I'm repeating in full, this very important advice posted by Dr Rick Furman in the CLL/SLL Groups.io forum, due to the risk of incorrect interpretation from a paper which Dr Furman says should never have been accepted for publishing. Dr Furman is well known for his early move to 'non-chemo' treatment of his CLL patients and would be among the most, if not the most experienced CLL specialist prescribing Ibrutinib for his CLL patients and was involved with the early Ibrutinib clinical trials. His opinion should be seriously considered.
The bottom line is DO NOT REDUCE YOUR IBRUTINIB DOSE WITHOUT THE GUIDANCE OF YOUR CLL SPECIALIST.
"Re A pilot study of lower doses of ibrutinib in patients with CLL #abstract
From: Rick Furman
Date: Thu, 27 Sep 2018 21:49:12 ACST
This is a very dangerous and incorrect publication that should never have been accepted for publication. We have always known that the minimum dose of ibrutinib in order to fully inhibit BTK is 2.5 mg/kg daily. The dose of 5 mg/kg was selected to guarantee some room for error in order to not under dose patients. The 420 mg dose was then selected to provide adequate dosing to almost everyone. I do dose reduce patients frequently, but always remain safely above the 2.5 mg/kg dose.
The ability of ibrutinib to bind BTK is not dependent upon the amount of BTK present (as stated in the paper), but on the concentration of ibrutinib in the serum. This concentration is going to depend upon dose and weight of the patient. The paper does not report the weights of any patients. Theoretically, if this were a population of 60 kg adults, there would be every expectation that these would be the results. One might assume that since the impact of weight on serum concentration is a basic PK principal that was ignored in the paper that there was bias in enrolling patients on the trial.
Additionally, the peak ibrutinib level, dependent upon body weight, also translates into the total exposure and time to a plasma level below which adequate inhibition will be achieved, that more rapidly proliferating cells might survive and proliferate during the times ibrutinib’s concentration is below adequate levels. This would be expected from deletion 17p and 11q CLL. The paper indicates that there were no 17p nor 11q patients included in the analysis, but chance. One would have to assume this was also biased referral as no physician would refer a high risk patient to potentially be under dosed.
While I certain appreciate, and experience every single day of my life through my patients, the cost of ibrutinib, there is no greater cost than failing to adequately treat a patient and cost them their life. Subtherapeutic dosing will likely lead to resistance, which is of no value to anyone. I implore everyone to not take chances with their health.
Rick Furman, MD
(My emphasis)
Here's the paper referred to by Dr Furman: bloodjournal.org/content/ea... just so that we know what he is concerned about. Again, do not self experiment. As Dr Furman says "DO NOT TAKE CHANCES WITH YOUR HEALTH!"
Basically the paper reports the results from a group of patients which are not representative of the wider population taking Ibrutinib and because of that unrepresentative selection, extrapolating the findings to the wider Ibrutinib community could result in unnecessary fatalities from inadequate CLL management.
I've previously been criticised for my stand against self experimenting with Ibrutinib dose reduction. Perhaps the above words from Dr Furman, who has been significantly involved in championing Ibrutinib use for CLL and arguably has the largest experience with its use (he no longer uses chemo treatments to my knowledge) can bring home how very seriously this issue needs to be taken.
Dr Furman is not the only doctor concerned about the risk of reducing your dose of Ibrutinib. Dr Jeff Sharman, another CLL specialist involved in early Ibrutinib clinical trials, notes that "When you swallow a pill of Ibrutinib it gets into the bloodstream and either quickly binds to the BTK protein or it gets eliminated from the body. Within just a few hours of taking a pill there is virtually no free drug in the blood. Instead, it is all bound to the BTK protein - completely shutting down that signaling pathway until the cell makes more BTK. This is very different than most oral drugs where we are trying to make sure the levels are still high enough right before you take your next dose.
:
You can then ask how many people have how much of their BTK protein "occupied" or inhibited by ibrutinib at different doses. If we set the bar pretty low at 75% occupancy, any dose above 280mg (two pills) is pretty effective. 96% of patients achieve that level of occupancy at any of those doses. that may seem good but unfortunately, that low bar means that the pathway is only 75% "turned off." It is more like a dimmer switch on the lights instead of an on/off. 75% occupied means that there is a lot of room for cells to try to discover ways to become resistant. If you set the bar much higher at 90% occupancy, the standard CLL dose of 420mg (three pills) can accomplish that in 86% of patients but only 75% of patients who take two pills and 53% of patients taking one pill. In short - dose matters. You get more complete pathway inhibition with higher doses of ibrutinib.
:
I also worked on another BTK inhibitor that is no longer in development called CC-292. We never really got it to behave as well as ibrutinib until we started giving it to patients twice daily."
cll-nhl.com/2015/05/take-yo...
Addendum from Dr Rick Furman regarding whether to start with a lower dose of Ibrutininb - 14th Jan 2019 (again from the CLL/SLL Groups.io list, with my emphasis)
"Ibrutinib: starting with low dose ?
From: Rick Furman
Date: Mon, 14 Jan 2019 09:47:15 ACDT
This is a very important subject that we have visited several times and is of great importance for patient well being. BCR antagonists, likely ibrutinib, acalabrutinib, idelalisib, all inhibit their target kinase at a level that is dependent upon their concentration in the serum. Currently, most agents are dosed well above the necessary level to achieve 100% inhibition. The critical question is that we don't know what level is the minimum level required for therapeutic effect. In the absence of knowing that 80% inhibition is still effective, we always target 100%.
We do have some suggestion from the children who are missing BTK (X-linked agammaglobulinemia) that you need to loose 85% activity before you develop the immunodeficiency. But whether this translates to CLL therapy is unknown, as the children are missing the whole protein, while patients will just have kinase inhibition. The importance is seen in the fact that the children with no BTK develop no B cells. Our patients still do develop normal B cells and have some normal immunoglobulin production.
The phase I study of ibrutinib demonstrated complete inhibition of BTK at a dose of 2.5 mg/kg. In the conversion of flat dosing, many patients will be far higher and perhaps a few lower than necessary. A 420 mg dose, should be adequate for anyone up to 360 lbs. Likewise, a 140 mg dose should be sufficient for a 120 lbs patient. The dosing is dependent upon concentration of the drug, NOT the number of cell or molecules being inhibited, and therefore it is not correct to believe a lower dose is possibly effective as maintenance. The paper published looking at lower doses does not include any information on body weight and therefore does not indicate any information on the potential loss of efficacy.
Some toxicities are dose related (diarrhea, bruising) and will respond to lowering the dose. If the dose is lowered to a level where efficacy is compromised, that would indicate the need for another therapy. For other toxicities, like atrial fibrillation, we don't have any indication that they are dose related. So attempting a lower dose is still potentially exposing a patient to the adverse effects of ibrutinib without the therapeutic benefits. This is the worst case scenario.
We have many excellent therapies now available to us. It is important that they be used correctly.
A modification of an important physician adage, "The first most important thing for a physician is to do no harm. The second most important thing is to not deny our patients effective therapies".
Rick Furman, MD"
Then there is Dr Furman's further update of posted in response to Daniel Gianola's posts to CLL/SLL Groups.io on a clinical trial reported at ASH2018 and completed in January 2019, investigating lower doses of ibrutinib:
clinicaltrials.gov/ct2/show... , referencing:
ncbi.nlm.nih.gov/pubmed/302...
"Re: Is ibrutinib-based therapy the preferred initial treatment for all patients with CLL?
From: Rick Furman
Date: Mon, 15 Apr 2019 07:07:06 ACST
I am very troubled by these data and the idea behind this trial. We know that the dose necessary for full BTK inhibition in CLL is 2.5 mg/kg. Based upon this, 420 mg would be the dose for a 168 kg adult. The rationale for fix dosing and guaranteeing no one is underdosed, drove the decision to dose at 420 mg. Most oncology drugs are dosed at the maximum tolerated dose. We tested doses of 12.5 mg/kg in the phase I trial without any dose-limiting toxicities. The decision was made to use the lower dose based upon what we saw scientifically and in a clinical trial testing 420 mg versus 840 mg daily.
I do not understand the data cited that gives rise to this clinical study. When we discuss the kinetics of enzyme inhibition, it is based upon a concentration of the inhibitor, never the concentration of the target. The rationale for the study cites a drop in the number of targets as justification for the lower doses. Even though ibrutinib is a non-reversible inhibitor, its ability to bind its target is completely based upon its concentration and the IC50 (inhibitor concentration for 50%) of the enzyme.
The IC50 for ibrutinib on BTK is 0.5 nM. (There are many differences between cell free and non-cell free assaying. The 0.5 nM is cell free, so the likely needed concentration is going to be higher.) In the paper, the authors cite the mean ibrutinib levels were 22, 22, and 8 nM for 420 mg, 280 mg, and 140 mg respectively. The authors show, in the nine patients they studied, that the 280 mg and 420 mg doses did not achieve different concentrations in the blood. This would support the fact that for these 9 patients, 280 mg was sufficient. But at the lowest dose there was a very significant fall off of the mean serum levels, and thus everything depends upon whether the 8 nM is still sufficient to inhibit BTK. This is also the mean, and we don't know what the time of exposure that is required to achieve full inhibition.
With this being said, it seems worrisome to take a chance with dosing a drug that is potentially saving one's life. The authors publish on flat dosing without including patient weight, so it is not possible to generalize these data. We do believe subtherapeutic dosing is a recipe for developing resistance. It would seem prudent to me to follow recommend guidelines, that are proven effective and only dose reduce for toxicities, which are, in essence, and clinical read out of dose level.
Rick Furman, MD"
1st November 2019 Update
Today I couldn't find the paper in Blood that concerned Dr Furman, so it may have been withdrawn.
These recent community post on this topic of Ibrutinib dose reduction may also be of interest:-
Do side effects reduce with a lower dose?
healthunlocked.com/cllsuppo...
General discussion
healthunlocked.com/cllsuppo...
Neil
Last updated 25th August 2021
