BTK Inhibitor Treatment Selection in Waldenström Macroglobulinemia


An overview of BTK inhibitors available as first-line therapy for Waldenström macroglobulinemia, and variables that impact treatment selection and the switching of agents throughout the course of therapy.

Bhavesh Shah, RPh, BCOP: There are different BTK [Bruton tyrosine kinase] inhibitors that we have options for. The next question for our pharmacy colleagues is, in Waldenström macroglobulinemia, we have 2 BTK inhibitors in which we’ve seen significant amount of data. If you look at the NCCN [National Comprehensive Cancer Network] Guidelines, both zanubrutinib and ibrutinib are category 1 recommendations. We’ll talk about the pivotal ASPRE trial that recently led to the approval of zanubrutinib for Waldenström. But we know that there are differences in off-targets that these agents have, specifically with zanubrutinib having fewer off-target implications vs ibrutinib. We also know there are implications for toxicity because zanubrutinib probably has fewer off-targets. Maybe we can talk a little about the BTK selectivity and the off-target implications for the 2 agents available for Waldenström.

Steven Treon, MD, PhD, FACP, FRCP: Yes. As you mentioned, we have 2 approved BTK inhibitors by the FDA. Hopefully very soon the EMA [European Medicines Agency] will approve zanubrutinib. It has already approved ibrutinib, so these options will also be available in Europe. In Canada, zanubrutinib is approved. There’s a difference where ibrutinib still remains to be approved. There are differences in access to therapy. It’s important when you think about selectivity. Selectivity can work both ways. There are targets that BTK inhibitors also go after as an off-target that are very critical to the growth and survival. HCK [hematopoietic cell kinase] is a good example. Ibrutinib and zanubrutinib both hit it very hard, but acalabrutinib doesn’t. There are these differences. But as you mentioned, there are also off-targets, which are going to be very important for therapy itself and treatment-related toxicity.

In case people aren’t familiar with it, the ASPEN trial was a head-on trial of MYD88-mutated patients who got either zanubrutinib twice daily at 160 mg or ibrutinib once daily. There was also a second cohort that had no MYD88 mutation. They were MYD88 wild-type patients, and they got zanubrutinib alone. It was a very thoughtful trial. We learned quite a bit. We learned that the rate of major responses was similar between the 2 BTK inhibitors, but there were slightly more VGPRs [very good partial responses], so deeper responses. That may be important in some patients who have IgM-related morbidity. That’s why it’s important to keep that difference in mind.

But where the story was really important was in toxicity. Atrial fibrillation [AFib] is a problem with ibrutinib. You see it in about 15% of patients across different trials. There are 2 time-dependent points for atrial fibrillation. People who get it fairly quickly after going on drugs usually have a predisposition or prior history of AFib. That’s an important key to the pharmacist. If you see a prior history of a AFib or palpitations to cold medicines, or some hint that they’ve had a prior arrhythmia, then you want to steer away from a drug that may have a higher tendency for AFib. We also saw differences in bleeding risk. There were differences in diarrhea. There were far fewer of those events with zanubrutinib. Conversely, there was more neutropenia and G-CSF [granulocyte colony-stimulating factor] usage with zanubrutinib, but the rate of major infections was the same across the board, so it didn’t affect infection risk.

When you’re looking at these 2 FDA-approved drugs, the key question is, “How am I going to steer myself as to which 1 to choose?” This is where we as clinicians need to be thoughtful. This isn’t one that you just check off the box. You have to think this through. It’s a gift to have 2 approved drugs for an uncommon disorder. But what you do is you look at it and think about the convenience of administration and compliance. Zanubrutinib is twice daily vs ibrutinib once daily, but the label also says you can give zanubrutinib once daily. There may be that patient in whom you might want to use once-daily dosing.

You want to think about depth of response, because there could be morbidities that are IgM related, where even that numerical advantage with zanubrutinib could be important. Conversely, if you see somebody who has cytopenias, particularly neutropenia, you might want to steer away from zanubrutinib. Classically, if you have somebody with brain disease, CNS [central nervous system] disease, such as Bing-Neel syndrome, the data that we have are mostly with the ibrutinib, although there is 1 case report of zanubrutinib being effective.

Another very important point to the pharmacist is around intolerance. We’re seeing that most people who come off zanubrutinib come off not for progression but because of intolerance. You get these chronic grade 1/2 arthralgias, rashes, things that drive patients crazy. We have data that show that switchover could be very beneficial to patients. It was presented at EHA [European Hematology Association Congress] by Dr [Jeff] Sharman. We saw that in three-quarters of cases, the intolerance event that existed with ibrutinib didn’t recur with zanubrutinib. There’s this role of switchover, which isn’t trivial. If the patient is progressing and they have a BTK cysteine mutation, the switchover isn’t going to help, whether it’s ibrutinib, zanubrutinib, or acalabrutinib. They all bind to the same covalent CS481 molecule.

Other noncovalent drugs may have a future there, but it’s important for the pharmacist to recognize that these 3 covalent BTK inhibitors bind to the same position. But switchover is something we’ve seen. There are good data with zanubrutinib. There are even great switchover data with acalabrutinib or ibrutinib. We’re blessed because we can continue treating people with BTK inhibitors by virtue of having these other options.

Transcript edited for clarity.

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