Risk of Venous Thromboembolism in Acute Leukemias: A Meta-Analysis
Authors: Waldron Madeline , Siebenaller Caitlin , Hobbs Brian P. , Earl Marc , Schleicher Mary , Carraway Hetty E. , Advani Anjali S. , Nazha Aziz , Gerds Aaron T. , Hamilton Betty K. , Sobecks Ronald , Kalaycio Matt , Sekeres Mikkael A. , Mukherjee Sudipto 
Published: October 2019

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.