14 replies to this topic

[scuba]

Two Papers/Posters to be presented at this years ASH Conference highlight the impact of dose reduction on outcome related to myelosuppression.

http://ash.confex.co...Paper44523.html

Conclusion:  Although dose reductions are frequently required for pts with CML treated with dasatinib or nilotinib, dose reductions did not lead to adverse outcome. Dose adjustments can be used when required to manage AEs. This approach allows in most instances continuation of these highly effective therapies.Â

http://ash.confex.co...Paper42039.html

Conclusion:  MS is a common AE among pts receiving therapy with dasatinib or nilotinib as initial therapy for CML that frequently leads to dose reductions, and is associated with an inferior outcome.  Whether the worse outcome reflects decreased dose intensity, or whether the outcome and decreased tolerance to therapy reflect an intrinsic difference in disease biology remains to be determined.

Two very different conclusions!

[CallMeLucky]

If I understand it correctly, the one with the favorable outcome was for people who had adverse effects (broad range, including some myelosuppression).  In the second one, it appears they focused just on people with myelosuppression, and in those cases there were less favorable results when dosage was reduced, although still not too bad (36 mo OS 100% in either scenario).

The second one is raising a different question - does severe myelosuppression suggest a more difficult to treat scenario independent of the drug/dosage.  They end by saying it needs more research.

[Trey]

This is one of the reasons why Gleevec should not be ruled out for initial treatment of CML.  Myelosuppression from Tasigna or Sprycel can result in slower response due to frequent drug breaks.

[rct]

Myelosuppression sucks.  It drastically alters the Miracle Drug look of these things when you are living through it.  Sure, we're glad she's alive.  But another couple years of this and we won't be.  It sucks, and they don't really know why it happens.

rct

[scuba]

Reply to Trey:  Not sure I concur.  I suffered severe myelosuppression with Gleevec.  It worked initially to drop my counts to normal, but after several months, my counts kept dropping.  Eventually I had treatment interuptation with Gleevec as well as eventual reduction to 300mg, but had cytogenetic failure (Ph+ = 100%).  And I still experienced additional myelosuppression.  I stayed off Gleevec until counts resumed and then I was placed on 70mg. Sprycel.  Sprycel did the same thing as Gleevec vis a vis myelosuppression, but I at least had a cytogenetic response. 

The question which is not resolved is dose.  Many Oncologists interrupt treatment and then resume at full dose or slightly lower dose.  Dr. Cortes prescribed dramatically lower dose Sprycel in order to calibrate the myelosuppression against response.  And in my case it seemed to work.  Cell counts stabilized upward and I continued to have significant response in the bone marrow (PH+ = 0; PCR = 0.1). 

I would be concerned that low dose Gleevec (i.e. <300m) is not as effective in disease management as low dose Dasatinib seems to be.  They are not the same.

[scuba]

RCT:  What dose does your wife take currently?

[rct]

400.  We've done the three hunnert and the two hunnert.  PCR changes.  Sure, only a little, but in the wrong direction.

Basically they have a PCRu patient that has to shoot Neupogen to stay out of the toilet for counts.  She is back on neupogen after a pretty good while of not having to use it, ANC back under 500 again.  They, including Druker, would rather have a PCRu patient on Neupogen than change stuff up and lose the response.  The patient would rather not be using that stuff.

January visit may bring a change.  Last time she tried she didn't get two weeks into Tasigna and her ANC tanked bad.  May have to try the other if it will get her off the Neupogen.

rct

[scuba]

Dr. Cortes switched me to Sprycel and dropped my Sprycel dose by 4/5ths from the normal 100mg  in order to get my myelosuppression under control.  He did not want to use Neupogen on me without first trying low dose first Sprycel.  He has had 100's of patients on 20mg. with great success.  I am now one of them.  Perhaps this may be a useful strategy to your wife.

One very significant benefit of the low dose is that I have no side affects (with which I am aware).

[rct]

Ok, well, I may mention Cortez in Texas, right?  If he's got more than one on 20 they might want to talk to him if he is having success with you and others.  Thank you for the tip.

rct

[scuba]

Absolutely you should have your Oncologist collaborate with Dr. Cortes at MD Anderson.  He has 100's of patients on 20mg. of Sprycel with success.  My response I was told was in the middle:  CCyR at 7 months.  Some took longer, some were quicker.  This was complete loss of the PH+ chromosome by Bone Marrow cytogenetic which is just another word for FISH.

I have maintained adequate ANC levels (between 1.0 - 1.6 without stim shots).  He did say that my response was quicker than he thought given my history (see papers above), but maybe Curcumin is having a role.  We don't know, so I continue to take Curcumin.  It benefits the body in other ways.  His lab techs told me he starts no one on Sprycel greater than 70mg. and quickly drops dosage dramatically when myelosuppression appears often stopping therapy for counts to recover before re-starting on the lower dose.  I was at 70mg to start - lasted two weeks before ANC went to 0.1 (those were the days), stopped TKI therapy for 3 months as my counts slowly recovered to 1.0 ANC, re-started on 20mg Sprycel, my counts fell back again, but this time stayed above 0.5-0.6 - and I was kept on Sprycel 20mg. - then over the next 8 weeks or so my counts started to rise to a record high of 1.6 where they leveled off for months.  My last ANC was down to 1.0 again, but has since risen.  I have a suspicion that I still don't have enough normal stem cells in my bone marrow yet.  The chronic myelosuppression - to me - reflects a continuing battle with CML making stem cells.  The Sprycel is getting them, but my normal cells are not expanding in order to re-populate my marrow.

Also my PCR which was stubbornly high during my Gleevec, TKI drug break days began it's march downward to very close to MMR once I was able to stay on 20mg. Sprycel.  I anticipate further PCR reduction at my next 3 month check to put me squarely in MMR category. 

I do have concern about myelosuppression since your story on how your wife was PCRu for a long time with stable blood and then suddenly her counts dropped.  I don't know if additional mutations are the culprit behind myelosuppression.  

[Trey]

Michael.

Gleevec may not have worked for you, but that does not prove anything about Gleevec as a front-line CML drug.  There are many counter-examples to your experience, as yours is quite unique. 

Also, the Sprycel dosage was established based on patient response curves during years of clinical trials.  There is a good reason it was not set at 20mg instead of the current 100mg.  That does not mean it cannot be tweaked for individual patients, which it should be.  For some, maybe you, and maybe a few others, there may be a good reason to use lower dosages.  But that is not automatically the case for everyone.  Examples using the experiences of a handful of patients do not disprove years of clinical data.  But it is certainly worthy of testing further.  And I agree that RCT's wife might benefit from low dosage Sprycel due to her individual experiences to date.

[scuba]

Trey:

No general disagreement on Gleevec.  I just wish I had been started on Sprycel from the start as Dr. Cortes would have done if I had seen him first (he was not my first Oncologist because I had no idea what the hell was wrong with how I was feeling).  And my case is not that unique.  Dr. Cortes in his own words told me I fit right into the pattern of many who have myelosuppression and have fine outcomes.  Myelosuppression with Sprycel is fairly typical.

Dr. Cortes feels strongly based on the trial data that 100mg is too high.  The highest he prescribes is 70mg.  The difference in response between 20 and 70 was very small according to the data (marginal increase in benefit vs the toxic risks (i.e. pleural effusion, etc.)).  The benefit of the lower dose was the dramatic lower side affects without meaningful loss of response.

I am not suggesting anyone drop their dose.   I do recall you suggesting that dose needs to be studied further and that max dose may not necessarily be needed to maintain response.  I am a living example that it seems to work. 

I want to repeat:  Dr. Cortes lowered my dose in order to manage myelosuppression as the first priority without more drug breaks.  He wanted to find out at what point my cell counts would stabilize on their own WITHOUT stim shots.  And then at that point, once stable, he wanted to see if I had response.  It turns out I did have a good response.  He now wants to keep me here - no increase in drug - to monitor my progress.  He did not drop me gradually - from 70 to 50, 40, 20.  He went from 70 to 20.  And when he saw that I became Ph+ zero in a total of seven months - he said there is no reason to increase my dose and risk more myelosuppression.  In his words, "Once I find what works,  leave it alone".

[scuba]

2768 Impact of Dose Reductions and Interruptions Due to Adverse Events (AEs)on Efficacy in Newly Diagnosed Chronic Myeloid Leukemia in ChronicPhase (CML-CP) Patients (pts) Receiving Either Dasatinib (D) or Imatinib(IM): Analysis of the DASISION Trial

Conclusions: Results of this analysis suggest that CML-CP pts receiving dasatinib achieved similar response rates despite dose modification for the management of AEs. Data for pts with and without dose reduction and/or interruption due to AEs are consistent with DASISION 24-months results, showing higher rates of response with dasatinib than with imatinib.

[scuba]

Thanks Billie.  I'm doing all right so far, but not out of the woods sort of speak.  When I get a zero in the PCR number, I will believe that the molecular expression of the Ph+ chromosome is finally under control.  It is that number that indicates liklihood of progression.  I also have monosomy 7 and trisomy 8 to deal with.  I am told that these conditions are not a big deal in CML and usually resolve themselves (i.e. go away), but I have to have more bone marrow work done to verify in six months.  So until that is achieved, I do have a 0.5% risk of progressing to AML.  Very low, but very real.  The good news is that the population of Ph+ progenitor cells is going down to where they don't see them under a microscope anymore. 

The Ph+ stem cells?  I probably still have plenty of them.