O'Brien Covers Evolution of Ibrutinib in CLL

Susan O’Brien, MD, discusses the impact that has been seen with ibrutinib following the long-term follow-up of the RESONATE studies in chronic lymphocytic leukemia.

Susan M. O'Brien, MD

Ibrutinib (Imbruvica) has played an important role in the development of treatment for patients with chronic lymphocytic leukemia (CLL), and long-term follow-up of the RESONATE and RESONATE-2 studies are evidence of the long-lasting responses with the BTK inhibitor.

The phase III RESONATE trial investigated ibrutinib in the second-line setting compared with ofatumumab (Arzerra) in patients with relapsed/refractory CLL. In the long-term follow-up analysis, ibrutinib demonstrated a superior progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) versus ofatumumab.

The median PFS was not reached with 74% of patients alive and progression free at 2 years, and second-line ibrutinib PFS outcomes were significantly improved compared with patients receiving it in later lines of therapy (P = .0348). Additionally, the ORR was higher in the ibrutinib arm in all evaluable subgroups compared with ofatumumab (P <.0001). In addition, In addition, the complete response (CR) rate improved with 7% of patients.1

Ibrutinib was investigated in the frontline setting in the phase III RESONATE-2 study for patients with CLL and small lymphocytic leukemia (SLL), which included 269 patients who were 65 years or older. At 29 months of follow-up, frontline ibrutinib reduced the risk of progression or death by 88% versus chlorambucil.2 Additionally, the quality of responses has improved over time with 18% of patients with CLL and SLL achieving a CR or CR with incomplete platelet recovery with single-agent ibrutinib.

Treatment-related adverse events decreased in frequency, allowing 79% of patients to continue treatment with ibrutinib. OS remains significantly improved, resulting in 2-year survival rate estimates of 95% in the ibrutinib arm versus 84% in the chlorambucil arm. Moreover, ORR was 92% versus 36% in the ibrutinib and chlorambucil arms, respectively (P <.0001).

Five-year follow-up data of ibrutinib is also now available. Results of the phase Ib/II PCYC-1102 study, which evaluated 5 years with ibrutinib therapy in both treatment-naïve and relapsed/refractory patients with CLL/SLL, showed that the agent is efficacious and safe with 89% of both patient subgroups experiencing a complete or partial response to the therapy. Additionally, patients lived without disease progression longer when ibrutinib is administered earlier than in the third-line setting or beyond.3

With the PCYC-1102 study follow-up, the most frequent grade 3 or higher AEs with ibrutinib were hypertension (26%), pneumonia (22%), neutropenia (17%), thrombocytopenia (9%), and atrial fibrillation (9%).

At the 2017 ASH Annual Meeting, patient-reported outcomes were investigated for patients treated with frontline ibrutinib on the RESONATE-2 trial. With 3-years of follow-up for these patients, ibrutinib showed greater sustained improvements compared with chlorambucil.4 Additionally, ibrutinib was associated with increased quality-adjusted survival time at the time of primary analysis.

Having shown significant improvements as a single agent, the next step for ibrutinib will be in combination, according to Susan O’Brien, MD.

“It is normal to build on single agents by looking for combination partners based on preclinical data or agents that lack overlapping toxicities,” said O’Brien, a hematologist and oncologist at UC Irvine Health. “The idea of moving forward from a single agent to a combination is logical and we hope to do this further with ibrutinib.”

OncLive: Can you discuss the long-term data that we have seen with the resonate and RESONATE-2 trials?

In an interview with OncLive, O’Brien, discussed the tremendous impact that has been seen with ibrutinib following the long-term follow-up of the RESONATE studies and highlights where this regimen is headed in the future of treatment for patients with CLL.O’Brien: We now have 4-year follow-up from the original RESONATE study. That was the randomized trial of ibrutinib versus ofatumumab in relapsed patients, which led to the full approval of ibrutinib. We have seen very good data. The important message from this study is that responses can be very durable and that toxicity does not increase over time.

The one toxicity that is seen occurring is hypertension; therefore, we must monitor patients for that. In my experience, it is more likely to occur in patients that already had hypertension and they may just need an adjustment to their medicine. In general, the side effects that impact the patient's day-to-day living such as diarrhea, are diminished over time. We haven't seen any new safety signals.

We also know that the responses are very durable. Patients can be on this drug for years and do quite well. The follow-up on the RESONATE-2 trial is shorter, but it is about 3 years now. The RESONATE-2 trial investigated ibrutinib in the frontline setting for patients over 65. Since this is a frontline population, we see even better outcomes in that group. We saw the 3-year PFS of 85% in that frontline population. At 3 years, 75% of patients were still on ibrutinib.

In the poster that was presented at the 2017 ASH Annual Meeting, there was a quality-of-life (QoL) assessment. What was clear from that assessment in comparison with chlorambucil is that these patients have a significant improvement on several different types of quality-improvement assays. They looked at something called a Q-TWiST analysis, which is an integrative analysis incorporating both the patient-reported outcomes, toxicity, and long-term outcomes. This showed that ibrutinib was dramatically better than chlorambucil.

What common questions or statements do you hear from patients regarding how they tolerate ibrutinib?

From both trials, the remissions are very durable and are even more impressive in the frontline setting. But, there are no unexpected toxicities from a QoL point of view versus chlorambucil. We see significant improvements in QoL.If you look at the data, the most common reported side effects were diarrhea. However, that toxicity is the least problematic. In my experience, patients would go to the bathroom 2 or 3 times a day and it was not associated with urgency, so they are able to go about their daily life. The patients develop tachyphylaxis so that, over time even as they stay on drugs, the diarrhea tends to resolve.

Are there indications as to which subgroup(s) of patients will benefit the most from ibrutinib?

In my experience, the one toxicity that I have had to take people off drugs for is arthralgia. I have only done this rarely, but it has been problematic. I have not taken the patient off the drug because the arthralgia is severe grade 3/4, but if the patient has some discomfort or pain that can be frustrating. If a patient is going to be on ibrutinib indefinitely with no end date in sight, and that patient feels uncomfortable or has low-level discomfort on a chronic basis, that is something to consider.One subgroup where some physicians may be hesitant to use the drug is in patients on anticoagulants. That is because these patients have a greater likelihood of bleeding in general. We know that there is some increased risk with the addition of ibrutinib. There is a lot of hesitation in that setting and some physicians might prefer not to use ibrutinib for those patients. There was another abstract at the 2017 ASH Annual Meeting looking at aggregated data from several randomized trials with ibrutinib, and the outcomes in terms of bleeding depended on whether the patients were on anticoagulants or antiplatelet agents.

What are your thoughts on the combination strategies with ibrutinib?

There was no statistically significant increase in terms of serious bleeding compared with the control arm. There are rare patients who have serious bleeding—causing everyone to be more cautious when treating patients on anticoagulants. However, I do not believe that it is an absolute contraindication. I would give ibrutinib to a patient on an anticoagulant if it was the best treatment for them and the risk benefit was in favor of using it.They look very exciting. There are combinations of ibrutinib with venetoclax (Venclexta), antibodies, and venetoclax and antibodies together making a 3-drug regimen. There was a randomized trial presented at the 2017 ASH Annual Meeting that investigated ibrutinib and an antibody in patients with relapsed CLL. There was also a small cohort of patients in the frontline setting, all of whom had a 17p deletion or p53 mutations.

This trial showed that there was a more rapid response with the addition of rituximab (Rituxan). This is because you abrogate the lymphocytosis that you normally see with B-cell receptors.

What there didn't appear to be was a large increase in complete response (CR) rates or more durable PFS. Other than achieving more rapid responses, there is not a lot to suggest that giving an antibody with ibrutinib does anything in terms of deeper or more durable remissions.

There is another trial that also asked that question. It was a large randomized frontline trial that consisted of 3 arms of bendamustine with rituximab, versus ibrutinib, versus ibrutinib and rituximab. That trial is fully accrued and finished accrual about a year and a half ago, but the follow-up is short. We have not seen any data from that trial. This will be a second trial looking at whether adding an antibody to ibrutinib makes a difference.

In contrast, there are good data showing that adding an antibody to venetoclax appears to increase the likelihood of minimal residual disease (MRD) negativity. Recently, within the past month or so, the venetoclax/rituximab combination study in relapsed patients with CLL was published. The MRD-negativity rate in this relapsed population was 55%.

There are preliminary data that were recently published in the frontline setting in a small cohort of patients with venetoclax and obinutuzumab (Gazyva), the latter of which is arguably a more potent anti-CD20 antibody than rituximab. Adding obinutuzumab to venetoclax produced very high rates of MRD negativity in the frontline setting.

There were a couple of trials investigating venetoclax and ibrutinib that were presented at the 2017 ASH Annual Meeting—clearly showing that they could be combined with full doses of each agent. You get the side effects seen with each drug individually, which was expected, but there was more neutropenia with the combination since both drugs as single agents cause neutropenia.

With that combination, the response rates were dramatic. However, that brings me to 2 questions. If you are going to combine 2 small molecules, such as ibrutinib and venetoclax, will antibodies add anything? I do not think that it adds to ibrutinib, but it could potentially improve responses to venetoclax. We are not going to have randomized trial data to answer those questions, but we will have phase II data that may help.

What do you predict for the role of ibrutinib in the next 5 years?

The data with venetoclax and obinutuzumab is so impressive that one could ask a different question in that setting. When you have an antibody such as obinutuzumab and add it to venetoclax, will ibrutinib add anything beyond that? However, overall, the data seen with combinations have been exciting. We will have to compare across trials to get an idea as to which is the best treatment option for patients.There are going to be more combinations. Although ibrutinib is a beneficial drug, the CR rates are low—particularly in the relapsed setting where MRD negativity is not seen. There is room for improvement. Currently, venetoclax is the obvious candidate because it has a different mechanism of action to BCR inhibitors. There were preclinical data suggesting that the drugs would be synergistic; however, we are still unsure as to which is best.

Ibrutinib is a relatively easy drug to combine. It can be combined with chemotherapy, antibodies, and now it is being combined with venetoclax. We could envision that there might be other combinations in the future that might be effective.

We may see ibrutinib in combination with chemotherapy for patients with large cell lymphoma.


  1. Brown JR, Hillmen P, O’Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2017;32(1):83-91. doi:10.1038/leu.2017.175.
  2. Barr PM, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128(22):234.
  3. O’Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Blood. 2016;128(22):233.
  4. Tedeschi A, Owen CJ, Robak T, et al. Prolonged improvement in patient-reported outcomes (PROs) and well-being in older patients treated with treatment-naïve (TN) chronic lymphocytic leukemia treated with ibrutinib (IBR): 3-year follow-up of the RESONATE-2 study. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 1746.