Ibrutinib Remains Well Tolerated in Elderly Patients With CLL at 5-Year Follow-Up

In an interview with Targeted Oncology, Alessandra Tedeschi, MD, discussed the 5-year data she presented at the 2019 EHA Meeting for frontline ibrutinib as a treatment for patients with CLL. She also highlighted other research that may also benefit elderly patients with CLL, including the emerging combination of venetoclax and obinutuzumab.

Alessandra Tedeschi, MD

Treatment with the single-agent BTK inhibitor ibrutinib (Imbruvica) in the frontline improved progression-free survival (PFS) and overall survival (OS) in elderly patients with chronic lymphocytic leukemia (CLL) compared with chlorambucil, according to findings from the phase III RESONATE-2 trial. Long-term findings, presented at the 2019 European Hematology Association Congress, demonstrated that the drug was well tolerated among patients treated at a continuous dose.

The open-label, international, randomized phase III study enrolled 269 patients aged 65 years or older with CLL or small lymphocytic leukemia (SLL) who were previously untreated and without a 17p deletion. Patients were randomized to receive either a continuous oral dose of ibrutinib at 420 mg once daily or chlorambucil, the standard treatment at the time of the trial’s initiation. Primary endpoints included PFS, OS, overall response rate (ORR), and safety.

The 5-year PFS rate was 70% with ibrutinib compared with 12% in the chemotherapy arm. Moreover, at 60 months of follow-up, the OS rate was 83% with ibrutinib versus 68%. Additionally, 57% of patients crossed over to receive ibrutinib upon progression on chlorambucil. The ORR was 92%, including patients with both complete responses and partial responses with lymphocytosis.

The most common grade ≥3 adverse events (AEs) were neutropenia, pneumonia, hypertension, anemia, hyponatremia, atrial fibrillation, and cataract in the ibrutinib arm. However, no new safety signals were found in the 5-year follow-up analysis. Grade ≥3 AEs occurred in 5% of patients during the first year of treatment, but decreased to 2% during years 1 to 2, 3% during years 2 to 3, 1% during years 3 to 4, and 0% during years 4 to 5.

The rate of treatment discontinuation decreased overtime, as well as dose reductions due to AEs. At 5-years of follow-up, 58% of patients remain on treatment. Overall, 29 patients discontinued treatment due to AEs, while 8 patients discontinued due to disease progression.

RESONATE-2 led to the FDA’s approval of ibrutinib as a frontline treatment of patients with CLL in March 2016. The BTK inhibitor has since been approved in a number of settings in CLL, including in combination with obinutuzumab (Gazyva) for the frontline treatment of patients with CLL or SLL.

In an interview withTargeted Oncology, Alessandra Tedeschi, MD, Department of Hematology, Azienda Ospedaliera Niguarda Ca’ Granda in Milan, Italy, discussed the 5-year data she presented at the 2019 EHA Meeting for frontline ibrutinib as a treatment for patients with CLL. She also highlighted other research that may also benefit elderly patients with CLL, including the emerging combination of venetoclax (Venclexta) and obinutuzumab.

TARGETED ONCOLOGY: How has ibrutinib impacted this patient population according to the 5-year follow-up analysis?

Tedeschi:The matter of treating elderly patients has always been an open process because elderly patients are the most inflated with comorbidities, and they often do not tolerate chemotherapy. We needed a new drug. Ibrutinib was shown to be effective in the relapsed/refractory population, so this study was performed to evaluate the efficacy of ibrutinib compared to what was considered the standard at that period, which was chlorambucil. Of course, now, there are other treatments even for elderly patients, but at that time, chlorambucil was considered the standard.

Ibrutinib was not so toxic, well tolerated, and performed better than chlorambucil, but I would say that [ibrutinib] performs better than anything else in this population. It is true that is not very scientific to do a cross-trial analysis, but ibrutinib gave a very good PFS and importantly, a benefit in OS.

It is very well tolerated by patients. Most AEs are seen in the first year of treatment. Dose reductions and dose discontinuations are more frequent in the first year, so in the first year you may have some issues, but then patients are able to continue treatment. Now with a 5-year follow-up, we have 58% of patients still on ibrutinib.

TARGETED ONCOLOGY: Could you expand on the importance of analyzing toxicity over a longer period of follow-up?

Tedeschi:It was critical to have a longer follow up of these patients because this is the longest study with a BTK inhibitor in the first-line setting. For clinical use, it’s important to know what the AEs of continuous treatment are and if there are any issues with the continuous treatment [of ibrutinib].

No new safety signals were seen with continuing ibrutinib treatment. The most [common] AEs were those [that were noted in] the first preliminary analysis. Over the last few years, there was an incidence of patients that had to discontinue the drug for AEs. That’s important.

TARGETED ONCOLOGY: How do you see the treatment landscape for elderly patients with CLL evolving over the next few years?

Tedeschi:In this moment, I think we are still moving towards a chemotherapy-free period, so we don’t need to deliver chemotherapy. This is important in the elderly population, like I said, because they cannot tolerate chemotherapy. Ibrutinib is very well tolerated; the results are outstanding, but now we have another treatment coming out, which is venetoclax and obinutuzumab at a fixed dose. In the future, we will have to understand which of the 2 are better, the fixed dose of venetoclax and obinutuzumab or ibrutinib continuously. For now, the strongest data we have now is with ibrutinib at the moment. We need longer follow-up of the venetoclax plus obinutuzumab study to understand which of these 2 treatments are better.

As for now, the guidelines consider ibrutinib a good frontline treatment, even for the elderly and more unfit patients. That is important because CLL is a disease of the elderly, and the elderly are often unfit [for chemotherapy and have comorbidities].

TARGETED ONCOLOGY: Do you see the potential for an ibrutinib combination down the line in CLL?

Tedeschi:In the future, maybe we will have better combinations [with ibrutinib]. The better combination would, for sure, be ibrutinib and venetoclax, but that’s a treatment for the future. We have to deal with the present right now, and I think ibrutinib is outstanding in all patients, [whether they are] young patients, those with high-risk prognostic features such as unmutated patients, and in the elderly, or in all categories. I will say, though, ibrutinib is very well tolerated, and the benefit in the elderly patients is seen in our [study].


Tedeschi A, Burger J, Barr PM, et al. Five-year follow-up of patients receiving ibrutinib for first-line treatment of chronic lymphocytic leukemia. Presented at: 2019 EHA Annual Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract S107.