BTK inhibitors in relapsed/refractory MCL and treatment selection

Anthony R. Mato, MD, MSCE: I want Brian and then Michael on a different topic now. In CLL (chronic lymphocytic leukemia) and mantle cell lymphoma (MCL), I would say [that] we live in the world where there is the battle of BTK (Bruton tyrosine kinase) inhibitors. MCL is even more confusing because there is [are] 3 that are approved, as far as I know. Brian, let’s talk about the recidivist/refractory frame. We won’t be controversial [by] talk about using them [in the] First line [setting] since none of them are approved there, but [in the] relapsed/refractory context, how are we supposed to decide between ibrutinib, zanubrutinib, [and] acalabrutinib? Michael, I also want to hear your perspective on this.

Brian T. Hill, MD, PhD: Obviously, this group of drugs has transformed the treatment of MCL and has higher response rates and activities than any other class of drugs in the setting of relapse. The initial trial of ibrutinib had a median progression-free survival (PFS) of only about 2 years in the setting of a relapse. It was maybe 18 to 24 months [or] somewhere in that range, but it was much shorter than what we see in CLL. Seems it doesn’t really hold forever like it does in patients [with] LLC.

Since the approval of ibrutinib, as you pointed out, 2 additional BTK inhibitors have been approved for MCL. Next in chronological order was acalabrutinib followed by zanubrutinib. In these studies, the median PFS was longer, but I would point out that in the median prior treatment lines in the single-arm phase 2 trials of acalabrutinib and zanubrutinib, patients were less heavily pretreated than they expected. were in the ibrutinib study. In randomized CLL trials, [when compared] head-to-head with ibrutinib, we know there is [are] lower rates of cardiovascular toxicities, atrial fibrillation and hypertension with acalabrutinib and zanubrutinib. And these agents are very active in the MCL, [so] my preference would be to start with one from the second generation [agents] in the sick [with] Recurrent MCL: acalabrutinib or zanubrutinib.

Anthony R. Mato, MD, MSCE: Michael, should anyone be on ibrutinib at this point?

Michael Wang, MD: No. Because of my involvement with BTK inhibitors in MCL, people ask me all the time, “Which is the right agent?” Basically, there is no straight answer. We know, as Dr Hill said, [that the trial of] ibrutinib was [with] 3 prior treatment lines, acalabrutinib was [with 2] prior treatment lines, and ibrutinib was 1.5 prior treatment lines. If you have fewer previous treatments, the response rate is of course higher. In the randomized studies of Waldenström [macroglobulinemia] and CLL, you know [that] effectiveness has not been studied [in relation to] the difference between the 3. [Regarding] the difference that comes from toxicities, [for] ibrutinib, infection [and] atrial fibrillation [are] the highest, [and] the other 2 are lower. Acalabrutinib used to cause headaches, and sometimes it could be that bad, [which is] unique to acalabrutinib. Next, ibrutinib, of the 3, has the most neutropenia. You have to individualize the [treatment for each] patient. What is most important [for] this? We are university doctors. We have to practice according to the existing data.

If, for example, you want to use ibrutinib with venetoclax [because] there is a synergy there [are] ongoing randomized trials, [so] you are welcome because it is already published in the New England Journal of Medicine by Dr. Cunningham. Can acalabrutinib be used with venetoclax? No, there is no such data. The [are] data from my center with a phase 2 study with the 2; the results so far are not very exciting. And can you use zanubrutinib with venetoclax? Not yet because the data is not there. I think we should practice based on the data we have and then add our individualized view of patients.

Anthony R. Mato, MD, MSCE: Alexey, quick question for you then. Forget which BTK inhibitor we choose, as part of relapsed/refractory, is the standard of care in your practice as monotherapy, or do you combine them with CD20[-targeting agents]?

Alexey V. Danilov, MD, PhD: In my practice, I always use BTK inhibition as monotherapy in MCL. As you know, they cannot be compared head to head. Data with combination are still very limited, especially in the context of relapses. I guess I tend to transfer some of the data on CLL where adding CD20 to ibrutinib didn’t necessarily improve PFS outcomes, so I use monotherapy.

Anthony R. Mato, MD, MSCE: Matt, by now you’ve heard some comments about the AE (adverse event) profile associated with BTK inhibitors. It is not unique to MCL, but regardless of the disease, can you list [the] the 3 main AEs that pose a problem in your practice? Do you have any specific tips for management? It doesn’t have to be MCL; we’ll cover that now for CLL and MCL.

Matthew S. Davids, MD, MMSc: Generally, some of the most common things we see are cardiovascular toxicities, especially hypertension and atrial fibrillation. These occur more frequently with ibrutinib compared to acalabrutinib or zanubrutinib in comparative studies. Of course, the risks of bleeding are also there. We see minor bleeding, which can include bruising in probably up to half of patients. Still, [there are] higher rates with ibrutinib compared to acalabrutinib in the ELEVATE-RR study (NCT02477696) in CLL. Major bleeding rates are relatively low with BTK inhibitors, but they seem to be more equivalent between these 3 drugs within a range of about 5%, so we need to monitor patients for this. The [are] a variety of other troublesome AEs that we commonly deal with: things like arthralgia, myalgia, and fatigue.

Some tips and tricks may include dose adjustments [or] dose reductions, especially with ibrutinib. [These] can sometimes be useful, [as can] supportive care measures [with] NSAIDs (nonsteroidal anti-inflammatory drugs), [acetominophen], or even prednisone has sometimes been useful at low doses for arthralgia. These drugs, as we have discussed, are different. Sometimes just switching to another BTK inhibitor can help. If you put a patient on acalabrutinib and they’re really having headaches and you can’t get them to switch, you can switch to ibrutinib or zanubrutinib, and you might have some resolution of that toxicity .

Transcript has been edited for clarity.

Martin E. Berry