Managing the cardiovascular risk of Bruton's Tyrosine Kinase Inhibitors in chronic lymphocytic leukemia

[CLLerinOz]

The American Society of Hematology journal Blood Advances published an important "International Consensus Statement on the Management of Cardiovascular Risk of Bruton's Tyrosine Kinase Inhibitors in CLL" on 5 July 2022.

It provides "a management guideline for CV toxicities of BTKi developed by an international expert panel focusing on the treatment of patients with hematologic malignancies and risk of cardiovascular disease (CVD), with a focus on patients with CLL.'

The recommendations are the work of an international steering committee of 12 physicians including 'hematologists, oncologists, and cardio-oncologists with a specialist interest in CV toxicities to provide a diversity of clinical experience. The committee sought to make practical recommendations on the optimal selection of treatment for patients and effective ways to mitigate CV toxicities.' (my emphasis)

The statement provides an overview of current CLL treatments along with trial data regarding their CV toxicities.

The statement then provides some 'Practical recommendations for BTKi therapy' including advice in the following areas:

1 PRE-TREATMENT RECOMMENDATIONS including INITIAL WORKUP and SELECTING A COURSE OF TREATMENT

'Comprehensive patient history including:

Blood pressure measurement, Electrocardiogram, Concomitant medications, CV risk factor assessment: presence of diabetes, obesity, hypertension, dyslipidemia, chronic renal disease

History of valvular heart disease, History of arrhythmias, heart failure, or left ventricular dysfunction/reduced ejection fraction

History of ischemic heart disease

For patients with high CV risk or established CV disease: Echocardiogram, Baseline cardiac biomarkers, Consider using FRS-CVD65 score for stratification'

Patients with no CV risk factors: Any approved BTKi (If other safety concerns, favor more selective drugs (acalabrutinib or zanubrutinib) or Bcl-2 inhibitors)

Patients with CV risk (e.g. well-controlled AF, HTN): Consider 2nd-generation BTKis (acalabrutinib or zanubrutinib)'

2 RECOMMENDATIONS FOR PATIENTS WITH CV RISK

'Atrial fibrillation: Determine whether patient is high or low risk. Low risk cases may be safely treated with BTKis; Favor more 2nd-generation BTKis (acalabrutinib or zanubrutinib) or alternative treatments. BTKi treatment may be continued in consultation with MDT for patients with: Permanent/persistent AF, HTN, History of myocardial infarction. BTKis NOT recommended for patients with: History of ventricular arrhythmia, Family history of sudden cardiac death, Severe, uncontrolled HTN, Severe or uncontrolled congestive heart failure (LVEF<30%)

Hypertension: If HTN is well-controlled, BTKi therapy may be used; Monitor blood pressure at least bi-weekly for the first 3-6 months of BTKi therapy; Maintain early threshold for treatment during BTKi therapy

Congestive heart failure: Examine with echocardiogram; Restrict to <2 g daily sodium intake; Monitor weight daily; Monitor blood pressure twice weekly; Manage care with MDT (preferred) or in collaboration with a cardio-oncologist

Ventricular arrhythmias: Ibrutinib should be avoided; Risk of 2nd-generation BTKis (acalabrutinib or zanubrutinib) is not currently known

3 MANAGING CV TOXICITIES DURING TREATMENT

Emerging atrial fibrillation: Manage care using an MDT; If other risk factors are limited (e.g. CHA2DS2-VASc score = 0 or 1), BTKi therapy can be continued; Warfarin less preferred to alternative anticoagulant therapies; If recurrent events on ibrutinib, trial with acalabrutinib

Emerging HTN: Begin regular home blood pressure monitoring; New treatments for HTN or adjustments to ongoing treatments should be decided in conjunction with MDT; Follow management guidelines and avoid CYP3A4 ; inhibitors where possible; Non ACEi in the first instance; Use combination therapy if needed to attain systolic blood pressure control

Emerging CHF: Initiate ACEi/ARB/ARNI plus beta-blockers as tolerated and according to guidelines; Periodic echocardiogram or other EF assessment every 6-12 months in the setting of active CHF'

4 WHEN TO REFER TO CARDIO-ONCOLOGY

'Cardio-oncologists can be invaluable members of a patient’s MDT, however, there are still too few of these specialists to consult on all CLL patients with CV risk factors. It is therefore important to refer the most challenging cases, including patients with a history of ventricular tachycardia or arrhythmia or difficult to manage CHF, before beginning BTKi treatment. Providers should also consider referring patients with a history of substantial CV disease, including AF or CHF, difficult to control hypertension (more than 2 medications needed), or ongoing cardiac complications that require referral to a cardio-oncologist in cases of concern, but it is not necessary to do so routinely. In many cases, ongoing management by the patient’s own cardiologist is the most appropriate course of action. Additionally, a cardio-oncologist may be required to consult if there are any red flags in the initial workup, particularly AF on baseline.'

The statement concludes: 'BTKi therapy has changed the CLL treatment in substantial ways, but these drugs also present CV risks. New 2nd-generation BTKis have now been developed that are more selective for Band appear to have fewer off-target effects, providing the potential to reap the benefits of BTK inhibition while lessening the CV risks. The recommendations presented here take into account the available phase 3 data for BTKis in order to promote their safe and effective use. Optimizing heart failure, ventricular arrhythmia, and HTN control will likely improve tolerance and maintenance of BTKi therapy. However, additional studies are needed to identify the most optimal strategy across this growing class of drugs.'

More detail can be found in the full statement:

Farrukh T Awan, Daniel Addison, Feras Alfraih, Sergio J Baratta, Rodrigo Noronha Campos, MARIA SILVANA CUGLIARI, Yeow Tee Goh, Valery Alexandrovich Ionin, Stefanie Mundnich, Aaron L Sverdlov, Constantine S. Tam, Loïc Ysebaert; International Consensus Statement on the Management of Cardiovascular Risk of Bruton's Tyrosine Kinase Inhibitors in CLL. Blood Adv 2022; bloodadvances.2022007938. doi: doi.org/10.1182/bloodadvanc...

(After opening the link, select the PDF option for the full text version)

Abbreviations:

ACEi = angiotensin converting enzyme inhibitor

AF = Atrial Fibrillation

ARB = angiotensin receptor blocker

ARNI = angiotensin receptor-neprilysin inhibitor

CHF = Cardiac Heart Failure

CV = Cardiovascular; CVD = Cardiovascular Disease

FRS-CVD = Framingham risk score-cardiovascular disease

HTN = Hypertension

LVEF = left ventricular ejection fraction

MDT = multidisciplinary team

Note: This is an UNLOCKED post

[Sushibruno]

I know that every patient doesn't experience these side effects. But even if we've never had CV issues these Btk's can cause them. One of the reasons I fear treatment.

[CLLerinOz Administrator in reply to Sushibruno]

Be encouraged by the fact that the medications are improving all the time with fewer “off target” side effects. Also, this paper provides excellent recommendations for screening patients before their treatment is selected, so appropriate treatment choices can be made, and then managing them closely so that, as much as possible, any problems can be averted or much reduced,

[Sushibruno in reply to CLLerinOz]

Thank you CLLerinOZ. My anxiety takes over but I'm working on it. Maybe this watch and wait has me feeling this way.

[cllady01 Former Volunteer]

Thank you for your precision in giving us a very readable and understandable post. Much better delineated than the article itself.

[CLLerinOz Administrator in reply to cllady01]

😄 I’m pleased you found this post so helpful and readable.

To be fair, it focusses most on the consensus statement’s summary of advice, which the authors provided in three boxes at the end of the full document, while the full version contains much more information, including details about different BTK inhibitors and evidence for the advice.

[kitchengardener2]

I have never had issues with heart problems and after almost a year on Acalabrutinib everything was fine. Prior to starting Acalabrutinib and whilst I was watching and waiting, I noticed a loud heartbeat at night and reported that to my consultant and to my GP. Both said it was nothing to worry about because my blood pressure was excellent and I wasn't overtired. My blood numbers quickly improved with Acalabrutinib and all was good until two weeks ago. Then I had a nasty accident when I fell whilst I had a kettle full of boiling water in my hand. This resulted in a badly scalded leg. I was taken to hospital by ambulance and treated but whilst there an ECG was done. The A&E doctor decided that my heart rhythm was irregular and prescribed Apixaban and Bisoprolol. I wanted to speak to my consultant before taking these. She said if the GP prescribed them (it was the hospital not GP) then it was ok. I tried to speak to a GP who poo poohed my worries and advised taking them even after a perfectly normal ECG. My pulse rate dropped like a brick after only days of taking Bisoprolol and it was stopped. I have continued with the Apixaban and taking blood pressure readings three times each day. My numbers are now normal again but I have noticed a woozy feeling most of the day which I didn't have before. I will take my blood pressure diary to the surgery this morning and again request a GP's face to face consultation (this is like asking for gold) and I shall probably be fobbed of with a doctors little helper. I shall be 70 in a couple of weeks and I lost both parents to heart attacks/stroke so if I am advised that I need medication I will take it but don't want to have to stop my wonderful Acalabrutinib.

[CLLerinOz Administrator in reply to kitchengardener2]

I read about your accident when you first reported it and winced at what you were going through. I hope your burn is well and truly healing now. I understand you've been dealing with some worry about your CV issues since then and hope that you can start to get some answers to your concerns at your appointment today.

Do let us know how you get on - you might want to do that through a separate post or with an update to your earlier locked post where you previously received some good advice and support, too. Thanks for telling your story here; it sheds some light on how important this consensus statement by this international group of experts is.

[kitchengardener2 in reply to CLLerinOz]

Thanks for your good wishes, it will be a long job to heal properly. I have no skin at all on a large area so that needs to heal and grow new skin. I just hope it does and I don't need skin grafts. My bikini days are over🤣😂I just want someone to listen to my concerns, I do agree that if there's a problem with my heart that I must and will take medication but all I want is a proper diagnosis. The NHS are constantly bleating about money being wasted and yet they hand medication out too freely.

I know of people who had doctors in the family who would send family members to GP's with a list of symptoms that they didn't have. The reasoning was that because of language difficulties, they were given carrier bags full of medication which was then sent back to Pakistan and Eastern Europe. No charge because the pharmacy fees were covered by benefits. BUT nobody throughly checks if these medicines are actually being taken by the 'patients '.

[Mtk1]

Thank you, very interesting article and definitely pertinent to me, I think I should print this off and take to my haematologist on Monday, but will probably get scolded for reading too much again ( he doesn’t like it when I question his wisdom) I had to stop acalabrutinib twice because of heart problems, I’m now back on full dose but only getting 6 weekly checks and I think this will increase to 3 monthly after Monday. It’s 4 months since my mi and stent fitted but have heard nothing from my cardiologist since. I was supposed to get consultation after 3 months, I just keep getting fobbed off by my Gp and cardiologist secretary. On a happy note I am doing well and feeling good. Dave

[kitchengardener2 in reply to Mtk1]

Hi Dave, have dropped blood pressure readings in but it was z rather dizzy receptionist so not holding out much hope of a call back. Banging heads and brick walls come to mind!! This woozy sensation since stopping the Bisoprolol is concerning me and I wouldn't feel happy driving.

[Mtk1 in reply to kitchengardener2]

Hi Alice, yes I would not be driving, I see you have stopped bisoprolol, this can cause dizziness, I hope you get some answers soon, I know what you mean about receptionists, I have just rang my Gp because my wife has tested positive for covid, I was asking for advice on what I should do ( by the way I tested negative) she told me to ring 119, I did this and they said they don’t give medical advice and to phone my Gp. 😤😫, hope you get sorted soon Dave x

[kitchengardener2 in reply to Mtk1]

Argh!!

[SamanthaJane123]

Dave, I think more power to you for reading to seek knowledge. Particularly when it's from good sources. As they say information is power.

[Kwenda in reply to SamanthaJane123]

Knowledge is the best medicine....

Andrew Shorr, Patient Power, who has been a member of our CLL community for many a year.

Dick

[SamanthaJane123 in reply to Kwenda]

I have learned a lot from that very informative site, Patient Power.

Two months after my diagnosis I sat at the same table as Andrew Shorr when I attended my first CLL conference in Niagara Falls, Ontario. I didn't know at the time who he was and I count my lucky stars that I went to that conference. Wonderful people, great info. and resources.

My only regret is that I didn't learn about healthunclocked until year five of my diagnosis. I think this site would have helped me a lot in the beginning. At least I know about this place now.