A phase 1 study of lenalidomide and ibrutinib in combination with rituximab in relapsed and refractory CLL

Abstract

Attempts to improve upon the activity of ibrutinib in chronic lymphocytic leukemia (CLL) include the addition of targeted therapies. The combination of lenalidomide and rituximab demonstrated an overall response rate (ORR) of 66% with a complete response (CR) of 12% in the relapsed/refractory setting. Based on these data, we conducted a phase 1 study of rituximab (R), lenalidomide (L), and ibrutinib (I) in relapsed/refractory CLL. Patients received R 375 mg/m2 cycles 1 to 6 day 1, L on cycles 1 to 12 days 1 to 21, and I until disease progression. Dose escalation used a standard 3+3 design from a dose level (DL) of L 5 mg (DL1) and increasing to 15 mg (DL3) for a total of 3 dose levels. Twelve patients were enrolled; there were 2 dose-limiting toxicities of grade 4 neutropenia at DL3; thus, DL2 was the recommended phase 2 dose. A high incidence of sustained grade 4 neutropenia occurred at all dose levels, prompting study withdrawal in 5 patients, despite growth factor support. The ORR was 67%; ORR at the RP2D was 100% (1 CR). The 12-month progression-free survival at the RP2D was 83%. Preliminary efficacy data with the triplet did not appear superior to prior reports of the rituximab-lenalidomide doublet or single-agent ibrutinib. Given these findings and the sustained neutropenia, this regimen was not pursued. The study was registered at www.clinicaltrials.gov as #NCT02200848.

Conflict of interest statement

Conflict-of-interest disclosures: C.U. has been a consultant for and received research support from Pharmacyclics, been a consultant for Genentech, and on a speakers bureau for AbbVie. A.S. and N.K. have been on a speakers bureau for Genentech. B.D.C. has consulted for Celgene, Roche-Genentech, and Pharmacyclics, and research support was provided to this author’s institution by Roche-Genentech and Pharmacyclics. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

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Graphical abstract

Figure 1.

Progression-free survival.