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Randomized Controlled Trial
. 2014 Jul 17;371(3):213-23.
doi: 10.1056/NEJMoa1400376. Epub 2014 May 31.

Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia

John C Byrd  1 , 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
Collaborators, Affiliations
Randomized Controlled Trial

Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia

John C Byrd et al. N Engl J Med. .

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.).

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Figures

Figure 1
Figure 1. Progression-free and Overall Survival
The durations of progression-free survival (Panel A) and overall survival (Panel B) were significantly longer in the ibrutinib group than in the ofatumumab group. At a median follow-up of 9.4 months, the median duration of progression-free survival 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; the median duration of overall survival was not reached in either study group.
Figure 2
Figure 2. Subgroup Analyses of Progression-free Survival
Shown are forest plots of hazard ratios for death or disease progression among subgroups of patients in the ibrutinib group and the ofatumumab group. The size of the circle is proportional to the size of the subgroup. The dashed vertical line indicates the overall treatment effect for all patients. The only test for heterogeneity that was significant was for geographic region (P = 0.02), although the treatment effect remained significant within each region (P
Figure 3
Figure 3. Best Response to Therapy, as Assessed by Independent Reviewers and by Investigators
Shown are rates of patients’ best response to therapy, according to independent assessment (Panel A) and investigator assessment (Panel B) with respect to complete response (CR), complete response with incomplete hematopoietic recovery (CRi), partial response (PR), partial response with lymphocytosis (PR+L), stable disease (SD), and progressive disease (PD). Data were unknown, missing, or could not be evaluated for 5 patients in the ibrutinib group in both the independent assessment and the investigator assessment and for 15 patients in the ofatumumab group in the independent assessment and 17 patients in the group in the investigator assessment.
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