Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia

Abstract

This study investigated the activity of lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Lenalidomide was given at 10 mg daily with dose escalation up to 25 mg daily. Three patients (7%) achieved a complete response (CR), one a nodular partial remission, and 10 patients a partial remission (PR), for an overall response (OR) rate of 32%. Treatment with lenalidomide was associated with an OR rate of 31% in patients with 11q or 17p deletion, of 24% in patients with unmutated V(H), and of 25% in patients with fludarabine-refractory disease. The most common toxicity was myelosuppression, and the median daily dose of lenalidomide tolerated was 10 mg. Plasma levels of angiogenic factors, inflammatory cytokines, and cytokine receptors were measured at baseline, day 7, and day 28. There was a dramatic increase in median interleukin (IL)-6, IL-10, IL-2, and tumor necrosis factor receptor-1 levels on day 7, whereas no changes were observed in median vascular endothelial growth factor levels (20 patients studied). According to our experience, lenalidomide given as a continuous treatment has antitumor activity in heavily pretreated patients with CLL.

Trial registration: ClinicalTrials.gov NCT00267059.

Figure 1

Response duration. Response duration (months) in 14 patients.

Figure 2

Kaplan-Meier survival curve. Thirty-two (73%) of 44 patients are alive with a median follow-up time of 14 months.

Figure 3

Total lymphocyte and T-cell counts. Total lymphocyte and T-cell counts in peripheral blood in 22 patients at baseline, month 3, and month 6 of treatment. The boxes represent the interquartile range, which extended from the 25th percentile to the 75th percentile, and the line across the box indicates the mean; error bars represent 95% confidence intervals.

Figure 4

Changes in circulating angiogenic and inflammatory factors during therapy with lenalidomide. Peripheral blood was collected from patients receiving lenalidomide therapy at baseline and after 7 days and 28 days of treatment. Plasma samples from patients with stable disease or no response (SD + NR, gray lines) and partial response or complete response (PR + CR, black lines) were analyzed for the angiogenic factors FGF-basic, VEGF, and IL-8; the inflammatory cytokines IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, and TNF-α; and the soluble cytokine receptors IL-2R and TNF-RI. Longitudinal analysis of SD + NR shows significant changes over time in IL-6, IL-10, IL-2R, and TNF-RI. PR + CR show significant changes over time in FGF-basic, IL-10, and IL-2R. The change in VEGF concentrations was not statistically significant for either group. Plasma concentrations are reported in mean (± SEM) picogram per milliliter.

Figure 5

Responders to therapy with lenalidomide have significantly different plasma concentrations of angiogenic and inflammatory cytokines. Cross-sectional analysis of plasma angiogenic and inflammatory factors shows that patients who responded to lenalidomide therapy (PR + CR, ) have significantly lower plasma concentrations (mean ± SEM) of the angiogenic factor FGF-basic (A) and the inflammatory cytokine IL-6 (B) than patients who failed to respond to treatment (SD + NR; ▩). Plasma samples were taken at baseline and following 7 days and 28 days of lenalidomide therapy. Although a trend suggesting decreasing VEGF concentrations in responders was noted, no statistical difference in VEGF plasma concentration was observed between the SD + NR and the PR + CR groups (C). *P < .05 (A); P = .018 (B).