Insights From: Brad Kahl, MD, Washington University School of Medicine; John P. Leonard, MD, Weill Cornell Medical Center
Brad S. Kahl, MD: There are some new agents in mantle cell lymphoma that look like they could have a role. For example, there is the small-molecule BCL2 inhibitor, venetoclax, which has impressive single-agent activity. And just based on the mechanism where venetoclax blocks BCL2 function and lowers the cell’s apoptotic threshold, that drug is particularly attractive to use in combination. Another new novel agent that looks promising is acalabrutinib, which is a second-generation BTK inhibitor. It appears to have somewhat less off-target effect than ibrutinib does, and so our hope is that it will have just as much activity as ibrutinib with fewer issues with bleeding, arthralgias, myalgias, hypertension, and atrial fibrillation, some of the side effects of ibrutinib that can become problematic for patients.
Acalabrutinib appears to be a cleaner inhibitor of BTK, so it has less off-target effect. It hits other kinases less potently than ibrutinib does. For example, it appears to leave the kinase TEK alone, which appears to contribute to the platelet dysfunction, the bleeding, with ibrutinib. So, the more favorable side effect profile appears to be due to less off-target effects.
Acalabrutinib has been studied in mantle cell lymphoma. It’s being tested as a single agent in relapsed/refractory mantle cell lymphoma, so that trial will help characterize the activity and the side effect profile. And it’s also being tested in the frontline setting. It’s being combined with bendamustine/rituximab in a randomized clinical trial that could have a major impact on the frontline management of older patients with mantle cell lymphoma.
John P. Leonard, MD: Ibrutinib is a Bruton’s tyrosine kinase inhibitor that is active and approved in mantle cell lymphoma, and it has a high response rate. The problem is that there are patients who don’t respond to it and that the duration of response is limited. Patients tend to relapse in the studies in the relapsed setting in the range of 1 to 2 years. So, obviously, there are patients who are going to relapse. Most patients are going to relapse after ibrutinib, and there are some studies that suggest that after ibrutinib, patients have an unfavorable outcome. There are some nuances to that study and its interpretation, but it’s pretty clear that you’d like to either make ibrutinib work better so that patients didn’t relapse, or relapsed later, or you’d like to have options that work after ibrutinib. One strategy would be to ask, “Well, are there better or different Bruton’s tyrosine kinase inhibitors that have different pharmacokinetic properties, different binding to BTK, different mechanisms of resistance that might be more effective in some settings versus ibrutinib or overcome resistance?”
And so, acalabrutinib is another BTK inhibitor. It’s in clinical trials. It’s clearly active in mantle cell lymphoma, and the question will be, is it better or does it offer advantages relative to ibrutinib that may lead to being used more? And I would say, at this point in time, we really don’t know. We’re awaiting those studies. There are also a number of other Bruton’s tyrosine kinase inhibitors in clinical trials that, again, will be tested similarly and may or may not have advantages versus what the standard BTK inhibitor is now, which is ibrutinib.