Pleural Effusion Again ! Should we change from Dasatinib to Imatinib and BCR-ABL redecteded

Hi there

Sorry to hear about the ongoing problem with pleural effusions. I'm nowhere near as knowledgeable as others on this site, but just wanted to give you my two cents' worth as someone who shifted from dasatinib to imatinib:

First, it's clear that your response to dasatinib is excellent with your very low level of 0.0042% (It took me more than 6 years to reach that level). I believe that there can be an association between good drug response and bad side effects as both are determined by your sensitivity to the drug. Have you discussed 20mg? I know that there are several people on this very low dose and it works brilliantly for them, but I guess the pleural effusions may still be a problem given your high sensitivity.

Second, I'm not sure that I agree that "the CML has come back in a short space of time" and that TFR is going to be unattainable. The difference between undetectable and 0.0042% is 42 cells in a million (assuming that your lab where you are is sensitive to MR5). As others on the site will hopefully confirm, doctors only consider TFR attempts to have failed if you lose MMR. In my own case, I tested undetectable only once but was forced to stop all treatment because of bad side effects - the count rose immediately to 0.003% after one month and then to 0.0042% a month later - but it has stopped there for now and dropped back to 0.003%. Yesterday I received my latest result and it is still 0.003% after 8 months. It may be possible to live with very low levels of BCR-Abl for a long time!

Third, it's definitely possible to shift "backwards" from a second generation TKI to a first generation one. I did it when, after a few years on dasatinib, I developed lymph node swelling that got progressively worse, and I was switched from dasatinib 100mg to imatinib 400mg. For some reason, doctors don't seem to be that keen to lower the dose of imatinib. Not sure why - but I read somewhere that dasatinib is over 350 times more potent than imatinib, and the safety / toxicity profile of imatinib is quite low. Imatinib and nilotinib work in a different way to dasatinib as they bind to a different area of the BCR-Abl gene, so it may well be that either one of these will be effective at getting you back to undetected without the hassle of the pleural effusions.

Lastly, my doctor is planning to start me on asciminib if my TFR attempt fails. This one works differently too and I don't even think it's a TKI - from what I understand it inhibits a different kind of protein. Maybe this would be an option?

Just some thoughts that hopefully make sense! Best of luck with these decisions and keep us updated.

Martin

Scuba, David, Alex – Awaiting your inputs please

Thanks, Scuba.

Like always your replies are guiding and very helpful.

Even we would like to continue on Dasatinib but in India convincing doctors for a lower dose is highly unlikely. So far we have consulted 4 doctors till date and none in last 2.5 years agreed for a lower dose than 100 mg. Only one doctor was somhow ok to try a 50 mg and with the plearal effusion happening again he was keen to make a move to imatinib or nilotinib.

Considering nilotinib has to be taken under a strict lifestyle and has some heart implications we were left with the choice of Imatinib only.

We are still having the 50 mg dose and the diuretics and steroids to bring the pleural effusion down and have a consultation in 2 weeks. I will keep you posted on what we got to chose.

Thanks much, Scuba.

Take care !

Hi Scuba,

Our doctor isnt keen to try 20 mg. When the PE was detected the second time we were told not to discontinue the TKI but take steroids to get rid of PE. After a while, from the ultrasound it became evident that PE was not going as we were still taking 50 mg dasatinib.

Then we stopped dasatanib and continued the steroid to get rid of PE. Its almost 2 months now that we are still on sterioids and have still 20 ml of fluid left.

The first time the fluid was more but we stopped the TKI and started with Sterioids and PE resolved faster. This time it has taken over 2 months.

We were told by the doctor to be ready for change ( from 50 mg dasatinib to 400 mg imatinib) as we were not keen for other TKI's.

We are meeting the doctor today and will keep you posted if our last try to come on 20 mg is suceessful or not as without doctor prescription we wont be able to get the TKI.

The other reason our dcotor is alarming us is that too much of tweaking with medicine may create issues with drug response and can impact bone marrow which is kinda scary to hear.

Thanks

Our doctor has simply given up on dasatinib. He asked to chose between Imatinib and Dasatinib and considering it is once a day drug we chose Imatinib. Lets see how this goes

I so agree with you. But the sad part it these drugs are only available upon doctor prescrpition. Lets see how it goes. If there would be more side effects then we would request to shift a 20 mg. Hopefully he agrees then.

Thank you , Felix.

Hi, the rash was really awful for me on Imatinib had it on my face and top of torso it was so itchy and burning used a vitamin E cream to help but it didn’t do much ,that is another reason for changing to Dasatinib ,I have non of the side effects of Imatinib they were truly awful .I don’t like the sound of your doctor ,can you change ,I took all the decisions of my treatment and my Doc just had to follow what I wanted to try .I am on 10 mg now of Dasatinib if she had her way I would be on 100 mg and half dead ,she never once suggested a decrease in meds ,I just told her what I had done
when I felt was the right time for me .

Hi, if you want to try 200 mg of a Imatinib or 20 mg of Dasatinib and your doctor doesn’t agree then you just buy a pill splitter and take the dose you want .You don’t have to tell them ,just wait and see how your bloods respond .Like I said it’s your body ,you are the one who has to cope with the side effects ,and some are unbearable and ruin your life .Good luck I hope you get sorted soon .See if you can get a better doctor that is more up to date with treatment .

Your wife's case is an example of someone who is "perfect" for dasatinib if only there was no pleural effusion.
What I mean by that is she is very sensitive to the drug which is why it worked so well. 50 mg dsatainib is way too high a dose. She doesn't need it. It's too toxic.
(I was never on 50 mg. only 20 mg and then 10 mg because I was sensitive to the drug as well, myelosuppression & rashes. I would have developed pleural effusion, no doubt, but was never on a high enough dose long enough to trigger it.).

Given that she is below the precision and accuracy of the PCR test (i.e. bcr-abl < 0.01%) which is indistinguishable from "undetected" statistically, she can easily go on a on and off again therapy in order to manage pleural effusion and still likely maintain excellent response. I have a suspicion, however, that if her dose were lowered to 20 mg daily, pleural effusion may not re-appear, but if it does, stop therapy until it resolves. At bcr-abl < 0.01%, she is not in any danger of progression. Let me repeat that, at PCR < 0.01%, in fact at PCR < 0.1% (an order of magnitude higher), she is not in any danger of progression. I assume you also take vitamin D, selenium and curcumin? - especially vitamin D to help strengthen you immune system (good for both of you).

Changing drugs is always an option, but given her current status (i.e. borderline "undetected"), I would be concerned about full dose any drug.

(Consider 20 mg every other day. This was prescribed to me by by one of the authors in the papers cited below, but it is not standard protocol. Cutting edge research never is)

https://pubmed.ncbi.nlm.nih.gov/34195988/
https://ashpublications.org/blood/article/138/Supplement%201/3607/479750... (switcing to Imatinib was not as effective as staying on dasatinib)
https://pubmed.ncbi.nlm.nih.gov/30093398/

Dr. Jorge Cortes, one of the top researchers in Leukemia is a specialist in CML and is involved in most of the trials for various drugs including dasatinib back in the day.
He prescribed for me 20 mg dasatinib as first line therapy. You might mention this to your doctor.
When I achieved PCR < 0.01%, however, I cut my 20 mg dose in half on my own to 10 mg (more or less) and then I just took 20 every other day. Over a few months my CML went undetected. After 3 years, I stopped therapy altogether. I have been off dasatinib for an additional 3+ years.

Dasatinib is a threshold drug - once a patient is taking sufficient dose, it works at a maximum level. More is not better with dasatinib because of its toxicity profile and half-life (5 hours). More actually impairs the immune system from assisting dasatinib do its job. Each patient needs to discover what that optimum dose is and it is almost certainly not 100 mg (clinical trial dose for adverse events & efficacy). The new standard is becoming 50 mg starting dose. Eventually it will likely be the protocol. Some people need more dose, some less.

We do know that certain groups of patients are 'exquisitely' sensitive and responsive to dasatinib who also suffer myelosuppression, rashes, and pleural effusions. They are the most likely to respond very well to dasatinib. This is why (my doctor) wanted to keep me on it even though I suffered SEVERE myelosuppression. And why he wrote papers on helping patients stay on dasatinib even though they had pleural effusions. The key is dose management. He would rather me go on and off the drug to manage side effects than switch drugs. He said my response to dasatinib was just too good to pass up. Not all patients are in this category, but worth finding out.

Scuba - Does this plan looks fine?

Thanks

I do not take a multivitamin for the reasons Felix (Denise) cites. Most of the amounts are not sufficient for efficacy and do not occur in nature in this form.

It is best to take specific supplements for which a deficiency exists and where food does not contain enough. These include vitamins and minerals our ancestors were able to "eat" in abundance and modern farming has reduced greatly. What I take includes:

magnesium (need 400 mg per day - minimum)*selenium (200 mcg per day)
vitamin C (500 mg minimum, ideally twice a day)
*Vitamin D as D3 (between 125 - 250 mcg per day UNLESS I am in the summer sun in the Bahamas at noon scuba diving)
Curcumin (2 grams per day MINIMUM if MMR, ideally 4- 8 grams if not)
vitamin K2 (200 mcg per day minimum, ideally 400 mcg per day OR eat fermented foods such as Natto)
Zinc (15 mg) - except when eating oysters.
Omega-3 (as fish oil high in EPA)

*Blood test is recommended to know base line blood levels. Important to stay in the range 60 - 100 ng/ml)

The above list, from my research, are critical to a healthy immune system and facilitates natural anti-cancer fighting properties as well as anti-viral. In addition, therapeutic dosing (much higher than the minimum requirements usually listed) works synergistically with our TKI's, but vitamins should not be taken at the same time as a TKI (minerals are o.k. to take at the same time (e.g. magnesium)). I have been on the above protocol for more than 10 years and while taking dasatinib. When I am fasting for multiple days, I still take the above list (although D & K2 are not likely as well absorbed).

I also take on occasion biotin (I was deficient), quercetin (anti-histamine and a strong anti-oxidant), resveratrol, B-complex when I am not eating meat and B12.

Vitamin D & K2 are fat soluble requiring fat for absorption (avocado, cheese). Vitamin C is water soluble and should not be taken at the same time as D & K2.

Other vitamins & minerals (especially calcium) is easily obtained from food (fruits & veggies). If you don't eat fruit much (as in Keto), then adding a potassium supplement makes sense. I take potassium when doing Keto.

Thanks, Felix . This helps.

Hi, gosh this doctor is in a terrible hurry .Don’t give up on Dasatinib yet it hasn’t had time to work .Your poor wife’s body is confused with all this changing of meds .Stay your ground and give it time .Iam sure it will work for her .Hang on in there .

Felix is spot on!
Stay at 20 mg. You need 3 months for it to work (or not) and then have the bcr-abl test.
At 0.05%, she is in MMR which is a very very - very - low residual disease level. As long as she is below 0.1%, she has room to test.

When a doctor suggests stopping cancer treatment may lead to "resistance" they often are confusing a bacterial infection vs cancer.

Cancer and bacterial infections are fundamentally different, and the analogy of treatment resistance does not hold true in the same way for both. Cancer is a complex group of diseases characterized by the uncontrolled growth and spread of abnormal cells in the body, whereas bacterial infections result from the invasion and multiplication of bacteria within the body.

In the case of bacterial infections, some bacteria can mutate and develop resistance to specific antibiotics through mechanisms such as genetic mutations or acquiring resistance genes from other bacteria. This can make certain antibiotics ineffective in treating the infection, and alternative antibiotics or treatment strategies may be required.

On the other hand, cancer cells can also undergo genetic changes, leading to the development of resistance to certain cancer treatments. This is often referred to as acquired resistance. However, the mechanisms of resistance in cancer are diverse and complex, and they typically involve multiple genetic alterations and cellular pathways. Cancer cells do not develop resistance in the same way as bacteria, where they acquire mutations in response to the treatment.

In cancer treatment, the concept of resistance is often related to the ability of cancer cells to adapt and survive despite treatment interventions. This can happen through various mechanisms such as alterations in drug targets, activation of alternative signaling pathways, or changes in the tumor microenvironment. When cancer treatment is halted or interrupted, it is not due to the fear of cancer cells developing resistance during the break, but rather for other reasons such as allowing the body to recover from treatment side effects or to assess treatment response.

Resuming cancer treatment after a break does not typically lead to the same kind of resistance development seen in bacterial infections. Instead, stopping and resuming treatment is a tested way to manage adverse events (pleural effusion, etc.) while maintaining killing pressure on the cancer cells.

Scuba,

With Dasatinib being taken in the morning how to do you recommend taking magnecium, curcumin and other supplements in the day. Please guide on that as well.

Also, in India we do take turmuric as a part of our diet and the maximum curcumin tablent in mg we can get is 1000 mg. Since you recommend 2 gms at least guide us how much gap should we give between the two. Can other supplements be taken along curcumin.

Thanks

Thank you, Scuba. This helps.

I would assume the magnesium you are taking is the "oxide" version. It is very common, easy to produce (inexpensive) and not beneficial for our purposes at 167 mg. Separating drug/ supplements by 12 hours assures no interaction. After two hours, the interaction would be near zero anyway.

I take 400 mg of Magnesium taurate per day separated in two doses of 200 mg each (morning and evening). When I was taking dasatinib before my cessation trial (which is still ongoing), I would take my 200 mg evening at the same time as dasatinib. Magnesium taurate absorbs easily along with the dasatinib. Keep in mind, dasatinib (many drugs, in fact) is complexed and manufactured with magnesium stearate as an excipient.

I personally avoid magnesium oxide. It's only benefit (my opinion) is to speed things through the digestive tract - because it doesn't absorb well. Perfect for a colonoscopy!

Magnesium citrate is fine.

Curcumin's benefits is dose dependent. The more you take (up to about 8 grams per day), the greater the positive impact. Any dose less than a couple of grams per day is probably not worth the cost. The issue with Curcumin is its bioavailability. Pepper helps curcumin absorption, but to get therapeutic levels in the blood, more curcumin in the gram weight amounts is needed.

In addition, turmeric (usually a powder) is only a few percent curcumin. Taking turmeric supplements does not provide any meaningful levels of curcumin. However, turmeric, as a spice, has other beneficial properties when taken with food such as anti-oxidant properties. I use turmeric regularly, but as a food, nothing more.

Below is a link to a nice summary of Curcumin's benefits in clinical trial settings.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535097/

I take 2 grams per day Curcumin C3 complex mostly for osteoarthritis (which I no longer feel or have since taking Curcumin!). If for any reason, my CML were to re-appear (currently undetected), I would increase my dose back up to 4, 6 or 8 grams per day straight away. (or any other cancer). The only reason I only take 2 grams per day instead of six or eight grams per day is cost. Curcumin is expensive.

What is her doctor recommending?

The trend is up significantly indicating a possible clone breakout not susceptible to low dose dasatinib treatment. Switching to a different drug makes sense.
Given that she had pleural effusion, increasing dasatinib dose is not an option even if a higher dasatinib dose could work.

I would have a mutation test to learn what's changed in the bone marrow. This will guide a doctor as to what alternative TKI is recommended.

Does she have any blast cells? (blast cell count/percentage)? If no blast cells, she has time for this to get sorted out.

TKI alternatives when dasatinib not working:

Nilotinib (Tasigna): Nilotinib is another TKI used to treat CML. It has shown efficacy in patients who have not responded to or have become resistant to imatinib or dasatinib.

Bosutinib (Bosulif): Bosutinib is approved for the treatment of CML in patients who are resistant or intolerant to prior TKI therapy, including imatinib and dasatinib.

Ponatinib (Iclusig): Ponatinib is used to treat CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in patients who have failed other TKIs or have the T315I mutation, which confers resistance to other TKIs.

Low dose dasatinib was worth a try - and given no blast cells means she has time to try other TKI's.
Increasing dasatinib dose increases the risk of pleural effusion and low dose has already failed to keep CML in check.

Her doctor is likely to recommend a new drug at full dose. And that's fine in order to reverse the CML trend. Once she is undetected, a dose reduction is worth trying again. Of course new drug side effects will have to be closely monitored.

(Trying 40 mg dasatinib is up to you of course, just watch for pleural effusion closely and monitor bcr-abl 30 days later if you want to go that route.)

In my own case, I went straight to low dose dasatinib (20 mg) due to severe myelosuppression at a higher dose (dangerously low neutrophils!). But once I was able to stay at 20 mg, my CML plummeted to below 0.01% and then undetected. In your wife's case, she went to 20 mg and her bcr-abl levels are rising. This suggests either the dose is too low OR another clone has emerged which is not sensitive to low dose dasatinib. A higher dasatinib dose may work, but given prior pleural effusion, likely best to switch drugs and avoid the risk. I can appreciate sticking with a drug you know and tolerate. And many pleural effusion patients succeeded on 40 mg dasatinib (instead of 100 mg prescribed).

Nilotinib is similar in the way it works with imatinib. I considered nilotinib when imatinib failed, but the strict dosing and not eating schedule wasn't for me - and then I met Dr. Cortes who wanted me on low dose dasatinib straight away.

I would consider staying on drug at whatever dose her doctor prescribes until undetected occurs as it did before. Once undetected, lowering dose after a few successful test reports is worth considering.

The big issue with nilotinib is qt prolongation (heart rythem )
https://www.drugs.com/medical-answers/you-tasigna-food-3557749/

According to data on nilotinib(Tasigna):
You may lower your chances for having QTc prolongation with TASIGNA if you:

Take TASIGNA on an empty stomach
Avoid eating food for at least 2 hours before the dose is taken, and
Avoid eating food for at least 1 hour after the dose is taken
Avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract during treatment with TASIGNA. Food and grapefruit products increase the amount of TASIGNA in your body.
Avoid taking other medicines or supplements with TASIGNA that can also cause QTc prolongation.
TASIGNA can interact with many medicines and supplements and increase your chance for serious and life-threatening side effects.
Do not take any other medicine during treatment with TASIGNA unless your health care provider tells you it is okay to do so.

Probably best to avoid supplements unless you have a deficiency and check with your doctor. I assume your doctor briefed you on nilotinib adverse events.

Your doctor should have reviewed the side effects possible with nilotinib (Tasigna)? Qt-prolongation is not a minor side effect.
All TKI's have side effects. Which is why getting off them or reducing dose is a worthwhile goal.

You may ask your doctor about bosutinib (Bosulif). It doesn't have the same profile as nilotinib and you will be able to maintain your supplements protocol. When dasatinib doesn't work, bosutinib is often prescribed as an alternative.

Regarding dasatinib, I am concerned that low dose did not work for you. But there is evidence that increasing to 50 mg may work and help avoid significant pleural effustion:
https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(16)30568-7/fulltext

My doctor was the prime author of this paper.

SS86, I've been following your thread and hoping your wife would do well on the low-dose dasatinib. I'm sorry that is not the case. I have a long history with pleural effusions and dasatinib, even on very low dose, 20mg—every other day. I had a Pleurx catheter for almost 2 years so I could drain the fluid at home and still stay on dasatinib at that very low dose since it worked so well for me.

However, realizing I did not want to do this forever I did eventually switch to nilotinib. I started at 150 mg twice a day and I'm now taking 150 mg once per day. I've been undetected since 2016 (I was on dasatinib until 2019) with an occasional blip to detected in the early years, but still with extremely low transcripts. The plan is to attempt TFR this January.

I have an ECG every 6 months (every 3 months at the beginning) to check for QT prolongation issues. Good luck to your wife - I understand the sadness at having to switch from a medication that worked so well, except for one adverse reaction, though an important one. There is also an enjoyable life on nilotinib, too.

Pat

Two months on Nilotinib 300 mg BD while has reduced the Bcr abl count to .019 but the recet blood test shows an increase in bilirubin.

Upon fibroscan it shows first stage of liver fibrosis. Previously on dastainib 50 except for pleural effusion all seemed under control.

The doctor is of the opinion that this isn’t due to the medication and we should continue the same full dose.

The bilirubin increase has happened in the last two months only.

Please advise what to do

Thanks