Paul Barr, MD, Highlights Robust 8-Year Follow-Up Data of Frontline Ibrutinib in Older Patients With CLL

In an interview with CancerNetwork®, Paul Barr, MD, discusses 8-year follow-up data from the phase 3 RESONATE-2 trial, assessing first-line ibrutinib in patients 65 years of age or older with chronic lymphocytic leukemia.

Although the follow-up data from the phase 3 RESONATE-2 trial (NCT01722487) assessing first-line ibrutinib (Imbruvica) in patients 65 years of age and older with chronic lymphocytic leukemia (CLL) are mature, Paul M. Barr, MD, noted that continued monitoring of this patient set will be important as the median progression-free survival (PFS) has yet to be reached nearly 8 years later.1

Study investigators highlighted a long-lasting PFS benefit following treatment with ibrutinib (HR, 0.154; 95% CI, 0.108-0.220), as well as a 7-year PFS rate of 59% vs 9% with chlorambucil. The benefit also extended to patients with high-risk genomic characteristics, including del(11q) (HR, 0.033; 95% CI, 0.010-0.107) or unmutated IGHV (HR, 0.112; 95% CI: 0.065-0.192). Barr highlighted how these long-term findings may lead to further benefit for this patient population.

“I want my colleagues to keep in mind the future of CLL. The combinations that we’re investigating, the ability to induce deeper remissions, and, at the same time, potentially stopping therapy, [will allow] patients to enjoy their life treatment free for a period of time. Given this and some of the novel agents being investigated, I want everyone to realize that we’re probably improving the overall survival [OS] even further with these additional studies and hopefully moving closer towards a cure for CLL.”

In an interview with CancerNetwork®, Barr, a professor of hematology/oncology in the Department of Medicine and medical director of the Cancer Center Clinical Trials Office at the University of Rochester Medical Center, discussed how frontline ibrutinib has impacted the treatment paradigm and the promise it shows in combination with other Burton tyrosine kinase inhibitors.

Before we get into the long-term findings, what had read out of the RESONATE-2 trial thus far?

RESONATE-2 was a randomized clinical trial that led to regulatory approval for ibrutinib in the first-line setting. It compared older patients [who were] treated with single-agent Ibrutinib and chlorambucil-based therapy. [The trial] previously demonstrated, not surprisingly, a substantial PFS and OS benefit for ibrutinib. One important point to remind everybody of is while chlorambucil is certainly a historical standard at this point, if you take this study and other first-line studies together, they demonstrate that the novel small molecule inhibitors are certainly improving OS [for patients with] CLL.

Could you discuss the 8-year follow up data from this trial?

The median follow-up in that analysis is 7.4 years, so pretty mature follow up. [It] really gives us the understanding as clinicians that we need to be able to tell patients what to expect long-term from ibrutinib and other BTK inhibitors. At this timepoint, the 7-year PFS rate was 59% for ibrutinib and 9% for chlorambucil. Obviously, that’s a substantial difference but it’s just impressive to realize that, at this follow up matures, we still have not reached the median PFS for ibrutinib. We still need to keep monitoring this study so we can help our patients understand how long they can expect, on average, to receive the benefit of Ibrutinib and BTK inhibitors. We also found that for patients with higher-risk features, such as del(11q) and unmutated IGHV genes, the PFS rate was the same as those without high-risk markers. At the same timepoint, the OS rate still looks very good at 78%.

Did the long-term findings reveal anything with regard to safety?

The long-term follow up of clinical trials such as this are really important to understand if there are any new adverse effects [AEs] or cumulative AEs that happen over time. The takeaway from long-term follow up of RESONATE-2 is [that] there weren’t any new safety concerns; there weren’t any new long-term or cumulative effects that we hadn’t previously seen. Looking at the absolute numbers, it’s important that we as clinicians guide our patients on what to expect. With that in mind, at this long term follow up, we observed grade 3 atrial fibrillation in 6% of patients and grade 3 or greater major hemorrhage in 7% of patients [treated with ibrutinib]. Twelve percent of patients had grade 3 hypertension.

We always worry about the AEs. Thankfully, those numbers are relatively modest, and many of the AEs can be managed with dose reductions or dose holds. In fact, most patients were able to restart ibrutinib when those strategies were employed. Nonetheless, about a quarter of patients did ultimately discontinue for AEs related to ibrutinib. It does stress the fact that we need to be vigilant and watchful of these AEs. We need to know how to manage them. But it also speaks to the importance for novel strategies and combination studies so we can induce deep remissions and have the ability to stop therapy.

Are there any first-line combination trials with ibrutinib that are currently ongoing that you feel are promising?

There are a huge number of combination studies that are ongoing. I’d say the most promising and mature ones at this point are various combinations of ibrutinib or other BTK inhibitors with venetoclax [Venclexta]. What we’re seeing across the board is the ability to induce responses in nearly all patients enrolled, including high-risk patients. We’re achieving deeper levels of response, meaning rates of undetectable minimal residual disease [MRD] are higher than what we previously saw with chemoimmunotherapy. In a very short term, it looks like it’s translating into very promising PFS rates.

One example that comes to mind very quickly is the [phase 2] CAPTIVATE study [NCT02910583] combining Ibrutinib and venetoclax.2 In that study, there were different strategies, [including] a fixed-duration cohort and an MRD-guided cohort. Across the board at 2 years, the PFS rates are still hovering in the 95% range. Again, we’ll need much longer follow up to understand how this will guide future practice, but [these] are very promising early results.

Since the FDA approval of ibrutinib in frontline CLL several years ago, how do you think the drug has impacted the treatment paradigm?

Everyone agrees that Ibrutinib and the other BTK inhibitors have caused a sea change in how we take care of patients in this country and around the world. Across all the clinical trials, it’s not a stretch to say we’ve universally seen better outcomes and less toxicity compared with chemoimmunotherapy. Certainly, there are risks and we need to keep those in mind. This study helps us understand what those are long term. But, certainly ibrutinib has changed how we take care of patients.


  1. Barr PM, Owen C, Robak T, et al. Up to 8 years follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Advances. Published online April 4, 2022. doi:10.1182/bloodadvances.2021006434
  2. Wierda WG, Allan JN, Siddiqi, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study. J Clin Oncol. 2021;39(34):3853-3865. doi:10.1200/JCO.21.00807