Corrales-Medina

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

The United States ◽

Haemophilia A ◽

Advisory Committees ◽

Inhibitor Development ◽

Increased Risk ◽

Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

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Peripheral Neuropathy in MGUS and Progression to Amyloid Light-Chain Amyloidosis: A Population-Based Study Including 15,351 MGUS Cases

Blood ◽

10.1182/blood-2019-131514 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5444-5444

Author(s):

Sæmundur Rögnvaldsson ◽

Ingemar Turesson ◽

Magnus Björkholm ◽

Ola Landgren ◽

Sigurður Yngvi Kristinsson

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Large Population ◽

Diagnostic Delay ◽

Population Based ◽

Lymphoproliferative Disorders ◽

First Year ◽

Advisory Committees ◽

Population Based Study ◽

Increased Risk

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: 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; Karyopharm: 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.

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