John Byrd, MD, Discusses Acalabrutinib vs Ibrutinib for Patients With CLL

John C. Byrd, MD, D. Warren Brown Chair of Leukemia Research, Distinguished University Professor, Ohio State University College of Medicine, shares the initial results of a phase 3 trial comparing acalabrutinib with ibrutinib in patients with pre-treated chronic lymphocytic leukemia (CLL); these data were presented at the virtual 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.


Hi, my name is Dr John Byrd. I am a distinguished university professor at the Ohio State University and the lead author on this study.

For many years, we've had a first‑generation irreversible Bruton's tyrosine kinase inhibitor, ibrutinib, that really has changed the landscape of treatment for CLL.

With the development of this successful therapy, a second‑generation Bruton's tyrosine kinase inhibitor, acalabrutinib came forward, was approved by the FDA, and on the basis of efficacy, but also in other studies, showing less cardiac and other adverse events.

With these data set up, the question was ibrutinib and acalabrutinib similar in terms of efficacy, as well as side effects, or were there differences? That forms the basis for this study.

Our study was a head‑to‑head comparison in an unblinded fashion of ibrutinib versus acalabrutinib in previously‑treated CLL patients who had high risk factors, deletions 17p and 11q.

This study was set up as a non‑inferiority study. Non‑inferiority studies typically try to show the two therapies are at least similar, and that there potentially are other differences, either adverse events, costs, or something else, that would drive using a second agent that's equally good.

The study enrolled over 500 patients, and in fact, demonstrated very similar results with the hazard ratio looking at progression‑free survival being 1, essentially telling us that the therapies are identical in terms of efficacy.

When we look at adverse events, which once the inferiority test was done and shown to have hit that, we saw in the study that cardiac events—in particular, atrial fibrillation—was, in fact, more common with ibrutinib, as were many other adverse events, including hypertension, bruising, interstitial pneumonitis, and several other things.

In balance, there were a few side effects that were more common to acalabrutinib, headache and cough. That last finding was of some surprise, and it likely reflects that when you look at a lot of side effects, you can find things sometimes that are different that occur by statistical chance.

The relevance of this study are several, including that in a head‑to‑head comparison, it was shown that acalabrutinib appears to be safer and is equivalent to ibrutinib, setting the stage that this may be used more frequently for both the treatment of previously‑treated CLL, and also in the earlier frontline therapy of CLL.

The application of this abstract and the findings of this study to clinical practice are many. First, we have two Bruton's tyrosine kinase inhibitors approved in the United States. This is the first study to show that acalabrutinib is equivalent to ibrutinib, but has an approved safety profile.

In the study, what we care about in real life is not only how long is the therapy going to work, but how do our patients tolerate it? Some of the side effects impact outcome as it relates to overall survival. This study also showed that, although progression‑free survival is similar, the hazard ratio of 1, overall survival, although not significant was favored by acalabrutinib with a hazard ratio .82.

I think the next step in CLL is going to be developing combination therapies. There are several combination studies that are ongoing that are looking at getting patients to having no detectable disease as the first step to cure, and then getting patients off therapy.

Any time you do combination studies, the first and most important thing is having medications that are well‑tolerated, because then you can better combine. Acalabrutinib, by being more selective, enables it to be combined with other therapies better. As I say, that's where we'll be moving forward in the future with clinical trials and with this agent.

We'd like to thank the patients and the physicians who put patients on this study, because this study, along with many of the others with Bruton's tyrosine kinase inhibitors, have really advanced the field of CLL.

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