Final Results of RESONATE Trial Show Long-Term Benefit of Ibrutinib in Relapsed or Refractory CLL

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Paul M. Barr, MD

Paul M. Barr, MD

Daniel Persky, MD

Daniel Persky, MD

After 6 years of follow-up, extended treatment with ibrutinib showed sustained progression-free survival benefit and depth of response in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including those with high-risk genomic features, according to the final analysis of the phase III RESONATE trial.1 Ibrutinib has redefined treatment paradigms in the treatment of CLL and SLL, and these results further establish the long-term benefit and tolerability for continuous ibrutinib treatment in patients with relapsed or refractory CLL/SLL, according to the investigators.

These findings were originally presented at the 2019 ASCO Annual Meeting by Paul M. Barr, MD, of the University of Rochester Medical Center, and colleagues.1 The study was later discussed at the Best of ASCO Austin by Daniel Persky, MD, of the University of Arizona Cancer Center, along with other top selected abstracts in lymphoma and CLL.2

Clearly, ibrutinib continued to dominate over ofatumumab, in both the intention-to-treat population for progression-free survival and in the genomic high-risk population.
— Daniel Persky, MD

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“[The data from this mature analysis] show us that the results continue to be excellent,” said Dr. Persky. “I would agree that ibrutinib continues to be effective, and the side effects mostly wane; there have been no new toxicity signals.” However, he added, these findings have become “less impactful,” since the study was conducted in a relapsed setting and ibrutinib is now commonly used in front-line therapy.

Sustained Efficacy

The study was first published in The New England Journal of Medicine in 2014.3 At the time, the study showed an advantage in both progression-free and overall survival in the ibrutinib arm after a median follow-up of 9.4 months. Now, after 6 years of follow-up, Dr. Persky said, “the long-term results of single-agent ibrutinib in patients with relapsed CLL are holding up.”

The trial enrolled 391 patients with CLL or SLL who had undergone at least one prior therapy and were not candidates for purine analog therapy. Patients were randomly assigned 1:1 to oral ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity (n = 195) or intravenous ofatumumab for up to 24 weeks (n = 196). A total of 86% of patients assigned to ibrutinib and 79% of those assigned to ofatumumab were in the genomic high-risk population: del(17p), del(11q), TP53 mutation, and/or unmutated IgVH.

At final analysis, the median follow-up was about 5.5 years in both arms. The median treatment duration was 41 months with ibrutinib and 5.3 months with ofatumumab, and 68% of patients randomly assigned to ofatumumab crossed over to the ibrutinib arm.

Safety remained acceptable, with low rates of treatment discontinuation due to adverse events, and no new safety signals were observed over long-term therapy. A total of 37% of discontinuations from ibrutinib were due to disease progression, and 16% were due to adverse events.

Long-Term Benefit Consistent Across Subgroups

A significant and sustained progression-free survival benefit was observed with ibrutinib compared with ofatumumab, with a median progression-free survival of 44 vs 8 months (P < .0001) that was consistent across baseline subgroups.

“A total of 29% of patients in the ibrutinib arm continued on it for more than 5 years,” Dr. Persky noted. “Clearly, ibrutinib continued to dominate over ofatumumab, in both the intention-to-treat population for progression-free survival and in the genomic high-risk population.”

RESONATE Trial: Final Analysis

  • With up to 6 years of follow-up, extended ibrutinib treatment yielded sustained efficacy in patients with relapsed or refractory CLL and SLL when compared with ofatumumab, according to the final results of the phase III RESONATE trial.
  • Safety remained acceptable, with low rates of treatment discontinuation due to adverse events.
  • These results establish long-term benefit and tolerability of ibrutinib in the treatment of relapsed or refractory CLL.

Among patients treated with ibrutinib, median progression-free survival trended longest for patients with del(11q), at 57 months, and was similar between patients with del(17p) and those without del(11q) or del(17p) abnormalities, the investigators reported. IgVH status did not affect progression-free survival.

“When looking at the ibrutinib arm separately by chromosomal deletion and IgVH mutation status, median progression-free survival with del(17p) and/or TP53 mutation was reached at 41 months,” he said. “However, this is much longer than we would have expected from chemoimmunotherapy.”

Depth of Response Improved Over Time

“Depth of response continued to improve,” said Dr. Persky. “At the time of the initial report, it was 2% to 3%, and it improved to an 11% complete remission rate.”

With long-term follow-up on ibrutinib, the overall response rate was 91%. Median overall survivals were 67.7 months and 65.1 months in the ibrutinib and ofatumumab arms, respectively. “This is including the two-thirds of patients on the ofatumumab arm who were allowed to cross over, which means as long as they crossed over, they still achieved the benefit in overall survival,” he explained. “To be honest, there was an initial concern as to whether or not it was important to start with ibrutinib.”

Responses were seen in 10 of 27 patients who went on to next-line therapy (venetoclax, idelalisib plus rituximab, high-dose methylprednisolone plus alemtuzumab, and investigational agents) after experiencing disease progression with ibrutinib.

“This is saying, in effect, that disease progression doesn’t necessarily impart a poor prognosis,” Dr. Persky added. “Patients can still achieve responses with other agents that work through different mechanisms of action.” 

DISCLOSURE: Dr. Barr has served as a consultant or advisor to AbbVie, Celgene, Genentech, Infinity Pharmaceuticals, Janssen, Merck, Novartis, Pharmacyclics, Seattle Genetics, and TG Therapeutics and has received institutional research funding from Pharmacyclics. Dr. Persky has served as a member of an independent data and monitoring committee for MorphoSys and Debiopharm and has served as an advisor to Bayer.


1. Barr PM, Munir T, Brown JR, et al: Final analysis from RESONATE: Six-year follow-up in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma on ibrutinib. 2019 ASCO Annual Meeting. Abstract 7510. Presented June 3, 2019.

2. Persky DO: Hematologic malignancies—Lymphoma and chronic lymphocytic lymphoma. 2019 Best of ASCO Austin. Presented July 26, 2019.

3. Byrd JC, Brown JR, O’Brien S, et al: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371:213-223, 2014.