Reduced Dose of Acalabrutinib

[naddude]

I am on a 50% reduction of Acalabrutinib (once a day). Does anyone know if this will also reduce the irreversible binding of the drug and therefore accelerate resistance o eh drug? Is there any data on this?

Thanks.

[AussieNeil Partner Administrator]

The reason why the acalabrutinib clinical trials were conducted with the acalabrutinib taken twice daily, rather than once daily as was done with ibrutinib, is that acalabrutinib's half life is much shorter than ibrutinib's. Hence there's a requirement to take acalabrutinib more frequently than ibrutinib, to keep the blood serum concentration sufficiently high, so that any new CLL cells from cell division are promptly inhibited from further division. Otherwise there's a risk of resistant sub-clones developing.

I'm not aware of any studies on whether the efficacy of acalabrutinib in maintaining inhibition of CLL might be affected by reducing the dose by having one 100mg capsule per day, rather than two per day12 hours apart. There were some similar studies on ibrutinib dose reduction, but that was through taking less ibrutinib per day, not by taking it alternate days, plus patient weights weren't reported. Unfortunately, because there's no 50mg capsule, acalabrutinib dose reduction can only be done by dropping to one capsule per day, as you should not open the capsules.

So in summary, theoretically it's best to take acalabrutinib twice daily, but there's a growing number of patients who are taking it once daily to hopefully reduce, for them, what's considered an unacceptable side effect profile. Keep an eye out for reports. You've got growing company wondering along with you.

Neil

[naddude in reply to AussieNeil]

Hi Neil:

Thanks for that information. It is a concern as I do not want to become drug-resistant. There were quite a few side effects. It's been 12 months now on a half dosage. I will be watching.

Best wishes.

[bhayes84 in reply to AussieNeil]

Why shouldn’t the caps be opened?

[AussieNeil Partner Administrator in reply to bhayes84]

BTKi drugs are designed so that the coating dissolves for absorption in the gut at the right place for maximum effectiveness and minimal side effects. Even the stomach acidity has an effect with acalabrutinib/Cakquence, which is why you need to time the taking of antacids with respect to when you take acalabrutinib. Per the instructions on the official site, with my emphasis cllsupport.calquence.com/hc...

Take one capsule by mouth, twice daily, about 12 hours apart. CALQUENCE can be taken with or without food. Swallow CALQUENCE capsules whole with a glass of water. Do not open, break, or chew capsules. It’s important to take CALQUENCE exactly as your doctor tells you to take it.

Do not change your dose or stop taking CALQUENCE unless your doctor tells you to. Your doctor may tell you to decrease your dose, temporarily stop taking, or completely stop taking CALQUENCE if you develop certain side effects. Be sure to talk to your doctor about recommended dosing.

If you need to take an antacid medicine, take it either two hours before or two hours after you take CALQUENCE. If you miss a dose of CALQUENCE, take it as soon as you remember. If it is more than three hours past your usual dosing time, take your next dose of CALQUENCE at your regularly scheduled time. Do not take an extra dose to make up for a missed one.

Neil

[bhayes84 in reply to AussieNeil]

Interesting. Thanks.

[CLLnewbie]

I'd be interested in what your docs told you if you asked them compared to AussieNeil's thoughtful reply.

[naddude]

Hi Neil: My docs were not too worried about the reduced dosage and resistance for 2 reasons. First, I have been on a reduced dosage for one full year and my blood work is unchanged. Secondly, they say "everyone builds up resistance to BTK inhibitors at some point."/ (The second reason does not make me comfortable. On another note I am also on CBD oil for pain management and that is known to intensify the efficacy of BTK inhibitors. Would that possibly be a substitute for the gradual reduction in strength of the med during the day? Thanks.

[AussieNeil Partner Administrator in reply to naddude]

Having a low tumour burden certainly would appear to be a better situation to use a reduced dose, but the comment "everyone builds up resistance to BTK inhibitors at some point." is hardly helpful, when we have an increasing amount of actual data quantifying that risk. Some early patients now have over a decade of CLL management from ibrutinib. Also, we know that the newer, non-covalent bonding BTKi drugs generally work when resistance develops to the covalent bonding BTKis.

Taking CBD oil complicates what could be happening, because of the two mechanisms involved and there's no available data.

1) As you've raised, CBD oil contains strong CPY3A inhibitors pubmed.ncbi.nlm.nih.gov/213... which increase the half life of drugs reliant on CYP3A liver enzymes so can also increase drug side effects

2) There's evidence that cannabinoids counter the relocation of CLL cells into the blood, so that they move back into the nodes: healthunlocked.com/cllsuppo...

It's a pity that you can't find something for your pain that is less likely to interfere with your CLL treatment than CBD oil.

Neil

[naddude in reply to AussieNeil]

Hi. Neil

Those articles are very convincing. I will be discontinuing the CBD. For the minimal amount of relief it doesn’t appear to be worth the risk.

Thanks again. I hope you are feeling better as you have had quite a journey yourself!

Best wishes.

[Sushibruno in reply to AussieNeil]

How do we know if we have a low or high tumor burden?🤔😏

[AussieNeil Partner Administrator in reply to Sushibruno]

Low ALC (WBC), small nodes, spleen normal, other blood counts around normal = low tumour burden

High ALC (WBC) or enlarged nodes/spleen, low haemoglobin, platelets and or neutrophils = high tumour burden

[Sushibruno in reply to AussieNeil]

Then I have a high tumor burden with wbc at 187?

[Sushibruno in reply to Sushibruno]

I also have alt of nodes all over my body🤔.

[AussieNeil Partner Administrator in reply to Sushibruno]

Lower than it was plus CLL cells don't do much of anything in the blood. They can quickly melt away if you ever get around to needing treatment .

[Sushibruno in reply to AussieNeil]

🙃🥳🥳 thanks Neil..

[naddude in reply to AussieNeil]

Hi again Neil: I spoke with a senior pharmacist at BC Cancer (our cancer agency) and she said it is still relatively unknown what the effect would be with respect to the drug (Acal and CBD) interaction and in theory since they are both inhibitors as opposed to inducers it shouldn't be a problem but after hearing about the trial referenced in ASH you referred to, she thought it would be best to err on the side of caution and not combine the two drugs. Here is the link to the drug Monogram and in particular page 5 footnote. bccancer.bc.ca/drug-databas...

[AussieNeil Partner Administrator in reply to naddude]

That was an excellent decision to check with the senior pharmacist at BC Cancer. It's good to see the monograph footnote confirming my point 1 about the CPY3A inhibitor issue of mixing CBD oil and acalabrutinib. I hope that you see an improvement in your side effects now.

Neil

[naddude in reply to AussieNeil]

Neil:

Actually, I have noticed a small but noticeable reduction in side effects but sadly an equal amount of increase in the pains that the CBD was Rxed for. But I think it is wise to stop the CBD for now until more is known. I am very grateful for your thoughtful and well-informed input and wish you well in your own CLL journey!

Cheers

[AussieNeil Partner Administrator in reply to naddude]

The only CLL specific uses for CBD, for which reasonable evidence exists, are nausea and pain. Some clinicians even question whether CBD is better than what's usually offered for these symptoms. That said, everyone is different and you may be a case in point where CBD does work better for you than the usual offerings. Adequate pain management can be very challenging to achieve in some situations unfortunately. Is it worth revisiting this with your doctor?

Good to know that you've noticed a slight decrease in side effects. I wouldn't be surprised if you observe a greater observable reduction over time.

Neil