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Advice on 3 months mark /new here

Hi everyone,

So happy to bump into this forum here! I got diagnosed with CML in July this year.
After the first shock I read a lot of stuff to calm myself and now I have somewhat accepted this long journey on which I must go.
Been searching for some more info but couldn’t find a lot, but it is really awesome that such a good forum does exist here!
I was kind of ok√© with all of this (just relieved that it was ‘just’ CML) and I now know it is a disease (or rather ‘condition’) with very good prognosis. Also, most of the time I don’t have time to think about any of this, because I have 3 young children to raise;)
However, just got my 3 months results back which are a bit disappointing. So I have a few questions which I would like to ask here if possible.

Short history:
When diagnosed I had a WBC of 247 (which climbed to 268 the day after). Platelets 667. And a (very) large spleen. Diagnose was chronic phase and I was put on (generic) Imatinib 400mg right away.
One month later I reached (almost) CHR: WBC 9,6; Plt 385. I now know that CHR is the least difficult hurdle to take...

My 3 months-mark results:
BCR-abl is at 72,9%
WBC 9,8. Plt 316, and (definite) CHR ‘cause all the small other white cells are at zero or almost zero. Only basophils at 0.29 which should be zero.

So NOT the results I was hoping for of course. My hematologist will now test me for levels of imatinib because she suspects I might not absorb it well enough (of course I have not missed a single dose). Second, she will test for mutations although she doesn’t think it likely will be any mutation because then the Imatinib wouldn’t give such good results blood-wise.

My questions:

- I read here somewhere that young people (30’s-40’s) tend to not react to Imatinib as well as others. Do any of you know if there is any literature on that topic? I couldn’t find it so far. As I’m 40 yrs old this could be a cause for my bad numbers maybe?

- It seems that a lot of members here started on Dasatinib right away if I’m right? Was there any specific reason for that? In my case, I’m in the Netherlands, there was almost no other option than to start with Imatinib as the doctors stated that the other TKI’s have a lot of side-effects and if I would start directly on a 2nd gen TKI, there’d be no way back.

- I’ve read some articles which imply that when started directly on Dasatinib, chances for a deeper response are higher and especially the chance to stop somewhere in the future is higher. (Although I learned from reading here that the chance to lower my dose would be much higher and more preferable than to actually quit altogether). My hematologists keeps saying that although 2nd gen TKI does give faster results, in the long run it doesn’t really matter (this was what she said at diagnosis, presuming I would respond well to Imatinib).

- I’m not keen on switching because I have almost no side-effects on Imatinib (besides fatigue, but that’s inherent I guess). But of course will do if necessary for better response.

- Is it also possible that i’m just a little bit slower in responding because I had such high wbc’s at start (also suggested by my hematologist)?

I would be very grateful for any advice/tips/whatsoever on why my results are so bad after 3 months or any similar experience maybe. I’m starting to panic a bit more now...:(

Ps Apologies for this long post...

Welcome to CML Support Marilyn,

I'll have a go at answering your questions.

- I read here somewhere that young people (30’s-40’s) tend to not react to Imatinib as well as others. Do any of you know if there is any literature on that topic? I couldn’t find it so far. As I’m 40 yrs old this could be a cause for my bad numbers maybe?

It may be that younger folk sometimes have a slower response to treatment.  I don't recall reading any research about it.  Do you know if your BCR-ABL% was the result of a PCR or a FISH test?  When the BCR-ABL% is above 1%, the FISH test can give a more accurate analysis of your situation.  The PCR test becomes more informative as the FISH result approaches 0%.

- It seems that a lot of members here started on Dasatinib right away if I’m right? Was there any specific reason for that? In my case, I’m in the Netherlands, there was almost no other option than to start with Imatinib as the doctors stated that the other TKI’s have a lot of side-effects and if I would start directly on a 2nd gen TKI, there’d be no way back.

Dasatinib is often more potent at reducing CML faster than imatinib.  Dasatinib seems to often have more worrying side effects and is less forgiving when the dose is too high.  It's not true that you can't switch back to imatinib if it's found to be effective for you.  I've used both of them and am currently taking 300mg/day imatinib.

- I’ve read some articles which imply that when started directly on Dasatinib, chances for a deeper response are higher and especially the chance to stop somewhere in the future is higher. (Although I learned from reading here that the chance to lower my dose would be much higher and more preferable than to actually quit altogether). My hematologists keeps saying that although 2nd gen TKI does give faster results, in the long run it doesn’t really matter (this was what she said at diagnosis, presuming I would respond well to Imatinib).

There are advantages for each TKI, and they can be specific to each patient.  The important thing is to determine which TKI is most effective for you with the least severe side effects.  Unfortunately, it seems to be a trial and error process for each of us.  It has been borne out that overall survival rates are similar for treatments with imatinib, dasatinib and nilotinib

- I’m not keen on switching because I have almost no side-effects on Imatinib (besides fatigue, but that’s inherent I guess). But of course will do if necessary for better response.

Hopefully the test for your blood level of imatinib will help determine the best path forward for you.  I think having adequate acidity in the stomach is needed for good drug absorption.  Also, taking it with a meal that contains some fat, can aid in drug absorption.

- Is it also possible that i’m just a little bit slower in responding because I had such high wbc’s at start (also suggested by my hematologist)?

It's hard to say why your BCR-ABL% hasn't come down faster.  Have you had your vitamin D level checked?  It would be helpful to consult a CML specialist.  But it's not a common specialty because it's not a common malady.  I've heard that Dr. Brian Druker will consult by email.

 

Hopefully you can get it all sorted out soon so you don't have to spend any extra effort worrying about CML and spend all your time enjoying your family!

Kirk

I found this study from last year that indicates the newer TKIs do have an edge over imatinib.  Here is their conclusion:

Our meta-analysis of RCTs of patients with CML-CP
found that NG-TKIs were associated with superior OS at
12 months. Although there was no long-term survival advantage,
patients treated with NG-TKIs had a greater molecular
response at all time points. Furthermore, NGTKIs
were better at “softer” clinical outcomes, such as
progression to AP/BC and CML-related mortality. Further
large-scale clinical trials with longer follow-up periods
are required to assess long-term survival outcomes.

 

The title of the study is:

Systematic Review and Meta-Analysis of New-Generation Tyrosine Kinase Inhibitors versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia

DOI: 10.1159/000501537

Pan Pan
a Lijuan Wang
b Yanjun Wang
c Li Shen
a Pingping Zheng
a
Chunli Bi
a Anning Zhang
a Yaogai Lv
a Zhiqiang Xue
a Mengzi Sun
a
Chong Sun
a Jiagen Li
a Lina Jin
a Yan Yao
a

Thank you so much Kirk for your response! 

Yes they used the PCR test, not the FISH. Do you think it will differ in outcome if I were to ask for this test?

I had my vitamine D levels checked in August and it was 97nmol/L so I was told that was normal or even above average.

The article is very interesting indeed. It confirms my (already existing) doubt that I should have been put on Dasatinib right away, due to my enlarged spleen and high Sokal score.

I don’t know exactly what to do next, my hematologists is supposed to be a specialist on CML. I’m just afraid now that I will miss the ‘early response’ months (while waiting for the outcome of the next tests it’ll be december and then it’ll be close to 5 months already).
I’ve read a lot of articles which keep saying that if the early responses (in 3 and 6 months) are less than optimal, overal survival will be less favorable than in those cases with optimal responses.

So trying to keep calm but I find it difficult at the moment...

Thank you again,

Marilyn

 

Hi Marilyn,

Very likely a FISH test would give a different result and it should provide a more accurate picture of your current response to TKI therapy.  The FISH test actually examines a few hundred white blood cells and then gives the percentage of BCR/ABL cells in the sample.

Your vitamin D level is considered adequate for the average person.  There are some who would consider a level double your result better for fighting CML.  I'm currently supplementing with 7,500 IU per day.

It's totally normal to be anxious about CML, especially if you're not meeting the recommended milestones.  You have made progress, so that's really good. If your results keep trending in the right direction, that's the important thing to watch for.  I would ask your doctor what her protocol is for recently diagnosed patients who aren't meeting the recommended milestones.  Hopefully she's following your case closely and providing you with education and options for your particular situation.  It sounds like she is following recommended protocols by testing your drug plasma level and checking for BCR/ABL mutations.

It seems like my test results were usually available within a week.  Do you have online access to your test results?

You're very welcome!  There's a lot to learn about CML when you are first diagnosed!

You may find this article of interest:

How I treat newly diagnosed chronic phase CML
Jorge Cortes1 and Hagop Kantarjian1
1The University of Texas, MD Anderson Cancer Center, Houston, TX

From www.bloodjournal.org

 

It's from 2012, so they may have updated it since I downloaded it.  If you can't find it online, let me know and I can email you a copy.

 

Hi Kirk,

Thanks for your reassuring words. It’s what you say and what probably everyone experiences here, that it is a stressful period when waiting for results. The weird thing is, I wasn’t so stressed in the 1st three months because of the overal good prognosis of this disease. But then if you become one of the exceptions it feels like a total game changer. 

Thanks for the article, I’ve read it, there’s not been an update but I have read some other articles which mention sort of the same outcomes. 
What I don’t understand yet is why the overall survival rate is somewhat the same for most tki’s, but 2nd gen tend to have a stronger response. A lot of literature mentions the importance of early deep responses and how that could benefit progression-free survival. How is it then that the overall survival rate stays the same for both? 
Will ask my hematologist about this and the suggestions you made about the protocol. 

Thanks again!

Hello Marilyn

Please watch the following short video if you can:

https://cmlsupport.org.uk/videos/second-and-third-generation-tkis-%E2%80...

You will catch the 50% of super-responders who brag about their results on places such as Facebook. It is wonderful for them but disheartening for the 50% of us who are not.

About 10% do not respond at all to imatinib. But you have responded. It might have been useful if could have had a FISH during this early stage. FISH beats PCR at this early stage.

You may or may not need to  switch to a second generation TKI in due course. It is early days and you consultant appears to be providing good and consistent advice. 

 

Regards, Stephen

PS: The kinase-domain mutation is quite rare. But even if you have one, there are strategies to address this.

 

Thank you Stephen for your kind words. 
I’ve watched the video and it was very helpful for a lot of questions I had. 

And in response to Kirk, yes I can see my results online, but especially the bcr-abl test takes almost 2 weeks, so last time my doctor called me first with the results. One week sounds a lot better:)

I contacted my doctor to speed things up, hopefully she will contact me soon, the waiting takes forever. But I’m sure you are all familiar with this...
Regards, Marilyn

A few words of advice:

Don't allow them to increase your Imatinib dosage

If switched to Dasatinib/Sprycel don't allow them to start you at a higher than normal dosage.

TKIs are toxic medications. 

Hoping things are better at six months.  It's likely, if necessary,  that you will find a TKI that works well for you

Best of luck,
Buzz

Hi Buzz,

Thanks for answering me. 
May I ask as to why you’re advising against increasing the Imatinib dosage? Not that I have any clue, but I’m guessing (after reading some stuff) that would be indeed the next move from my hematologist (as I’m only on 400mg/d). Would 600 mg be too toxic?

 

IMO, higher doses likely cause more problems than they solve and should only be used as a last resort.  

First, wait for the results of your six month test to both confirm the results of the first test, again displaying the ineffectiveness of Imatinib.  You might want to retest earlier rather than waiting that long.

If necessary, switch to the starting dose of another TKI; you mentioned Dasatinib/Sprycel.

Ah I understand, I also read about that somewhere. 
Yes I probably will be tested soon, so hopefully I know more soon. 
thanks again!

Hi Marilyn and welcome to this forum,

You may find the following NCCN and European Leukaemia network guidelines for optimal treatment for CML in chronic phase helpful when looking at your 3 month test results. I understand why you are worried by your apparent lack of a major molecular response to imatinib 400mg at 3 months... it may be that you do need a higher dose (600mg) or a change of TKI.

All TKIs have side effects and how intolerant you are to any particular TKI depends on you as and individual. Imatinib is now a generic and therefore less expensive than the 2nd/3rd generation TKIs. It was the first TKI so there is a lot more data (20 years +) on this therapy which is why some doctors do prescribe this TKi in first line.

Nevertheless, you need to talk to your doctor about your lack of an optimal/adequate response at 3 months. It may be that you are slow to respond, but please read the following recommendations for optimal/sub-optimal responses at 3/6/12 month milestones.

Given your spleen was enlarged at diagnosis, your platelets were at the higher end of normal, your Sokal (?) score was high, your doctor needs to either increase your dose to 600mg or change your therapy to a 2nd gen TKI such as dasatinib, bosutinib, nilotinib, ponatinb etc...

Please keep us updated.

Sandy

Milestones for treating CML: https://www.nature.com/articles/s41375-020-0776-2/tables/4

European LeukemiaNet 2020 recommendations for treating CML: https://www.nature.com/articles/s41375-020-0776-2

NCCN https://www.nccn.org/patients/guidelines/content/PDF/nccnquickguide-cml-patient.pdf

I have read your original post and a few of the subsequent ones and thought i would tell you about my own experience.  I was diagnosed in my 30s and Immatinib had only just been discovered and was my only option.  I got a slow response but it continued to drop steadily. My dose was increased and another drop.  It was a good few years later that it was suggested that i might get a better response from Nilotinib so I changed.  I am now 18 years since diagnosis with a BCR of 0.02.  It has taken a long time to get here and the medication options have changed significantly.  I am sure if your consultant was concerned your dosage would be upped or the option to change drugs would be recommended.  I know it is scarey and there is a lot of information out there but I have always found it is best to trust your consultant unless there is a very good reason not to. 

I am sure the children are a good distraction and an insentive to fight for the best treatment. My daughter was 7 when i was diagnosed in the days when the possibility of death was very real as the immatinib long term effect wasn't known.  I was determined to see her through school and now she is through all that and working hard.  You wont have that fear but children do tend to balance out the worries.

Hi Sandy,

Thank you very much for your helpful response and the info you gave me. I’ve read all of it and especially the guidelines were very clarifying. 
I think it all makes a little more sense now, and it was nice to read some up to date info as well (and there were plenty of references to do some further research).

Just a short note about the Sokal score (which you noticed). Isn’t it strange that they used this ‘old’ score? From the moment I was diagnosed I did not hear the word ELTS (or EUTOS) mentioned once...and the thing is, I don’t know the size of my spleen ‘below costal margin’ (only the size in total), so it’s kind of difficult to calculate the ELTS score now.

Well, I’ll definitely address my questions and concerns the next time I’ll see my hematologist. I had a blood test last week so I’m now waiting for all the results to come back. 
Thanks again,

Marilyn

Hi Christine,

Thank you so much for your kind words and for sharing your storing. It’s very comforting to know that there were (or are) others that didn’t respond ‘by the book’ as well but are doing really well now. Although I can really imagine it was probably much more scary for you back then than it is for us newly diagnosed nowadays. Your story about your daughter, that it gave you determination, really resonated with me. That’s exactly what happened here. I’ve got 3 girls: they are 4 and 6 now. So enough motivation (and distraction;) 

You’re definitely right about my specialist: I still trust him, he definitely knows a ton more than I do at the moment. When I thought of it more, I think it comes down to communication. Which of course all has to do with this annoying covid-thing as well. Almost all of my appointments are by telephone and my doctor is part of a ‘corona-crisis-team’ in the hospital which means less availability for other patients. And I worry he is less on top of my case as I would want him to be. 
But you’re probably right, if he’d be really worried he would call me right away. 
Thank you again,

Marilyn