In the study we aimed to evaluate the connection between inflammatory markers and the risk of VTE development in the cohort of lymphoma patients, and the relationship between VTE and the treatment course of patients with lymphoma. Our analysis found that the inflammatory markers correlate well with the risk for VTE development in lymphoma patients, with NLR and CRP being the most accurate VTE predictive markers, based on statistical analysis. Further, we identified that an insufficient therapeutic response on (immuno)chemotherapy is a risk factor for VTE in lymphoma patients. Summarizing, immune dysregulation in lymphoma settings has a substantial impact on VTE occurrence.
In our study of patients with different types of lymphoma, the rate of VTE development was 9.8%. In a meta-analysis by Caruso et al.,(13) which included 18,018 patients with lymphoma, the rate of VTE development was 6.4%. In that study, a higher rate of VTE development was observed in NHL patients than in HL patients. In a study by Mahajan et al.,(14) the cumulative 2-year incidences of acute VTE were 2.1%, 4.8%, and 4.5% in patients with low-grade, intermediate/aggressive, and high-grade lymphomas, respectively. Two studies(15,16) focusing only on diffuse large B-cell lymphoma (DLBCL) found that the rate of VTE development was 11% and 11.1%, respectively. In a study examining the frequency of VTE in cancer patients, Khorana et al.(17) observed that 4.8% of NHL patients developed VTE, whereas 4.6% of HL patients developed VTE. In the study by Antic et al.,(18) the rates of VTE development among lymphoma patients were 5.3% in the derivation cohort and 5.8% in the validation cohort. In a recently published article(19) focusing on DLBCL and follicular lymphoma, the reported rate of VTE development was 13.4%. These observed variations in the VTE rate in lymphoma patients are notable and may have several causes, including focusing on distinctive types of lymphoma, study methodology (e.g., retrospective vs. prospective), and publication time (more recent studies have been dedicated to CAT). Our results are similar to those of studies focusing only on aggressive lymphoma, which is in accordance with the fact that more than half of our study population had aggressive lymphoma.
In our study, the NLR, PLR, ESR, CRP, and LDH were significantly higher in lymphoma patients with VTE than in those without VTE, whereas the TP and albumin were significantly lower in lymphoma patients with VTE than in those without VTE. The ROC curve analysis indicated acceptable specificity and sensitivity of the NLR, PLR, and CRP in predicting VTE in lymphoma patients. In particular, the univariate regression analysis indicated that the NLR, PLR, TP, albumin, LDH, and CRP were prognostic factors for VTE development in lymphoma patients, although the multivariate regression model demonstrated that only the NLR and CRP were independent prognostic factors for VTE development. Both the NLR and PLR have been used as prognostic markers in a variety of pathological conditions, including sepsis, lupus erythematosus and solid tumors.(20) Additionally, the NLR and PLR have been suggested as adverse prognostic markers in patients with DLBCL(21) and mantle cell lymphoma,(22) although some publications have found conflicting results.(23) Regarding the association of the NLR and PLR with thrombotic events, some previous studies have shown the predictive power of the NLR and PLR for VTE development.(10,24) In contrast, Artoni et al.(25) failed to find an association of the NLR and PLR with an increased risk of VTE or cerebral vein thrombosis. To the best of our knowledge, there are no published studies using the NLR and PLR to assess the risk of VTE in lymphoma patients.
An increasing number of studies aim to define the relationship between inflammation and thrombosis, as well as the specific mechanisms underlying this relationship, but the most important mechanisms are yet to be discovered. The best studied mechanisms that have been shown to trigger thrombosis development or have been frequently observed in patients who develop thrombosis are increased levels of tumor necrosis factor-alpha (TNF-α),(26) hyperexpression of interleukin-6,(11) neutrophil extracellular traps,(27) soluble CD40 ligand,(28) and microparticles (MPs).(29) Kapoor et al.(30) significantly advanced our understanding of these processes by introducing a fourth element to Virchow’s triad-immune dysregulation, naming it the “tetrad of thrombosis.” They clearly stressed that there is a sufficient amount of evidence supporting the impact of immune dysregulation on the pathophysiology of thrombosis. A few publications identified higher CRP in patients with VTE (mainly DVT),(31) whereas the study by Antic et al.(32) published results similar to ours, showing the effect of a broad inflammatory and hemostatic biomarker spectrum (including D-dimer, Factor XIIIa, von Willebrand factor, TNF-α, protein S, β2Glycoprotein I, MPs, urokinase-like plasminogen activator, fibronectin, and plasminogen activator inhibitor type 1).
Similar to the results of previous studies,(13,14,33) we found that patients with advanced disease more frequently developed VTE, although this was not statistically significant. A “bulky” tumor mass, mediastinal involvement, and ECOG PS were identified as prognostic factors for VTE development in lymphoma patients in the univariate analysis. A large mediastinal tumor mass is an important risk factor for the development of VTE, mainly because of the mechanical compression of blood vessels and consequent narrowing of the lumen.(34,35) Performance status is included in newer VTE risk assessment models, underlining its importance in VTE development.(18,35) Immobility has been recognized as a contributing factor for VTE. It is of particular important in patients with CNS lymphoma, as they have a strikingly high rate of VTE development (59.5%).(36)
In our cohort, patients with aggressive lymphoma had a higher rate of VTE development (11.8%) than did patients with indolent lymphoma (5.8%) and HL (8.4%). Aggressive histology is predisposed to complicate the clinical course of lymphoma due to VTE.(13,14,19,33,35,37) However, one large study by Sanfilippo et al.(38) concluded that the VTE risk for DLBCL is lowered after adjusting for additional risk factors. In general, aggressive lymphomas have higher proliferation rate which enables them to advance promptly and to obtain VTE risk factors more rapidly (“bulky” tumor mass, extranodal localizations, poor performance status), consequently increasing the risk for VTE development.
Complementary to our results, the predominant timing of VTE occurrence in lymphoma patients is prior to or within 3 months from the initiation of specific hematologic treatment. (34,39,40) These data draw attention to the role of thromboprophylaxis, which remains underused in cancer patients.(18,41) Considering the absence of statistical significance for thromboprophylaxis between lymphoma patients with and without VTE, our data confirm the underutilization of thromboprophylaxis. There are several reasons why thromboprophylaxis continues to be underused in lymphoma patients: the lack of reliable and widely accepted usage of a VTE risk assessment model for this heterogeneous group of patients, the lack of prospective studies with risk stratification and randomization for thromboprophylaxis,(37) excessively diverse data throughout the literature concerning this topic, and overestimation of bleeding risk in combination with anticoagulant therapy in cancer patients by clinicians. Further disease specific and adequately designed clinical trials on thromboprophylaxis are required in order to achieve high quality evidence to ameliorate clinical guidelines.
Importantly, lymphoma patients who achieved unsatisfactory therapeutic responses were more susceptible to the development of VTE. This finding is in accordance with published data that confirm the connection between aggressive lymphoma and advanced stage, resulting in shorter overall survival (OS) and a higher mortality rate.(14,33,34,42) However, one study(43) did not observe an OS difference between lymphoma patients with and without VTE. The biology of aggressive lymphoma leads to aggravate clinical course. Moreover, immune dysregulation in aggressive lymphoma subtypes is probably impaired to a greater extent, which contributes to the risk for VTE occurrence.
In our study, patients receiving intensive first-line or “salvage” chemotherapeutic regimens experienced a higher rate of VTE development than patients treated with standard first-line therapy regimens (R-CHOP, CHOP, and ABVD). Chemotherapy itself is known to be a risk factor for VTE development.(3,35) The incidence of VTE is higher in lymphoma patients treated with dose-intense regimens.(44) Further, anthracycline drugs are associated with an increased risk of VTE.(19,38) Intensive first-line therapeutic regimens are used to treat more aggressive lymphoma subtypes, and both intensive regimens and aggressive subtypes are potential risk factors for VTE development. Relapsing lymphomas are inclined to follow a more aggressive clinical course, primarily because of the biology of the disease and the development of resistant features. Consequently, those patients are treated with more intensive, so-called “salvage,” chemotherapeutic regimens. These patients frequently have other VTE risk factors, such as poor performance status and advanced disease, which significantly increase the risk of VTE development.
Our data comes with several limitations to be mentioned. The main limitation is the heterogeneity of the study population, which possibly affects the results and subsequent conclusions. The impact of VTE onto survival rates of lymphoma patients was out of scope of this study. Perhaps, that would further contribute to the assessment of actual clinical impact of VTE in lymphoma patients.