A number of people in the CLL forum seem to have the same problem. That is, they can’t tolerate 400 mg of venetoclax. However, they seem to do fine on 200 mg or even 100 mg including ALC under 1.
It seems to me that it is a good research question to ask whether anything is gained by increasing the venetoclax dosage when it only lowers neutrophils, platelets, and hemoglobin rather than lymphocyte count. I guess one would need to do flow cytometry to see if the tumor count decreases even though the ALC does not. Does anyone know if there is any research on this?
Written by
profrich
To view profiles and participate in discussions please or .
I can answer this in general. Most all drugs go through phases of clinical trials. Part of phases 1 and 2 of the trials are to find the safest and optimum dose of a drug, balancing efficacy and side effects. Typically this results in a recommended dose for everyone.
This is where your doctor, or learned intermediary, steps in. He decides what dose is best for you. The safest bet is for the doctor to use the dose suggested on the label. That said, a doctor might determine based on his or her clinical experience, that his 95 lb female patient should get a slightly lower dose than suggested and his 400 pound sumo wrestler patient a higher dose.
Doctor’s can reduce the optimum dose to deal with unwanted side effects. It might be a drug is 25% less effective at a lower dose, but that’s worth it to overcome intolerable side effects.
So back to your question. Presumably phases 1 and 2 of the clinical trials venetoclax has been through have already balanced the dangers of dropping neutrophils with the dangers of taking a sub optimum dose of venetoclax which might not be enough to do the job. Whether a higher or lower dose is better for you is a question for your doctor. Some doctors are more willing than others to deviate from recommended doses.
It really is unchartered territory. Any individual doctor may have a different opinion. I think it is more than weight. I seem to require a much smaller dosage of other medicine to obtain a good result (e.g. blood pressure meds) than most others.
E.g. in the first big calquence study, patients doing 100 mg a day did fine from the beginning. However, Byrd (first author) told me they were switched to 200 mg after I think about 6 months. So, we don't know how they would do eventually.
I don’t see it as uncharted so much. The trials determined the optimum dose. Venetoclax and ibrutinib are relatively new drugs, so experience over time and retroactive studies might result in dose modifications. I guess in that sense you could say uncharted.
I agree weight is not the only reason one might modify a dose. That’s why doctors are called learned intermediaries by the pharmacy industry and why doctors are free to determine on their own if someone needs a dose reduction. There are any number of reasons a doctor might find the recommended dose should be altered, up or down, for a particular person.
I think most doctors will keep a patient at the recommended dose on the label so long as they can tolerate it. I approached my doctor about reducing my ibrutinib dose once and his response was that I should stay at 420 (full dose) to get maximum benefit. If I developed intolerant side effects, then we might reduce the dose. There is risk in reducing dosages of any med, typically the risk is reducing a dose can lessen the efficacy of a drug.
Insofar as the impact venetoclax has on neutrophils, I am sure that was a consideration in the dosing phases of the trials. Sure, a lower dose might work for you or me and lessen side effects. It might also make the venetoclax sub therapeutic. That’s why I think in general the strategy for doctors is to keep us on the recommended dose unless there is some reason, typically bad side effects, that warrant a reduction.
These are questions I have too and wonder if parameters of the clinical trial I’m on (I&V) may influence clinical decisions. I’d be concerned to see my neutrophils dropping along with the ALC and intend to discuss this with the specialist next consult.
Obviously the BMB will heavily influence decision making, as it should but I’m interested in how the trial accommodates reduced dosage should it become necessary.
However, so far so good with the dosage (side effects excluded of course!).
My ALC was the same on 400 mg as 200 mg (about .8), but my neutrophils and hemoglobin were significantly lower. So, I wonder if the 400 mg had any additional benefit.
My doctor (who is great in many ways) seems to push towards the recommended dosage based on the clinical trials no matter what. I had to quit venetoclax for a while I think because I went back up to 400 mg when I seemed to do well with 200 mg.
There are people in this forum who dosages were reduced in the trials and did well.
I think we all want to be on the minimum dose necessary to do the job of any medication, particularly those meds that have side effects. I think our doctors want the same for us.
Venetoclax is so new, I don’t know that the data is there yet to help us quantify the risk of a reduced dose. The fact some “did well” on a reduced dose doesn’t tell us enough. We’re there those also who did not do well? What does do well mean in the long run? Will those who did get remissions on lower dose relapse faster than those who took the full dose.
I think it just goes back to the individual and their doctor. Cll treatments are not one size fits all. This is where it’s great to have a Cll specialist who can use their instincts to tinker with our meds to get the best recipe for us. I still think the default position for most docs would be to rely on the dose found best in clinical trials unless someone has tolerance issues.
A topic of great interest for all of us no doubt, and not only for venetoclax. I for one would like to feel better and spend less.
A fair speculation here is relative to your doctor's statement "seems to push towards the recommended dosage based on the clinical trials".
For many reasons, the medical community leans heavily toward the go with what you know strategy. In addition, a significant number of patients who state that they are on the 400mg dose are actually still in trials that require the measure.
With the recent approval of venetoclax, we may see a practice of lowering doses in the future as with ibrutinib, however, this too will be primarily the product of research data. I would propose that not many private practice oncologists would be willing to experiment with venetoclax dose variating, as they are less equipped to measure molecular influences.
Given the observation of changing neutrophils, platelets, hemoglobin etc...; We might conclude that there is much more than meets the eye happening at the molecular level than just a tolerability aspect. I think you are correct about the flow cytometry and beyond.
Another point of interest is that unlike ibrutinib which is currently a continuation drug and more in the context of FCR treatment, research is considering venetoclax as a discontinuation therapy. In this way, the drug may need to be dosed at the higher end of tolerability so that long duration remission occurs.
Although I would like to take less and feel better, I am actually looking forward to stopping the drug.
Good point for discussion, "to attain the best of both worlds".
Check out the Prescribing Digital Reference site which gives a rundown on trials and prescribing which includes the lowering of dosage in specific instances for specific cancer situation. I doubt it is definitive because of the lack of clinical experience, but it does give some possibilities. (WARNING: you have to scroll-- use the blue index list and scroll some more--looks to be never ending in its content on V.
CAUTION: Only change your dosage on the advise and consent of your treating physician.
I preface my comment with the perfunctory comment that any dosage adjustment must only be made under the guidance of your doctor. Never try to second guess their advice and put your health in jeopardy.
OK, this being said, it simply defies logic that these powerful drugs are in the "one-size-fits-all" category. The efficacy of these drugs is influenced by the level of saturation per unit of given blood volume. Getting to the proper level is important. A small person has less blood volume than a large person. Therefore, a small person should require a lower dosage to achieve the desired saturation level.
Why do we care about this?
First, there is a concern about side effects. Most of these drugs have undesirable off-target effects. Overdosing is likely to magnify these side effects.
Second, there is a potential cost issue. With just about any prescription drug, the price charged is adjusted based on the dosage. More drug costs more money.
What is needed is a clinical study to verify or invalidate this hypothesis. In the real world, this sort of study is unlikely to ever occur. One may ask why this is unlikely. The reason is simple. Most clinical studies of drugs are funded by the drug companies. And the drug companies have little motivation to reduce their income by selling less of their product. Greed wins again!
I think we all want to take the dosage used on the trials, but for some the side effects are too much. My doctor has previously had my increase dosage to the point where the side effects made me quit. So, we do need to talk to our doctors and others to arrive at a decision.
I think a very important factor is being missed. Historically, there has been no non-surgical treatment for cancer that is curative. It is always assumed that the dosage must be maximized to offer hope for a cure. Therefor phase II trials are designed to identify the maximum tolerable dose.
That is the million dollar question. If hemoglobin is 10 and ANC is 1.2 on 400 mg but normal on 200 mg, is 400 mg tolerable? It seems to me if ALC is the same on the two dosages, we should make the judgement call to say it is not tolerable. However, if ALC is way lower on 400 mg, perhaps call it tolerable.
However, ALC is not really sufficient. We need flow cytometry to see what percent is tumorous.
That is what I was wondering if you meant about tolerable, "lab numbers", rather than physical side affects experienced such as joint pain, nausea, arthalgia etc...
Clearly, we mean both. I had PVCs on acalabrutinib, which were hard to tolerate, but labs were ok. So, I switched to veneteclax. Now my doctor wants me to do both. I am very apprehensive about adding it back in.
I’ve repeatedly asked my oncologist about a reduction in my 420 mg dose of Imbruvica. My numbers are excellent and I’m not dealing with any major side effects. Another oncologist that I visited for a short time spoke of excellent results at 280 or even 140 mg
My oncologist takes the position that if 420 is working ... stick with it. Additionally she says “ the drug maker advises against reducing dose “.... well duh.... pretty simple to figure that out.... reduced dose means less revenue in pharma coffers. That to me explains why the mfgr tried to convert Imbruvica to one size pill 420 mg bs the 140 mg pills. Their rationale... patients can’t figure out how to take multiple pills.
It seems if you do not experience major side effects, it makes sense to stay on 420. The question is how much should you tolerate to stay on a large dosage? As you note, recent studies show people can do well on less. So, it makes sense to drop if the side effects are too much. I am guessing that with the newer drugs (venetoclax and acalabrutinib) people can do well on less too. There just has not been time to find out.
Also, there is the question of drug metabolization, etc. 420 for you may be like 280 for someone else. So, 420 might be your ideal dosage, whereas 280 might be the other person's ideal dosage.
If you ask a room full of CLL experts about reduced dosage for Ibrutinib or Venetoclax, I would predict you will get a wide range of answers.
-
I have heard Dr. Furman explain that he strongly prefers to stay with the full recommended dose for each drug. He will reluctantly reduce dose only when the patient has tried and failed several different approaches to resolving the side effects. When there is no other option, he will reduce dose.
-
Dr. Keating and the team at MD Anderson are on the opposite side of that discussion, so they are running a clinical trial on reduced dose Ibrutinib - (sponsored by MD Anderson- so no drug company involved) , that steps the dosage down from 420 mg to 140 mg over the first 3 months for previously untreated patients.
I’m one of those people who takes 200mg of Venetoclax daily. I’m on the Venice II phase 3b clinical trial which runs for 2 years and is designed to see what effects the drug has on quality of life. I started the trial back in late April 2018 and have been on 200mg since November - so, by the time the trial ends, I’ll have been on that dose for 18 months. So far so good. I’m composing this from Aitutaki in the Cook Islands where I came to celebrate my 72nd birthday. I’m clinically in remission and feeling great. This is my 5th overseas trip since starting the trial and being able to make these trips has a profound effect on my quality of life.
As a retired pharmacist I am of the opinion that if a certain drug at a certain dose has been shown to work in a drug trial- then go with it as the old saying "when you are on a good thing stick to it". But of course there are variations in the way people react to drugs and so if there are side effects of course dosage adjustment may be necessary or another medication. Weight is certainly a factor in determining dose and that is a pharmacist rule. There are mathematical formulae as to working out doses of many drugs, particularly for child doses . If someone is extremley under weight or conversley overweight then dose may need to be adjusted. I am now on 400mg Veneteclax ( as of the last 2 weeks)after ramping up over 5 weeks. Fatigue is my problem and a few twinges of pain, a little nausea but am trying to stay with it. I am due for a complete blood test in about 2 weeks and that will be the guide for me to make sure I am ok on 400mg Veneteclax.. The blood picture should always be the indicator as to whether a drug is safe or causing problems.And I was amazed that when I had my first Rituximab infusion last week my height and weight were measured and then the pharmacist made up the drug there and then before I received it. It was not prepared ahead of time as the dosage was dependant on my individual body.
Yes, they did the same for me when getting rituximab. So, why don't the do the same for pills? I am 5 10, 160 lb (male). That may map to only 300 mg venetoclax.
I weigh less than that and am only 5.5 but I am on 400mg Veneteclax. My specialist is the professor who ran the trial on Veneteclax last year in Melbourne as in case you don't know V is an Australian product ie was developed here. If anyone knows about the maintenance dose of 400mg Veneteclax it is my specialist I have to trust. I think for your weight 400mg is ok of course only if you don't suffer any side effects. I must say I am getting a few side effects but nothing to untoward. Anyway time will tell. Of course us pharmacists ( am retired after 50 years in the game- qualified at 20) I always worry. In my lifetime as one I saw so many "miracle drugs" and years later so many drugs were revealed to have nasty adverse future reactions. I wonder how Veneteclax will be viewed 20 years from now? Still it s one of the best they have at this point in time.
I just reduced venetoclax to 300mg due to low ANC to see if reduced dose will allow the body to correct itself . I've been on venetoclax since about 3 months now
Good luck. I am back on venetoclax, ramping up again. I am currently on 100 mg. Before I did fine on 200 mg and not on 400 mg. This time I will try bumping to 300 mg. I agree with my doctor that, all other things being equal, we should try to go as high as possible. However, I think there is still the possibility that 200 mg for one person might be like 400 mg for someone else, as far as both effectiveness and side effects.
I have a dr that believes in taking the max dosage when doing well, and now the dr wants to see what will happen on reduction. Likely if I do well again dr will want me on 400mg again which means the possibility of effectiveness at lower dose is dismissed by the dr. as just a short term solution
You can always go back up to 400 mg if you do well on 300 mg, but you have to monitor your blood levels closely.
I am asking my doctor to do more regular MRD tests to see if things are improving on 200 mg or 300 mg. The thing is that it is temporarily uncomfortable and even dangerous to play with too high of a dosage. E.g. I was doing okay with BR along with 200 mg of venetoclax (ANC 1.81). I had gone down from 400 mg because things were too low. Because I was now doing okay my doctor had me go back up to 400 mg. I ended up with an ANC of .55 and sores in my mouth. I had to quit venetoclax entirely until I finished the BR.
I will have to ask after my next appointment about possibilities, but I already got the sense that my dr is afraid to have me on reduced dosage after talking today at my appointment. If your dr is willing to do MRD tests that would be great to persuade them to keep the dose lower if all went well. I thought MRD tests were hard to get because so far all I got were BMB, and flow, FISH - the usual tests.
What is you ALC? Is it different when you are on 200 mg versus 400 mg? Mine is pretty low (after BR and returning to venetoclax 0.37), and at least before it did not change when I went to 400 mg (stayed at 0.79); rather my hemoglobin and ANC dropped a lot.
My doctor says low ALC is not a good prognostic indicator. He says all that matters is whether it is in the normal range. However, I questions this. This is why I want the MDR analysis.
neutrophils are now at 744 after 3 months on venetoclax, WBC is 2.6, I didn't get a ALC number (not yet uploaded onto my chart). Two months ago in May neutrophils were 1536 and absolute lymphocytes were 1872 with WBC at 4.0.
I go back to dr in 2 weeks to get another test to see how reduced dose goes
I am not following your decimal points. Neutrophils, lymphocytes, and a few others add up to WBC. so, I am guessing if we are consistent, your neutrophils are now .744 and were 1.536. Yes, I think 1.536 is okay but .744 is too low. I told my doc yesterday that if neutrophils go below 1.25 I will cut back. He agreed. Judging by your numbers, it looks like lymphocytes are now a little lower also. You did not say what they are.
I do stay away from people when I can as a habit now, and I wear gloves all the time. You're right, it's time to get out my masks and wear them again around people!
Content on HealthUnlocked does not replace the relationship between you and doctors or other healthcare professionals nor the advice you receive from them.
Never delay seeking advice or dialling emergency services because of something that you have read on HealthUnlocked.
Confused? Venetoclax 400 v. 300
Opportunity to support the listing of Acalabrutinib and Venetoclax for the treatment of Australians with CLL 
ABSOLUTE LYMPHOCYTE COUNT 
Puzzled
