15 replies to this topic

[xxgirl]

What does "There is a 35-nucleotide insertion between exon 8 and exon 9 which may represent alternative splicing" mean?

 

Anyone else have this?

Attached Files

•  doc20150623081020.pdf   77.22KB   26 downloads

[Trey]

TKI drugs work by binding to the ABL kinase portion of the leukemic BCR-ABL.  This TKI binding shuts down the proliferation of leukemic blood cells.  Kinase mutations can cause blockage of the TKI drug binding site on the ABL kinase, either total or partial.  What affects one TKI drug may not affect the others.  Some of these kinase mutation have names such as T315i (the worst), or G250E, F317L, Y253H, etc, etc.  There are over 100 known ABL kinase mutations. 

 

You have a kinase mutation which does not have a short name since it is an insertion mutation.  That does not necessarily make it worse, just different.  It affects about 2% of patients.  This mutation can cause Gleevec to work less well, but it should not be an issue for the other drugs, especially Sprycel (which you are already taking).  So I would say it should be ignored. 

 

Last I knew you have very low blood counts.  How is that going?  You didn't say, but maybe you took a drug break and it affected your FISH or PCR results?

 

http://www.ncbi.nlm....pubmed/21895409

http://www.ncbi.nlm....les/PMC2259473/

[xxgirl]

Thank you Trey. All information that I could find regarding 35ins was inconclusive.

Blood counts remain persistently low. I've had 2 blood transfusions (one with hemoglobin at 6.8 and the next at 7.9), and three procrit shots. Platelets remain low coming in the last 3 weeks between 32-36, with the lowest so far at 22 at the end of May. While WBC is not extremely low at 2.8 , ANC is at 700 as of yesterday.

No drug breaks, although, it was considered when platelets went down to 22, and I haven't had another PCR since the end of April which came back at approximately 12%. Next PCR in 2 weeks.

Is it unusual for the insertion mutation to show up while on Sprycel? Can mutations develop over time - meaning is it possible to develop a mutation that is not currently present?

[Trey]

The mutation probably was there from the beginning and just showed up over time.  You are still within the first couple years of diagnosis when these things play out and come to the forefront.  So it is not that it was caused by Sprycel. 

 

There is no hard evidence regarding how kinase mutations "develop" (probably the wrong term), but since they almost never show up after the first couple years, I believe they are there from the beginning.  It takes about two years for the CML to show all its cards.  The TKI drugs do not directly kill leukemic cells, which is why I do not believe they can cause mutations by only halfway killing a leukemic stem cell.  That does not make sense to me. 

 

Many CML patients have slight variations in the BCR-ABL, and most of them do not affect how the drugs work, but some do affect drug binding. 

 

Here is a reiteration of what I have previously written about kinase mutations:

1) The NCCN CML Treatment Guidelines authorize low dosage TKI drug dosages.

2) Leading CML Oncs regularly authorize reduced TKI drug dosages (Dr Cortes at MDA has patients on 15% dosage -- is he trying to induce mutations to perform some evil experiment?  If so, can we watch?)

3) Dr Druker has changed from worrying about low dosage TKI drugs a few years ago to authorizing low dose Gleevec for long term "maintenance therapy" after several years PCRU, as reported by one of our members here.

4) Most kinase mutations occur while patients are taking full dosage TKI drugs (from what I have observed on this L&L website).

5) There are over 100 known kinase mutations, and most do not prevent the TKI drug from working, although they can sometimes reduce effectiveness, and only a very few can prevent the TKI drug from working.

6) Our TKI blood level concentrations change all day long.  Peak concentration occurs a couple hours after taking the drug, then it declines continually until the next dose.  So aren't we all on "half dose" or less most of the day and night?  Why isn't that a problem if the theory of low dosage mutation applies?

 

And more stuff I have written on this subject:

http://community.lls...ons#entry159133

Edited by Trey, 24 June 2015 - 08:45 AM.

[scuba]

Your blood counts dropping is a concern. You are on Sprycel full dose (100 mg.) after having switched from Gleevec. The same was done for me. I had severe myelosuppression with Sprycel as well and at only 70mg. I was taken off Sprycel to let my blood counts recover enough to resume. Dr. Cortes' approach at M.D. Anderson in my case was to use drug breaks to manage the low counts and not rely on stim shots or transfusions. I had weekly CBC tests to monitor.

 

ANC below 700 is a concern. ANC below 400 is dangerous. You should be having weekly CBC tests to monitor your lowering counts. My strong recommendation is for you to ask your doctor to use dose interruption or dose lowering until your counts stabilize at an acceptable level. If your counts keep dropping on a lowered dose you may need to stop therapy until your counts recover. After my forced cessation from 70mg Sprycel, I was placed on 20mg. Sprycel. My counts did start to drop again, but not as bad and they stabilized. My dose was never increased and my counts slowly came up. And on only 20mg Sprycel, I was able to achieve PCRU (although I do take Curcumin which may enhance low dose effectiveness).

 

Sprycel is powerful. It is a threshold drug unlike Gleevec. When sufficient Sprycel is working more doesn't make it work any better. And in fact, less may be better to get the best result (balance with suppression). Some people need full dose to get to their threshold amount and others less. Myelosuppression (which you are experiencing) is a sure indicator that too much Sprycel is in your system.

[xxgirl]

Michael -

 

I know that the low counts are concerning, that is why I AM currently on the weekly CBC schedule.  It's been almost 3 months with consistently low blood counts.  The thing that I think is strange is that I had normal blood counts for 9 months on Gleevec with a falling BCR-ABL, and now, 14-15 months post diagnosis, blood counts do not seem to want to normalize at all on Sprycel.  

 

I think that you are, indeed, correct and that the 100mg dose may be too much for me, but with a NO log reduction in my BCR-ABL, I think that my onc is reluctant to put me on anything less than a full dose at this time, or even to take a drug break, unless platelets fall below 20, or there is a rise in my BCR-ABL.  He feels like low Hgb is treatable, and that my "good cells" are going to kick in and up their production any time now.  

 

To be quite honest, I think I am an anomaly that is challenging his standard protocol, and he doesn't know quite what to do with me, except monitor me closely, act when absolutely necessary, and wait and see.  

 

Until my PCR results come back with numbers only on the other side of the decimal point, I'm coping with the myelosuppression, and dutifully following drs orders.  When/If that happens, I may fight for a dosage reduction.

[xxgirl]

Trey,

 

Thank you for the more in depth info on Kinase Mutations.  Hopefully all of the cards are already on the table, and nothing else "pops up" in the next year or so. 

[Trey]

There is not one best drug for every patient.  If one TKI does not do the job, it is often a good idea to move on to the next.  TKI drugs are a trial and error approach.  Maybe you should try Tasigna if the next PCR does not budge much.

[scuba]

Michael -

 

I know that the low counts are concerning, that is why I AM currently on the weekly CBC schedule.  It's been almost 3 months with consistently low blood counts.  The thing that I think is strange is that I had normal blood counts for 9 months on Gleevec with a falling BCR-ABL, and now, 14-15 months post diagnosis, blood counts do not seem to want to normalize at all on Sprycel.  

 

I think that you are, indeed, correct and that the 100mg dose may be too much for me, but with a NO log reduction in my BCR-ABL, I think that my onc is reluctant to put me on anything less than a full dose at this time, or even to take a drug break, unless platelets fall below 20, or there is a rise in my BCR-ABL.  He feels like low Hgb is treatable, and that my "good cells" are going to kick in and up their production any time now.  

 

To be quite honest, I think I am an anomaly that is challenging his standard protocol, and he doesn't know quite what to do with me, except monitor me closely, act when absolutely necessary, and wait and see.  

 

Until my PCR results come back with numbers only on the other side of the decimal point, I'm coping with the myelosuppression, and dutifully following drs orders.  When/If that happens, I may fight for a dosage reduction.

 

Since you had good response with Gleevec, Tasigna might be a good alternative. It is designed similarly to Gleevec but with a better  chemical fit to the ATP socket that interrupts and shuts down CML cells. You will probably not have the same side effects you had with Gleevec. Whatever you decide - staying on 100mg Sprycel is probably not doable longer term so even if your PCR drops down, you may likely have to reduce dose or interrupt treatment. Doing that can be a roller coaster emotional ride. Talk to your doctor about changing drugs.

 

(For what it is worth, I never had normal blood counts on Sprycel - even 20mg. My counts did recover getting close to normal over time, but RBC's stabilized 25% below normal and Neutrophils stabilized right at the low normal mark. It took a long time for recovery. Even though I am off Sprycel now for 4 months, my RBC's are only now starting to climb upward and my hemoglobin and hematocrit just crossed the low normal boundary. The anemia I was feeling during high intensity exercise is fading. My Neutrophils are still low normal. So something has definitely changed in my bone marrow post treatment that looks like it will take awhile to clear. Of course CML could come roaring back while I am off Sprycel ... or not)

[xxgirl]

I would like to reduce Sprycel dosage, eventually, but am leery of jumping ship just yet.  Gleevec worked well for me - until it suddenly didn't, and PCR jumped from 6% to 46% in three months.  Side effects on Gleevec were...different that Sprycel, with more nausea, bone pain, and muscle aches, and fewer blood count, skin and mouth sore issues.  Ideally, I'd like to see a large drop in my PCR, and then broach the topic of experimental dosage reduction with my doctor to see if a lower dosage will stabilize my blood counts at all, while still being effective in lowering my PCR.  

 

I am not opposed to trying Tasigna, if necessary.  Would the mutation that I have be a factor in that, since - in my understanding - gleevec and tasigna are chemically similar?  From the information that I've been able to gather the insertion mutation may be Imatinib resistant, but not nilotinib, or dasatinib resistant as far as they know, correct?

[Trey]

I don't think it can be known whether Tasigna would work unless you try it.  It may be that the 35 Insertion is not causing reduced response on Sprycel, but maybe it is.  Trial and error is usually required.

[Pin]

Hey Scuba, can you please explain a bit more about what you mean by Sprycel being a "threshold drug unlike Gleevec"?

I don't think I've heard that said before - sounds interesting.

[Trey]

Sprycel...is a threshold drug unlike Gleevec.

 

Pin,

Bovine sharts can often sound interesting. 

[scuba]

Hey Scuba, can you please explain a bit more about what you mean by Sprycel being a "threshold drug unlike Gleevec"?

I don't think I've heard that said before - sounds interesting.

 

Pin, 

Don't pay much attention to Trey, he's had a bit too much fiber in his diet lately ....

 

A threshold drug is one where above a certain plasma level it's effect is most pronounced and quickly. This is mostly true for drugs whose half-life in the blood is measured in only few hours or less. Sprycel does not last in the blood very long (5 hour half life) whereas Gleevec's half-life is near 19 hours. Sprycel has to do its work fast. When the threshold is reached, the drugs effectiveness is very pronounced. More can be toxic and does not mean better response. Less and there is no effect. The key is finding the threshold. For some - they need 100mg, others - only 20mg (like myself). 

[Trey]

No such thing as a "threshold drug".  You are referring to the "dose response relationship" which relates to all drugs (including Gleevec, Tasigna, Sprycel, etc, etc).

 

https://en.wikipedia...se_relationship

[scuba]

No such thing as a "threshold drug".  You are referring to the "dose response relationship" which relates to all drugs (including Gleevec, Tasigna, Sprycel, etc, etc).

 

https://en.wikipedia...se_relationship

 

I am well aware of dose response relationships and what a threshold dose means. That wasn't my point.

 

From the reference you cite above:

 

"The first point along the graph where a response above zero (or above the control response) is reached is usually referred to as a threshold-dose. For most beneficial or recreational drugs, the desired effects are found at doses slightly greater than the threshold dose. At higher doses, undesired side effects appear and grow stronger as the dose increases. The more potent a particular substance is, the steeper this curve will be."

 

In conversations with M.D. Anderson staff when they switched me from Gleevec to Sprycel, they referred to Sprycel as a "threshold drug" because the dose response curve is steep for Sprycel, they refer to it as a threshold drug. It's a term they use.