Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia

Author:

Burger Jan A.1ORCID,Sivina Mariela1,Jain Nitin1,Kim Ekaterina1,Kadia Tapan1,Estrov Zeev1,Nogueras-Gonzalez Graciela M.2,Huang Xuelin2,Jorgensen Jeffrey3,Li Jianling4,Cheng Mei4,Clow Fong4,Ohanian Maro1,Andreeff Michael1,Mathew Thomas1,Thompson Philip1,Kantarjian Hagop1,O’Brien Susan5,Wierda William G.1,Ferrajoli Alessandra1,Keating Michael J.1

Affiliation:

1. Department of Leukemia,

2. Department of Biostatistics, and

3. Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX;

4. Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and

5. Division of Hematology/Oncology, University of California, Irvine, CA

Abstract

Abstract Ibrutinib, an oral covalent inhibitor of Bruton’s tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m2; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53 mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.gov as #NCT02007044.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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