Pro-Apoptotic Effect of Lenalidomide (L) in Patients with Chronic Lymphocytic Leukemia (CLL) Is Possibly Mediated through Interruption of the Phosphatidylinositol Pathway.

Introduction: In a phase II clinical trial we reported the antileukemic effect of L in CLL pts. In this clinical trial 24/34 (70.5%) pts with detectable tumor cells (ALC > 5,000) in peripheral blood demonstrated a decrease in ALC within 8 days of treatment. Although, the exact molecular mechanism for its antitumor activity remains undetermined, L has been reported to down regulates production of various cytokines including VEGF, IL-6 and TNF-alpha. In order to investigate the underlying mechanism(s) responsible for the antileukemic effects of L in CLL, we examined down stream targets of VEGF and IL-6 signaling pathways in CLL cells obtained from pts pre and post 8 day treatment with L.

Method: Pts with accessible tumor cells in blood (ALC > 5000) who received L were identified. Tumor cells were obtained prior to (baseline) and 8 days after treatment with L. Whole cell lysate was prepared and expression of down stream targets of VEGF, AKT and Erk determined through immunobloting assay.

Results: In cells obtained from pts who had received 8 days of treatment, we observed that L decreased the expression of pAKT and pErk1/2 without changes in corresponding total protein. Conversely L did not have any effect on protein expression of the Bcl-2 or Bcl-xl, though Mcl-1 was decreased compared to pretreatment control.

Conclusion: This is the first time that the antileukemic effect of L in CLL may at least be attributed to down regulation of VEGF and IL-6 mediated prosurvival pathways. Our observation that L does not interrupt the Bcl-2 pathway are clinically intriguing and propose the possibility of combining L with Bcl-2 inhibiting agent(s) to augment the antitumor response in CLL.