MUST READ for those on Ibrutinib/Imbruvica - concerning advice in pilot study on lower dosing - incl. danger of starting with a lower dose

[AussieNeil]

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

[Oleboyredw-uk]

Thank you for sharing this really important item Neil.

As someone who has had Ibrutinib AND I’m 11q del it is close to home. So much so that I did the maths for myself. Comfortably safe... phew.

best to all, rob

[AmericanRonin]

To add some weight figures to this, that would mean 420mg/day at the “extra safe margin” of 5mg/kg. matches a patient who is 84kg. or 184.8 pounds — with a risky rock bottom minimum dosage of half that amount.

[Newdawn Administrator]

Important warning Neil because I know how concerned we’ve been on here when a few people have mentioned reducing their dosage. It helps to understand the mechanics behind it.

Newdawn

[BettinaB]

No-one should reduce their dosage on the basis of a preliminary study and without their doctor's advice, that much is clear. Still: this is a peer-reviewed journal, and note some of the co-authors of the paper: Keating and Wierda. These are not young upshots. Again, obviously this paper is no basis for experimenting with one's Ibrutinib dose, but I guess I resist the idea of Dr Furman telling everybody what "the truth" is. Thanks for sharing, Neill, I fully understand where you're coming from. I'm commenting as someone who regularly deals with academic controversy as part of their job. (And, once more, I am not making a plea for dose reduction. But I think I've mentioned this... ; ))

[AussieNeil Administrator in reply to BettinaB]

The abstract concludes "Clinical efficacy of lower doses needs to be systematically evaluated". No argument there and indeed Dr Furman has highlighted criteria critical for that systematic evaluation. Academic controversy can be a excellent means of improving the robustness of investigations and for the sake of the CLL community, I hope Dr Furman's feedback is incorporated into a larger trial, where patient weight is recorded and also reasonably represents the patient weight distribution of patients and also the range of genetic markers in those prescribed Ibrutinib.

It is also worth noting that all 14 authors are from M. D. Anderson and indeed there are some well respected CLL specialist expertise among them. Ironically there are more authors listed than patients who completed the trial of just 9 patients. (Under the Figures and Data tab, the Supplementary Materials document provides an analysis of how many patients need to be included in the trial to provide statistically valid results, concluding 12 would be sufficient, yet only 9 completed the trial.)

I don't know how involved M. D. Anderson researchers were during the early days of Ibrutinib research. FCR was developed at M. D. Anderson and it is worth bearing in mind that Dr Furman and M. D. Anderson have professional differences regarding continuing the use of FCR, with M. D. Anderson arguing for its continued use in patients with a good probability of effectively achieving a cure, while Dr Furman doesn't use it due to his concerns about the long term implications of DNA damage.

Neil

[PaulaS Volunteer in reply to BettinaB]

hi Bettina,

Thanks for your post. It does disturb me though, that Dr Furman (a renowned CLL specialist), is calling a publication "dangerous and incorrect" which has fellow CLL specialists Dr Keating and Dr Wierda amongst its co-authors!

Maybe I've been naive about these things, but I would have hoped that different specialists would consult with each other rather than write such a damming public response to something like this. Or have I misunderstood the significance of having a long list of names as co-authors? Keating and Wierda are towards the end of the list of authors - could it be that they didn't actually have much to do with the writing of it?

Very interesting to hear your take on it, Bettina, as someone who is more used to academic controversy.

Paula

P.S. Thanks AussieNeil for the original post.

[BettinaB in reply to PaulaS]

Hi Paula,

Yes, the fact that their names appear towards the end of the line means that they've been less involved than thise nearer the front, but still they've put their name to it - this means they approve.

It is very unusual for Dr Furman to take this kind of controversy to a patient forum, and in extremely strong language at that. I do have an opinion on this - but many people on the forum speak very highly of Dr Furman. I've never met him, and it is highly unlikely that I ever will, so I'm not qualified to comment

[Awksom]

Unfortunately the high cost of ibrutinib, especially in the US, can lead people to take such risks. Thanks for the warning.

[Name-1]

I have only 40 kg.?

[SZUR]

Hi Neil if Dr R.Furman doesn’t use Chemotherapy what is he using: Imbruvica and? Stasia

[AussieNeil Administrator in reply to SZUR]

Mainly Imbruvica, plus I presume some on clinical trials and presumably Idelalisib if Imbruvica resistance develops. lankisterguy would know better than me.

Neil

[SZUR in reply to AussieNeil]

Thank You if I develop ibrutinib resistance I will go to see him in NY.Stay well StasiaURos

[Cllcanada Top Poster CURE Hero in reply to SZUR]

Generally the order recently mentioned when failure occurs is Imbruvica (ibrutinib), venetoclax and idelalisib. This was a video in the past few weeks... can,t remember who... Dr. O'Brien or Dr. Wierda

~chris

[snaillady in reply to AussieNeil]

Venetoclax as well I believe

[Indolent]

So, even with Dr. Furman's revised conservative number of 5mg/kg or 2.27mg/pound, a person who weighs 120 pounds would need 272 mg. While a great number of folks have not seen 120 pounds in a long time, there are certainly some that do. So if they stuck with the standard 420 mg dosage, they would be severely over his very conservative guideline. And not only would they be well over his guideline, they would be more likely to experience side effects as well.

As always, no one should experiment with their medications without their doctor's oversight. What would be helpful here is for this issue to be properly studied with all the rigor and discipline of a clinical trial. Sadly, this is unlikely to happen because of the lack of support from the drug companies who control the financial resources for most clinical trials. They are not willing to venture into any realm that would justify using less of their product.

[sandybeaches in reply to Indolent]

I am very interested in reading about Dr Furman's doseage guidelines as I am barely over 120 lbs and if requiring treatment with Ibrutinib in the future, would be very concerned about having side effects from the higher doseage most patients are on.

Perhaps if more awareness of the dose reduction safety net figured in Dr Furman's dose recommendations for patient weight, more countries would be willing to pay for the drug ( ??? ). Just a thought, though.

Sandy Beaches

[Miller1960 in reply to sandybeaches]

Sandy beaches my thought exactly. I'm 112 pounds, I want Ibrutinib to work without the extra toxicity.

[Lola69]

Great link Aussi! Merci!

[MsChief]

Neil - Thank you for sending Dr. Furman’s position on Ibrutinib dosing. As an 11q patient with significant s/e at the outset of taking the drug, of course I am concerned. I currently take 140mg 4 days a week and 280mg 3 days a week. My numbers are WNL. I’m 75. Weighing S/E (which I have anyway) vs longevity is a dicey choice.

[lukejensen27]

I’m in the Ven plus Ibrutinib Clinical Trial at MD Anderson with Keating as my Dr. I had been having really bad joint pain and he recently reduced my Ibrutinib dose to just 1 pill. I was worried to do this but he insisted that just 1 pill is more than enough to block the BTK. I don’t know if only having .2% CLL left in my Bone Marrow makes a difference with lowering the Ibrutinib dose?

[Hoffy]

Dr. Furman is great!! Very smart and detailed.

[AdrianUK]

The company got a lot of stick for introducing “flat pricing” for the various dose strengths. In my view they did the right thing and perhaps should have had flat pricing in the first place. Definitely don’t want unscrupulous dose reduction with a view to saving money for insurance companies that’s for sure.

[Wroxham]

Thanks AussieNeil.

[kimiD]

Thanks for the post Neil. Dr F, and the co-authors from MDA are all highly regarded in the CLL community. While I agree that one should not attempt a dose reductions without the advice of their specialist, I do think in some cases it is appropriate. Dosing by weight should not be the only consideration. Many people are sensitive to meds, metabolize them differently, regardless of their weight. There are tests now that can predict medication efficacy based on how they are metabolized. We are all different, and what works for one person could be disastrous for the next. By closely monitoring labs while reducing the dose of ibrutinib, problems can be addressed accordingly. I'm strictly speaking from personal experience here, but on the full dose of ibrutinib I could barely function. I feel like my old self most days on the reduced dose, and have monthly labs to stay on top of any changes. Even though these drugs were studied extensively in clinical trials, they are new enough that those of us on them are finding unreported side effects and response times. I guess what I'm trying to say is there is not a one size fits all calculation for what works.

Wishing wellness upon all of us.

Kim

[Miller1960]

Thanks for the post AussieNeil very informative.

[Wroxham]

Thank you Neil for your reply. Remember downloading and reading now.

Older age creeping up.

Sue

[AussieNeil Administrator]

Frustratingly, two years on and we STILL don't know crucial dosing information

Review Finds Questions Remaining About Ibrutinib Dose Modification in CLL

ajmc.com/newsroom/review-fi...

In their search of medical literature, the authors found a total of 29 studies to review; 14 were clinical trials and the remaining 15 were “real-world practice” studies.

The authors’ analysis showed similar discontinuation rates among the clinical trials and real-world studies (32% and 33.5%, respectively). One difference, however, was the cause of the discontinuations; in the clinical trials the more common reason was CLL progression, while toxicity was more common in real-world settings, they report. In the largest of the “real-world” studies, the most common toxicities were arthralgia, atrial fibrillation, and rash.

Current dosing recommendations suggest a reduction in ibrutinib dosing for patients who also require a moderate or strong CYP3A inhibitor.

The authors note that physicians may see this an opportunity for cost savings, by routinely placing patients with ibrutinib on a lower dose and pairing it with an inexpensive CYP3A inhibitor.

“However, the safety of this approach, the long-term tolerability, and the clinical efficacy of ibrutinib therapy in this context has not been formally evaluated,”

More broadly, Gabrilove and co-authors also report that prolonged reductions or interruptions in ibrutinib dosing appear to worsen outcomes in patients, “though it remains unclear whether it is due to the patient’s inability to receive the standard dose, or whether it results from the dose modification itself.” Those findings are not universal, however. Some studies have suggested dose reductions do not negatively affect treatment efficacy. Such findings are controversial, the authors report, but also serve to highlight the significant questions remaining.

At present, the authors suggest sticking with the best practice of reducing ibrutinib based on concomitant use of CYP3A inhibitors or due to patient liver disease comorbidity.

“Based on this review, these dosing recommendations, as well as clinical judgment, should guide dosing parameters in an effort to optimally balance clinical therapeutic efficacy and safety,” they write.

[CLLerinOz Administrator Volunteer]

A recent article published on 23 August 2022 in the Blood Cancer Journal provides an interesting perspective on the question of medication dosages and how they are determined through clinical trials.

Titled, "Determining drug dose in the era of targeted therapies: playing it (un)safe?", it explores the traditional toxicity-driven 3 + 3 phase I trial design that is still dominating in the era of targeted therapies. "While pharmacodynamics biomarkers were studied in most of the reviewed trials, these biomarkers did not weigh heavy when determining the phase II dose. If the pharmacodynamic biomarkers had been used more stringently to guide dose selection, the recommended dose would in the majority of cases be set lower than the currently recommended dose. As dose reductions can lower treatment-related and financial toxicity that patients and health care systems experience, and do not result in inferior outcomes, we believe it is overdue to let the targeted effects of targeted agents guide dose selection."

The authors explore whether a change to the traditional 3 + 3 phase I trial design may be more appropriate in an era of targeted therapies, especially for ones which are designed for long term use.

"In the traditional 3 + 3 phase I trial design [3], initially used to study cytotoxic agents, dose-limiting toxicity (DLT), rather than pharmacodynamic biomarkers, is used to guide dose escalation (Fig. 1). Three patients are first enrolled to a specified dose cohort. In the absence of any DLT, three additional patients are enrolled to a higher dose cohort. If one patient in the cohort develops a DLT, three more patients are enrolled to the same dose cohort. If no additional patients develop a DLT, that dose is defined as the maximum tolerated dose (MTD). If two or more of the six patients develop DLT, the MTD has been exceeded (Fig. 1). Notably, the MTD is determined already in the first cycle of therapy. Molecularly targeted therapies require longer treatment regimens than cytotoxic agents, and treatment emergent toxicities may appear later in the treatment course. While alternative phase I designs have been proposed for novel agents (Box 1) [4,5,6], the 3 + 3 design is still commonly used in chronic lymphocytic leukemia (CLL) trials (Table 1)."

This is a discussion worth watching as it could have an impact, not just on trial design but on the way treatment dosages might be prescribed for different types of patients in the future.

Skånland, S.S., Tjønnfjord, G.E. Determining drug dose in the era of targeted therapies: playing it (un)safe?. Blood Cancer J. 12, 123 (2022). doi.org/10.1038/s41408-022-...

3 + 3 Phase I Trial Design