Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.

Abstract

BACKGROUND:

In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.

METHODS:

In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.

RESULTS:

At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.

CONCLUSIONS:

Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

• Authors: John C Byrd, Jennifer R Brown, Susan O'Brien, Jacqueline C Barrientos, Neil E Kay, Nishitha M Reddy, Steven Coutre, Constantine S Tam, Stephen P Mulligan, Ulrich Jaeger, Steve Devereux, Paul M Barr, Richard R Furman, Thomas J Kipps, Florence Cymbalista, Christopher Pocock, Patrick Thornton, Federico Caligaris-Cappio, Tadeusz Robak, Julio Delgado, Stephen J Schuster, Marco Montillo, Anna Schuh, Sven de Vos, Devinder Gill, Adrian Bloor, Claire Dearden, Carol Moreno, Jeffrey J Jones, Alvina D Chu, Maria Fardis, Jesse McGreivy, Fong Clow, Danelle F James, Peter Hillmen, RESONATE Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 371 Issue 3 Pg. 213-23 (Jul 17 2014) ISSN: 1533-4406 [Electronic] United States
• PMID: 24881631 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• Protein-Tyrosine Kinases
• Agammaglobulinaemia Tyrosine Kinase
• Adenine
• ofatumumab

Topics

• Adenine (analogs & derivatives)
• Adult
• Agammaglobulinaemia Tyrosine Kinase
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (adverse effects, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Cough (chemically induced)
• Diarrhea (chemically induced)
• Disease-Free Survival
• Fatigue (chemically induced)
• Female
• Follow-Up Studies
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, mortality)
• Male
• Middle Aged
• Piperidines
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazoles (adverse effects, therapeutic use)
• Pyrimidines (adverse effects, therapeutic use)
• Recurrence
• Survival Rate