Acalabrutinib in the Treatment of Chronic Lymphocytic Leukemia

Experts provide insight on the use of acalabrutinib in treating chronic lymphocytic leukemia.

Paolo Ghia, MD, PhD: Recently, we have a second-generation BTK [Bruton tyrosine kinase] inhibitor now approved and available in Europe. The second generation BTK inhibitors have been developed to decrease the adverse events that occur with the first-generation inhibitors, which is mainly ibrutinib. We know that continuous treatment with BTK inhibitors, ibrutinib in particular, is characterized by a number of so-called adverse events of clinical interest, including cardiovascular toxicity, atrial fibrillation, and hypertension. In the long term, they might also have arthralgia, myalgia, and an increased risk of bleeding.

With more specific BTK inhibitors [BTKIs], we might decrease the number off-target effects and therefore adverse events as well. We now have a second-generation BTKI approved in Europe, acalabrutinib with or without obinutuzumab in the first-line setting or acalabrutinib monotherapy in the relapsed/refractory setting. The approval in the first-line setting is based on the elevated treatment-naïve patients and a combination of acalabrutinib alone or a combination with obinutuzumab being compared with relapsed/refractory disease in the older, comorbid patient, and it showed the benefit in terms of progression-free survival [PFS]. It is not clear, though: There are 2 arms in monotherapy vs the combination with obinutuzumab. It is not clear at this moment if there is any benefit of the addition of obinutuzumab to acalabrutinib because PFS is high in the range of 90% after 2 years of follow-up.

If you look at the previous experience with ibrutinib plus rituximab, for example, or obinutuzumab, it does not look like the addition of an antibody to BTK inhibitors changes the long-term benefit in terms of progression-free survival.

What is true is that the addition of obinutuzumab to acalabrutinib is increasing the number of complete responses, which is still always very few in the context of BTKI as monotherapy. Second of all, we can even achieve undetectable minimal residual disease [MRD] status with the addition of obinutuzumab. This might open the path in the future to stop treatment in patients based on the achievement of undetectable MRD. This is in the future, of course.

The presence and access to second-generation BTK inhibitors, of course, increases the range of alternatives for the treatment of patients with chronic lymphocytic leukemia [CLL]. If the benefit in terms of safety as shown in the ELEVATE-TN study are also confirmed in the real-world setting, then acalabrutinib could be a good option to rescue the patient who has to discontinue ibrutinib because of an adverse event or to start from scratch, particularly in patients with cardiovascular comorbidities or an increase in the risk of bleeding.

Jennifer Brown, MD, PhD: The next-generation BTK inhibitor, acalabrutinib, was approved for the treatment of frontline CLL with or without the addition of the anti-CD20 antibody obinutuzumab based on the ELEVATE-TN study. In this study, the primary end point was comparing acalabrutinib-obinutuzumab to obinutuzumab-chlorambucil. Both the single-agent acalabrutinib and the acalabrutinib and obinutuzumab were significantly better than the obinutuzumab-chlorambucil. They had 2-year progression-free survivals of 93% with the obinutuzumab vs 87% with single-agent acalabrutinib. That is a 6% difference with the addition of the obinutuzumab. The study was not powered to evaluate that difference, nor was it a planned comparison, unfortunately. 

It looks intriguing, and the shape of the curves looks interesting. We are going to want to see longer-term follow-up to understand that. It is an interesting observation. In my practice [at the Dana-Farber Cancer Institute], I tend to add obinutuzumab only for patients who are high-risk and have large-volume disease who I want a rapid response in.

Interestingly, in the study, the patients who benefited from the obinutuzumab were the lower-risk patients with IGHV mutations, which is a somewhat consistent finding that we have seen with targeted agents in patients with mutations: A single-agent drug does not have a PFS benefit over the chemoimmunotherapy, but adding an antibody getting a deeper remission does. This is probably consistent with the biology of mutated IGVH patients, and if we can get a deep remission, it is often sustained well over time.

Stephan Stilgenbauer, MD: Acalabrutinib is a second-generation BTK inhibitor. It was recently approved by the EMA [European Medicines Agency], and it was previously approved by the FDA for the treatment of patients with CLL in either the treatment-naïve or in the relapsed/refractory setting. Acalabrutinib is a second-generation BTK inhibitor. It is targeting BTK more specifically than ibrutinib did. At least theoretically, this may lead to better tolerability because off-target treatment effects are redacted with acalabrutinib compared with ibrutinib. 

Acalabrutinib is licensed as a single agent for the treatment of CLL or combined with CD20-antibody obinutuzumab. Both treatments provide good efficacy and good tolerability: at least in cross-trial comparisons, it looks like some of the ibrutinib adverse effects are reduced with acalabrutinib treatment. To prove this point, we obviously need head-to-head comparisons of ibrutinib-based therapy vs acalabrutinib-based therapies. Nevertheless, we already know that acalabrutinib was providing an important new treatment option for our patients with CLL.

Transcript edited for clarity.

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