hi everyone
Unless I’m mistaken, people on ibrutinib become resistant at different times. Some can tolerate for decades and some for 5 or 6 years let’s say. I’m wondering if anyone knows of trials that have required participants not to take a dose every day ? I was wondering if by taking less ibrutinib would it possibly extend the time before resistance or tolerance sets in ? Thanks
Gettin,
The STATIC trial in the UK is investigating stopping the Brutinib after reaching 6 years of continuous treatment and comparing it to the other arm continuously taking it.
When the arm if the trial that stopped treatment needs treatment again, the Brutinib is restarted to see if it works again.
The Darwinian pressure to form a mutated clone may be reduced versus continuous treatment.
However, deep remission is rarely achieved with single agents but is worthwhile to investigate.
Jeff
I am gonna look up the trial and see where they’re at - much appreciated
Further to Justasheet1 's reply, the number of doses per day is influenced by the blood serum half life, while the amount taken is determined in phase 1 clinical trials. These parameters are set to optimise effectiveness with acceptable toxicity. Experience with BTKi drugs like Imbruvica/ibrutinib, has shown that it may be possible to reduce the dose once the CLL tumour load has been significantly reduced, but an early ibrutinib trial found that only 10% of participants reached uMRD after 4 years. That increased to 15% after 10 years. cllsociety.org/2024/05/pati...
The risk if the blood serum level drops too low from reducing the dose or over extending the time between doses, is that some CLL cells can escape inhibition and divide to produce resistant sub-clones.
Neil
Hi Gettin,
I thought I would share my experience with you. I started my clinical trial in 2019. They were comparing Ibrutinib and Obinutuzumab vs Ibrutinib, Obinutuzumab, and Venetoclax. I am on the 2 arm . Three years into the trial I developed severe neuropathy and joint pain……going from being very active to needing a walker to get to the bathroom in just a matter of a few weeks. To make a long story short, I did consultations with orthopedics and the neural surgery department at Duke University all coming up empty handed as to what the cause of problems were. I relayed all this information to Mayo’s where they reduced my dosage from 420 mg to 280mg and in a short period all neuropathy and joint pain dissipated. It is interesting to note that in that time frame of nearly 3 years I have achieved UMRD on the 280mg.
Not sure there is any meaning in this as I am only one individual. And I am certainly not advocating for drug reduction. Just sharing my experience. I wondering if there are any studies out there on drug dosage/body weight and whether or not after being on a drug for extended period of time with normal blood work ups, that a reduction in dosage would be better than complete stoppage of the medication. I can see resistant strains developing either way. Anyway, that is my story for whatever it is worth. Wishing each and everyone of you much success in this interesting journey
Varney
Varney, there were at least 3 trials on ibrutinib dose reduction done at CLL research centers within a few years of it being used for CLL management. Clinicians were concerned at what was seen as an unacceptable percentage of patients discontinuing taking ibrutinib, due to intolerable side effects for them. Frustratingly, none of those study reports reported patient weights. Since then, more data has accumulated showing that some patients are able to keep their CLL managed on a reduced dose, but it's something that patients should only do after discussion with their specialist, so closer monitoring can be provided.
Thankfully, the approval of second generation BTKi drugs with significantly fewer off target effects, means that people who shouldn't try dose reduction, may have the option to switch to these alternatives, e.g. acalabrutinib/Calquence and zanubrutinib/Brukinsa. Specialists generally recommend staying on ibrutinib if the patient is tolerating it.
Neil
Many thanks for getting back. It was my thinking that after the tumor load has been greatly diminished, a lower dosage might be given as a maintenance dose without initiating an early resistance response. I realize this maybe faulty reasoning given the short 1/2 life of Ibrutinib, plus the fact determining an individual's safe maintenance dosage would be hard to ascertain. All in all, it is a moot point since most people are on the newer BTKi drugs which offer significantly less side effects.. So thanks for all your valuable information and for all the time and effort you put into this site helping so many people. Take care.
V
The doctors at MD Anderson explained to me that taking a reduced dose of acalabrutinib could actually increase my chances of developing BTK resistance. I could never tolerate the full dose of ibrutinib, and took it for 3 years before starting acalabrutinib.
Nice to have MD Anderson doctors confirming my earlier reply, thanks, healthunlocked.com/cllsuppo... where I said that "The risk if the blood serum level drops too low from reducing the dose or over extending the time between doses, is that some CLL cells can escape inhibition and divide to produce resistant sub-clones." Basically cancer develops because some of the DNA self checking and correcting mechanisms after cell division have failed, so the normal apoptosis (programmed cell death) mechanisms that are supposed to be triggered in this situation don't occur. Clones are hence more likely to accumulate more DNA errors and when those provide resistance to the treatment drug, the CLL becomes refractory to that treatment therapy as the resistant clone grows.
Neil
So Neil if the gent above mentioned a dosage study it sounds like you would be surprised if there were new findings? Given that as you say there have been several studies conducted already ?
As Varney said above healthunlocked.com/cllsuppo... "All in all, it is a moot point since most people are on the newer BTKi drugs which offer significantly less side effects." There isn't going to be any interest in doing further studies when better alternative BTKi drugs are becoming available. I think the only remaining advantages ibrutinib has over the newer drugs, are the additional years of patient experience and the off-target activation of T cells and reduction of T-cell exhaustion not seen in other BTKis. Ibrutinib did have the advantage of only needing to be taken once per day, but zanubrutinib/Brukinsa can be prescribed once per day.
Neil
The UK only STATIC trial mentioned before should have been called stutter. After six years of V+I without reaching uMRD4 on UK FLAIR trial, one arm "clinical need" will continue on continuous Ibrutinib. Two other arms are randomised for patients that did reach uMRD4 but after 3 years and were thus still on V+I at 6 years. One arm will continue on continuous Ibrutinib. The other will halt Ibrutinib until CLL is detectable, then resume Ibrutinib until again at uMRD4.
cancerresearchuk.org/about-...
There was no statistically significant difference in overall response rate (ORR), clinical benefit rate (CBR), median progression-free survival, and overall survival (OS) between the dose-reduced and standard-dose groups (SDGs). These results extended to all patients, irrespective of whether the modification was made within three months of treatment initiation, or later.
pubmed.ncbi.nlm.nih.gov/306...
Two very well known names on this report but n=11:
A pilot trial evaluated stepwise reduction of ibrutinib dose in patients with CLL from 420 to 280 to 140 mg/d over three 28-day cycles.
BTK occupancy, signaling, and biomarker data show that a lower dose of ibrutinib after 1 full dose cycle is enough for biological activity.
ashpublications.org/blood/a...
Dose reductions and holds are frequent in real world.
Started imbruvica 10/2018. On 12/2018 my count came to 750,000!!! Dose reduced to 280 for 2 years while counts came to normal values ~7,500.
I suffered from side effects like nails, joint pain, etc.
And i decided to cut the medicine even further.
For the last 3 years i take 210mg (half a pill).
My counts are within limits. No change. Side effects almost none.
I did not know you could cut the 280 dose in half and it would equal 210. I have been on Ibrutinib 280 for five years, In the 4th year my blood pressure became a problem and still is, my regular MD has changed my prescription several times with no improvements. Now I just started having bone pain and a lot of coughing. I had X-rays and my lungs are clear. I believe my dose should be lowered.
I was on it for eight years. My understanding is that it’s regardless of dosage there will eventually be a time when it stops working. It’s great, but it’s not a cure….that’s in the future 😉
Starting Imbruvica today!
Neutropenia/low ANC and Ibrutinib/BTK Inhibitors 
stopping ibrutinib after 5 years
Remission and temporary discontinuation of Ibrutinib
Imbruvica adverse effects. 
