Efficacy and predictors of response of lenalidomide and rituximab in patients with treatment-naive and relapsed CLL

Paolo Strati, Koichi Takahashi, Christine B. Peterson, Michael J. Keating, Philip A. Thompson, Naval G. Daver, Nitin Jain, Jan A. Burger, Zeev Estrov, Susan M. O'Brien, Hagop M. Kantarjian, William G. Wierda, P. Andrew Futreal and Alessandra Ferrajoli

Key Points

  • The combination of lenalidomide and rituximab is highly effective in patients with CLL and low baseline β2-microglobulin levels.

  • Mutations in the NOTCH signaling pathway are associated with worse outcome in patients with CLL treated with lenalidomide and rituximab.


This phase 2 study was conducted to prospectively evaluate how clinical and biological factors correlate with outcome in patients with treatment-naive (TN) and relapsed (R) chronic lymphocytic leukemia (CLL) treated with lenalidomide and rituximab. Oral lenalidomide 10 mg was administered daily starting on day 9 of cycle 1. IV rituximab 375 mg/m2 was administered weekly during cycle 1 and every 4 weeks for cycles 3 to 12. Sequencing of a custom panel of 295 genes was performed in pretreatment bone marrow samples. The study included 61 patients with TN CLL and 59 with R CLL; the overall response rate (ORR) was 73% and 64%, respectively. A baseline β2-microglobulin level <4 mg/L was associated with higher ORR in both groups (both, P = .03), and absence of mutations in the NOTCH signaling pathway showed a trend for association with higher ORR in R CLL (P = .10). Median PFS was 50 months in TN patients and 28 months in R patients. On multivariate analysis, age ≥65 years (P = .02) was associated with shorter PFS in TN patients, whereas according to univariate analysis, >2 previous therapies (P = .02) was the only factor associated with shorter PFS in R patients. A trend for association between mutations in the NOTCH pathway and shorter PFS was observed in TN CLL (P = .15). Further exploration of the NOTCH pathway may help optimize the efficacy of this combination in patients with CLL. This study protocol was approved by the University of Texas MD Anderson Cancer Center institutional review board and registered at (#NCT01446133).

  • Submitted January 9, 2019.
  • Accepted March 26, 2019.
View Full Text