BTK Inhibitor Dose Adjustments in Waldenström Macroglobulinemia


What pharmacists need to know about BTK inhibitor drug activity, dosing, and interactions in Waldenström macroglobulinemia.

Bhavesh Shah, RPh, BCOP: You covered a lot of important aspects that a pharmacist should be aware of. We see drug interactions all the time, and we’re always concerned about long-term toxicity. We saw in the ASPEN trial that a lot of these toxicities were cumulative. Over time, there was an increase in the frequency of patients having these toxicities. They may not initially have this toxicity within the first year. It may be more of a cumulative toxicity that they develop in the long term. Patients aren’t always warned about this when they’re initiated on treatment that after 12 months, they may see an increase in hypertension, so we may be looking at their blood pressure more closely. Essentially, a patient who has never had to monitor their blood pressure or be concerned about it suddenly has to be on top of it after a year of therapy. It’s important to set those expectations before they’re going to be started on a drug, especially with a higher cumulative incidence in the long term.

A lot of times, you report a toxicity to payers and tell them that you’re changing therapy, and they will deny that therapy because they think, “They’re going to have the same toxicity if you changed it to a different BTK [Bruton tyrosine kinase] inhibitor.” Having that evidence is going to help. It will be helpful for a pharmacist who’s supporting a provider who’s switching therapy when that provider doesn’t know why insurance is denying it when they’re switching from 1 to another based on actual data that have been published or are available. Those are great points.

Acalabrutinib isn’t approved in this setting, but in case a patient is ever on acalabrutinib, there’s the PPI [proton pump inhibitor] interaction that acalabrutinib has. Gastric suppression therapy can reduce AUC [area under the curve] for BTK inhibitors, specifically acalabrutinib and PPI. That’s something that a pharmacist should be aware of within other B-cell malignancies that they may be using BTK inhibitors for. There are also data that talk about higher BTK occupancy in peripheral blood cells and lymph nodes with zanubrutinib vs ibrutinib. Are there any clinical implications from that?

Steven Treon, MD, PhD, FACP, FRCP: Yes. What’s important to keep in mind is that compartmental effects are very important in this disease. As you look at the different compartments, whether it’s blood, bone marrow, or lymph nodes, you’re going to have different levels of drug and drug activity. This is also true of CNS [central nervous system] phase. But there’s a critical threshold for ibrutinib—for instance, with CNS disease. We tend to start patients on 560 mg a day of ibrutinib as opposed to 420 mg a day. Trying to get more drug into the brain becomes important because you see only about 3% of the total peripheral blood drug level existing in the CSS [cause-specific survival] phase. It’s important to keep in mind the compartmental effect. For patients who have bulkier disease, this might also be important for zanubrutinib. We’ve yet to study the impact on bulky disease because it tends to be so uncommon in Waldenström, particularly in newly diagnosed patients.

Bhavesh Shah, RPh, BCOP: Dr Treon, as pharmacists, 1 question that we’re always involved with is, when is it appropriate to dose modify? When do you consider managing dose-related toxicities? How do you manage those, specifically GI [gastrointestinal]?

Steven Treon, MD, PhD, FACP, FRCP: With BTK inhibitors, we’ll consider dose reduction. It’s important to try to understand what’s acting as the center of toxicity. Is it the drug itself, or is it the disease? You need to separate that. With regard to GI toxicity, you do see this with drugs like ibrutinib. The first thing we try to consider is what time of the day we’re administering it. If the patient is taking the drug in the morning on an empty stomach, it might be better to take it in the evening, even after they’ve had their meals. We try to look at when the drug is being administered before we start dose modifying, because dosing is really important.

But if you have somebody with chronic arthralgias or rashes, dose modification in the case of ibrutinib becomes very meaningful. It’s the same with cytopenias. Particularly with heavily pretreated patients, thrombocytopenia is very common, and dose reduction will invariably be required. We try to resist when we can, but we accommodate when we do. There’s also switchover to another BTK inhibitor, particularly given Dr [Jeff] Sharman’s data, which show us that you can switch from ibrutinib to zanubrutinib in the majority of cases and still maintain activity.

Transcript edited for clarity.

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