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Hi friends, I'd love to know your opinion.  Looks like the second TKI is failing me. 

BCR/ABL journey 

63%   Nov. 2021 at diagnosis. Started on Dasatinib 100mg. reduced in 1 month to 80 mg due to side effects

24%   April 2022 @ 50mg

57%  July 2022  @ 70 mg. 

56% Sept 2022 and bone marrow biopsy which showed NO mutation

60% Nov. 2022 Switched to Nilotinib 300mg twice a day

50% Jan 2023

54% Feb 2023

I met with my doc yesterday and he 'supposes' I should switch again.  He is thinking maybe Asciminib, but he is a general oncologist.  I asked him to consult with a specialist in Denver, Texas, or Georgia, and his response was that he would give me a referral to go there for an appointment, because the docs would probably want to see me.  I'm very discouraged.

I have had daily joint pain with Nilotinib, and recently I've developed a visual distortion in one eye, as well as light-headedness all the time.  I've been taking collagen daily to help with joint pain, and time restricted eating in a 7 hour window.  I also take vitamins B; C; D3K2; Magnesium; iron; zinc; and NAC

Would it make sense to try another tki before moving to asciminib?  There is bosutinib, but it is a second generation tki like the two I've already tried.  I am really hesitant to go to ponatibib because a) I have no mutations, and b) it has a black box warning.  If I try asciminib next and it doesn't work, can I go back to try the two tkis I just mentioned?  I know these are questions for my doctor, but he really had no info for me.  This is a scary time, and especially more so because I don't feel like I have a doctor to trust.

So I am turning to you all again.

You should be taking 400 mg twice a day of nilotinib  with these readings and check again for mutations and maybe a bone marrow aspirate is needed to check in what phase you are as for example dasatinib is better suited in advanced phase than nilotinib.

Make sure to get familiar with the guidelines too for cml. 

Kindly see a specialist urgently as I am not sure why you are taking less than the ideal dose in this setting. If side effects are a concern, you should seriously considering a bone marrow transplant as low dose therapy is out of the question in this scenario.

I recall something about P190 CML requiring a different approach so maybe that is something to ask about. Most CML is P210. This is not related to mutations but it is worth asking about. https://www.nature.com/articles/s41375-020-01082-4 I hope you get referred to a very knowledgeable oncologist is short order and praying for the best outcome for you.

It is important you see a specialist in one of the major medical centers (such as M.D. Anderson in Houston, Georgia Cancer Center in Augusta, Georgia). Dr. Jorge Cortes, in Georgia, is an expert in CML and I believe is still seeing patients (he is the director of the Georgia Center) and was my doctor before he moved.

What is your blast cell percentage number? Assuming you are taking adequate vitamin D3 so your blood level is ~70 ng/ml and your blast cell counts are zero, you have time and your CML is chronic phase. Even though your bcr-abl percentage is higher than it should be at this stage, if your blasts are zero, you have "working room".

Nilotinib (similar to imatinib) is dose dependent and I am puzzled why your doctor has you on a low dose at 300 mg twice a day. The standard is 400 mg twice a day and sometimes higher. It may be side effects related.

Your response on dasatinib is interesting. You had to have your dose lowered due to side effects. Usually, when this happens, it is because a patient is "responsive" to dasatinib in an over-sensitive way. In this case, dose management (lowering) can be an effective strategy (it was for me). Dasatinib can actually work better on lower dose. It is more of a threshold drug and not dose dependent. More drug does not necessarily yield better results. A patient/doctor has to find the sweet spot for best response.

You might also consider adding Curcumin to your your protocol (4 - 8 grams per day, 8 grams initially (4 in the morning; 4 at night) and test your response. Curcumin (C3 version) down regulates CML cancer pathways (primarily nf-KB and Jax2). This slows down CML and interrupts it's ability to rapidly expand. It may very well augment your TKI therapy and get you trending downward. It might also enable you to switch back to low dose dasatinib (50 mg or lower) which together can give you breakthrough. You do have other choices (TKI's), and you will get there.

Let us know what dose of vitamins/minerals you are taking (especially vitamin D3). And add selenium to your list (200 mcg per day).

 

 

 

Hi Rocky Mountain Gal

I'm so sorry you're having to go through this challenge with nilotinib not working well. Unfortunately I have no experience with any of the other drugs you're considering, but all I can say is that my doctor seems to consider asciminib to be a really good alternative as it targets BCR-Abl in a different way to the tyrosine kinase inhibitors (from what I understand it's not a tyrosine kinase inhibitor at all). So it may well be that it overcomes whatever resistance there is to nilotinib and dasatinib, both of which have a similar mechanism of action. I don't know ponatinib at all, and I don't even think it's available in my country, but I'd choose something without that black box warning any day. Just my two cents.

I also just wanted to send you my thoughts and prayers from South Africa - hoping that they can get to the bottom of this issue as soon as possible for you and that you can see a downward trend soon! Rooting for you from the other side of the world.

Best wishes

Martin

Hi Rocky Mountain Girl! Like the rest of the group I’m and so sorry you are going through the problems with your numbers. My advice would be to contact Sloan Kettering immediately. I am a patient of Dr Mauro. He does telemedicine with me and sends me to a local lab for my blood work. He is a wonderful doctor and one of the worlds foremost experts on CML. You need a specialist. My numbers plateaued on Dasatinib and I became concerned about the care I was receiving with a less specialized oncologist and he was happy to quickly take me on. Since then, I have taken Dasatinib, bosutinib and am currently doing great on asciminib. I have had MMR (our goal for me is to get to undetectable so that I may try treatment free remission in the future) with all of these drugs and have not had any serious issues with any of them. When I stalled out on Dasatinib I was so discouraged and thought once I tried another TKI I could never go back. This turned out to not be the case for me. Bosutinib did make me nauseous but taking with a meal resolved that issue. With asciminib I have been hovering at a PCR of .04-.06 for the past several months. In sincerely hope that you make the call and that you find a TKI that gets you back on track. If you have any questions that I may be able to answer, please let me know!

Update: I saw a specialist yesterday from MD Anderson! He just happened to have relocate to Denver, which is a MUCH shorter drive for me than Texas.

Colorado Guy; my breakpoint is p210, but thanks for giving me extra ideas. My new doc is very knowledgeable and it was apparent that he is indeed a specialist about 15 minutes into the appointment. Thank you for your prayers! I value that!

Scuba; My vit D was 65.7 when I was diagnosed. It has remained in the 60's, so I don't think that's the magic bullet for me. I live where it is very cold, so not a lot of direct sun exposure in the winter. I supplement with Vit D-5000 IU daily. No blast cells, so I guess that means I have working room. For reasons that are unknown, I did not responded the way you did on Dasatinib. I guess that is why there are 6 different meds, because we are all so different. My previous oncologist told me 'no' to Curcumin with Nilotinib. He started me on a low dose because of the side effects I had with Dasatinib.

Martin; thank you for the encouraging words. Yes, I am with you about the black box warning! Avoid at all costs! Well, almost all. I'm currently off Nilotinib because of an ecg abnormality. My new doc has ordered asciminib for the exact reason you mentioned! You are so wise. He said it is being considered as a first line of defense, it has been such a strong performer. Thank you for the prayers! I value that!

Jmonzione; thank you for your info. I'm glad to know Sloan Kettering offers telemedicine! This is definitely a cancer that relies on blood work, so really, why go in at all? My doc has told me that we can have zoom appointments as well. First one was in person. You and I have the same goal, to be treatment free in the future. My new doc told me the same thing, that you can go back to tki's that didn't work the first time. He was so positive that we would get this under control, I left my appointment feeling so hopeful! Now I'm just waiting for my asciminib to be delivered. I might contact you later for side effects management.

Thanks for your encouraging responses friends. It really helps to 'talk' to people who know what it's like to go thru this journey. Bless you all.

Indeed. Vitamins/minerals are not a magic bullet when it comes to cancer!

It is gratifying to learn, however, you do not have any blasts which vitamin D is very effective at 'helping' to differentiate even leukemic blasts. Keeping your vitamin D level where it is is key to helping blasts differentiate. Blast crisis is what kills in CML.

I disagree with your "nilotinib" doctor regarding Curcumin. He doesn't know what he is talking about.. Curcumin is synergistic with TKI's:

For example, a study published in the journal Cancer Letters in 2015 found curcumin enhanced the effects of dasatinib in inhibiting the growth of chronic myeloid leukemia cells in vitro.

Another study published in the journal Oncology Reports in 2016 reported curcumin enhanced the anti-tumor activity of the sunitinib in a mouse model of renal cell carcinoma.

A study published in the journal Oncology Reports in 2017 found curcumin enhanced the anti-tumor activity of nilotinib in a mouse model of chronic myeloid leukemia.

Another study published in the journal Frontiers in Pharmacology in 2019 reported curcumin enhanced the anti-proliferative and pro-apoptotic effects of nilotinib in human pancreatic cancer cells.

I have a suspicion your M.D. Anderson doctor will have no issue with Curcumin. M.D. Anderson has done research with Curcumin and cancer with successful results, but unfortunately, the dose required is high and bioavailability is an issue. I take Curcumin as a monkey-wrench to cancer, not as a cure. I took it with imatinib (similar in the way it works to nilotinib) and with dasatinib. Now that I am off dasatnib, I continue to take Curcumin. I will every day for the rest of my life. It's good for the skin too!

Hello,

You may want to create a detail list of all medications, food and supplements you've been taking since the diagnosis and ask your doctor to review it with a CML specialist. If you've been taking collagen 2 for joints, it's often combined with hyaluronic acid which reduces the effectiveness of TKIs. I made that mistake several times over several years while on imatinib and noticed the effects in the test results, but wasn't aware of the issue at the time. Another one is ginseng, which may completely block TKI.

You may also ask the doctor to start monitoring TKI plasma levels as it may indicate what's going on if multiple TKIs failed to produce better response. E.g. st worth john and vitamin c will speed up elimination of TKI, so the results will be below expectations.

Definitely follow Scuba's supplementation list (curcumin, magnesium, selen, D3+K, fish/krill oil, zink etc) and make sure your vitamin D levels are above 50 ng or 120 nmol.

How much NAC you've been using? NAC is very good, but in your case it may interfere with something and produce undesirable effects (e.g. increasing cellular glutathione). It's a precursor of glutathione which protects CML cells against TKI.

Good luck!

Antileukemic Activity of hsa-miR-203a-5p by Limiting Glutathione Metabolism in Imatinib-Resistant K562 Cells
https://pubmed.ncbi.nlm.nih.gov/36547099/

N-acetylcysteine - a safe antidote for cysteine/glutathione deficiency
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540061/

N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide
https://pubmed.ncbi.nlm.nih.gov/19153832/

BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895841/

A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities
https://www.bloodresearch.or.kr/journal/view.html?doi=10.5045/br.2021.20...

Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes
https://pubmed.ncbi.nlm.nih.gov/22538170/

Dasatinib increases endothelial permeability leading to pleural effusion
https://erj.ersjournals.com/content/51/1/1701096

Effects of antioxidants on apoptosis induced by dasatinib and nilotinib in K562 cells
https://onlinelibrary.wiley.com/doi/10.1002/jcb.26686

Safety of N-Acetylcysteine at High Doses in Chronic Respiratory Diseases: A Review
https://link.springer.com/article/10.1007/s40264-020-01026-y

UPDATE: I am so happy to report that after ONE MONTH on Asciminib, my BCR/ABL dropped from 54% to 10%!!!!! My new doc is brilliant. I refer to him as Marcus Welby, MD because he has really taken ownership of me as a patient. He takes calls from the pathologist about my case while on vacation. He tells me "I was thinking about your case over the weekend, and think we should consider this". He has discussed treatment options with me, instead of telling me what I should do (or guessing). He has consulted with Cortez, and his MD Anderson replacement. The drive to his office is a hassle, but the care is absolutely worth it!
I really appreciate all of the support I have gotten on this forum!
3oK@, thanks for your input. Wow, you've really done some deep diving! Thank you for all of that information.

Additionally, I've noticed less joint pain on Asciminib. I'm going to the eye doctor tomorrow for what might be retinal detachment. Not sure if that is a side effect of the drug or a side effect of too many trips around the sun. Ha!

Glad to hear it. I hope this gets you comfortably under 1.0 soon. Even deeper. Why not?

Excellent news, so happy for you!

That’s fantastic! It so great when you find a doctor on the same wavelength as you, and you can work with. Different patients need different things from their doctor and I know I wouldn’t chance mine for the world. I dread the day she moves on from her current post!

David.