Introduction Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. VTE rates vary significantly based on malignancy type, suggesting that mechanisms promoting thrombosis are tumor-specific. Patients with lymphoma carry a particularly high risk of VTE, but our understanding of the pathogenesis and association between lymphoma subtypes and VTE risk is limited.

Cancer cell genotype is increasingly recognized as an important factor for VTE development. In solid cancers, somatic alterations in KRAS, CDKN2B, and MET have been associated with an increased risk of VTE. However, there are no data investigating somatic genomic determinants of cancer-associated thrombosis (CAT) in lymphoma.

The purpose of this study was to characterize VTE risk across B-cell lymphoma subtypes and to assess potential associations of molecular signatures with CAT.

Methods We queried institutional databases to identify all adult B-cell lymphoma patients who had Memorial Sloan Kettering HEME-IMPACT testing (i.e., targeted tumor sequencing) performed between December 2016 and December 2022. Observation start was the date of the first HEME-IMPACT report; the event of interest was the first CAT episode, defined as any instance of pulmonary embolism or lower extremity deep vein thrombosis (DVT). Line-associated thrombi were excluded. Thrombotic events were initially identified with the natural language processing (NLP) platform CEDARS+PINES and confirmed with manual review by a physician.

Competing risk analysis was used to estimate the risk of VTE, and cause-specific Cox regression estimated associations between somatic alterations (mutations, copy number alterations, and rearrangements) and the risk of developing CAT.

Results We identified 3,403 eligible patients; the median age at sequencing was 66 years (IQR: 57-73); a majority were male (58%) and identified as white (84%). The most common lymphoma subtypes were chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL, n=1,175, 35%), diffuse large B-cell lymphoma (DLBCL, 638, 19%), follicular lymphoma (FL, 543, 16%), mantle cell lymphoma (MCL, 357, 10%), and marginal zone lymphoma (MZL, 326, 10%).

Among all patients, the 1-year cumulative incidence of VTE was 2.4% (95% confidence interval [CI], 1.9-2.9%). Subgroup analysis revealed higher 1-year incidence in aggressive vs. indolent lymphomas (4.0 vs. 1.6%; P < 0.05); correspondingly, when broken down by subtype, 1-year incidence of VTE was highest in DLBCL (4.9%; 95% CI, 3.3-7.0%) and MCL (3.0%, 95% CI, 1.5-5.5%) and lower in CLL/SLL (1.7%, 95% CI, 1.1-2.6%), FL (1.7%, 95% CI, 0.79-3.1%), and MZL (1.5%, 95% CI, 0.49-3.5%; P < 0.0001).

Alterations in BIRC3 (hazard ratio [HR], 4.04; 95% CI, 1.85-8.81; P = 0.0001), CDKN2A (HR, 3.67; 95% CI, 2.01-6.70; P < 0.0001), CDKN2B (HR, 3.97; 95% CI, 2.09-7.56; P < 0.0001), and PRDM1 (HR, 5.37; 95% CI, 2.32-12.40; P < 0.0001) were associated with an increased risk of CAT independent of tumor type and remained significant after adjustments for multiple comparisons. Frequencies of these alterations were modest: BIRC3 (n=96, 3%), CDKN2A (n=215, 6%), CDKN2B (n=164, 5%), PRDM1 (n=60, 2%).

In subgroup analysis, somatic alterations in CDKN2A (HR, 6.42; 95% CI, 2.25-18.26; P = 0.0004) and CDKN2B (HR, 7.06; 95% CI, 2.48-20.09; P = 0.0003) were associated with an increased risk of CAT in indolent lymphomas. Frequencies of alterations in this subgroup were low: CDKN2A (n=56, 2%), CDKN2B (n=50, 2%). This effect appeared to be driven by the CLL/SLL population in whom CDKN2A (HR, 10.08; 95% CI, 2.31-43.97; P = 0.003) and CDKN2B (HR, 10.38; 95% CI, 2.38-45.24; P = 0.002) alterations were highly associated with VTE.

There were no genomic alterations in aggressive lymphomas that were found to be associated with a significantly increased risk of CAT. Similarly, no statistically significant associations were identified in the DLBCL, FL, MCL, or MZL subgroups.

Conclusions This is the first large-scale analysis to elucidate genomic alterations associated with the development of CAT in patients with lymphoma. Tumor-specific somatic alterations of BIRC3, CDKN2A, CDKN2B, and PRDM1 were associated with an increased risk of VTE across all patients; alterations in CDKN2A and CDKN2B were strong predictors of thrombosis in indolent lymphomas. Further work is needed to validate these findings, elucidate the pathogenesis of these associations, and translate them to clinical practice.

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2025
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