Long-term follow-up of the RESONATE™ phase 3 trial of ibrutinib versus ofatumumab

John C. Byrd, Peter Hillmen, Susan O'Brien, Jacqueline C. Barrientos, Nishitha M. Reddy, Steven Coutre, Constantine S. Tam, Stephen P. Mulligan, Ulrich Jaeger, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Patrick Thornton, Carol Moreno, Marco Montillo, John M. Pagel, Jan A. Burger, Jennifer A. Woyach, Sandra Dai, Remus Vezan, Danelle F. James and Jennifer R. Brown

Key points

  • Extended treatment with ibrutinib showed sustained PFS in previously treated patients with CLL including those with high-risk cytogenetics.

  • Overall survival outcomes were sustained and no long-term safety signals have emerged with 4 years of follow-up on ibrutinib treatment.


Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE™, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the US and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR] 0.133; 95% CI, 0.099-0.178) was observed. Overall survival benefit continues (HR 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS versus without these factors. Median duration of ibrutinib was 41 months with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL, and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at as NCT01578707.

  • Submitted August 21, 2018.
  • Accepted January 26, 2019.