Key Safety Considerations

Carrie Lenneman, MD, MSCI: In general, is there any sense of rates of intolerance to BTK inhibitors and the nonspecific kinase inhibition leading to toxicity?

Farrukh Awan, MD: That’s a great question. It depends on what you’re looking at. That’s the key because all 3 drugs have different specificities. Some are more specific than others, and some have more off-target, unnecessary effects that we don’t care for. For example, if a target is EGFR in the skin, you’ll have more incidence of skin rashes in certain drugs, but all 3 drugs do a good job of targeting BTK. That’s clear. It all comes down to what kind of off-target effects each drug has. We start with ibrutinib. Early on we saw 1 of the things that stood out early on with ibrutinib or, for that matter, acalabrutinib. Even zanubrutinib to some extent is the risk of bleeding. Bleeding cases and bleeding risk was described in patients with ibrutinib. That’s why there were precautions that we took for patients who were participating in the early ibrutinib trials and acalabrutinib trials, and they weren’t allowed to be on concomitant warfarin. That was very important for those patients.

We figured out later on, and we published on this, that when you combine an antiplatelet agent, the incidence is higher of major bleeding than, for example, if you talk about anticoagulation with apixaban or rivaroxaban. This was interesting because we didn’t know why that was happening. There are more mechanistic studies of the impact of BTK inhibition on platelet dysfunction and how it resembles the von Willebrand phenotype, and that’s much clearer than what it was a few years ago. We’ve learned this along the way. As we get more comfortable, the risk of minor bleeding or clinically relevant minor bleeding is down to less 30%. It used to be high in the beginning when we weren’t aware of all these interactions. The risk of bleeding is in the 10%-to-30% range, including major bleeds and minor bleeds. It depends on the risk factors for the patient.

Another thing we saw was the risk of atrial fibrillation [AFib]. If you look at the clinical trials, the risk of incidents of atrial fibrillation was maybe in the 10%-to-15% range. Patients who get enrolled on a clinical trial have to meet certain criteria and have a certain level of fitness. I’m not sure if that necessarily translates to the patients I might see in my clinic, who has 27 different comorbid conditions. They’re older, they have cardiac issues, they have kidney issues, they have many other problems, and they’re on a laundry list of medicines. It has been consistently shown that in the real-world data, the incidence of atrial fibrillation could be as high as 30% to 40%, which translates into discontinuation rates. If you have poorly controlled atrial fibrillation, that risk would be higher for you to discontinue the drug. Patients who have a previous history of atrial fibrillation tend to have close to 30%, 40% incidents. If you’ve never had atrial fibrillation before, the risk was much lower. In the head-to-head study with acalabrutinib and ibrutinib, 1 of the major end points was to look at the incidence of atrial fibrillation. It was around 10% to 15%. Acalabrutinib was around 9%, and ibrutinib was around 15% to 16%, so there was a clear difference in the incidence of atrial fibrillation. Similarly, for zanubrutinib, we’ve seen atrial fibrillation. It appears to be higher than what you would expect in a normal population of this age, but it appears to be lower than other drugs, especially ibrutinib. We’ll see how that pans out when more people are being treated with this agent.

We’ve reported on ventricular arrhythmias. That’s a very uncommon adverse effect, but certain cardiac deaths have been reported. Incidence is very low, fortunately. A big problem in the operations with ibrutinib is hypertension. About 60% to 70%—maybe higher—of patients who start ibrutinib will require adjustments of their antihypertensives or the addition of a new medicine and then our adjustment of the dose. You can call it new or incident or refractory hypertension, but it’s not just hypertension. It’s the incidence of MACE, or major adverse cardiac events. All those events appear to be higher with the use of ibrutinib. Similar studies have been done with acalabrutinib, whether or not we will see the same degree of MACE, where the acalabrutinib remains to be seen. But at ASH [American Society of Hematology Annual Meeting], we’ll have a few presentations on that, so we’ll learn more. There’s a lot of excitement. Fortunately, the incidence is low if you look at the clinical trials. But in the real world, the incidence is probably much higher in our practice. That’s why people need to be aware of those, so they can manage these adverse effects better and then have a plan for when that happens. Our patients can benefit because it’s also been shown that outcomes directly correlate with compliance. It’s almost like an HIV analogy. If you take antiretroviral medications, you’ll do really well with your HIV/AIDS. It’s pretty similar for BTK inhibitors: if you’re able to consistently take the medicine at the appropriate dose, your outcomes will be better. That’s what I had to say about those. For you, Carrie, as a cardiology perspective, what’s your impression from dealing with these issues? I’m sure you’re seeing more patients now.

Carrie Lenneman, MD, MSCI: I do. You hit the nail on the head when you said you look at real world. Real world is a lot different from our clinical trial data, for sure. It’s also important because our paradigm is shifting. As you said, oncologists have moved away from conventional chemotherapy in which patients are coming in and getting infusions. This is great. These BTK inhibitor therapies allow patients to be home and take their meds. Compliance is important, but engaging patients, so they know about their potential adverse effects, is crucial. I’ll get referred a patient who is high risk for developing AFib, hypertension, coronary disease, diabetes, chronic kidney disease. My oncologist will say, “What are your thoughts? Can we start a BTK inhibitor? How can we prophylactically go about screening the patient during their first few months of treatment?” We also know from the data that if they’re going to have a hypertensive response, if they’re going to have AFib, it tends to happen relatively early, in the first few months of treatment rather than years down the line.

Following these patients early is important. Commonly, I will bring a patient in, evaluate them, engage them to start checking their blood pressures at home, let them realize a good tight blood pressure control—130/80 or less is where we’re trying to have the target blood pressure. When they start this and start seeing hypertension, they let us know so we can adjust their medications and start a new medicine if needed. The trial data looking at ibrutinib saw more major adverse cardiovascular events for patients who became hypertensive and who weren’t on therapy, who were not adequately treated. We know paying attention to those numbers is important.

The other thing is that the incidence of AFib is high. We know it’s higher in the real world, probably closer to 30%. My view is very jaded because I get a lot of AFib referrals. I will do an occult monitor. I’ll usually do a 30-day event monitor once we get started on a BTK inhibitor. There’s no great guideline for that, but that helps us look for occult AFib. I’ve had a lot of patients with no symptoms of AFib, but we detect it and then need to figure out how we think about treating these patients and balancing their CHADS-VASc [CHA2DS2-VASc score] or their HAS-BLED score. They’re already at increased bleeding risk because they’re on these BTK inhibitors—how do we select and tailor potentially start some anticoagulant therapy? There are some consensus papers in cardio-oncology suggesting, for some patients who might have a high CHADS-VASc as well as increased risk of bleeding, looking at something like Eliquis and doing half dosage, 2.5 mg twice a day, to initially start and make sure they don’t have bleeding episodes. If they seem to be doing well enough, we have a recurrence of AFib. We definitely think about bringing them up to maybe full dose.

There are some newer strategies with AFib, looking at half your left atrial occluding devices. It’s more in the cardiology realm. It’s long-term management because, as you said, these therapies are very effective. If a patient is tolerating it and AFib is the only adverse event, how do we manage these patients with AFib? There is a Watchman, a left atrial occluder device that we can use to put in patients who are on treatment for CLL [chronic lymphocytic leukemia]. We can temporarily hold their therapy for a 45-day window in which we have them on aspirin and Plavix. Then we take them off Plavix, and they’re just on aspirin. For someone who has had bleeding risk, we need to manage AFib and the need to decrease their risk for being on long-term anticoagulants. A left atrial appendage occlusion device is a potential option. Like a Watchman. That’s a possibility for some select patients.

This transcript has been edited for clarity.