Updates in CLL: A Closer Look at Adverse Events - Episode 8

Experts Answer Audience Questions Related to Adverse Events of BTKi

Carrie Lenneman, MD, MSCI, and Farrukh Awan, MD, close out the program answering audience questions regarding potential adverse events surrounding the utilization of BTK inhibitors in the management of chronic lymphocytic leukemia.

Carrie Lenneman, MD, MSCI: In light of time, I’ll move to a couple of questions if you’re ready for that.

Farrukh Awan, MD: Yes.

Carrie Lenneman, MD, MSCI: The first one is, Have you seen low heart rate or bradycardia with ibrutinib?”

I can honestly say no, I have not seen that be a problem that wasn’t preidentified early. I don’t know what your experience is.

Farrukh Awan, MD: I have not seen a bradycardia. I have seen myocarditis, and that can cause issues with all sorts of problems. But as such, sole bradycardia is not something that I remember having to deal with.

Carrie Lenneman, MD, MSCI: “For a patient taking ibrutinib to treat CLL [chronic lymphocytic leukemia] and who has acquired A-fib [atrial fibrillation] due to this agent, what is the likelihood that the condition of A-fib will become more manageable or even go away when the treatment is stopped?”

I see a very skewed view of patients. I see a lot of patients with a lot of risk factors for A-fib in general. I tend to manage the A-fib and deal with the CLL concurrently. I don’t know what your perspective is, being an oncologist, maybe you’re not seeing quite as high risk of a population as myself.

Farrukh Awan, MD: In my experience, every single time I’ve stopped the BTK inhibitor, the A-fib goes away in patients who have no prior history. In patients who have a prior history, they almost always tend to go back to the baseline, which may be better-controlled A-fib…. When the new A-fib person stops the BTK, it goes away most often.

Carrie Lenneman, MD, MSCI: “Have you seen an AIHA [autoimmune hemolytic anemia] remission with any of the CLL drugs?”

Farrukh Awan, MD: We’ve published on this before. This has been clearly shown with ibrutinib, and a similar mechanism with acalabrutinib. Autoimmune hemolytic anemia responds very nicely to BTK inhibitors. Starting a BTK inhibitor early allows you to get off rituximab, [and] allows you to get off prednisone. It’s a prednisone-sparing approach, and it works beautifully in those patients. As you control the disease, and not just the disease, it also has some T-cell effects, especially with ibrutinib it is very clear that if you start these medicines for autoimmune hemolytic anemia, it does get better.

Carrie Lenneman, MD, MSCI: “When do you consider anticoagulation a contraindication to BTK inhibitors?” An example may be if they’re already on dual antiplatelets or DOACs [direct oral anticoagulants] or vitamin K antagonists or have a strong history of GI [gastrointestinal] bleeding. Similar to the patient you were just talking about, who’s on a mechanical mitral valve who really can’t come off of that. What are some other cases or scenarios you might have?

Farrukh Awan, MD: Specific cases where I will not consider anticoagulation is No. 1, warfarin. No. 2, if they have end-stage liver disease and if they have varices and if they have a high risk for variceal bleeding. Past history of bleeding is not necessarily a contraindication. It would be a relative contraindication. If they’re not actively bleeding and the bleeding issue has been resolved, I don’t really mind that too much, but I do keep it in my mind. If they have to be on other drugs that interact, we can actually do a pretty good job with a lot of these drugs. For example, if they have to be on posaconazole or fluconazole or any of the azoles, the ibrutinib concentration will go up 17, 20 times. It’s not percentages, it’s multiples, it’s a logarithmic increase. We manage those cases by monitoring the toxicity. There are clinical ways of dose adjustments, and dose reductions to manage drug-drug interactions. It just depends on what kind of adverse events you’re seeing. There are very few absolute contraindications, but those would be the 2 that jump to mind. If they have an active CNS [central nervous system] bleed issue, if they have a GI issue, variceal bleed, end-stage liver disease issue, or both.

Carrie Lenneman, MD, MSCI: “When a patient develops A-fib, how do you decide to manage it while continuing the BTK inhibitor, or stopping a BTK inhibitor and switching to a different BTK inhibitor, or to a different class of agents?”

I’ve had a couple of scenarios where a person’s developed severe heart failure from poorly controlled A-fib with RVR [rapid ventricular response]. In those cases I’ve talked to the oncologist, when they’ve been admitted to my service because of heart failure and they’re on the BTK inhibitor. I’ve talked to that oncologist and said, “Hey, have they failed a lot of the therapies? What are their options?” Usually we’ve come to some better alternative for another option, usually a non-BTK inhibitor. Once you develop heart failure from poorly controlled A-fib, I think that’s just saying you’re just not going to potentially tolerate even another BTK inhibitor as well. What are your thoughts?

Farrukh Awan, MD: I think if they get to your service, that’s a contraindication. That’s how I look at it. If it’s clinically asymptomatic and I pick it up on routine physical examination and the EKG [electrocardiogram] that I do in my clinic for surveillance. I don’t do that on all patients at all visits. I do it on patients if they complain of having skipped a beat, or I feel their pulse. This is something that I do occasionally. I know we don’t do a good job at doing physical exams anymore, but I do look at the pulse for my patients on BTK inhibitors. If I feel that there is an abnormal heart rate, I do an EKG right there in the office. If the patient has clinically asymptomatic A-fib, I do not stop the ibrutinib. I talk to the cardiologist and we come up with a plan. If they have clinically relevant A-fib requiring admission to the hospital, I do give them a break.

There is a caveat to that. If they’re early on in the disease course and their disease is poorly controlled when you stop the BTK inhibitor, invariably they will have a tumor flare, which can be pretty distressing for the patient. It’s not a big deal. You can give them steroids for a few days and it’ll shrink. But the lymph nodes swell up, and the white blood cell count goes up and down. Platelets go up and down. So it’s distressing for the patient. If you’ve been on ibrutinib or acalabrutinib for 2, 3, 4 years, then you have good disease control, and they tend not to flare as much when you stop it. I don’t change drugs without trying to manage them medically. If I fail, try the lower dose, and if they still do that, then yes, I will switch.

Carrie Lenneman, MD, MSCI: The next question, “Is there an ejection fraction [EF] on echocardiogram for which you would avoid a BTK inhibitor?”

We’ve had this come up. When we’ve found a new reduced EF of 30%, 35% or less, we’ve all been very nervous about going forward with a BTK inhibitor, at least to start off with without understanding what their etiology of the heart failure was. There’s no official guidance on this. I know heart failure can happen when people start a BTK inhibitor. It’s relatively low, 3% or 4% in real-world retrospective data. What is your thought? That would be a number where I would say we’re having close conversations about things.

Farrukh Awan, MD: Why is the EF low? I guess that’s one question. The same thing would apply for heart rate. Why is the heart rate low? If it’s in the 40s [beats/min] or if the EF is 25%, 30%, I’m guessing that’s invariably from a cardiovascular incident, or coronary artery disease, or some sort of cardiac issue, if they had this prior to going on the drug. If they obviously develop it while they’re on the drug, then I would imagine that you would stop the drug in pretty much all cases. I think this next question about the bradycardia is kind of the same thing. If you went on a BTK inhibitor with a preexisting bradycardia or low EF or CHF [congestive heart failure], then it’s probably not the drug that’s causing it. Now, can it make it worse? Sure. If it does get worse, do you want to switch it? Probably. This is exactly where the cardio-oncology consultation is so important.

Carrie Lenneman, MD, MSCI: Yes, I think you’re right. It really depends, was the bradycardia preexisting or not for the patient? Obviously if it’s during the treatment I’d be a little more curious and think about giving a drug holiday or switching it, especially if a lot of cardiac testing has been done and they’ve not found a source for it. And especially if that was new on that therapy. I can’t say I’ve seen it happen, but there could be unique things out there.

The next one is, “In the real world, are BCL inhibitors significantly safer than BTK inhibitors, since in the community our patients tend to be older with multiple comorbidities?”

Farrukh Awan, MD: Not necessarily because remember with BCL2 inhibitors, a lot of times you have to have the first cycle, the first 2 or 3 months of therapy can be little interesting for various reasons. No. 1 is you invariably start them with a CD20 antibody. So cycle 1 neutropenia or low counts can be a big problem that has to be managed aggressively. In a small community setting where there is not a lot of support and not a lot of people experienced to handle that, that can be a little tricky. No. 2 is that if you’re in a small town that doesn’t have access to real-time laboratory results, you can’t even get a potassium level or a kidney function. So if you’re treating a patient who has high risk for tumor lysis that can be a little tricky. If you have the resources in a good, well-established hospital or community center, a big clinic in the community, then that’s fine. It’s not automatic that just because it doesn’t have the cardiac issues, it automatically makes it safe. That’s the first thing.

The second point is there hasn’t been a head-to-head trial comparing long-term outcomes of patients as far as the disease is concerned with ibrutinib versus venetoclax, or acalabrutinib or zanubrutinib. So is venetoclax necessarily better just because you can stop and start? In the long run we just don’t know. The big debate in the field right now is whether on-off strategy is better than on perpetually. If the goal is to live 20 years without disease, which strategy will get you to that 20 years? That’s the issue. If you’re 79 years old or 85 years old, if you want to get a few good years, fine. You stop a drug after 12 months, a reasonable approach. If you are 50 years old or 60 years old, you still have 20, 30 years to live. Now in that case, is it 12 months or 24 months of venetoclax on-off, on-off versus perpetual ibrutinib? I don’t know the answer to that because long-term data with ibrutinib and acalabrutinib are looking pretty darn impressive.

Carrie Lenneman, MD, MSCI: Good point. The last one, “What are the common errors you are seeing being made at community centers when it comes to the management of cardiovascular adverse events?”

I will tell you, my first day when I moved to UAB [University of Alabama at Birmingham], I had one of the fellows present a patient, saying, “I’ve got a patient with CLL, a new consult for A-fib. I want to do dilt [diltiazem]. I want to put him on full dose Eliquis [apixaban], whatever.” I was like, whoa, wait. I said, “Is this person on ibrutinib?” Then my cardiology fellow is like, “I don’t know what cancer medicine they’re on. Why do I care? I’m here for the A-fib.” I said, “Listen, this matters.” What I see, the biggest thing is just lack of awareness and appreciation for how we need to care for these patients with CLL differently than all-comers with A-fib. As we highlighted before, the delicate management of anticoagulation, prioritizing do we really need that anticoagulation? Can we consider a lower dose of anticoagulant? So that, and then also underappreciating the drug-drug interaction. The amiodarone, the dig [digoxin], the dilt [diltiazem]. Being aware of those drug interactions and that you need to reach out to our oncology colleagues, or vice-versa, oncology needs to reach out to cardiology and say, “Hey, here’s what’s going on. How do we co-manage these things together?” Those are the biggest things I see that happen in the community. I’ll turn it over to you to see what your thoughts are.

Farrukh Awan, MD: That is the No. 1 pet peeve that I have. And that’s coming from a cardiology fellow who is more involved and engaged. I see this all the time, “It’s a chemotherapy, the oncologist will deal with it.” It’s the same for hypertension. A blood pressure 180/100 mm Hg is not necessarily white coat hypertension in the setting of ibrutinib because it never gets checked at home. Those are the minor things that just because of lack of awareness, nurses ignore it, the nurse practitioners, the physician assistants, the physicians. I think the whole health care team historically unfortunately has. They know how to manage ibrutinib, they know how to manage aspirin, they know how to manage metformin. They know how to manage warfarin. Even Eliquis for that matter, or Lovenox [enoxaparin]. IR [interventional radiology] knows exactly when to stop the Eliquis before they do a procedure. But they never bother about asking about our drugs if the patient is on this chronic suppressive therapy for life. It gets relegated to the chemotherapy bucket, which unfortunately I think is doing a disservice for the patient. We can prevent a lot of untoward adverse events, bleeding issues, and a lot of problems if you just pay attention to the patient and deal with it like you’d deal with anyone who’s on chronic therapy.

Carrie Lenneman, MD, MSCI: I agree. I get questions about, “When do we start ibrutinib for their dental extraction?” So good point. We do need to think about stopping it for high-risk bleeding things.

It’s been great chatting with you. I really have enjoyed our conversation together.

Farrukh Awan, MD: Thank you. I really enjoyed it too, and I learned a lot. Hopefully people who are listening might have taken something that might help their patients.

This transcript has been edited for clarity.