Frontline Ibrutinib Shows Sustained Survival Advantage Over Chlorambucil in CLL at 7 Years

Tadeusz Robak, MD, discussed the 7-year safety and efficacy data from the RESONATE-2 trial examining frontline ibrutinib in CLL.

Ibrutinib (Imbruvica) continued to confer sustained progression-free survival (PFS) and overall survival (OS) benefit when used in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to 7-year follow-up findings from the phase 3 RESONATE-2 trial (NCT01722487) presented during the 2021 International Workshop on CLL (iwCLL).1

Data showed that the median PFS had not yet been reached with ibrutinib vs 15.0 months with chlorambucil (HR, 0.160; 95% CI, 0.111-0.230); this translated to an 84% reduction in the risk of progression or death with the BTK inhibitor. At 6.5 years, 61% and 9% of patients, respectively, were estimated to be alive and free of disease progression.

The median OS has not yet been reached in either of the treatment arms, but those who received ibrutinib experienced a 49% reduction in the risk of death (HR, 0.514; 95% CI, 0.312-0.848). At 5 years, the OS estimates in the investigative and control arms were 83% and 68%, respectively.

“What is important in this study is that the advantage of [ibrutinib] was observed for [several] subgroups analyzed, [such as] patients with bulky disease, IGHV-mutated and unmutated [disease], those with comorbidities, etc.,” lead study author Tadeusz Robak, MD, said. “We confirmed in this study that the drug was better for all [patients with] CLL [who were] older than 65 years [of age].”

In an interview with OncLive®, Robak, who is also a professor of hematology at the Medical University of Lodz, and chief of the Department of Hematology at Copernicus Memorial Hospital, in Lodz, Poland, discussed the 7-year safety and efficacy data from the RESONATE-2 trial examining frontline ibrutinib in CLL.

OncLive®: What were some of the earlier data from the RESONATE-2 study?

Robak: The first results [from this study were] published in 2015 in the New England Journal of Medicine, [although] the study was started [several] years earlier. The name of the study is RESONATE-2, in contrast with phase 3 RESONATE trial [NCT01578707], which was previously performed [and evaluated] ibrutinib vs ofatumumab [Arzerra] in previously treated patients with relapsed/refractory CLL.

[RESONATE-2] was initiated in previously untreated patients and the major inclusion criteria was that the age of the patients [needed to be] above 65 years. Importantly, patients with 17p deletions were excluded. Due to the comparator, which in this study was chlorambucil, a standard treatment for that time when the study was planned, we knew at that time that chlorambucil was not an acceptable agent for this patient population in contrast with ibrutinib.

In the publication in the New England Journal of Medicine, we showed the advantage of ibrutinib over chlorambucil in [terms of] overall response rate [ORR], progression-free survival [PFS], and overall survival [OS]. Therefore, 3 major parameters were better for patients who received ibrutinib.

The major concern for the patients treated with ibrutinib were cardiac adverse effects [AEs] and bleeding. In contrast with chlorambucil, which is given for a limited time of 1 year, ibrutinib was planned to be administered until progression or unacceptable toxicity. This is the reason why patients received the drug for a very long time. After this short follow-up of 24 months in the original publications, the need to observe the patients treated with ibrutinib was obvious. How long can we give the drug? Forever, probably.

A previous report [had] a follow-up of 6.5 years, and all the parameters I originally mentioned [still favored ibrutinib] with the longer follow-up; longer follow-up did not change the main results of the study. [We saw] better ORRs in addition to more and more complete responders after a longer follow-up, as well as an advantage in OS and PFS.

What was found with longer follow-up?

Importantly, after 5 years of the study, an amendment was [made] to observe patients not just for 5 years as originally planned, but for 10 years. As such, the patients are still [being] observed.

It is a very important report that I presented during the iwCLL meeting because we have very long observational [data]: the median follow-up of the patients is 7 years. [The follow-up ranges from] 75 months up to 7 years; [this means that the] patients [who were observed for the longest period] were those who were treated for 7 years, but those with shorter [follow-up] were also included.

What we observed at 6.5 years, was a [estimated] PFS [rate] of 61% for ibrutinib and only 9% for chlorambucil; this is a great difference.

What was one of the most interesting findings to be revealed with these data?

A complete response [CR] was obtained in one-third of the patients. Ibrutinib, in contrast with venetoclax [Venclexta], another the new agent for CLL, [elicits a] special response [in] the leukemia. At the beginning of the treatment, we observed an increase of lymphocytes in the peripheral blood. We started the treatment and unexpectedly, we saw an increase of lymphocytes or leukemic cells in the blood.

Fortunately, with time, the lymphocyte [count] started to decrease, and finally, especially after longer observation like [what we had] in our study, [we saw that we could] even obtain a CR. This is important because very few patients obtained a CR in [RESONATE-1.]

What was found in terms of safety?

In addition to hematological AEs, the special AEs for ibrutinib were breathing and cardiac complications, especially atrial fibrillation. We observed fewer such complications with time, which is also important. Another key observation from this study is that only 12% of the patients treated with ibrutinib progressed on the drug.

In RESONATE-2, 23% of the patients stopped treatment [with ibrutinib] due to AEs. [When looking at] the total population of the patients treated with ibrutinib, most were on treatment when we analyzed the results for this report. As such, half of the patients, after 7 years of follow-up, are still on the drug. The [other] half [discontinued] mainly due to toxicity.

Could you speak to what was learned regarding outcomes following ibrutinib discontinuation?

Ibrutinib discontinuation and subsequent treatment was observed in 19 patients. Chemoimmunotherapy was given to 9 patients, and these [options] included fludarabine cyclophosphamide, plus rituximab [Rituxan]; bendamustine/rituximab; [and vincristine plus rituximab]. Two patients received only chemotherapy and 7 patients received novel agents, which included 4 who were treated with venetoclax. Some patients received venetoclax plus rituximab [as their second subsequent or later line of therapy after ibrutinib].

It is worth it to note that in patients who stopped ibrutinib, immediate treatment is not necessary until progression. Several patients, despite the fact that they stopped the treatment, were still in good remission without progression and did not require [subsequent] treatment.

What are the next steps for this research?

These are the major observations we had after 7 years of follow-up. The paper with our 6.5-year observations [has been] submitted for publication, and this [report] will perhaps be published [in the future].


  1. Roback T, Ghia P, Owen C, et al. Ibrutinib treatment for patients with chronic lymphocytic leukemia in the first-line setting: up to 7 years of follow-up in the RESONATE-2 study. Presented at: 2021 International Workshop on CLL; September 17-20, 2021; virtual. Poster 1084078.