What are BTK inhibitors and how are they used to treat CLL? So BTK inhibitors are a class of drug that really have revolutionized the way that we treat CLL. There are three approved BTK inhibitors for the treatment of CLL. They are Ibrutinib, Acalibrutinib, and Xanibrutinib. Ibrutinib is the drug that revolutionized the way we treat CLL and multiple other hematologic malignancies. It's considered a first-generation BTK inhibitor. And Acalibrutinib and Xanibrutinib are called second-generation BTK inhibitors. The reason why we designate them as first-generation for second-generation is that when first-generation Ibrutinib was developed, it led to a lot of toxicities, specifically cardiovascular toxicities, including atrial fibrillation, hypertension, and bleeding. And so the second-generation inhibitors were meant to be safer as they were more targeted for the BTK, the thing that they target. That's why they're called BTK inhibitors. So Acalibrutinib and Xanibrutinib are safer than Ibrutinib, as shown in two clinical trials. And so in general, when we're thinking about the BTK inhibitors, for the most part, we're using the second-generation BTK inhibitors, Acalibrutinib and Xanibrutinib, because they are safer and work just as well as Ibrutinib. Acalibrutinib and Xanibrutinib, Acalibrutinib is taken twice a day, whereas Xanibrutinib, you can take either twice a day or once a day. They've never been compared to each other, so there's a lot of debate in our field about which one is better and which one you should use for which patient. They're taken continuously, meaning that we take them and we don't stop them. The only times that we stop them is when or if we develop intolerance, toxicity to the drug, or up until our disease progresses, which usually is somewhere in the realm of five to seven years. But I've seen a lot of people go past that and some people go before that. So this is a continuous drug that you take for five to seven years until progression or you stop earlier due to intolerance. Side effects of these drugs are cardiovascular, just like Ibrutinib, so we pay close attention to whether or not our patients have a fluttering in their heart or palpitations. That might be a sign that they could be having atrial fibrillation. It could also cause joint pains, usually in the hands. It could also cause easy bruising and bleeding. And specifically for Acalibrutinib, it can cause headaches. And specifically for Xanibrutinib, it can cause worsening hypertension. So these are the things that I monitor my patients for. And it's very important to try to stay on the drug because there are studies that show that patients who come off drug have worse outcomes. And so it's important to discuss toxicity that you may be experiencing with your doctor because there are various things that we can do with the drug, including doing holds or dose reducing that may make the drugs more tolerable. So overall, these drugs are very well tolerated. The Acalibrutinib is taken twice a day. The Xanibrutinib can take twice a day or once a day. And we take them until progression. And so that's like the difference between the Venetoclax, which you take for a time limit of therapy usually is one year, but it's a little bit more toxic, a little bit more monitoring. How are side effects of BTK inhibitors managed? In terms of toxicities, I think the one that we all pay the closest attention to is the atrial fibrillation risk and the hypertension risk. I'll talk a little bit about bleeding risk too, because it's important to know how to address that as well. So for cardiovascular risk, if I'm thinking about putting somebody on one of these drugs who has a baseline cardiac disease, I usually refer them to a cardiologist just to make sure that their cardiac function is optimized prior to starting this therapy. Now if somebody runs into issues while on therapy, if they have palpitations and it's confirmed that they have atrial fibrillation, normally it's okay to stay on drug and then just treat the atrial fibrillation, whether that be with your classic beta blockers or some other drugs that are currently used for the treatment of that specific disease. If things become a little bit more complex, say somebody needs an ablation procedure or they are in multiple therapies for their atrial fibrillation, that's when I'll start to consider taking them off therapy. So really they have to have atrial fibrillation that has been well treated and attempted to treat and get control of before I consider stopping therapy. In terms of the hypertension, we do monitor this throughout the drug as the patient is taking it, we do manage their blood pressure. And once again, I try to keep patients on drug, but if they start to require multiple drugs for their blood pressure, that's when I'll consider a dose reduction or a dose hold or consider an alternative agent. Lastly is the bleeding. So it's very common that my patients get subcutaneous bleeding, otherwise known as bruising. And so very much my patients have bruises on their arms, they report bruising that they don't know where it came from. But the biggest thing that we have to pay attention to is when you get a procedure. So if you're having a minor procedure, you should hold your BTK inhibitor for three days before and three days after the procedure. And if you're having a major procedure, you have to hold your BTK inhibitor seven days before and seven days after your procedure, because there is a risk of increased bleeding with these drugs. So it's important that if you're having an elective procedure that you discuss with your oncologist, how long you should be holding your BTK inhibitor before and after the procedure itself. Why do BTK inhibitors eventually stop working? So the main reason why patients come off of BTK inhibitors, there's two main reasons. Either they are intolerant to the drug, right? So they develop atrial fibrillation that can't be controlled, hypertension that can't be controlled, et cetera, or they progress on the drug. So slowly but surely their white count continues to rise or their lymph nodes start to get bigger. This is still being investigated, but the primary reason why patients progress on these covalent BTK inhibitors is because they develop something called a C481S mutation on the BTK protein. So when we're talking about these drugs, they bind specific to the protein at a certain spot. And so you need to have this certain bond that's created, this covalent bond for the drugs to bind to the protein. And so cancer, what cancer likes to do is cancer likes to mutate. So over time it's dividing and then over time something happens where basically where the drug is bound becomes mutated. So that's the C481S mutation. And that makes it harder for these covalent BTK inhibitors, Ibrutinib, Acalibrutinib, and Xanibrutinib to bind to the BTK anymore. And so that is the reason why patients progress. Right now we're checking these mutations at academic centers. We're not being checked as often in the community practice because we're not really sure what we should do about it once the mutation occurs. I do have patients who develop the mutation and still have years of time before their disease actually progresses. But typically once a mutation occurs, progression usually happens within a year or two. And so it's good to help guide patients to give them a idea of when we might need to change treatment. But if a mutation is detected, I wouldn't do anything until they had true progression, either with a rising white count and decreasing hemoglobin in platelets and big lymph nodes that require a change in treatment.