BTKi vs BCL-2

[Lil0ppie]

Does anyone have a good understanding of the advantages/disadvantages of BTKi’s and BCL-2’s? Trying to understand my doctor’s recommendation for treatment. Why would one choose a BTKi like acalabrutib over a BCL-2 like venetoclax, and vice versa? Thanks.

[AussieNeil Partner Administrator]

Our "When will I need treatment?" pinned post healthunlocked.com/cllsuppo... includes links that covers this. Hopefully your specialist will use a tool like this treatment algorithm, to guide their recommendations nature.com/articles/s41408-...

You'll note that recommendations depend on risk stratification - previous treatment history, prognostic markers, patient fitness, comorbidities, effective age, etc.

Basically, from experience gained with venetoclax/Venclexta, we know that when used as a monotherapy, resistance develops faster than is the case with covalent BTKi drugs - we don't yet have much experience with the newer non-covalent BTKi versions. (There are about 15 BTKi drugs approved or in CLL clinical trials healthunlocked.com/cllsuppo... ) Venetoclax also works very rapidly, whereas BTKi drugs work much more slowly; only about 10% achieved uMRD after 4 years on ibrutinib. That makes venetoclax an excellent drug to couple with other treatment drugs to have a very good chance at achieving complete responses and at least uMRD4 (less than one CLL cell in 10,000 white blood cells) after fixed term treatment of about a year. That's why you'll see venetoclax + an anti-CD20 monoclonal antibody (obinutuzumab or rituximab), or venetoclax with a BTKi. Both combinations work well, with the latter combination particularly effective. That's because venetoclax doesn't penetrate nodes as well as the smaller BTKi molecule and one of the mechanisms by which BTKi drugs work is by blocking the adhesion signalling whereby CLL cells stay in the nodes where they are protected by the Tumour Micro-environment. healthunlocked.com/cllsuppo... The BTKi drives the CLL cells in our spleen and nodes into the blood, where venetoclax makes short work of them.

One potential disadvantage of venetoclax, is that it works so very quickly, that without using clinical trial established protocols, there's a risk of TLS (Tumour Lysis Syndrome) - CLL cell die off is so rapid that our bodies can't manage what's released from the dying CLL cells. That's why it's usual to prescribe the accompanying BTKi or monoclonal antibody for the first month to fairly quickly knock down the tumour level, then ramp up the venetoclax in the next month. Your specialist should use an algorithm to assess your risk of TLS; if it is high enough to put you at risk during venetoclax ramp-up, then you should be admitted to hospital for observation until the risk has passed.

There have been a few specialist presentations for CLL patients about BTKi vs BCL-2 recently, such as this one:

healthunlocked.com/cllsuppo...

We also have new generation BCL-2 drugs in clinical trials, such as Sonrotoclax (BGB-11417), which may change the treatment choice algorithm!

Neil

[Walkingtall62 in reply to AussieNeil]

Am I wrong to say that there just appears to be so many treatments coming up now for CLL, it’s amazing. I guess I don’t know too much about treatments of other cancers, but just so glad God picked this one for me. The CLL society, and Health Unlocked are really unprecedented tools compared to when I was young. Thanks everyone

[ClassyLady3 in reply to Walkingtall62]

I wholeheartedly agree!

[ClassyLady3 in reply to AussieNeil]

Is the combination more effective if your cancer is at stage 1-2? What if your cancer is found much later (stage 3-4)?

[Walkingtall62 in reply to ClassyLady3]

Good question

[AussieNeil Partner Administrator in reply to Walkingtall62]

ClassyLady3 and Walkingtall62,

There have been a number of clinical trials run over the last few decades to determine if earlier treatment of higher risk patients is advantageous. Bear in mind that with CLL, staging provides a poor prediction of when treatment may be needed - it's other factors that are used, such as worsening anaemia, falling platelet counts, a very enlarged spleen, very enlarged nodes, extreme fatigue, rapidly doubling lymphocyte count etc, which are used.

Offhand, I can't recall a clinical trial of early stage patients for FDA approval endeavours. That makes sense given over a third of those at an early stage may never need treatment. There have been some small trials of alternative treatments for those in early stages, however. The challenge is that if you enrol someone at an early stage into a clinical trial, they may have been better off not entering the clinical trial, given they may not have ever needed treatment. The other issue, is that by starting treatment earlier than needed by current guidelines, those that don't achieve long remissions, could run out of treatment options that would be less likely to occur if they waited until they met current treatment guideline recommendations.

Neil

[Walkingtall62 in reply to AussieNeil]

Thanks Neil

[antonb in reply to AussieNeil]

in EU and other parts of the world they have approved I+V as a fixed 15 month novel therapy for naive patientes last year.

3 months on Ibrutinib or other BTK and 12 on Venetoclax

Btki makes the risk of TLS with Venetoclax less risky, as in those three months a good rate of CLL burden will have dissapeared with BTKi .

Also Venetoclax rampage will be easier

[Skyshark in reply to antonb]

That was my impression as well up until last December.

When re-staged at end of week 3 on V+O after first 3 doses of Obinutuzumab and before first 20mg Venetoclax the number that remain at "high risk TLS" for the Venetoclax ramp-up is much reduced. UK NHS re-stage with a CT scan during week 3.

ash.confex.com/ash/2023/web...

Captivate FD trial V+I fig 5 (sorry the attached image is very smudged by scaling).

ashpublications.org/blood/a...

TLS risk V+O v's V+I

[Lil0ppie in reply to antonb]

Is this line of treatment approved in the US?

[Lil0ppie in reply to AussieNeil]

This is great. Very informative. Thank you. I’m on Acalabrutinib and starting Obinutuzimab either this week or next. This fits with what has been explained to me so far.

[Floxxy in reply to AussieNeil]

Thank you so much for your excellent explanation x

[Walkingtall62]

Good question

[Skyshark]

There are no right or wrong choices. Questions about sequencing are still unanswered. All reports regarding Ven after cBTKi or cBTKi after Ven show short medians but the cohorts analysed had shorter than median PFS on prior therapy.

tandfonline.com/doi/full/10...

The weighting of the scales for TP53mut (del17p) is only for IgHV unmutated and doesn't apply if IgHV mutated.

Weighing CLL treatments

[SofiaDeo]

There are pros and cons to both, and no way to know ahead of time if you have side effects from one drug but not another, even within the number of BTKi options available. Sort of have to pick one & see how you react/if it works without bad side effects *for you*. I've had a number of treatments, some drugs I had very few side effects, one was intolerable & I stopped it, even though it was "working beautifully" according to that doc.

[Walkingtall62 in reply to SofiaDeo]

thanks for replying