10 replies to this topic

[ChrisC]

Thanks to cousinreg for posting this in one of the discussions; didn't want it to get lost.

http://www.eventure-...congressId=4634

CESSATION OF DASATINIB OR NILOTINIB THERAPY IN CHRONIC-PHASE CHRONIC MYELOID LEUKAEMIA PATIENTS WITH SUSTAINED COMPLETE MOLECULAR RESPONSES

Author

MD, PhD Rea, Delphine, Hopital Saint-Louis, APHP, Paris, France (Presenting author)

Co-author(s)

Rousselot, Philippe, CH de Versailles, Le Chesnay, France

Nicolini, Franck, Hopital Edouard Herriot, Lyon, France

Legros, Laurence, GH l'Archet, Nice, France

Tulliez, Michel, Hopital Henri Mondor, Creteil, France

Guilhot, Francois, CHRU de Poitiers, La Miletrie, France

Mahon, Francois-Xavier, Hopital Haut Leveque, Bordeaux, France

Topic

8. Chronic myeloid leukemia - Clinical

Keywords

Chronic myeloid leukemia, Tyrosine kinase inhibitor

Background: Despite the outstanding efficacy of tyrosine kinase inhibitors (TKI) in chronic myeloid leukaemia (CML), the curative potential of these drugs remains uncertain. Recent results from the STop IMatinib trial suggest that imatinib may be safely discontinued in patients with long-lasting complete molecular responses (CMR) (Mahon et al. Lancet Oncol. 2010).

Aims: We asked whether second generation (2G)-TKI could ever be stopped in CML patients intolerant or resistant to imatinib who had achieved durable CMR. The primary objective was to evaluate the risk of losing major molecular responses (MMR: BCR-ABL/ABL internationally standardized (IS) ratio ? 0.1%) and the key secondary objective to measure treatment-free survival.

Methods: Patients aged at least 18 years with chronic phase (CP)-CML with prior imatinib treatment were proposed dasatinib or nilotinib discontinuation provided that (1) no prior progression to accelerated phase or blast crisis occurred (2) CMR was achieved and sustained on continuing therapy. CMR was defined by RQ-PCR, using a detection threshold of BCR-ABL of at least 4.5 Log (CMR4.5). After 2G-TKI discontinuation, BCR-ABL transcripts were quantified monthly during the first year and every 2 to 3 months thereafter. Dasatinib or nilotinib re-introduction was triggered by the loss of MMR which defined relapse.

Results: As of February, 2011, 17 patients entered the study after informed consent. The results presented here focus on a subgroup of 12 patients with a minimum follow-up 6 months (median 12, range, 7-18). These were 7 females and 5 males, with a median age of 59 years (range, 34-81). The Sokal risk group was low in 8/12 (68%), intermediate in 1/12 (8%), high in 1/12 (8%) and unknown in 2/12 (16%). Imatinib was discontinued owing to intolerance (n=11) or resistance (n=1) and replaced by dasatinib (n=8) or nilotinib (n=4) after a median duration of therapy of 50 months (range, 3-92). At start of 2G-TKI, 1 patient had a complete hematologic response only, 2 had a partial cytogenetic response, 1 had a complete cytogenetic response but lacked MMR, 3 had a MMR without CMR and 5 had a CMR. The median time on 2G-TKI therapy prior to discontinuation was 33 months (range, 21-56). The median duration of sustained CMR was 29 months (range, 21-39).

Subsequently, 30% (4/12) of patients lost MMR by 6 months. MMR was rapidly regained upon early 2G-TKI re-introduction. Treatment was also re-started in 1 patient without MMR loss but showing CMR loss on 2 consecutive assessments. Seven patients remained off therapy at the last follow-up after a median of 11 months (range, 7-18), with either a stable CMR or weakly detectable BCR-ABL transcripts on one or more occasions. Treatment-free survival rate by 6 months was estimated to 58.3 % (95%CI: 21.7-31.3).

Conclusion: 2G-TKI may be safely discontinued in CML patients with stable CMR4.5. Importantly, a very low level of detectable residual disease after 2G-TKI withdrawal may be compatible with treatment-free survival. A longer follow-up is required to ascertain whether CML will recur. Our study provides a reasonable basis for subsequent prospective clinical trials. Updated results will be presented.

[jrsboo]

Really????  They are claiming 58% success rate after 6 months?????  With a slow growing disease?  Gee,  I would spend the rest of my life worrying and worrying and worrying that it was coming back, only this time resistant to all the drugs.

Silly French!

Caroline

[ChrisC]

An earlier report on the study maybe explained it more clearly — or else I'm just seeing what I want to see? I didn't see anything to fear in it, anyway. Those that remained CML-free after stopping their medication (Gleevec in the following report, though this new study seems to say similar results for Sprycel and Tasigna too) have continued to be monitored for over two years so far. Those that relapsed did so in the first six months, then restarted treatment and quickly went back to being PCRU. Bravo to the researchers and to the study participants. I want to hear more, or to be corrected if I'm misunderstanding the findings, please.

http://www.physorg.c...-treatment.html

Some leukemia patients may be able to safely stop treatment

(PhysOrg.com) -- New medical trials suggest some chronic leukemia patients who are in complete remission may be cured by the standard drug used to treat the condition and can safely discontinue its use.

The trials showed that when doctors stopped treating chronic myeloid leukemia (CML) patients with the standard drug imatinib (also called Glivec) some remained completely free of the disease two years later. This contradicts the prevalent belief the treatment should be continued for life because the leukemia would always return if treatment was stopped due to the presence of leukemia-initiating stem cells resistant to imatinib.

The research team, led by Professor François-Xavier Mahon of the Victor Segalen Bordeaux University in France, aimed to find out if treatment with imatinib for CML could be safely discontinued, since little research on this had been done and the drug treatment is expensive. Their study, called the Stop Imatinib (STIM) study, was a prospective, non-randomized trial of 69 CML patients at 19 medical institutions in France. All participants had been taking imatinib for at least two years and were in stable "complete molecular remission" (CMR).

The results were that of the 69 patients followed for at least 12 months, 42 patients (61 percent) relapsed, with 40 of them relapsing in the first six months. The remaining patients did not suffer relapse in the two years they were followed. Imatinib treatment was reinstated for all patients who relapsed and all of them responded well.

The researchers concluded the results of this interim study suggest if patients have been in remission for at least two years it may be possible to discontinue the drug safely, and some patients will remain in remission, effectively having been cured by the drug. The results also suggest a better prognosis can be expected for male patients who have been treated for a long period with imatinib and who have a low prognostic Sokal score. Longer-term studies are continuing.

Chronic myeloid leukemia is a slow-developing form of leukemia. The majority of people with CML have a genetic abnormality in their blood cells called the Philadelphia (Ph) chromosome, which causes the production of an enzyme called tyrosine kinase. The enzyme produces an abnormal protein called BCR/ABL. Imatinib, a tyrosine-kinase inhibitor, is a standard drug for the disease but does not often produce complete remission. For this reason the option of discontinuing imatinib will only apply to around 10 percent of CML patients.

The paper was published online in the journal The Lancet Oncology and will appear in the print version of the journal.

Message was edited by: ChrisC

[scuba]

"Conclusion: 2G-TKI may be safely discontinued in CML patients with stable CMR4.5. Importantly, a very low level of detectable residual disease after 2G-TKI withdrawal may be compatible with treatment-free survival."

This post should generate lots of discussion from Trey.  Any detectable presence of bcr-abl, according to Trey, means you have CML.   Whether you grow the cancer in 1 year or 10 years - it's going to bite you in the butt sooner or later.  I am in the camp that the general population produces the PH+ chromosome as a natural course.  Most are able to defeat it and it never gets "detectable".  Some of us are not able to handle the PH+ transcripts and we go down the path of disease.  What is unknown is if one can beat the disease back far enough so that the body is able to regain control?  It is interesting that some patients who had CML (full blown, high WBC's etc.) were able to stay undetected for years after TKI treatment.  It is also interesting to know that when the disease reappeared, they were able to go back on their TKI and beat it back fast.  

The reality is that any one of us who finds a way to get to PCRu will always have to be tested. .  You just may have 30 years without disease (functionally cured?) - or six months.  What has me hopeful is that one does not need to be on a TKI every day for the rest of ones life.  You can get off the drug(s) for a time - and if lucky - for a long time.  But you have to be tested regularly.  CML is slow - it takes months for it to "regroup" when beaten down.

Look at my case.  I was taken off Sprycel for 5 months !!  No drugs.  And my WBC's hardly budged and I felt great.  My PCR and FISH kept dropping although I still had plenty of data suggesting disease (cytogenetics).  I am back on Sprycel (low dose) for 5 weeks now to try and get the cytogenetics down to zero cells out of 20.  I don't know if I am one of the 5% who can't handle long term TKI's in order to get to MMR or better.  I don't have a side affects issue, but I do have a myelosuppression issue.  It's definitely been tough for me since I am chronically low on Neutrophils.  But if I can get the population of good cells to re-capture my bone marrow relative to CML cells then the battle can be won.  It's all about population dynamics and keeping the pressure on the CML cells so the body makes more normal cells.  According to Dr. Cortes that can take years.  The key is avoiding blast crisis.  That is my concern.

Also - for what it is worth.  Socialized medicine country's have an incentive to get people off drugs.  I suspect that is the true motivation for the French study.

[Trey]

People who like TKI cessation may also like this:

http://www.youtube.c...h?v=i_ad7rXb-T0

[helenet]

But what about at least a nice rest from the TKI?

[Susan61]

Maybe I am a bit crazy, but I never look a gift horse in the mouth as they say.  I have never even entertained stopping my TKI which is Gleevec.  As long as I am living a somewhat normal life, and have gotten to PCRU why would I stop my Gleevec to see what could happen.  I will probably never see a cure in my lifetime, but as long as I go on as I am God Willing I will just keep doing what I am doing.  If I ever have to switch to another TKI, it might not even work for me.

I feel very blessed in so many ways since the beginning of my journey with my CML in 1998.

Susan

[ChrisC]

Trey has it clear, as always: some see a snake and others see a piece of string. The world is as we see it!

[CallMeLucky]

The difference is, Susan, you have seen the worst of it.  You did the Interferon, and you had to deal with a diagnosis when doctor's weren't telling you "don't worry, you'll be fine" you had quite the opposite and I'm sorry you had to go through that.  When I think about what I went through it was scary enough and everyone was telling me how lucky I was and not to worry about it, "just take a pill each day and you'll be fine".  I can't even imagine what it must have been like for you generation of CML when the doctor would look at you with very little hope.  Thankfully you were part of the first CML generation to see Gleevec.  For us newbies it is a little harder to be ok with being on the drug for rest of our lives.  We were scared, but we had something to hold on to and if we are lucky enough to be doing well, we start to think, hmm, maybe this could be even better, it's just typical human reasoning -I want something better than what I have today.  I don't want the side effects, I don't want the cost of the drugs and the challenges if I change jobs, I want to be cured. 

I'm actually pretty conservative in my approach to this and a functional cure concerns me.  This whole idea of we stopped the drug, they lost CMR, but have maintained a MMR.  So what does that mean?  One school of thought says "look how wonderful this is, the body is keeping it under control".  Another school of thought says "well it's just a matter of time before that relapses or worse, mutates!".  The assumption is that you can go back on the drug and be ok.  To the end that you could try to stop the drug and not lose CMR, maybe that is worth the risk, although I would like a more sensitive PCR to take that leap.  But to me, if you lose CMR, even if you are holding MMR, I don't know about that one.  This isn't just my thinking, I had this exact conversation with my Dr and she is very leery of this.

One other thought though.  It is understandable to an extent why doctors in the US, even the best experts, and doctors in Europe have different enthusiasm for this.  In the US, it is very profitable to be sick.  In Europe it is quite a drain on the society.  They have different incentives for getting people off drugs than we do.  I'm not sure who is right.  If I can hold a deep CMR for a few years, I might consider taking a closely monitored break and see what happens, but first sign it was back I would likely go right back on the drug, I don't know that I would be willing to live with MMR while not on a drug.  I'm hoping in the next couple of years there will be some good trials that will look at some new treatments aimed at cure, rather than just cessation and hoping for the best.

[GerryL]

Can I suggest a different view of what is happening in Europe and other countries as opposed to what happens in the States - perhaps it just comes down to who is sponsoring the research. If it is a drug company they would be looking for something that will give them a return, which is fair enough as they invest a lot of money in the development of something that may never amount to anything. Anything that works plus requires long time use is probably the jackpot for them.

Where as research conducted using grants and fund raising would be hoping that they can find something and possibly make a profit out of it, but profit would not be the main basis.

Gerry

[valiantchong]

I  believe presently CML could be 'cured', the data from medical records showed on interferon showed 12% could be off medication over 20 years, now 5% of the patient with CMR on Imatinib  could be off medication over 5 years, and with present 2 nd Generation TKIs is faster CMR response, it suppose to have a higher % of functional 'cured'. I would estimate base on the data about 52% could be off 2nd Generation TKIs in the future trial.

  I hope that with newer drugs or vaccine therapy, one day may be over 90% of patients will be able truly cured rather than define as functional cure.

Hopefully within 10 yrs.