Hello to all,
It looks like I will need to go back on my TKI.
I have been off from last week in November until now. My PCR’s one month apart have been 0.0000, 0.0099, and as of yesterday my number is 0.0293.
Chest X-ray reveals a small amount of pleural effusion is still there.
😔
I wanted to provide an update.
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.
Hi Scuba,
I am surprised how much it changed from last month. I am concerned I will lose MMR by next test in a month. Then I may have to go on a higher dose.
When I go back to the drug, I definitely want the lowest dose.
I am discouraged to say the least, but grateful that we have a treatable disease.
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?
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.
"He is concerned about Sprycel 20 mg not being strong enough to be effective."
I just met with Dr. Cortes. He is the one who prescribed my 20 mg sprycel. His quote to me back in the day was, 'minimum dose necessary to cause response is the best dose. More is not better, especially when it comes to sprycel'. Later research on my part showed that sprycel is a "threshold" drug meaning - that once response is achieved, more drug does not deliver any faster or deeper response, just more toxicity which may, in fact, lower immune response to CML. Once I was able to stay on 20 mg (following myelosuppression), my PCR plummeted. It is now "undetected" - still on only 20 mg.
This is not true for all TKI's. imatinib does have a dose dependent effect - more dose, in the case of imatinib, can lead to greater response - but higher dose is limited by toxicity.
Each patient is unique. Finding the correct dose that works is the job of the Oncologist. One size does not fit all.
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.
Another comment from my doctor was that if 20 mg didn't work, "we" can always increase dose. As long as you are in chronic phase (which you are), you have time to test low dose and work up if you have to.
https://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(16)30568-7/fulltext
https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=5&ved=2ahU...
The papers above describes pleural effusion management while taking dasatinib.
If I were in your shoes, I would definitely ask my doctor to let me start at 20 mg now and work up if needed or switch drugs.
Show him the papers linked above.
I feel like my numbers are close to losing MMR.
My doctor said I am in active disease with my 0.0293 number and wants to use the starting dose not reduced dose.
But also said he would give me the choice if I want to do the Sprycel 20 mgm, but we agreed to him consulting first with Mayo Clinic and hopefully Cortes.
But that can take a few days, so that is why I was using my 50 mgm until then.
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).
The reality is none of us are "all zero's". Being 'undetected" doesn't mean we don't have active disease. It just means the level is below detection. The precision of the technology only goes so far. We don't even know what level of PCR is sustainable - meaning lack of progression. There are many patients with higher PCR's than you who take no drug and yet maintain PCR levels bouncing around the 0.1% mark. The 3rd and 4th decimal place in PCR measurements are erroneous and useless to report. At M.D Anderson, they don't even report those digits. (i.e. 0.xx% is it). It's hard to convey 0.03% really is a very low level of residual disease. Under the microscope you would never see any CML cells, that's how low 0.03% PCR is. It is also why FISH is a more reliable indicator of disease status than PCR. FISH measures cells. PCR measures protein the CML cells produce.
My point is that for you it likely won't take much sprycel - consistently taken - to drive what little CML you have to below detection. Dr. Cortes told me that taking a lower dose every day is much better than taking double the dose every other day. It has to do with the pharmacokinetics of the drug. It's half life is only 5 hours.
My comments above are just for your edification. I am reacting to your P.E. history. You need to feel comfortable working with your doctor and have trust in his judgment. You'll work through this - and with PCR's < 0.1%, you have room to work.
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.
What about switching drugs - to Bosutinib?
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 think low dose of Sprycel could be doable.
i don’t know if low dies of Bousilif is as powerful as low dose of Sprycel
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).
Thanks Scuba for explaining all of that. It makes good sense.
I was on 50 mgm when the small PE I had grew into a big one. The small one started when I was on 100 mgm.
He is reaching out on my behalf. I hope he can communicate with Dr. Cortes.
Anyway, your thoughts and information on this are really helpful. I am going to take a day to digest all it and then decide on possibly trying the 20.
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.
Here is the elderly paper:
https://www.ncbi.nlm.nih.gov/pubmed/28396095
CONCLUSION:
Low-dose (eg, ≤ 20 mg) dasatinib therapy generates an adequate molecular response in most elderly patients with chronic phase CML without causing severe AEs.
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.
Hi Karinne,
First let me say I am sorry to hear about all the trouble with Plueral Effusions that you have had. I hope everything gets worked out well for you.
You asked for my thoughts:
I think Sprycel is a very potent drug. It worked wonders for me. I reached MMR within 3 months of diagnosis and my PCR numbers kept dropping from there even on reduced dose. I was on 50 mgm for the last 18 months with all zeros with my PCR (0.0000). Then, the plueral effusion resulted in removal of over a Liter of fluid. Yikes!! I believe that one was simply a continuation of a small one that I had for sometime that was lurking around, then it grew. I was also sick twice with respiratory and that may have contributed.
Now I too stopped the drug for almost 4 months, but it is now time to go back on a TKI. My last PCR two weeks ago was 0.0293. Even though that is still very low, I am uncomfortable about staying off the drug at this point, because if it continues to grow, I don’t want to have to resort to a high dose of TKI to get it back in control.
I want to try Sprycel 20 mgm but I am scared. What if the cml keeps growing?
My onc has discussed various options such as Gleevic full dose or stick with Sprycel at 50 mgm for a few days on and a couple days off each week to see if that works. He is willing to consider 20 mgm but wants articles, journals where this has been done to read.
I have wondered about 40mgm per day until I get to 0,0000 again and then reduce to 20 mgm.
Any way you shake it, the decision will be taking the plunge with some attempt to figure it out and hope it works.
Right now I am temporarily on Sprycel 50 mgm until a decision is made. Just keeping my fingers crossed that the PE doesn’t come roaring back.
I dread the thought of full Gleevic and all the edema which they say 80% of people have. I have also read it can reduce bone density which I already have. Then I read it can help with bones. So who knows!!
On Sprycel, I barely had no side effects to really mention others than shortness of breath which I really disliked. Otherwise, it was a good drug for me and it is suppose to be protective of bones. Which is a nice added affect.
So, I don’t know what to suggest. We will need to stay in touch to give each other support on here, so please post what you decide to do and so will I.
It is great that you have such low numbers. It looks like you have some wiggle room while you are deciding.
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.
Thanks so much for your post. We will stay in contact for sure.
Don’t forget about the Destiny trial: they had 2 groups of patients, stable at MR4/MR4.5 (0.01- 0.0032) and stable at MR3 (0.1) The results showed that 98% of patients could stay for a year at half dose of Gleevec in the MR4/MR4.5 and 80% in the MR3 group without losing MMR (0.1).
I think it means that 400mg of Gleevec might not be necessary when you are already low. We could ease into the drug and increase the dose only if necessary.
And for Sprycel, we both know that 50mg works well for us. Why not trying 20mg for a month and pcr test the effect?
It’s a difficult choice but 20mg sounds better than 200mg to metabolize.
To be continued....
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...
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.
Alison,
Thank you for sharing your husband’s journey. Your suggestion to see a CML specialist is well taken. I appreciate the points you made.
I have checked and no CML specialist near me.
Next best thing is to travel to see one. Selection of who is now the question. It would be nice to at least meet with one to look over my pathology report, current situation, etc.
@kali . Where do you live?
Kali,
I have a suspicion you will do just fine on 20 mg. Your PCR will fall back - perhaps even to 'undetected'.
Need to watch for P.E. of course.
All the best!
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
Correction: I didn’t mean there is no risk of resistance or mutation just because we are on a low dose or the CML experts wouldn’t be putting people on low doses. Is that correct?
I remember you saying there isn’t resistance to the drugs just because of low dose because they aren’t like antibiotics.
But I don’t remember if low dose means mutation could occur. I know it has been shared before that mutation usually happens in the first two years of diagnosis if it is going to happen. So that sounds like it isn’t related to the dose. Correct?
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.
