Advice on 3 months mark /new here

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

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!

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!

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

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?

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

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 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

Hi. Imatinib concentration is a tricky one, as the half life is pretty short, and so the concentration rises and fall significantly over 24 hours. This paper  talks to a therapeutic level of 1 mg/ml but doesn't say whether that was measured at the peak or the trough of the daily cycle. UK clinicians have told me they rarely check the levels because of this variation. I have seen a presentation where peak levels varied from 1-10 mg/ml for peak levels all on 400mg, and there was no clear reason for the differences. 

Marilyn,

In the early phase of CML treatment the preferred test to have taken is FISH. FISH is a physical measure of actual CML cells under the microscope. At diagnosis most of us test at 100%. A key milestone and treatment indicator is for FISH test results to fall to zero within 12-18 months. Many achieve this goal in less than 12 months. Survival prognosis once FISH = zero is over 95%.

PCR testing (bcr-abl) is a molecular test designed to quantify how much bcr-abl protein (CML) is circulating by comparing an amplified amount of bcr-abl to a control. It is a very sensitive test, but not truly specific to you. In my case at diagnosis, my PCR was 155%. It just means I was producing a lot of bcr-abl compared to control. It's a partial reason why PCR is usually not key until after FISH has fallen. There is a rough correlation where 1% bcr-abl is equivalent to FISH = zero. Because your bcr-abl is > 1%, you likely have FISH > zero as well.

You are going to be fine. I know it's hard in the beginning, but you are already responding to treatment and your CML was caught early. I would raise my vitamin D level to above 125 nmol/l (~ 50 ng/ml) and ideally seek to achieve a vitamin D level around 175 nmol/l (70 ng/ml). Data suggests vitamin D levels below 50 ng/ml do not confer as much anti-cancer properties as 70 ng/ml. The published normal range for vitamin D is out of date and was designed more for the prevention of rickets than for immune health. High normal levels of vitamin D will also drive blast cells (normal + leukemic) to differentiate. This can help prevent CML progression and augment TKI effectiveness.

I was started on imatinib and had poor response (never achieved FISH = zero). I was switched to low dose dasatinib as data suggested lower dose for many patients could actually be more effective than the pharmacokinetic dose (100 mg). I maintained 20 mg dasatinib, had no side effects and my PCR plummeted. I am undetected for over 3 years at this point and take 20 mg every other day. I will eventually stop and test remission.

You will too.

In my conversations with CML researchers (as opposed to clinical practioners) at M.D. Anderson, they told me their  research shows cytogenetic response (FISH = zero) to treatment is the single most important indicator of progression free survival. It is indistinguishable from those who achieve major molecular remission (i.e. MMR ~ 0.1% PCR). Survival rates are the same.

So the issue becomes more a management of the disease and side effects and not whether one lives or not. Once you achieve FISH = zero, the likelihood of CML killing you is reduced to near zero. This is outstanding given that just a few years ago, CML was a killer disease without hope. That is all changed now.

Another very important factor which affects risk of progression is blast cell count. At diagnosis many patients have blast cell counts greater than 5 percent. My own blast cell count at diagnosis was near 15% (i.e. very bad!). Blast cells are progenitor cells that normally do not stay as blast cells very long. They quickly differentiate into specific function 'daughter' cells. As such, most people don't have many blast cells to measure since they don't stick around.

The body produces many blast cells. These cells then quickly divide into their specific cell function cell. In CML, leukemic blast cells are damaged cells (they have the bcr-abl gene) and have difficulty differentiating and tend to accumulate. They tend to reproduce into more blast cells. The longer this continues, the worse the bone marrow's function becomes as blast cells begin to crowd out normal blood formation. This transformation from low level blast cell count to higher blast cell count is how CML kills. A person quickly enters blast crisis and the end is quick when this occurs (months). Research shows cytogenetic remission (FISH = zero) prevents blast crisis from ever getting started. There simply are not enough leukemic cells around to initiate the blast crisis cascade.

Interestingly - vitamin D is required in order for blast cells to differentiate. Blast cells are 'loaded' with vitamin D receptors (VDR). In order for a blast cell to differentiate it needs vitamin D to trigger the process. This is true for both leukemic blast cells as well as non-leukemic blast cells. In my own case, my blast cell percentage was always above zero (~5%) even after I was able to get my CML somewhat under control during the early days. But once I started my vitamin D protocol (i.e. D > 50 ng/ml), my blast cell count fell to zero. It has never been above zero since. In fact, anyone who has blast cell counts (normal or otherwise) above zero probably is vitamin D deficient (my theory).

• https://www.frontiersin.org/articles/10.3389/fimmu.2020.00966/full

Vitamin D is so important to immune health, I can't stress enough people should test and supplement regularly.

Hi Marilyn,

I have so many fond memories of my time in the Netherlands - especially by the ocean (Katwijk ann Zee) and strangely enough Madurodam. Amsterdam was a playground!

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

50 mg is the new starting dose for dasatinib. Much research is showing 100 mg has a high incidence of pleural effusions and myelosuppression. Assuming you must start at 100 mg, be very alert to these serious conditions. It would be important for you to have weekly CBC blood tests to monitor your white cell levels. If they fall too much, you will have to stop dasatinib and wait for your counts to recover. This happened to me - and I was never started at 100 mg.  My doctor took me off dasatinib until my counts recovered and then restarted me at 20 mg where I remained. It is unfortunate doctors practicing clinical oncology do not stay up to date involving these powerful drugs.

In the case of dasatnib, its effectiveness, which is unique to each patient (more or less) is more of a step function and bell curve, not a straight line when it comes to dose. There is a dose beyond which drug response begins and then will decrease due to its suppressive effect on the immune system as dose goes up. A patient needs to find the ideal level which trends CML down and at the same time doesn't lead to drug cessation due to suppression.

In your case, I would watch for myelosuppression and if it occurs, you will have to stop therapy and then insist on very low re-start dose in order to "discover" the correct dose for you. My doctor (top researcher in the field) re-started me at 20 mg and I had tremendous response. The same could occur for you. Of course, if at 100 mg you have no side effects which you feel and your response is good, then that is fine too. But be alert. Weekly blood tests are key.

Regarding vitamin D - I never use sunscreen like I did when I was younger. The sun has been above us for over 4 billion years. Life evolved under the sun. The body makes use of the suns energy to manufacture vitamin D both to protect from the sun and to benefit from it. It takes many weeks for vitamin D to accumulate and also many weeks for vitamin D to deplete. Half life of vitamin D is about two months. So during summer, if large portions of skin is exposed to the sun, vitamin  D accumulates and then becomes available during the winter. By avoiding the sun in the summer, we end up in a very depleted state as winter arrives and then bad things happen. Rickets was a big problem in children:

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133108/

I am convinced if I had known about vitamin D's importance to the immune system 15 years ago and supplemented, I never would have developed CML. My low vitamin D status was an open door to disease. Vitamin D maintenance is the single most important thing people can do to maintain health and avoid many diseases including Covid. Vitamin D's importance to the immune system is so well known now, it is surprising so little is said about it.

Hi Scuba,

Nice to hear you liked our little country, and Madurodam of all places :-) (only been there once myself as a kid). Next time you should visit more interesting places though:-) !

Anyways, I will definitely try to monitor the myelosuppression. I will ask for more frequent tests, because now I'm only scheduled for the brc-abl (and blood) test in 4 weeks. I think the specialist really insisted on the 100 mg because of my low through level of Imatinib. They're afraid it will be the same with Dasatinib otherwise. But will definitely address this at my next appointment. As soon as my numbers are (hopefully!) going down, I must see to a lower dose. I suspect their assessment of the 100mg could be right for now anyway, because so far (touch wood of course!), now on the 6th day in, I haven't had a lot of problems, beside a minor headache for a few hours day 1 and 2. And I am feeling better actually, because I discovered my fatigue was really due to Imatinib. Had thought this was because of the whole diagnosis and killing of cells and everything, but it miraculously disappeared when I stopped the Imatinib.

Now I can focus on what supplements to take, alongside the vitamin D (read your other post, thanks).
I can totally agree with your theory that if the levels of vitamin D were high, it could have prevented developing CML. But do you mean the higher end levels then, I guess? Because I tested my level one month after diagnosis and it was in the normal ranges (as you read above). I guess it should have been higher. And it also doesn't say anything about the previous years of course. Well it would be terrific if there'd be more research about this...

Well one last note: I have thrown out my tubes of sunscreen. Rather be old and wrinkly later on than no wrinkles with bad CML...;-)

Hi Marilyn

"....Also, short update: Had my appointment. The haematologist consulted with one of the best CML experts here, and they advised me to go on Sprycel 100mg now. I've discussed the 50 mg starting dose with him (shortly) but he insisted that I'd be put on 100 now, because of my meager responses so far. (my last BRC-ABL was 68% [IS], so not a lot of movement from 73% last month). He definitely said that it would be something to consider if my numbers would go down but for now he did want me on 100 mg. He also mentioned that if I would've been his patient from the beginning he definitely had put me on 50 mg from the start. So I've asked for a change in doctors, to go to this one. Hopefully it'll be granted, because he is quite busy I was told."

So glad you were able to change your doctor to a more pro-active one! Good luck for a quick response to dasatinib (Sprycel) no matter what your starting dose is. I am sure with a good response your 'new' doctor will reduce the dose, but meanwhile you can increase your plasma level of D3 (remember to take a formulation that included K2). Also it may be good to find out how D3 is measured in Netherlands. I suspect it is the same as UK? .... nmol per litre rather than ng per millilitre. You should try hard to get above 50ng/ml (= to 125 nmol/L) and hopefully you have a baseline measurement of your D3 level at diagnosis?

Sandy

Hi Marilyn,

I take a D3 supplement that includes K2 in a 'correct' percentage. K2 is recommended to ensure that D3 - at higher doses than is officially recommended - does not leach calcium from the bones, so is really an insurance against the 'perceived' dangers of higher doses of D3.

I think Scuba has already mentioned this but it is worth repeating, if you are light skinned and spend 15 minutes without sunblock at 12 noon in the summer, you will receive a dose of upwards of 10,000-15,000 ng/ml (some sources say 20,000). If you are darker skinned you will need to spend longer in the sun to receive those same daily doses.  

I personally take a supplement of 10,000 - 12,000 ng/ml D3 (with K2) per day in the winter months, less in the summer depending on how much sun exposure I get. I include magnesium and selenium, plus Vits/Minerals, on a daily basis.

'Magnesium lotion' (I like Ancient Minerals brand but there are others) rubbed into the feet before going to bed really helps relax muscles (and therefore cramps, restless leg syndrome etc) as well as promoting deep sleep. 

Sandy