Venous Thromboembolic Events in Diffuse Large B Cell Lymphoma. Incidence, Risk Factors and Outcomes
Authors: Ayyappan Sabarish , Prabhakar Dhivya , Gupta Vinita , Cooper Brenda , Lazarus Hillard M. , De Lima Marcos , Caimi Paolo F. 
Published: October 2019

Abstract
Venous thromboembolism (VTE) is a frequent complication of hematologic malignancies, including lymphoid malignancies. VTE results in significant morbidity and mortality in lymphoma patients. There is limited information regarding the factors affecting the risk of VTE in diffuse large B cell lymphoma (DLBCL) patients treated with chemoimmunotherapy. We conducted a retrospective analysis to identify risk factors affecting the incidence of VTE and the effect of this complication on patient outcome.
Methods: We searched the hematologic malignancies database of University Hospitals Seidman Cancer Center for patients newly diagnosed with DLBCL between 2004 and 2014. Records were reviewed for baseline demographics, evidence of known risk factors for VTE, disease characteristics, treatment history and baseline laboratory values. The univariate probability of overall survival (OS) and progression free survival (PFS) was estimated using the Kaplan-Meier method. The cumulative incidence procedure was used to estimate the incidence of VTE. To identify risk factors for VTE, univariate analysis was conducted on the potential risk factors for VTE and variables with P-value .25 were selected for analysis in the multivariate logistic regression model.
Results: 204 patients diagnosed with DLBCL were included. Patient characteristics are presented in table 1. The median age at diagnosis was 66 years and 63% had advanced stage at diagnosis. After a median follow up was 27 months, 34 patients (16.6%) presented a VTE, with a 3-year cumulative incidence of 13.7% (95% CI 9.2-20.3%). The VTE was a pulmonary embolism in 12 subjects (35%) and deep venous thrombosis in 22 patients (65%). The diagnosis of VTE was done in the presence of active disease in 23 subjects (67%) and the first VTE occurred during the first line of chemotherapy in 16 patients (47% of VTE). Risk factors identified by univariate analysis (table 2) included previous history of VTE, coronary artery disease and congestive heart failure, bulky disease, and absence of a complete response. Treatment with an anthracycline - containing regimen resulted in decreased risk of VTE. In multivariate analysis, only the presence of bulky disease, progressive disease after first line therapy and treatment with anthracyclines retained statistical significance (p = 0.05, 0.05 and 0.006, respectively).
After a median of 27 months of follow up 113 patients had presented progression after first line therapy and 72 had died. Overall, 3-year PFS was 58.6% (95% CI 51-66.2%), with lower PFS in patients experiencing VTE (3-year PFS: VTE 34.8%; no VTE 64.4%, p=0.002). 3-year OS for the whole cohort was 70.2% (95% CI 63.1-77.3%). Patients who presented VTE had a 3-year OS of 51.3% vs. 74.8% in patients without VTE (p=0.002).
DLBCL patients present a high risk of VTE, with approximately half of all VTE events occurring early in the course of the disease. We were able to identify the presence of bulky disease at diagnosis and the absence of response to first line therapy as risk factors for developing VTE. The use of anthracycline-containing regimens was protective against VTE, likely because of the increased rates of disease response. Patients with VTE had worsened outcomes, likely a result of the presence of persistent disease, although a direct effect of VTE on long-term outcomes cannot be ruled out. Our results highlight the need for a heightened awareness of the increased risk of VTE in DLBCL patients and the need for prevention strategies.
Table 1. Baseline patient characteristics Median age, years (range) 66 (20-92) Gender (%) Male Female 115 (56.3%) 89 (43.6%) Stage I II III IV 32 (15.9%) 43 (21.4%) 41 (20.4%) 85 (42.3%) R-IPI 0 1-2 3-5 18 (8.8%) 104 (51.0%) 80 (39.2%)
Table 2. Risk Factors and results of univariate analysis Risk factor Odds Ratio p value Age > 65 1.179 0.661 Male gender 0.847 0.659 Prior congestive heart failure 5.69 0.009 Prior VTE 4.016 0.07 Increased creatinine 3.479 0.181 Morbid obesity 5.121 0.252 Prior malignancy 1.283 0.674 Bulky disease 2.425 0.035 Stage II vs. I III vs. I IV vs. I 3.742 1.343 1.906 0.058 0.703 0.338 Elevated LDH 1.329 0.450 Hemoglobin <10g/dl 0.902 0.236 Platelets < 150,000/mcl 1 0.108 Non - GCB molecular subtype 0.658 0.439 Positive FISH for t(8;14) 1.668 0.568 Anthracycline 0.383 0.050 Rituximab 5.454 0.265 Response PR vs. CR PD vs. CR SD vs. CR 0.843 0.986 0.850 0.863 1.013 1.550

Disclosures
No relevant conflicts of interest to declare.