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Clinical Trial
. 2019 May 14;3(9):1533-1539.
doi: 10.1182/bloodadvances.2019031336.

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

Paolo Strati  1 , Koichi Takahashi  1   2 , Christine B Peterson  3 , Michael J Keating  1 , Philip A Thompson  1 , Naval G Daver  1 , Nitin Jain  1 , Jan A Burger  1 , Zeev Estrov  1 , Susan M O'Brien  1 , Hagop M Kantarjian  1 , William G Wierda  1 , P Andrew Futreal  2 , Alessandra Ferrajoli  1
Affiliations
Clinical Trial

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

Paolo Strati et al. Blood Adv. .

Abstract

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 clinicaltrials.gov (#NCT01446133).

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Conflict of interest statement

Conflict-of-interest disclosure: M.J.K. was a consultant for Celgene Corporation. W.G.W. was a consultant/advisory board member for Celgene Corporation. S.M.O. was a consultant for Celgene Corporation. A.F. received research support from Celgene Corporation. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Gene mutation distribution according to treatment arm. No difference in the frequency of gene mutations and mutated pathway groups before initiation of the study treatment was observed when comparing TN patients vs R patients. NOTCH signaling pathway: NOTCH1, SPEN, FBXW7; inflammatory/B-cell receptor pathway: BIRC3, EGR2, NFKBIE, KRAS, SAMHD1, BRAF; WNT signaling pathway: MGA, MED12, FBXW7; DNA damage and cell cycle control pathway: TP53, ATM, POT1, BRCC3, RB1; chromatin modification pathway: ZMYM3, IKZF3, ASXL1, CREBBP, SP140, KM2TC; and RNA and ribosomal processing pathway: SF3B1, XPO1.
Figure 2.
Figure 2.
Survival according to treatment arm. (A) PFS according to treatment arm. (B) OS according to treatment arm. mPFS, median PFS.
See this image and copyright information in PMC

References

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