Lenalidomide Therapy Increases VTE Risk in B-Cell Non-Hodgkin Lymphoma

Patients with B-cell non-Hodgkin lymphoma (NHL) treated with lenalidomide have an increased risk of developing venous thromboembolism (VTE) – similar to the increased risk observed in lenalidomide-treated patients with myeloma – according to results from a systematic review and meta-analysis published in Blood Advances. This risk appears to be consistent among patients with NHL who receive lenalidomide alone or in combination with biologic agents or chemotherapy.

To characterize the risk of VTE among this patient population, the authors, led by Samuel Yamshon, MD, from Weill Cornell Medicine in New York, searched literature databases (including Ovid MEDLINE and The Cochrane Library) to identify abstracts across all languages that assessed patients with either newly diagnosed or relapsed/refractory B-cell NHL who were treated with lenalidomide. Of 1,719 citations found in the initial review, 28 articles were included.

Researchers selected VTE events per 100 patient-cycles as the study’s primary outcome. A VTE event was defined as a grade ≥2 venous thrombosis (according to National Cancer Institute Common Toxicity Criteria, the Common Terminology Criteria for adverse events, or the World Health Organization criteria).

VTE rate was measured within three predefined cohorts:

  • patients treated with lenalidomide monotherapy (n=698)
  • patients treated with lenalidomide plus biologic agents (n=357)
  • patients treated with lenalidomide plus chemotherapy (n=378)

The median age among all three cohorts was between 65 and 68 years (ranges not specified). Patients in the lenalidomide-plus-chemotherapy group received a median of zero prior therapies, while those in the other two cohorts had a median of three prior therapies.

Overall, the 28 studies included a total of 10,332 lenalidomide treatment cycles with 77 VTE events reported. The pooled VTE rate per 100 patient-cycles among the entire B-cell NHL cohort was 0.77 events (95% CI 0.48-1.12).

In the sub-analyses of the three cohorts, rates of the primary outcome were as follows:

  • lenalidomide monotherapy: 1.09 events (95% CI 0.49-1.94)
  • lenalidomide plus biologic agents: 0.49 events (95% CI 0.17-0.97)
  • lenalidomide plus chemotherapy: 0.89 events (95% CI 0.39-1.60)

The authors also calculated the three- and six-month rates of VTE for the overall population (2.3% and 4.5%, respectively), which appeared to be similar to those reported among lenalidomide-treated patients with myeloma. (See TABLE for VTE rates among the three treatment cohorts).

Pooled VTE Events per 100 Patient-Cycles by Treatment Modality Using Random-Effects Models

“Although meta-analysis techniques do not allow for direct significance testing across the subgroups, the single-agent group appears to be associated with a higher VTE event rate,” the authors reported, offering several hypotheses for this association. “A reduction in tumor burden by the addition of a second agent may account for this relatively decreased risk in those patients treated with lenalidomide and an additional agent,” they wrote. “A direct interaction between lenalidomide and tumor cells is a possibility as well, with lenalidomide having an effect on the vasculature and mediators of coagulation.”

“Our systematic review and meta-analysis suggest that the rate of thrombosis in patients with lymphoma treated with lenalidomide is similar to that in multiple myeloma, where guidelines recommend VTE prophylaxis for all patients,” Dr. Yamshon told ASH Clinical News. “Given these similarities, and the emerging potential clinical applications of lenalidomide-containing regimens in various lymphoma populations, outpatient VTE prophylaxis should be carefully considered in patients with B-cell NHL treated with lenalidomide.”

The findings of this meta-analysis are limited by the lack of data on the total number of treatment cycles received by patients in certain included studies. In addition, this report examined studies that enrolled highly selected patients who were actively participating in clinical trials, which may limit the generalizability of the findings across the average B-cell NHL population. Also, “although the median age, stage, and performance status throughout the three cohorts were similar, other risk factors for thrombophilia could not be further differentiated with these study reports,” the authors noted.

“We hope that the data will help inform clinicians in evaluating the risks and benefits of VTE prophylaxis in this population,” Dr. Yamshon said. “In future trials of lenalidomide in NHL, it might be helpful to report VTE as a defined outcome stratified to risk factors such as age, comorbidities, and lymphoma subtypes, in addition to including it as an adverse event.” He added that “a randomized controlled trial comparing VTE preventative approaches in high-risk populations also could be clinically relevant, as there is no consensus for best practices for VTE prophylaxis in this group of patients.”

The authors report financial relationships with Celgene.


Yamshon S, Christos PJ, Demetres M, et al. Venous thromboembolism in patients with B-cell non-Hodgkin lymphoma treated with lenalidomide: a systematic