Cardiotoxicity in patients treated with acalabrutinib

[CLLerinOz]

The latest edition of the journal Blood has two articles that highlight the issue of cardiotoxicity in patients treated with acalabrutinib.

The cardiotoxicity of ibrutinib has been well recorded but the situation with the newer BTK inhibitor, acalabrutinib, has been less clear.

In the first article, "Ventricular arrhythmias and sudden death events following acalabrutinib initiation", Seema A. Bhat et al show that:

"Patients treated with next generation BTKi therapy acalabrutinib still see a >8 fold risk of ventricular arrhythmia and sudden death events.

Ventricular arrhythmias may be a class effect of BTKi therapy, and vigilance is needed."

ashpublications.org/blood/a...

The second of these articles, titled "Cardiotoxicity in patients treated with acalabrutinib" by Petra Langerbeins states:

"Although the observed cardiotoxic adverse events in nearly 3% of patients treated with acalabrutinib was lower than that reported in patients treated with ibrutinib, the percentage was eightfold higher than that in similar untreated control patients. These data indicate that VAs may be a class-specific effect of Bruton tyrosine kinase inhibitors (BTKi’s)."

"Bhat et al provide the first evidence of an increased risk for VAs in patients treated with the second-generation BTKi acalabrutinib. Although the frequency of this severe cardiotoxicity was less common than with ibrutinib, the data strongly indicate that there is a cardiotoxicity class effect with BTKi therapies. In clinical practice, this should translate into systematic cardiac monitoring of all patients treated with BTKi’s, with careful assessment of cardiovascular risk factors and a baseline electrocardiogram before treatment is initiated. During treatment with BTKi’s, clinicians should inquire about symptoms of VA (lightheadedness, palpitations, or syncope) and perform diagnostic electrocardiograms with a low threshold (see figure). Other targeted treatment modalities may be available, so patients who develop cardiotoxicity associated with BTKi’s may be advised to discontinue treatment with them and switch to an alternative treatment regimen."

Those with a risk of cardiotoxicity could consider a time-limited treatment to reduce the possibility of long-term toxicities (Bhat et al reported a median time to ventricular arrhythmia (VA) of more than 1 year). She also recommends clinical trials be developed to assess long-term cardiotoxicity.

"In conclusion, it is vital that patients and caregivers be aware of the severe cardiotoxicity associated with ibrutinib and also with the second-generation BTKi acalabrutinib. Consideration of cardiovascular adverse effects is an important decision-making tool for selecting treatment for CLL, even in a regimen based on acalabrutinib."

Note that, while this event was recorded at a rate eightfold higher than that recorded in similar untreated control patients, it was observed in just 3% of patients treated with acalabrutinib. It's a call for careful screening and monitoring, rather than a call for avoiding acalabrutinib. It's also a reminder to those whose screening identifies that they may be at risk to consider time-limited therapy while others who select acalabrutinib over longer periods should maintain vigilance and be monitored carefully throughout their treatment.

(my emphasis)

1. Seema A. Bhat, John Gambril, Leylah Azali, Sunnia T. Chen, Lindsay Rosen, Marilly Palettas, Tracy E. Wiczer, Sujay Kalathoor, Qiuhong Zhao, Kerry A. Rogers, Adam Kittai, Michael Grever, Farrukh Awan, Patrick Ruz, John C. Byrd, Jennifer Woyach, Daniel Addison; Ventricular arrhythmias and sudden death events following acalabrutinib initiation. Blood 2022; 140 (20): 2142–2145. doi: doi.org/10.1182/blood.20220...

2. Petra Langerbeins; Cardiotoxicity in patients treated with acalabrutinib. Blood 2022; 140 (20): 2096–2097. doi: doi.org/10.1182/blood.20220...

[CLLerinOz Administrator]

Note also: this comment from earlier in August by Stephen D Smith, Fred Hutchinson Cancer Center

ashpublications.org/blood/a...

[kitchengardener2]

Thanks, a lot of that goes over my head but I have been posting recently about possible irregular heart rhythm. I was diagnosed with this after an accident and high doses of morphine. Once that settled I was fine but still take Apixaban. I have an appointment on Wednesday with a cardiologist so will report back.

[CLLerinOz Administrator in reply to kitchengardener2]

All the best for Wednesday. It's been a long time since you've been dealing with the aftermath of your accident - I hope it's soon behind you well and truly.

[kitchengardener2 in reply to CLLerinOz]

So do I, it's been hanging around too long now x

[Sushibruno]

😢😢😢😢😢😢this is why I feel the way I feel about these meds. It's not right!

[CLLerinOz Administrator in reply to Sushibruno]

Stephen D. Smith wrote: "Overall, suggesting that VA represent a “class effect” of BTKi paves over likely differences between these agents, and is not useful when assessing the therapeutic index of an agent or monitoring therapy with a given patient." You're taking a very effective, targeted medication and you're being monitored by a top CLL expert so, no doubt as she has told you, let her do any of your worrying if needs be and concentrate on letting the med do its job to help make you feel a whole lot better. 😀

[Sushibruno in reply to CLLerinOz]

Im just feeling a bit overwhelmed. Thanks for your reply CllerinOz. Your hard work is very much appreciated🙂.

[SofiaDeo]

Dana Farber in the US will be starting a study of cardiotoxicities in BTK inhibitors. I would encourage any here on either acalabrutinib or ibrutinib to consider being in it if one of their study sites is easily accessible, or if you are a patient there. Especially if you have any cardiac concerns.

clinicaltrials.gov/ct2/show...

[country76 in reply to SofiaDeo]

Does she have any sites in the West?

[SofiaDeo in reply to country76]

That link will show all the study sites, once the study is in the recruiting phase. If your doc participates in studies, you can ask them to reach out to the principal investigator, to see if they are able to participate. It looks like Harvard University is the main sponsor, IDK if they can or would be willing to include other cancer institutes besides Dana Farber.

You can sort of "replicate" the study yourself, at home. Get seen by a cardiologist, get a portable ECG (some integrate with smartphone and can send data to the cloud, where you doc can view remotely in almost real time) and you can get the intense monitoring that this study will provide. When I next try a BTK drug, I will be getting one.

[country76 in reply to SofiaDeo]

Thank you. I do have a little EKG monitor.

[Mtk1]

Thanks for the information, I have said since the beginning of my treatment with acalbrutinib that this is the cause of my heart problems, I started treatment September 2021 and heart issues started in November 2021. I had never suffered with any heart related illness before starting treatment. When I asked cardiologist if he thought acalabrutinib was the cause he just shrugged his shoulders and said it was possible. My haematologist wants me to stay on acalabrutinib but I have my doubts now. I only speak with my haematologist every 4 months by phone appointment, so I’m a bit worried about the lack of monitoring.

Dave.

[SofiaDeo in reply to Mtk1]

Hmm, if it were me I would try to switch. I know that's easier said than done, in the UK. I do not know how you could advocate to change this, not knowing the NHS.

[Mtk1 in reply to SofiaDeo]

yes that has been my thoughts, but my haematologist is adamant I stick with acalabrutinib, he had originally said I would start with v&o but changed this because of my treatment for bladder cancer, saying it would be too toxic having both together, I suppose we have to listen to the experts. Dave.

[CLLerinOz Administrator in reply to Mtk1]

Dave, It’s tricky when you have a condition as well as your CLL that has to be considered. Sometimes, as you’ve experienced, it can be a delicate balancing act and we need to be guided by our specialists in those situations. I hope you can discuss your concerns with your health team and reach a point where you feel more confident about your situation. As well as that, I hope you have some better luck soon where your health is concerned; you’ve had a lot to deal with this year.

[Mtk1 in reply to CLLerinOz]

thank you.

[LeoPa]

Let's look at the bright side. Sudden death caused by ventricular arrhythmia is painless and the patient has no time to even realize what's happening before he finds himself on the other side. Most other ways of passing are much worse than this.

[Dahlia7 in reply to LeoPa]

Truth. Seldom appreciated.

[OaktownN in reply to LeoPa]

For those of us being treated with Calquence, comments like this are not appreciated. While this may be true, maybe consider rethinking comments like this prior to posting.

[LeoPa in reply to OaktownN]

I wonder why. It's a win-win. Either the disease gets under control or one gets an easy pass. Considering we are going to spend the major part of eternity not on this planet what is better than having a chance not to have to prepare for and mourn one's own passing. Not to mention avoiding the pain, not only physical associated with. I watched both my parents die and all I can say in hindsight is I wish they died of ventricular arrhythmia instead of the way they had to go. A few days ago we buried one of my middle school classmates. Early onset Alzheimer's. Give me ventricular arrhythmia anytime over that. Of course it is clear that all of us want to live as long as possible, but trying to find something positive even in the most negative can't hurt. But I appreciate that not everyone sees it the same way.

[OaktownA in reply to LeoPa]

wow, totally not a bright side and callous of you to even suggest it. Astonishing that you found it appropriate to say that.

[LeoPa in reply to OaktownA]

Not a bright side? Have you watched a metastatic cancer patient climb walls out of being in pain which absolutely no pain killers can handle? People committing suicide for the same reason? There are many ways to die and they are not all equal. There are better and there are worse. It sounds morbid but this is the truth.

[SofiaDeo in reply to LeoPa]

And we all know this, but we don't care to discuss it, I think. We prefer to focus on *positives* when possible. It's one thing to talk about the realities of side effects, or morbidity/mortality of disease, without interjecting the topic into a conversation that decidedly wasn't about said topic. This conversation is about potential cardio toxicity and a new recommended treatment algorithm. It's not about how "death from this side effect" is preferable to other causes of death.

[LeoPa in reply to SofiaDeo]

Is the new recommended treatment algorithm known for reducing the chances of sudden death by ventricular arrhythmia?

[SofiaDeo in reply to LeoPa]

It's a "new" recommendation, and as such there is no data. Things in our rare disease don't get modified/adjusted based on large amounts of previous data. It's prospective/cautious recommendations. Which I know you know, you are very intelligent. Are you feeling OK, you seem a little irritable/argumentative today? 😜

[LeoPa in reply to SofiaDeo]

Thank you for the clarification 🙂. I didn't mean to be argumentative. Perhaps my way of thinking is permanently biased being a practicing stoic and at ease with the thought of death, not that I wish it to arrive anytime soon!

[OaktownA in reply to LeoPa]

there’s no bright side to any of it - but I was under the impression that this forum was to help us all find solid footing, share information to help us manage living with CLL, and support one another as we navigate an uncertain landscape. No one is so naive as to pretend we’re all not going to meet our end somehow, certainly some more painful than others. But a certain level of tact and sensitivity would be appreciated, if not assumed.

[LeoPa in reply to OaktownA]

That's exactly what I was hoping to achieve with the comment. Support and solid footing. Highlighting there was nothing to be afraid of. Can we see the same thing so differently?

[Mtk1 in reply to LeoPa]

staying alive is a lot better though, don’t you agree.

[LeoPa in reply to Mtk1]

Of course! In order not to be misunderstood, the way I meant it is that if I was given a blank form with 10 different ways of passing with one being filled up and that being ventricular arrhythmia, and asked to fill the other nine ways which I would prefer without any influence on when they are going to happen I would be hard pressed to find alternatives I would like better. But staying alive and living to be 100 and only then passing of ventricular arrhythmia is my preferred way too 🙂.

[OaktownA in reply to LeoPa]

I hope you and all of us live to be 100! Sounds like you’ve had some difficult experiences with the death of your parents, and I’m so sorry for thst.

These are hard times, with or without CLL, and it’s scary to hear that one’s treatment - that thus far has been life changing and given the promise of better health, even if temporarily - might be toxic or dangerous, potentially fatal. I’m certain you didn’t intend for your statements to be hurtful, but I hope we can all consider how our comments might be taken by those feeling scared about treatment and its potential negative effects.

[Newdawn Administrator in reply to LeoPa]

Let’s just demonstrate a tad more sensitivity however Leo. Blunt and brutal realities are easier to digest when you’re not in that position and thankfully as an indolent, untreated person you have that luxury. Others on here face the stark, here and now concerns about BTK cardiac toxicity (including me). Advice that it’s preferable to drop down quickly than linger isn’t particularly reassuring in this context. In actual fact people can live untroubled with arrhythmias for some time and it’s mainly ventricular fibrillation which is the riskiest type.

It’s why and how this toxicity affects us and what we can do to identify risk and protect ourselves that’s the key issue for me. Somehow the ‘gruesome hierarchy of demise’ doesn’t help. I speak as someone who witnessed my father drop like a stone from cardiac arrest (several times and he survived because he was in hospital) but arrhythmias can lead to long term chronic conditions too which are not painless.

Newdawn

[LeoPa in reply to Newdawn]

Thank you, I see your point. I read the account of a person who almost died due to atrial fibrillation. Lucky for him it happened during a game of squash. The other guy promptly started resuscitation and called the ambulance, thus he survived. They asked him about this incident and how it all went. He said imagine someone started to dim the knob of light of your life. Gradually everything fades away. No pain. Nothing to fear. I thought to myself, wow, what a way to go. Granted to a precious few only. And this is how I think about it despite being still on the younger side and without treatment with a so far slowly progressing disease. I imagine how much less afraid I would be of such an outcome if I was older, in pain and feeling unwell. If that's strange I'm guilty of being strange.. Sorry 😔

[spi3]

Thank you - my hubby has been on Acalabrutinib for 9 months and he is doing good - question my hubby exercises a lot - does this reduce the chance of cardiotoxcity

[Mtk1 in reply to spi3]

short answer no.

[SofiaDeo in reply to spi3]

I would hazard a guess that if this effect is preventable, or minimizable, it would be a combo of factors (diet, exercise, stress reduction) than exercise alone.

[Mtk1 in reply to SofiaDeo]

I exercised regularly and had a good diet, but unfortunately developed problems, so that was the reason for my answer.

[jimvan]

I've been successfully taking ibrutinib for 5 years, but over the last year have had two episodes of syncope (fainting). I have been thinking about asking my hematologist (no specialists near me) to switch me to acalabrutinib, but this report gives me pause. I did do a 14 day heart monitor after the first syncope episode that showed exactly nothing out of the ordinary (at the direction of my internist). She suggested another monitoring after the second episode, so I may revisit that suggestion at our next appointment next month.

[BobbyFour]

I might be misreading this, but even though any risks are bad (of course) for those that are the unlucky ones, the overall rate is very low?

[CLLerinOz Administrator in reply to BobbyFour]

Yes, the message that I took from this report was that, although the risk of cardiovascular complications was much lower on acalabrutinib than that recorded with ibrutinib, it may not be zero risk. Therefore, screening to identify those with a heightened risk before the start of treatment is important and time-limited treatment, if available and suitable, should be considered for those identified as being at risk for heart complications. For those whose initial screening suggests continuous therapy should be ok, ongoing monitoring is advisable (as indicated in the graphic provided).

The comment by Stephen D Smith (linked in my previous reply to the post) is important. He gives details about the incidence of cardiovascular events in this study:

"Only 8 ventricular arrhythmias deemed related to acalabrutinib occurred, in a cohort with a median age of 64-- of whom 59% had HTN [hypertension]and at least 25% received antiarrhythmic agents at baseline—with 42 months of follow-up. It appears that most were symptomatic PVC’s [Premature ventricular contractions], and the severity or grading of these events is not known. The only cardiac sudden death was in an 85 year-old, and 6 of 8 patients with VA [ventricular arrhythmia] were able to continue acalabrutinib; only one had paroxysmal VT [Paroxysmal ventricular tachycardia] diagnosed requiring an implanted defibrillator. As others have suggested, symptomatic PVC’s may not comprise a clinically significant entity; PVC’s can be seen in 6% of the population on a given 2-minute EKG."

"Overall, suggesting that VA represent a “class effect” of BTKi paves over likely differences between these agents, and is not useful when assessing the therapeutic index of an agent or monitoring therapy with a given patient. While post-marketing studies are critical, careful selection of endpoints, and an appropriator comparator, are necessary before concluding that VA risk with acalabrutinib is either elevated or clinically important.

[julius_the_cat]

1st post for me and I’m very appreciative of this site, the admin and contributors.

I located the comment by Stephen D Smith after I didn’t scroll far enough initially). I think he provides balance and addresses important limitations of the report by Bhatt et al and effectively refutes the “Key Points” in my opinion.

Specifically, he references endpoint(s) which in this case report was “ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions”. I would compare this group to the following: lions, tigers and house cats. I would care a great deal about the number of lions & tigers in my neighborhood but much less about how many tabby cats. Grouping them together is imprecise.

He also contrasts the Level of Evidence for this study (probably grade 4 due to inappropriate comparator group) compared with randomized controlled studies (Level of Evidence 1a or 1b) which did not show increased risk. On the other hand, the initial trials were not specially designed to identify ventricular arrhythmias and likely did not have the statistical power to accurately detect differences.

BTKi drugs also inhibit other kinases. Others have suggested that perhaps the differences in rates of hypertension and atrial fibrillation between acalabrutinib and ibrutinib may be related to inhibition of one of these other kinases. I’d agree that labeling ventricular arrhythmias as a BTKi “class effect” seems premature.

TLDR; Too early to say. Reporting symptoms of irregular heart rhythm is still important.

[SofiaDeo in reply to julius_the_cat]

Right, people are "asking the question" which is totally different than "making a statement of fact". And the suggested algorithm is a precaution, because this particular group of side effects isn't as innocuous as some others like nausea or headaches. Being super cautious is warranted unless and until whatever correlations and severity and percentages actually get enough data to say something more definitive.

I like the transparency that medicine has nowadays. One of the major drawbacks though, IMO, is that people can and do read stuff and *extrapolate*; it's hard not to. Taking correlations as causations, etc etc. But I firmly believe that getting a portable ECG and doing at least daily readings will head off some if not the majority of the most severe outcomes. Since many arrythmias initially are asymptomatic, I wonder how many "silent" dysrhythmias actually occurred in those who had severe outcomes. Now that we are actively looking, the incidence of severe outcomes should decrease. IMO it's similar to how early in the Venclexta trials, people were unaware of the need to aggressively monitor for signs of TLS. Now that we do, we catch and correct things before they become serious. I am imagining this will be the future of BTK's, that anyone being put on one (especially with cardiac risk factors) must have at least daily portable ECG monitoring, so those who do present with dysrhythmias are caught before they become serious. Extra meds may be needed temporarily, or the BTK may be switched, but we will catch these before they become serious. I am sure at some point in medicine, folk didn't realize the importance of routine, regular liver function testing, or kidney function testing for certain meds, until they did. So at some point, I think cardiac function tests like ECG will also become more frequent and routine since the technology finally allows for compact devices that folk can easily do at home.

[AussieNeil Partner Administrator]

A note to be aware of supplement companies making unsubstantiated claims that their product will "cure, treat, mitigate or prevent cardiovascular disease or related conditions."

Today (17th November 2022) the U.S. Food and Drug Administration issued warning letters to seven companies for illegally selling dietary supplements that claim to cure, treat, mitigate or prevent cardiovascular disease or related conditions, such as atherosclerosis, stroke or heart failure, in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The FDA is urging consumers not to use these or similar products because they have not been evaluated by the FDA to be safe or effective for their intended use and may be harmful.

The warning letters were issued to: Essential Elements (Scale Media Inc.); Calroy Health Sciences LLC; Iwi; BergaMet North America LLC; Healthy Trends Worldwide LLC (Golden After 50); Chambers' Apothecary; and Anabolic Laboratories, LLC.

“Given that cardiovascular disease is the leading cause of death in the U.S., it’s important that the FDA protect the public from products and companies that make unlawful claims to treat it. Dietary supplements that claim to cure, treat, mitigate or prevent cardiovascular disease and related conditions could potentially harm consumers who use these products instead of seeking safe and effective FDA-approved treatments from qualified health care providers,” said Cara Welch, Ph.D., director of the Office of Dietary Supplement Programs in the FDA’s Center for Food Safety and Applied Nutrition. “We encourage consumers to remain vigilant when shopping online or in stores to avoid purchasing products that could put their health at risk.” 

fda.gov/news-events/press-a...

Neil