Update on Plueral Effusion and break from Sprycel

Kali - You can wait if you feel comfortable doing so and watch your PCR for a bit longer. As long as it is below 0.1% you can hold off. You are giving your body a chance to develop an immune response to the CML cells. There is a chance your PCR will fall back from where it is now.

If you do decide to go back on sprycel - consider a low dose (20 mg) which may be low enough to avoid PE getting worse and still drop your PCR. Patients who suffered PE's tend to be more responsive to lower dose sprycel.

"Will this time off help my immune system so when I try TFR in the future after more time on the TKI, I will have a better chance of making it?"

No one knows. We would be guessing.

But dose does not necessarily translate into more effectiveness. More is not better when it comes to dasatinib.

Update: my onc is suggesting Gleevec 400 mgm because it won’t interact with the sotalol that I am now on at 40 mgm twice a day.

Both Sprycel and Sotalol can cause qt longation.

He is concerned about Sprycel 20 mgm not being strong enough to be effective. 

He is going to consult with a cml expert from Mayo and also try to reach Cortes on my behalf and see what they suggest.

I took a 50 mgm last night to get started back on something, while he seeks consult with CML specialist, but I am nervous. I don’t know how long it takes to build up a plueral effusion again at 50 mgm if I am going to.

Hopefully, I will be a 50 mgm for a very short time.

I still believe Sprycel has a chance to work for me at 20 mgm. With me taking 50 mgm and having an EKG in a couple of days to check on qt, if it is good at 50 then it should be good at 20. 

I spoke with the specialty pharmacist today and she said there was small risk of qt and between Sprycel and Sotalol.

I feel like my numbers are close to losing MMR.

Kali - Here is another paper (Cortes, co -author) on 50 mg as new starting dose:

https://www.ncbi.nlm.nih.gov/pubmed/29723397

The pharmacokinetics of dasatinib is potent. Your doctor is reacting to old data and is not up to date.

As I wrote above - you can always increase dose. Starting off high (and that includes 50 mg) and getting P.E. again does you no good.

Start low and test your PCR in one month. If it goes down, you have your answer.

(I have no idea what active disease means. We all have active disease. I am PCRU and I am sure I have "active" disease (i.e. not cured). 0.03% is such a low PCR level. PCR of 0.01% is scientifically indistinguishable from "undetected". The good news is that once you get back on drug, your PCR will drop again. You have time to experiment. CML is slow at the stage you are at. It would take a year before it would get to symptom levels again, blast cells notwithstanding).

When my 0.0000 became 0.0099, he suggested I needed to go back on the meds at that time.

My doctor’s judgement is to go back on a TKI at full dose because that is what the drug company literature sets as the dose needed. But not take any Sprycel due to the plueral effusion I had. He also is concerned the 20 mgm is too low to be effective and I could get into trouble. He says we need a healthy respect of this disease so I don’t end up with a bone marrow transplant.

He is willing to prescribe 20, but it up to me completely. It is not his recommendation, because it concerns him.

So I am at a loss. I don’t want to make the wrong decision.

I am on sotalol 40 mgm twice a day (low dose) and it can cause qt and so can Bousilif and Sprycel. 

He says both can be severe. My specialty pharmacy says mild with Sprycel and higher concern with Bousilif but I can be monitored with ekg to keep an eye on out for it.

I am temporarily back on Sprycel 50 mgm and will get an EKG soon to see how it looks.

I don’t know how fast plueral effusion can come back if it is going to on the 50. I am using it to get the drug back in my system until a decision is made.

The reason he is involving me in the decision on what I am comfortable doing is because with the PE, I am not in the typical protocol anymore.

He is against trying the 20mgm if that is what I am comfortable with, but just isn’t sure if that low dose is efficient god the disease.  What if I develop resistance? Or it isn’t strong enough?

Those are the main concerns, plus clinical trials haven’t confirmed the efficacy of the low dose.

"He is against trying the 20mgm if that is what I am comfortable with, but just isn’t sure if that low dose is efficient god the disease.  What if I develop resistance? Or it isn’t strong enough?"

Kali,

I can only offer you my experience and conversations with one of the four top CML researchers in the world. Dr. Cortes prescribed for me the 20 mg dose. I did not pick it out myself. It is what his experience informed him regarding drug response and CML. He also told me that he has many patients on 20 mg who became MMR or better. There is no such thing as "resistance" when it comes to cancer. It is not like bacteria. It either works or it doesn't - clonal expansion not controlled by the drug at any dose is the reason for drug failure. Clonal expansion can occur at any time, but typically if it hasn't occured in the first few years of successful treatment it is not likely to ever occur. The major reason starting drug dose is where it is - is because of the way trials are done. They design clinical trials for maximum tolerance to side effects against response. MORE is not necessarily better. Many drugs have a bell curve response (similar to vitamin D, by the way.). Continuing research on dasatinib (TKI data gathering never ends) is suggesting that 100 mg starting dose may be too high. The newer protocols are suggesting 50 mg starting, with 20 mg suggested for myelosuppression and P.E.

Even Dr. Talpaz (an expert in CML) reports success with 20 mg:

https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.31232 (do a search for "20" in the  article).

I can appreciate your concerns - you have to be comfortable with your treatment plan. I suggest you invite your doctor to reach out to Dr. Cortes or  Dr. Talpaz regarding 20 mg and his experience.

To repeat, I don't think Dr. Cortes would have prescribed 20 mg dasatinib to me if he thought it would not be effective. Your doctor does not know this apparently and not a surprise. He is following the "rules" as set. I can't blame him - it is more of a liability issue for them. But consider how the rules have changed just in the last few years regarding drug cessation let alone lowering dose. It wasn't long ago that doctors said no way to stopping drug - you'll die. Now we have treatment free remission. It is possible if your doctor reads some of the links I sent you, he might feel more comfortable. If he refuses to read them, get a new doctor.

Tell him you know a patient (that would be me) who was borderline blast crisis (very high blasts), imatinib failed, was prescribed 70 mg sprycel (never 100) which led to a tanking of WBC's to dangerously low levels (neutrophils < 0.1), had to go on and off drug with PCR's > 50% (that is 5-0 no decimal point) and positive FISH (i.e. no remission whatsoever). I was put on 20 mg to allow my blood counts to stabilize and keep CML in check. To my surprise (and admittedly, Dr. Cortes was a bit surprised too), my PCR plummeted while on 20 mg. (*I also started taking Curcumin by then and increased my vitamin D markedly). When my blood counts recovered, I asked about increasing dose and Dr. Cortes said, "Your PCR's are dropping - trend is what matters. The lower the dose the better as long as it works". And my PCR's kept falling to where it is now - "undetected" ON 20 mg still.

There is zero doubt - zero doubt in my mind, that 20 mg can work. It did for me. But you must be comfortable trying. I worry more about your P.E. than your PCR at this stage. Getting a handle on the P.E. is what counts right now. 50 mg may work for you and that would be a good psychological outcome  - but so could 20 and you lessen the risk of P.E.

I have learned over the years that CML is as much a mental issue as it is physical. I applaud any decision you make to help you tackle CML and P.E. whether it's 50, 20, drug switch or yoga. Whatever works for you is what is important. And you have time to experiment (as long as P.E. is at bay).

Scuba,

The article https://www.clinical-lymphoma-myeloma-leukemia.com says error when I open it.

Can you send it another way?

Also do you have an article about the immune system potentially being stronger on lower dose?

Also one about the PE and killer cells and greater ability to fight the disease. I think that is how u described it.

Here is a link to the paper on P.E. associated with deeper dasatnib response:

https://www.spandidos-publications.com/10.3892/or.2016.5110

I'm looking for the other one - should be in my library.

Dear Kali,

I am in a very similar boat. I got a moderate pleural effusion on 100mg Sprycel. After 2 thoracenteses, a residual PE came back. My pulmonologist cleared me anyway to go back on Sprycel 50mg, hoping that the residual might be inflammation or scar tissue. The PE was stable for 7 months and then begun to increase again. I got another thoracentesis and stopped Sprycel again. My pcr went from     less than 0.002%IS to 0.003%IS in 4 and half months. So I am still on drug vacation hoping that my lung would be cleared soon. I will have a pcr test and chest x-ray on April 8th. 

I want to wait as long as I can without TKIs but if/when I need it, my preferred choices are Sprycel 20mg or Gleevec 200mg. Any thoughts? I am very interested in what Dr Cortes has to say.

Thanks again for sharing your story and thanks to Scuba for sharing his knowledge.

Karinne,

I have been thinking more about your situation. With your low PCR numbers and if you decide to go with Sprycel 20 mgm, I would get tested monthly to make sure it is working, You could ask your medical person if they think that is a good option for you or not. I would definitely get your medical person’s input to help you decide what is best for you, which I am sure you will anyway.

If I remember correctly, you have a fairly new diagnosis, so I don’t know if that is a good option or not. Scuba has by far way more knowledge on this than I do.

I know if my numbers were like yours, I would feel much more comfortable with trying 20 mgm. Even though I have been assured that my numbers are still low too, I see mine as much closer to .10 which I don’t want to get to.

Hi again!

I have been thinking today that resuming the Sprycel at 20 mgm for a month could be the first step and then see how my numbers look. I actually get tested again in two weeks. So I am thinking it is a good idea for now. 

Like Scuba pointed out, if there is progression, it will take some time and I will have time to go on a stronger dose of another TKI.

Thank you so much for your input. Best to you!

Yes, to be continued...

I am going to start the 20 mgm. Decision made. We will see how it goes. Fingers crossed!

Kali,

My husband was on 70 mg Sprycel and then 50 mg sprycel and experienced severe shortness of breath with no detectable PE.  He had been undetectable on both Tasigna and Sprycel since diagnosis in 2012 and one failed TFR attempt.  The shortness of breath got so bad that he went on a drug holiday a year ago and it took a good 10 months for it to be gone entirely.  Fortunately, he has stayed  mostly under .1 PCR this year and hasn't had to return to meds.....yet.  I was hoping he would go back on Sprycel 20 mg but he is so soured on it after this horrible experience that he will go on Bosulif if he has to return to meds.  I am concerned that you are not with a CML specialist that really understands dosage and drug holidays.  I understand your fear and wanting to return to meds with any sign of disease in your PCR, but it is still so low that a real specialist may have given you confidence to hold off longer on returning to meds.  My husband has a community oncologist for monthly tests but checks in for consultation with CML specialist about dosage questions, med changes, etc.  Even seeing this specialist, I would still like him to go to MD Anderson or to Oregon if he needs future med tweaks.  I really encourage you to find the most experienced CML specialist you can as close to where you live as you can -- even if there's out of pocket expense.

@kali. Where do you live?

Scuba,

Thanks for the encouraging comment. It is a little scary. You have said they have proven there  is no issue of resistance or mutation in low dose, otherwise they wouldn’t be putting me on low doses. Correct?

The main issue is if the numbers keep getting higher which would mean the low dose isn’t strong enough. Correct?

Thanks

Think of it this way .... 'lock and key'.

TKI's (key) are uniquely designed to bind to a specific active site on bcr-abl (lock). When CML first starts, chances are many clonal mutations are established. In any particular mutation, the active site structure only fits one TKI. The others are unaffected. This is not "resistance". The one dominating is typically sensitive to our TKI's and when attacked eliminates the risk of disease progression. The other clones may still be around, just not a threat (or detectable). Sometimes when the dominant clone - the one our TKI's attack - is reduced, the other clones are able to expand. If this occurs it is usually within the first two years of treatment if it is going to occur at all.

Dosing strategy is therefore evolving to minimize side effects with the best response - not just max dose based on toxicity. As long as PCR trend is down, and cell rate of growth is negative whatever dose is being used is sufficient. If a clone does grow and expand, then a different drug (key) is needed to shut it down. Fortunately - most of the clones (including the stubborn T315i) can now be attacked with various TKI's, imatinib being the first. This is also a reason why rotating TKI's during treatment is gaining traction - it may provide a way to attack clones not visible to give an overall greater success.

It is actually any wonder that our drugs work as well as they do in the first place. There are dozens of kinase domain mutations (http://www.bloodjournal.org/content/bloodjournal/118/5/1208/F1.large.jpg). It is possible that our immune systems are really the reason we are able to get ahead of CML. It is why I place so much emphasis on overall immune health (vitamin D, etc.) so that any clone that my TKI does not attack is never able to get a foothold. Truth be told - it's only a very few clones that truly cause disease. The rest are just garbage generated by our bodies. We generate a lot of garbage as we age.

Update:

I have been taking 20 mgm. for quite a few days with no side effects.

My doctor reached out to Dr. Cortes on my behalf and he shared that 20 mgm of Sprycel is often used in cases like mine. 

Scuba had already educated us on that, however, it was good my doctor reached out too.

Good response😊

No surprise - excellent!

Just an FYI ...

Any PCR level below 0.01% is indistinguishable from PCRU. 0.007 is meaningless. It's noise of the test. They could test a pure sample with zero CML and it show 0.007 ....

What's important is that on a reduced dose of sprycel (20 mg), your trend continues downward. This means your sprycel drug threshold is sufficient. You are in a very good place.

An additional note. There is a lot of discussion and even controversy on the counter-intuitive idea based on data that less sprycel can actually be more effective than more sprycel. Your response shows dropping dose improved your response - as it did mine. I am also on 20 mg sprycel. Only when I dropped to 20 mg did my PCR plummet  If they made a 10 mg version, I would try that! 20 seems to be the minimum available, however. And it was my Oncologist who prescribed 20 mg because he was on the leading edge of research regarding lowering dose.

My point is that sprycel is a myelo-suppressive agent. Your blood making system (read: immune system) has to work extra to overcome sprycel's tendency to suppress (mildly so) the immune system. By lowering the dose, you take the "yoke" - if you will - off your immune system so it too can attack CML. So there is a magic dose where your immune system is relieved and can fight CML AND the drug can also kill CML too. Finding that correct dose - which for many people - is likely to be well below 100 mg - is a smart way to maximize the benefit of the drug and maximize pressure on CML with the immune system.

I know it's hard to get away from the idea one wants to hit CML hard which translates into more is better. But biochemistry is not like that. More - in the case of sprycel - is not better.

It's true that some patients do need higher starting dose of sprycel to get the same benefit. But they are unique. For them 140 mg sprycel has the effect as my 20 mg sprycel in how our bodies respond. And some even have no side effects. But most invite pleural effusion and heart issues, the higher sprycel dose they take.

Congratulations on your response!

Yep - CML is in your rear view mirror. Worry about the Astros ....!

Kali - You've been off the Sprycel long enough to be rid of the effusion, so what's left is probably not going away if you wait another month or so.  BUT, if it's not giving you any symptoms, and a pulmonologist is OK with it, I think you can "walk around with it," which is where I find myself.  I have stayed stable on 20 mg Sprycel for well over a year at 0.006%IS.  On such a low dose, I have no side effects other than the minimal residual fluid.  My PCR got all the way up to 2. something, off drug - I hadn't been on that side of the decimal point in 9 years!  Pretty alarming.  But, it quickly plunged downward after re-starting Sprycel.  (I spent a few weeks at 50 mg, then split them into 25's with onc's OK until the 50's ran out, then got a realio trulio prescription for 20's.)  I would bet, along with Scuba, that a re-start at 20 mg might show you the same - just skip the 50 mg stage - why tempt the pleural effusion to increase?

For some reason, I had missed this entire thread - and I'm not sure where I just came in!  At any rate, I guess my reply wasn't too far off making any sense at all.  Glad you're doing well on 20 mg.  I had also asked Dr. Cortes, by email, when my onc was reluctant to go all the way down to 20 mg, and he reassured me that Sprycel operated a little differently and it was easier to muck about with dosage with Sprycel than with the others, in terms of resistance developing.  Another thing I wanted to add, my cardiologist completely waved the QT elongation thing away - if it doesn't show up on your entry EKG, you're not going to get it, he said.  Lastly, my pleural effusions began with 70 mg Sprycel, and came back twice on 50 mg.  I have only been stable on 20 mg.  So, all in all, I think you have made the right choice.  As I read through your long thread (which I had completely missed, as I say) it was like reading a story or watching a movie - I wanted to say to the screen:  No, you don't need to worry about QT!  Good, Dr. Cortes will tell you, Nah you'll just get another effusion on 50.  Fortunately, happy ending.  Or, have I missed something else? . . . . 

Kali - I'm glad you reminded me of the other thing I was "talking to the screen" about (lol).  There is NO problem taking sotalol with any of the TKI's.  Yes, I was on sotalol the whole time since diagnosis of CML - so that's with both Gleevec and Sprycel.  All doctors involved agreed, no problem taking them both.  

My Afib was considered "paroxysmal" (PAF), as in between bouts I had perfectly normal sinus rhythm.  Also, I was completely conscious of them - they were UNBEARABLE!!! - I am amazed to read that many, many older people live in perpetual afib and never even know it.  How is that possible, I wonder, after my experience.  Anyway, I had only four bouts:  the initial one, then one a year later, then two years later I had two a month apart, and that's when they decided to treat me.  My dose of sotalol was the same as yours and held me event-free for 13 years.  I was worked up with all the folderol - stress test, stress echo, yadda yadda - nothing.  So it was decided I'd stay on sotalol and be followed by a cardiologist for twice a year EKG's. I never had an abnormal one.  I never had any side effects from the sotalol, but I had the persistent fatigue we all seem to complain of on TKIs, and I was searching for something to help that.  On reviewing all my meds, the cardiologist said sotalol was the only one that could possibly be contributing and he was quite willing for me to try stopping it and strove to give me confidence that we could get right on top of another bout of afib should it occur.  I NEVER EVER want to have one of those again!!!!!!  Anyway, I've been fortunate in the extreme and haven't had any - it's been about a year now.  And, although it took longer than he gave me a timeframe for, for noticing a difference, I did get an enormous amount of energy back.  There had to have been a synergistic effect with the Sprycel, is all I can figure.

A plausible theory for me, the docs have said, is that there was some minimal scarring incurred when I had radiation after breast cancer on the left side.  This might be enough to interfere with the "electronics" of the heart's rhythm.  It's just a theory, and I'm working on my own theory that in the 13 years since, that scarring has reduced, or there's been a workaround in there, or something.  I'm going with thinking the PAF is gone for good.  But I have definitely found to my despair that the universe is pretty darned random, so I'm not saying it will never happen again.

No, never on blood thinners.  I remember your story of the thoracentesis-induced afib.  What a nightmare!  I hate mysteries, especially medical ones.  I wish we knew what caused this PAF.  At any rate, it seems that a very, very low dose of sotalol is protecting you from afib episodes and it's safe to take along with TKI's.  So, if there are no side effects, onward and upward - just take the sotalol and forget about it.  Just one more thing, right?

Oh, and PS:  I guess it's possible, your theory about cold-turkey, but that's what I was advised to do, and did.  Nothing happened.  Who knows?

Hello Kat73 and others,

With the pleural effusions I suspect are from 2 years on Sprycel, 80 mg, I am on a drug holiday...it has been about 6 wks now with only some reduction in the bilateral pleural effusions.  

Should I request the effusions be graded?  They have only been called mild to moderate.

How long should I expect it to take for the effusions to clear while on drug holiday?

How often should I expect the oncologist to obtain a chest x-ray or CT scan and the molecular genetics test?

Thank you, Susan

Hi Susan,

When I had my pleural effusion,  I was on Sprycel 50 mgm at that time. I had originally been on 100 mgm, then 70 mgm. And then 50mgm. The pleural effusion started out very small and grew over time and ultimately had to be drained. (the pleural effusion started when I was on 100 mgm and gradually got worse over time, which is the part of the reason I was taking 50 mgm. After the fluid was drained,  I stopped taking the drug (under doctor’s care), for about 3 months and then went back on it at 20 mgm. I have had no more pleural effusions and I have been undetectable on the PCR test (0.00000) for about 2 years or so. If I remember correctly, the chest X-rays were done after that pleural effusion twice in the year following the incident. 

kali, it's highly likely that you can successfully gradually reduce your TKI dosage down to 10mg/day by first skipping 20mg every fourth day, for an average of 15mg/day.  After testing undetected then begin skipping 20mg every other day, averaging 10mg/day.   Continuing to reduce your TKI dosage beyond 10mg/day could lead to a TFR attempt at some point in the not-too-distant future.

Buzz

Hello Kali, 

Thank you for the additional information on how you managed the pleural effusion.  Although we are all different, your experience with the effusions and the outcome is really encouraging to me.  I saw my oncologist yesterday and she is willing to give the 20 mg dose of Sprycel a go once the effusions have resolved.  Although she does not have any experience with the 20 mg dosage. 

I still had a small right and a small to moderate left pleural effusion on CT at 5 wks out from stopping the Sprycel.  They are very slowly reducing in size.  I was taking 80mg of Sprycel right from the start just over two years ago.  The oncologist did not think a short course of steroids would be of any benefit now, and she did not previously recommend steroids when we stopped the Sprycel.  We will repeat the CT 6 wks out from the last one, and that will be in about 3 more weeks.  And that should put me at 11 wks out from stopping Sprycel. 

Could you remind me, were you ever treated with a course of steroids?  I see there is some controversy as to whether or not a short course of steroids might be helpful in preventing effusion recurrence.  Or is waiting until the effusions have fully resolved before resuming with 20mg Sprycel just as effective?

Any additional thought would be appreciated.  thank you, Susan

Hi Susan,

I wanted to add the reason I went back on the Sprycel at the point that I did, was because my numbers began gradually coming back on the BCR-ABL test. I didn’t lose MMR, but personally didn’t want my numbers to get to that point. So I took the very cautious approach and started back at 20 mgm. And it worked! I was undetectable again after a couple of months or so on that dose. I take it at night. It was a little scary to go back on it, but also a little scary to not go back on it and wait longer to see what my numbers did.

So that is the decision I made and thankfully, so far, it has worked out.

kali, in response to your question, it took me 6 years on 50mg for another effusion to rear its ugly head. This one, however, did not go away so easily. We are all different on these drugs, however. I maintained CMR on 25mg every other day until we decided to switch to Tasigna. I'm taking 150mg. twice a day and maintaining CMR fluctuating occasionally with <=0.003. Good luck! 

*Sorry about the double post, I'm evidently too impatient to wait for the first one to post and unaware how to delete the whole thing. 

Susan, I thought I would chime in. I started Sprycel in 2009 at 100mg. In Feb. 2012 I developed my first PE on the right side only. I stopped Sprycel, not as quickly as I should have, and it got quite large. I had 2-3 thoracenteses during that time and was off the drug until May at which point I had lost CCyR. I was given a course of steroids and felt that was the turning point for me in terms of my PE drying up. I restarted Sprycel at 50mg and things went well for another 6.5 years in 2018 when I developed my second PE, this time in my left lung. Again I stopped Sprycel.

I am followed at Mayo-Rochester. When my PE showed no sign of clearing my case was presented at their Myeloid Board and the consensus was to try and keep me on Sprycel because I responded so well to it. At that point though I was about to lose MMR. I met with their interventional pulmonologist and we decided to insert a Pleurx catheter. That would allow me to drain at home and hope that the tube would irritate the pleura enough to cause pleurodesis. No such luck. I was taking 25 mg of Sprycel every other day to use the 50's up and then went on 20mg daily. I maintained my CMR through it all. However, I still had the darn PE. I was loath to give up my Sprycel but finally decided to try Tasigna at 150mg 2x daily. Still had my PE but continued at CMR or <=0.003. One of my pulmonologists told me about a study in Japan where they injected 400mg (10ml) of steroids into the pleural cavity with varying degrees of success. In May of 2021 that procedure was done and my drainage finally dropped enough to remove the catheter. My theory is, (because they really don't know the mechanism at work here) that the large dose of steroids was able to interrupt what ever was happening.

I still would go back on Sprycel 20mg in a second. I'm not sure what that says about me.  I wish you the best of luck as you navigate this situation.