Leukocyte Subtypes As Predictors for Venous Thromboembolism in Diffuse Large B-Cell Lymphoma
Authors: Gollamudi Jahnavi , Dharmavaram Gouri , Martin Petra , Boughan Kirsten Marie , Cooper Brenda , Gallogly Molly M , Malek Ehsan , Metheny Leland , Otegbeye Folashade , Tomlinson Benjamin K. , de Lima Marcos , Nayak Lalitha V. , Caimi Paolo 
Published: October 2019

Abstract
Introduction: Venous thromboembolic events (VTE) are a frequent complication of patients diagnosed with diffuse large B -cell lymphoma (DLBCL). Development of VTE portends poor prognosis. Previous studies have identified use of anthracyclines, advanced stage at presentation, obesity, and development of neutropenia and anemia after first cycle of chemotherapy as risk factors for VTE. Recent studies suggest leukocyte subpopulations may affect the risk of VTE; elevated neutrophil and monocyte counts have been associated with increased risk of VTE in solid malignancy patients. The role of leukocyte subpopulations in VTE risk in DLBCL patients has not yet been evaluated. We conducted a retrospective study to identify risk factors for VTE and specifically address the role of leukocytes and their subtypes in VTE risk assessment in DLBCL.
Methods: We accessed the Stem Cell Transplant and Hematologic Malignancies database of University Hospitals Seidman Cancer Center for DLBCL patients diagnosed between 2000 and 2016. Information collected included demographic characteristics, baseline laboratory and disease information, as well as treatment details. Patient records were reviewed for the presence of VTE, including radiographic confirmation. Progression free survival and overall survival were calculated from time of diagnosis using Kaplan Meier methodology, comparisons were done with log rank. Cumulative incidence of VTE was calculated considering death as competing risk. Univariate Cox regression analysis was conducted for baseline characteristics, risk factors and baseline laboratory parameters. Variables with a univariate p value lower than 0.1 were included in multivariate Cox regression. All analyses were performed using XLSTAT (Addinsoft, NY).
Results: A total of 542 patients were included in the study. Baseline characteristics are described in Table 1. At a median follow up of 48 months, 93 patients developed VTE, with 1 and 2 -year cumulative incidence of VTE of 13.5% (95% CI 10.9-16.8) and 20.5% (95% CI 17.3-24.3). In subsequent years, VTE risk increased more modestly, reaching 23.6% at 4 years (95% CI 20.2-27.7). Eighty percent of VTE occurred in patients with active disease. Sixteen percent of VTE were pulmonary embolism (PE), 53% were lower extremity deep vein thrombosis (DVT), and 31% upper extremity DVTs. Approximately 55% of upper extremity DVTs were line - related.
On univariate analysis (table 2), the risk factors with statistically significant odds for increased hazard of VTE included previous history of VTE, albumin less than 3 gm/dl, leukocyte count greater than 11,000/mcl, hemoglobin less than 12 gm/dl, absolute neutrophil count (ANC), ANC to absolute lymphocyte ratio (ANC: ALC) higher than 2.5 and presence of bulky disease at the time of diagnosis. In multivariate analysis, BMI > 35, bulky disease and ANC/ALC ratio ≥ 2.5 remained statistically significant risk factors for development of VTE.
Presence of VTE at any time after DLBCL diagnosis was also associated with worse overall survival (OS) and progression free survival (PFS) rates. Patients with VTE after diagnosis had an estimated 4 - year OS of 50.6 % (95% CI 39.7-61.6) vs. 71.3% (95% CI 66.9-75.7) in patients without VTE (p<0.0001) (figure 1). Four-year PFS estimates were 37.5% (95 % CI 27.1-48) and 60% (95 % CI 55.3-64.7), respectively (p<0.0001) (figure 2).
Conclusion: VTE is a frequent complication in DLBCL patients and is associated with increased mortality and risk of progressive disease. The first 24 months after DLBCL diagnosis appear to be the time of highest VTE risk, likely a consequence of active disease, treatment and other risk factors such as indwelling catheters. Leukocyte subpopulations appear to have a correlation with VTE risk; the ANC: ALC ratio is a measure of systemic inflammatory response, and in DLBCL patients, a ratio above 2.5 is correlated with increased risk of VTE. Incorporation of this laboratory measurement to currently available VTE risk assessment tools may help more precisely identify the at highest risk of VTE.

Disclosures
Malek: Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau. Tomlinson:Foundation Medicine: Consultancy. Caimi:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees.