Increased Incidence of Thrombosis with Lenalidomide in Chronic Lymphocytic Leukemia: Effect of Lenalidomide On Inflammation, Endothelial Cell Damage and Coagulation.

Abstract 455 There is an increased risk of deep venous thrombosis (DVT) in patients (patients) undergoing lenalidomide (L) therapy. Previous results from our group indicated significant upregulation of tumor necrosis factor alpha (TNFα) in CLL patients on L therapy. Here, we hypothesized that L may increase the risk of DVTs in CLL due to endothelial cell damage resulting from high TNFα serum levels. We studied 27 patients with relapsed CLL enrolled on an investigator initiated phase II single agent L trial (ClinicalTrials.gov Identifier: NCT00465127, 20mg for patients 1-10, 10mg for patients 11-27). The pre-specified accrual goal has been reached. L was given for 4 cycles of L daily for 21 days followed by 21 days off drug. Patients with at least partial response could receive treatment for up to 8 cycles. One patient did not receive therapy (patient9s choice). Venous doppler studies (VDS) were obtained at baseline, cycle 4, cycle 8 and when DVT was suspected. Aspirin prophylaxis was not mandated. Serum samples were evaluated for TNFα, soluble vascular endothelial adhesion molecule 1 (sVCAM) and C-reactive protein (CRP). Plasma samples were evaluated for quantitative D-dimer and soluble thrombomodulin (TM). 26 patients received on average 4 cycles of L (total 107, range 1 to 8 cycles). The median age was 64 years (36-78). Results of hypercoagulabel work-up prior to enrollment were: protein C deficient 0%, mild protein S deficient 12%, mild antithrombin III deficient 8%. Factor V Leiden heterozygosity was found in 1 out of 19 patients, prothrombin gene 20210 polymorphism was absent in all 19 patients tested. Five patients developed six incidents of DVT: hypercoagulability screen was negative in all; 2 patients were fully anticoagulated at the time due to previous DVT. Time to DVT was 134 days (56-259). DVTs occurred during cycle 2, 3, 4, 7 and 8. No PE was detected. Three out of 6 DVTs were treated with tPA thrombolysis. All 5 patients were maintained on full dose anticoagulation for 6 months and 4 continued L. One patient had a second DVT on routine VDS at the end of cycle 8. We have previously shown that L induces a prominent inflammatory state in CLL especially in the first cycle. TNFα was significantly upregulated on day 8 of cycle 1 (increase from mean 32 to 122 pg/ml, P = 0.01) and was persistently upregulated to day 22 (78 pg/ml, P P P =0.02). Next, we assessed effects of L on the coagulation system: D-Dimers increased on day 8 (from 0.5 to 1.1ug/ml, P P P P =0.04). Consistent with a link between TNFα and endothelial damage we found a strong correlation between TNFα and TM serum levels (r=0.61, P P Disclosures: Off Label Use: Lenalidomide is not FDA approved for chronic lymphocytic leukemia..