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Higher dose of Dasatnib causes lower response ??

THE HIGHER THE DOSE OF DASATINIB, THE LOWER THE MOLECULAR RESPONSES AS WELL AS THE GREATER THE DOSE-LIMITING TOXICITIES IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA

https://learningcenter.ehaweb.org/eha/2018/stockholm/216328/jangik.lee.t...

Conclusion
The higher Dose/BSA of dasatinib not only increased the chance of DLT occurrence but also decreased the probability of MR achievement. It appears necessary to administer a lower initial dose of dasatinib to an individual patient in order to achieve a higher MR as well as to keep a lower rate of DLTs in the treatment of patients with CP-CML.

This is 'radical' ... and it does seem to correlate with my experience. My response to Dasatinib 'increased' when my dose was lowered. I am not sure I believe this yet, but it is important that doctors administrating Dasatinib start with lower doses initially if for no other reason than to avoid toxicities and go down if response occurs.

This paper was brought to my attention by a CML patient in India.

This is completely counterintuitive.  The real question is whether or not the study was done properly and if so, would the same thing happen with Tasigna and Gleevec, and if not, why not?  I agree wholeheartedly with dose titration with all TKI's, and I understand in your case that myelosuppression forced you to 20 mg Sprycell, but how do you reconcile this with the DESTINY trials where people go to half dose and if they lose MMR, their dose is increased and close to 100% regain MMR????  Was Sprycel not in the DESTINY trials?  Same with STOP trials - when MMR is lost, patients go back to previous dose of TKI and almost all regain MMR.

Sounds too good to be true to me, but fascinating if it is.

 

I went to my oncologist today and discussed some stuff with
him about leukemia stem cells and their ability to continue
to replicate themselves and Scubas theory about fasting to coaxing
the quiescent LSC out of hiding and exposing these culprits
to daily TKI’s medicine.
He told me that might work.
He also told me that the secret is in the stem cell and
nobody knows who they are. They are the secret of God.
If we know what stem cells do and can’t do we can create life.
Only God or Darwin knows what stem cells will do.
I told him if CML is genetic than the progression of CML is also.
Looks that way he said. No matter what drugs you take.


Romo

I verified with M.D. Anderson ... they do see Sprycel more effective with less toxicity at lower doses. Unbelievable.

They are working on a protocol. It seems 50 mg may be the new starting dose and then go down form there. This is very interesting.

 

 

Scuba
Looks promising, I know people in the South Texas area going to MD Anderson after failure with there local primary care docs one in particular almost lost his eyesight with Gleevec. After 5 months WBC was still above 100,000 and PCR in the high teens he made the trip to Houston to see Dr. Benton, after three weeks on 50mg Sprycel, PCR was in the low teens. If my local oncologist does not come around to a lower dose I am considering moving over to MD Anderson not sure about the three hour drive.

Do you happen to have a link to the complete paper?   I’ve only been able to find the abstract.  

... just the link above.

Scuba, thanks for the link, seems like a new dasatinib dosing trend might be on its way. I keep my fingers crossed, I am at 80mg now and would love to lower it and get rid of the fear of PE coming back.

There's a couple of things I don't understand though.

1) The abstract always talks about dose/BSA (body surface area); from my understanding, in super simple terms, the bigger you are the more dose you need, and viceversa. Which is intuitive, and also a concern I've read a few times in forums (question like: "I am big, should I increase my dosage?" or "I am small, can I decrease my dosage?).

Yet the title removes BSA from the equation. Sounds a bit dodgie to me, removing a denominator from an equation is not something you do lightly...

2) The current dosage protocol for Dasatinib was established trough extended trials, and observed for quite a long time. If the 100mg baseline was excessive, well, I kind of have a feeling someone would have noticed it sooner.
On the other hand, this might be explainable by the fact that TKI are first tested on patients with a more difficult profile; for example, I believe Dasatinib was first tested with patients who could not get a result with Imatinib, or in accelerated phase, and so on. So maybe the dosage was not adjusted for your average patient.

Cheers,

Davide

 

It is indeed very interesting, but for me it would be very helpful to understand the detailed science behind this because it is contrary to every other drug I have had experience with (perhaps Sandy Craine could provide comment or perhaps we could get Trey to make a guest appearance). If this is really true, why isn't MD Anderson starting everyone at 20 MG as this would yield deeper response than 50 mg with lesser side effects?  If this is true, why doesn't Bristol-Meyers Squibb make a 5 MG or even a 1MG tablet because that would work even better than 20 mg.  At a minimum, there still has to be a threshold dose below which the cancer will progress.

I certainly hope this is true, but I think it is way too premature for us CMLers to start experimenting on our own without the knowledge and support of our oncologists.  I believe that all TKI's are threshold drugs and that the threshold varies by individual.  I also believe that more and more oncologists are beginning to work with their patients to find the appropriate dose that contains the cancer and minimizes side effects.  Some decide to titrate dose down on their own, but this instantly destroys the patient-doctor relationship.  Like you have said many times Scuba, if your doctor won't agree to dose reduction when it is obvious and/or necessary, you should find another doctor who will.

I am speculating, but the only way I see a lower dose working better than a higher dose toxicity aside is in regard to the immune system response overall.

We know that Sprcyel causes myelosuppression. It also kills CML cells. But CML cells are also killed by our immune system - just imperfectly for us who develop CML. My thinking is that as you add Sprycel from low to high dose before toxicity, CML is attacked hard and our immune system which is also attacking CML is not affected much by the low dose Sprycel. In fact, it might even be helping it by weaning out weaker immune cells susecptible to the Src kinase inhibition. As Sprycel dose increases, no change in CML attack (thrushold drug), but our immune system is now suppressed and the added attack on CML by our immune system is also suppressed. CML increases somewhat given that there is less overall attack.

This is just my thought on what might be going on to explain why researchers are now seeing better response when dose is lowered. And it may not be true overall, just in some cases.

What I would recommend to anyone taking Sprycel - especially those on full 100 mg dose who are CCyR (FISH  = zero) is to consider lowering dose immediately to 40-50 mg and monitor response over the next few months. If response goes up, lower dose further to find the right balance.

My dose was lowered due to myelosuppression (from 70 to 20 mg) and my response skyrocketed! I am PCRU currently on 20 mg.

Risk in trying this is near zero. Probably less than the risk of getting hit by lightening in Gobi desert - or drowning in the Sahara, or running out of Bourbon in New Orleans.

Your theory might be supported by my experience on full dose Tasigna.  Within 30 days of starting, I began to develop squamous cell skin carcinomas at an alarming rate - I had 9 confirmed SCC's and approximately 40 - 50 precancerous lesions removed from my arms and legs between December 2016 and March 2017. Until tasigna/cml, I had never had a single skin cancer. I reduced dose from 600 - 450 mg per day in mid March and haven't had one since.  Maybe the dose reduction allowed my immune system to start working again enough to inhibit the skin cancer - who knows but it is interesting as you say. 

If this theory is correct, then the less is better theory should work for all TKI's, not just Sprycel, at least until the threshold dosage is reached.

It's hard to know. We're just guessing of course.

It would take a significant double blind clinical trial to verify. I don't see that happening largely because the cost would be high relative to the operational gain. Doctors do have the ability to lower dose based on patient by patient experience. And because CML is a slow disease when in chronic phase and under deep remission (PCR < 0.1%), experimenting with dose is low risk (like the odds of U.K. winning the World Cup - ever - no, strike that - odds of the U.S.A. ever winning the world cup).

Take a look at this - a similar study and results for Tasigna:

https://www.cancertherapyadvisor.com/chronic-myeloid-leukemia/chronic-le...

Dasatnib is a targeted drug. If you are big or small your Leukemia stem cells
can still be the same amount or not.. You only need enough drug to for your LSC.
That’s the mystery. A 500 pound man might only have 10 Leukemia stem cells.
A 100 pound man might have 50 Leukemia stem cells.
The above is just an abstract example.
Figure out the dose that works for you and you got the best option.
We are our own Doctors.

Romo

TKIs save lives: now it's time to address overtreatment

This is a little bit off the topic of your thread Scuba, but I thought Dr. Rea's presentation was quite interesting.

https://vimeo.com/272187639

I read your theory, Scuba, to my husband. My husband said this is exactly what my hem/Onc said at my last visit. I think I was encased in brain fog or something.

Today was day 3 of dasatinib 20mg. Here is praying that my immune system is bulking up!

I just went to the doctor today and fought for a lower dose of Sprycel. I started off at 100 mg. At 3 months went to 70mg. Now I will be lowered to 50mg. My molecular response is at 1 now and it needs to go below 1. It started off at 83. Scuba, you said your doctor had given you 20mg right away? In a previous post which I cant find now you said where you went to and what doctor prescribed you 20mg. Can you tell me who it is?

M.D. Anderson Cancer center in Houston, Texas

Dr. Cortes is my Oncologist.

I take 20 mg of Sprycel at night. I am PCRU.

I intend to stop Sprycel by the end of this year and test cessation (my second attempt).