Inflammation, TNFα and endothelial dysfunction link lenalidomide to venous thrombosis in chronic lymphocytic leukemia

Abstract

Patients receiving lenalidomide are at an increased risk for deep venous thrombosis (DVT). Here, we prospectively investigated the DVT risk in patients with relapsed chronic lymphocytic leukemia (CLL) treated with lenalidomide (n = 32). Five patients developed six incidents of DVT over 1 year for an annual incidence of 16%. Three of these were considered drug-related. Median time to DVT was 105 days (range 56-259 days). No pulmonary embolism was detected. Hypercoagulability screen before study entry was negative in all patients who subsequently developed DVTs. Compared to normal volunteers CLL patients had increased baseline levels of D-dimer, thrombin-antithrombin, soluble vascular endothelial adhesion molecule 1 (sVCAM-1), and thrombomodulin (p < 0.001). After 1 week on lenalidomide D-dimer, thrombomodulin, sVCAM-1, factor VIII, TNFα, and C-reactive protein were significantly increased while protein C was decreased (p < 0.001). In patients with lenalidomide-related DVTs, TNFα, and sVCAM-1 were more strongly upregulated than in all other patients (p < 0.05) and TNFα and sVCAM-1 levels were significantly correlated (r = 0.65, p < 0.001). These data link lenalidomide associated DVTs with TNFα upregulation and endothelial cell dysfunction and suggest that aspirin may have a role for DVT prophylaxis in these patients.

Trial registration: ClinicalTrials.gov NCT00465127.

Conflict of interest statement

Disclosure:

The authors declare no competing financial interests.

The publisher or recipient acknowledges right of the US government to retain a nonexclusive, royalty-free license to any copyright covering the article.

2011 Wiley-Liss, Inc.

Figures

Figure 1. Lenalidomide exposure and cumulative DVT incidence over 1 year

The cumulative incidence of DVT is shown. The recurrent DVT in the second patient with that was noted on day 314 on routine ultrasound is omitted from this graph. Lenalidomide related DVTs are marked with an asterisk (*).

Figure 2. Abnormal coagulation parameters in CLL patients prior to initiating lenalidomide therapy

Parameters of inflammation, coagulation, and endothelial cell function at baseline (n=32) are normalized to the corresponding upper limit of normal that is set as 100%. The Whisker plot shows the 25th, 50th, and 75th percentile as part of the box, the dashed line indicates the range.

Figure 3. Effects of lenalidomide on markers of inflammation, and endothelial dysfunction and on coagulation factors

Measurements were obtained prior to therapy (pre), on day 8 of lenalidomide and on day 42 of cycle 1, 3 weeks off lenalidomide (post). Only patients with all 3 measurements are shown. The 0, 25, 50, 75 and 100th percentiles are shown in box charts. (A) CRP (n=32) (B) TNFα (n= 31) (C) sVCAM1 (n=30) (D) sTM (n=27) (E) D-dimer(n= 31) (F) Protein C (n= 29) (G) FVIII (n=24).

Figure 4. Correlation between TNFα, endothelial dysfunction and lenalidomide-related DVTs

A–D. Change of expression levels in patients without DVTs, DVTs unrelated to lenalidomide (Unrel. DVT) and related to lenalidomide (Rel. DVT), with exact p-value for comparison between patients with lenalidomide-related DVT and all other patients using the Wilcoxon rank-sum test: A. TNFα B. TF C. sVCAM1 and D. sTM. E–F. Pearson’s correlation between TNFα on day 8 of lenalidomide and E. sVCAM1 (n=30) and F. sTM (n=32).