Dasatinib increasing dose to 140mg for deeper response.

No_Fun_2022, taking Dasatinib 140mg in an effort to reach TFR, when you are already at a BCR-ABL ratio of 0.3, makes absolutely no sense whatsoever. Any PCR reading at 1.0, or lower, means that your CML presents no danger to your health. In addition, high TKI dosages are known to cause any number of side-effects, some of which can be permanent.

First of all, not everyone reaches undetected, let alone TFR. You are still very early in treatment and your trend is still down so it would be.best not to do anything different at this time.

I can cite a few other cases of super athletes in your age range who also struggled; a very high level of physical activity with diet, supplements, etc. seemed to work against them. One in particular reached and maintained undetected for a prolonged period of time but when she attempted TFR there wasn't any depth to her response; she very quickly lost MMR and tested at 2.0 after only three months off of her Dasatinib. That is quite unusual. She did regain her undetected status upon resuming her TKI and is currently reducing her dosage.

I found the testing history of the other super athlete:
3 Month 1.2
6 Month 0.64
9 Month 0.26
12 Month 0.21
15 Month 0.15
18 Months 0.11
20 Months 0.05
21 Months 0.05
24 Months 0.01 (started 50mg)
26 Months 0.04
27 Months 0.03
29 Months 0.34 (back to 100mg)
30 Months 0.19
31 Months 0.09
34 Months 0.03
36 Months 0.03
39 Months 0.02
43 Months 0.02
44 Months 0.01
45 Months 0.008 (started 50mg)
46 Months 0.02
47 Months 0.02
49 Months 0.05
51 Months 0.03
54 Months 0.02
57 Months 0.01
60 Months 0.04
62 Months 0.07
63 Months 0.04
64 Months 0.03
65 Months 0.07
66 Months 0.07
66 Months 0.08
67 Months 0.03
68 Months Undetectable
69 Months 0.08
72 Months 0.04
75 Months Undetectable
80 Months 0.03
83 Months Undetectable
86 Months 0.03
89 Months 0.007 (started on ~30mg)
92 Months 0.18 (back to 50mg)

Strongly consider Buzz's reply to your question.

Increasing your dasatinib dose to 140mg in order (you believe) to achieve a deeper response is likely to have the opposite effect.
You will be increasing your risk for adverse events at that dose. Dasatinib is a quickly metabolizing drug with a dose dependent profile that is threshold in nature (once a dose level is achieved that works, more is not better). Below is a summary of why this is so:

Saturation effect: In some cases, increasing the dose of a drug may not lead to a proportional increase in its therapeutic effect. This is because the drug may reach a saturation point, where additional doses do not produce any further benefit. At higher doses, the drug may also have more adverse effects, which can offset any additional therapeutic benefits.

Dose-dependent pharmacokinetics: The way a drug is metabolized and eliminated from the body can vary depending on the dose. At higher doses, the drug may be metabolized more quickly, leading to a shorter duration of action. In contrast, lower doses may have a more sustained effect, leading to better therapeutic outcomes.

Individual variability: The response to a drug can vary widely between individuals. Some patients may be more sensitive to the drug and experience a better response at lower doses. Conversely, other patients may require higher doses to achieve the same therapeutic effect.

Target specificity: Some drugs may have multiple targets in the body, and higher doses may lead to off-target effects that can reduce their therapeutic efficacy. Lower doses may be more selective for the drug's intended target and produce a better response. Dasatinib is in this class (multiple targets).

In the case of dasatinib, a tyrosine kinase inhibitor, studies have shown that some patients may achieve better outcomes with lower doses. This may be due to a combination of the factors listed above, including dose-dependent pharmacokinetics and individual variability.

As long as your trend is downward (even with a few 'plateaus'), dasatinib is working for you and lowering your dose can be tried. It takes years of "undetected" status before TFR can be attempted with a better than 50% chance of success. I tried once for TFR and it failed. I went back on drug (20 mg dasatinib) achieved "undetected" and stayed on drug and kept lowering my dose (10 mg) for 3 years before trying again. So far, this time, I have been in TFR for over 3 years.

Increasing drug dose does not (necessarily) increase response in the case of dasatinib, but will greatly increase the risk of adverse events (pleural effusion, liver & muscle issues, skin).

Heidi S, four years is a long time to be on a high TKI dosage. If you have been plateaued at a low CML level (i.e., below 1.0) for a prolonged period of time, there is a good chance that you can gradually reduce your TKI dosage without it having an adverse effect on your CML level. At prolonged low CML levels TKI dosage doesn't seem to matter in most cases. IMO, it would be worth a try; if it doesn't work you can always resort back to the Sprycel 100mg dosage. If it does work your CML level will typically drift lower with time and will do so regardless of the TKI dosage you are on. If possible, please post your testing history to provide a better understanding. Then if you choose to do so, lower your dosage to 70mg four weeks prior to your next quarterly PCR test. If your quarterly CML test level remains within your recent testing range continue to lower your dosage four weeks prior to your next quarterly test. Gradual dosage reduction would be 70mg, 50mg, 35mg, 20mg.

CML levels of a BCR-ABL ratio of 1.0, or less, present no danger to your health.

Your age and level of physical activity may work against you.

I would also advise against increasing Dasatinib to 140 mg.

I was on Imatinib 400 mg for years and never reached below BCR 0.011 so my hopes for TFR evaporated. Then after I received Moderna vaccine, I developed vasculitis for 2 months and then Imatinib stopped working. I increased it to 600 mg but wasn't able to tolerate it. There were no detectable mutations and my doctor was unable to explain what happened.

Then 3 different doctors advised against Dasatinib due to possibility of serious complications and suggested Bosutinib instead, but I insisted on Dasatinib as it's been in use for nearly 20 years. I insisted on 50 mg, but the doctor suggested 100 mg (let's hit it hard) since by that time I lost MMR.

I started 50 mg and BCR dropped from 45 to 30 in 4 months, which was not great but my peripheral blood normalised. I then increased it to 100 mg and will be testing again in 2 months. If I see significant BCR reduction, I will stay on 100 mg for maximum 6 months and then drop back to 50 mg and see what happens. If I see BCR still dropping on 50 mg even at slower pace, I'm going to reduce the dose to 20 mg and see how it goes. If there is no significant improvement on 100 mg in 4 months (I test every 2 months now) I will drop back to 50 mg and start discussing switching to Bosutinib.

I think your BCR reduction pace is okay and I would switch to 50 mg and see if it continues. It may actually improve on 50 mg, but even if it continues at the same pace, you reduce the risk of complications significantly. Scuba has a theory that less is more and I'm going to test it myself in the following months.

Consider supplementing with selenium and NAC (N-Acetyl-L-Cysteine) to minimise the adverse effects of Dasatinib toxicity.

Selenium up to 400 mcg is considered safe long term, but it's best to measure it and discuss the action with your doctor. There is correlation between low level of selenium and chemo resistance, but there is no evidence of causation. It seems the safest one is Selenomethionine which is available in Brazil nuts and many supplements. MSA and MSC are not available as supplements, and Sodium Selenite is genotoxic.

Therapeutic Benefits of Selenium in Hematological Malignancies
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323677/

A report of high-dose selenium supplementation: response and toxicities
https://www.sciencedirect.com/science/article/abs/pii/S0946672X04000112?...

The Interaction of Selenium with Chemotherapy and Radiation on Normal and Malignant Human Mononuclear Blood Cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214079/

Antitumor Effects of Selenium
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584251/

NAC (N-Acetyl-L-Cysteine) seems to enhance the effectiveness of Imatinib and protect us from toxic effects of Dasatinib. The effective dose used on mice was 50 times the dose of Dasatinib, which is in your case 5 g, but that's probably too high. The highest dose tested on humans was 3.5 g and it caused diarrhea for some patients. I take between 600 mg and 1.8 g without any adverse effects, but if I don't see improvement in BCR reduction on 100 mg Dasatinib, I'm going to discontinue it between 2 tests and see if it helps. The problem with NAC is that it's used for synthesizing Glutathion and there is correlation between high levels of Glutathion in malignant cells and resistance to TKI. Selenium actually makes LSC vulnerable to TKI by depleting their levels of Glutathion.

Glutathion is also the most important antioxidant and we cannot live without it. :)

A narrative review on adverse effects of dasatinib with a focus on pharmacotherapy of dasatinib-induced pulmonary toxicities
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721448/

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

Glutathion is synthesized from Glutamine, Glycin, NAC and vitamin B6. All these are available through our standard diet and if you want to increase it normally it's not necessary to supplement Glutamine and B6, but only Glycine and NAC (ratio 2:1). But some of us may have high levels of Glycine, so supplementing NAC may be sufficient. So we should be careful even when using only NAC and always discuss and agree with your doctor and keep an eye on BCR trends.

Glycine and N‐acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002905/

NAC + Glycine Powder > Science & Research
https://www.pureencapsulationspro.com/nac-glycine-powder.html

If you are starting another medication or supplement, best to start it following a blood test and if there are negative effects/trends then stop it asap. Also, it's best not to start multiple supplements at once and record the dose and dates of start/stop/pause. I avoid pre-mixed stuff with too many ingredients like AG1.

Next time I see my doctor I will also ask for advice and a prescription for Misoprostol which has been discussed on this forum.

Prostaglandin E1 and its analog misoprostol inhibit human CML stem cell self-renewal via EP4 receptor activation and repression of AP-1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678929/

I will also ask about Tigecycline + Chloroquine autophagy inhibitor. I don't know how inhibiting authophagy would affect our overall health and is it something that's actually practiced on humans, but it's worth investigating.

Inhibition of autophagy enhances the selective anti-cancer activity of tigecycline to overcome drug resistance in the treatment of chronic myeloid leukemia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345227/

Chloroquine, an autophagy inhibitor, potentiates the radiosensitivity of glioma initiating cells by inhibiting autophagy and activating apoptosis
https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-016-0700-6#:....

Lys05 - A new lysosomal autophagy inhibitor
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442884/

I will post back if I learn anything useful and actionable.

Hi Sorin,

Sorry for the confusion.

Fasting is a great holistic therapy for the entire body, especially our immune system, and I doubt that CML cells could gain additional benefits from it.

It seems TKI induces authophagy and LSCs know how to use it to live forever.

Authophagy inhibitors can be used only if combined with something that can target only LSCs, but that has not been discovered yet.

Chloroquine is used againts malaria, but it proved to be not very effective authophagy inhibitor. I think Lys05 has not been approved for human consumption and if applied without targeting mechanism, it would probably devastate the body.

Tigecycline is a dangerous antibiotic used for skin, abdomen and lung infections and it was linked to multiple deaths, so no one is going to prescribe it without an obvious emergency.

I also fast ocasionally and I take curcumin whenever I can.