Prospective Evaluation of the Risk of Thromboembolic Complications in Patients Treated with Lenalidomide-based Therapy and Genetic Associations

Abstract ²⁸⁷²

The introduction of IMiDs (thalidomide, lenalidomide and recently pomalidomide) has been a major advance in the treatment of multiple myeloma. These agents have shown significant efficacy both in the relapsed/refractory setting and at the initial therapy of the disease, especially when combined with dexamethasone. However, it has been recognized that all IMiDs are associated with a significant increase in the risk of thromboembolic complications, especially when they are combined with high dose dexamethasone and chemotherapy. Genetic and environmental factors may modulate the risk for venous thromboembolism (VTE). Specific genetic polymorphisms have been associated with an increased risk of thromboembolic complications in patients treated with thalidomide-based regimens and who did not receive standard thromboprophylaxis. These single nucleotide polymorphisms (SNPs) have not been evaluated in patients treated with lenalidomide.

In order to evaluate the frequency of thromboembolic complications in patients treated with lenalidomide, we analyzed 200 patients treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece). All patients treated with lenalidomide-based regimens received low dose aspirin, unless there was a clear indication for other form of thromboprophylaxis (low molecular weight heparins (LMWH) or warfarin) due to: atrial fibrillation, prior thromboembolic event or immobilization (Dimopoulos et al, Leukemia 2011;25 :749–60). We also screened 6 SNPs that have been associated with increased VTE risk in patients treated with thalidomide by direct sequencing of peripheral blood derived genomic DNA. The analysis included ALDH1A1 (rs610529), CHEK1 (rs506504), CINP (rs7011), NFKB1 (rs3774968), TNFRSF17 (rs19222317), XRCC5 (rs2440) in 83 patients who received lenalidomide-based therapy.

Sixty seven patients were previously untreated: 54 received first line therapy with lenalidomide plus low dose (weekly) dexamethasone (Rd) and 13 received lenalidomide with melphalan and prednisone (MPR). Among 133 previously treated patients, 84 received lenalidomide plus high dose dexamethasone (RD) and 49 received lenalidomide plus high dose dexamethasone with bortezomib (BRD). Thromboprophylaxis consisted of low dose aspirin (100 mg daily) in 165 (82.5%) patients, LMWH in 20 (10%) patients and warfarin in 15 (7.5%) patients.

Eleven patients (5.5%) suffered a venous thromboembolic event (VTE), which included 8 episodes of deep vein thrombosis (DVT) while 3 patients suffered pulmonary embolism. None of the patients died because of the VTE. All VTEs occurred in patients who were receiving aspirin prophylaxis, thus, the frequency of VTE in patients receiving aspirin was 7% vs. 0% for patients receiving LMWH or warfarin. The frequency of VTEs was 9.4% for previously untreated and 5.4% for previously treated patients. Among previously treated patients, 5.6% of patient receiving RD suffered a VTE vs. 4.9% receiving BRD.

We then analyzed 73 patients who received low dose aspirin, 7 of which developed VTE, for possible associations of VTE risk with specific SNPs. A trend towards increased risk for VTEs was found for 3 SNPs in genes involved in response to DNA damage and cytokine mediated apoptosis. The frequency of SNPs in patients that developed VTE vs. the ones without a thromboembolic event is the following: CHEK1_rs506504 (11% vs. 0%), XRCC5_rs2440 (15% vs. 8%) and NFKB1_rs3774968 (17% vs. 7%). For patients carrying all three SNPs, VTE rates were 50%.

In conclusion, the frequency of VTE in patients treated with lenalidomide-based regimens was 5.5% but all events appeared in patients who received thromboprophylaxis with low dose aspirin. The administration of LMWH in patients at high risk for thromboembolic complications (atrial fibrillation, prior thromboembolic event or immobilization) may abrogate the risk of VTE. The identification of SNPs that confer susceptibility to thrombosis in patients treated with lenalidomide may help stratify patients according to risk for VTE and guide the choice of appropriate thromboprophylaxis.