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CML Drug Response, Resistence, & Relapse

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RESPONSE TO THERAPY :

The term used by the leading CML specialists is "response", not "remission", since remission implies a cure.  This is more than just a technical difference, since other types of curable cancer have remission, but we have response to drug therapy.  The exception is a bone marrow transplant where remission (cure) is the goal.  The goal of our drug therapy is to gain maximum response to the drug therapy which halts disease progression and put the disease into a continuous state  of  very low level chronic stage CML.  So we have various levels of response to treatment, not remission.  But if family and friends don't understand that, then using the term "remission" is certainly understandable.  But then "remission" would be hard to categorize, since one would need to assign an arbitrary point where "remission" occurs, or begins to occur.


Stages of CML "Response":

- Diagnosis: A zero response baseline from which to measure response to drug therapy

- Complete Hematological Response (CHR): The WBC and platelets return to normal ranges and the spleen shrinks back to normal size

- Complete Cytogenetic Response (CCR or CCyR): Either a BMB or FISH is negative, or 2 log reduction in PCR from diagnosis or lab baseline average

- Major Molecular Response (MMR): PCR shows a 3 log reduction  in leukemia from diagnosis levels or lab baseline average

- Complete  Molecular Response (CMR): PCR is negative/undetectable (PCRU), so BCR-ABL transcripts are undetectable by PCR testing (leukemia levels too low to detect)

- Cure: 5 years of continuous PCRU with no therapy -- rare today without  a  BM transplant, but research looks promising and could change that  some  day soon.

It is most important to see the WBC count drop quickly. The red counts/HGB/HCT and maybe others will be unstable for a while, probably for months. The body must get used to Gleevec and figure out how to establish a "new normal" blood system, because the good cells are being put back in control instead of having the leukemic cells in control.  The anemia will likely persist for a while. Many of us struggle with  that  issue, but it often improves over time.


Before other TKI drugs were approved, Gleevec had been effective for 88% of CML cases in a large sample of early users of Gleevec:

http://www.prnewswire.com/mnr/novartis/31035/

Other data shows that for those who initially respond well to Gleevec for several years, it is 99% likely that they will continue to respond well.

Here is an interesting paper on response to CML treatments.
http://bloodjournal.hematologylibrary.org/cgi/reprint/108/6/1809.pdf

If a person with CML responds well to drug therapy, then disease progression is halted. This is generally shown by declining BMB, FISH and PCR numbers. In the current era of drug therapy, if a person responds well and quickly to drug therapy, there is only a small chance of progression to later stages. When reading literature on CML, statistics such as disease progression, are out of date, which can be confusing.  A 2 log reduction on the PCR is considered to be a Complete Cytogenetic Response (CCR), even without a negative FISH or BMB.  A 3 log reduction by PCR is not a requirement, but it appears to be an accurate statement - from what we know - that the deeper responses are generally highly likely to be stable over the longer term, even though lesser responses are often stable as well.


In CML monitoring there are two levels where doctors use the term zero.   The first is CCR where either BMB or FISH (cytogenetics testing) shows   zero. But that is not a deep response. Then there is a   negative/undetectable/zero PCR (CMR or PCRU), which is a deep response.   The following discussion applies only if we are discussing a zero PCR.

 

The deeper the level of response the greater the likelihood of continuing   such response. Even if someone only achieves the minimum level of   response the probablity of remaining at that level or even better has   been shown to be 75%, and if someone achieves the deepest levels of   response the probability of staying there is 98%. This data was over 3.5 years, and generally the data shows that the probabilities remain   fairly constant over time. So the odds of doing very well over a long period on Gleevec are quite high as long as some level of response is   achieved. And the better the response, the higher the long terms odds.

Most Oncs will say that if you continue to see lower PCR results, even if   somewhat slowly, then you should stay on Gleevec. If your PCR results go up for a couple PCRs in a row, you will probably need to switch. If   your PCR results are flat, there is no agreed-to recommendation, but   most will recommend staying with Gleevec until the trend changes   direction.


If PCR results rise unexpectedly and significantly, there are several   issues to consider. A re-test is a good idea to validate the result, since sometimes the tests can produce inaccurate results due to   contamination, errors, or other issues. Personally I would ask that the re-test be done right away instead of waiting a month, since if you  have  become resistant to Gleevec, then you are essentially having no  therapy at all currently. Or if you are going to wait, I would request  to  increase Gleevec dosage now. If the PCR is shown to be accurate, then you will want to have the Onc order a bone marrow biopsy (BMB) and  also a  Gleevec resistance test (also called a Kinase Mutation Test).
Here is one lab's description of the resistance test:
http://www.aruplab.com/TestDirectory/resources/TechnicalBulletins/BCR-ABL1%20Kinase%20Domain%20Mutation%20Jan%202007.pdf

If  tests show you are not resistant to Gleevec, then increasing the  dosage could be an option. Otherwise, a switch to Sprycel or Tasigna  would be needed.  If the resistance test shows a T315 mutation (rare),  then these other drugs will not work and other options would be needed.

The   leukemia treatment guidelines used by oncologists in the US is the   National Comprehensive Cancer Network (NCCN) Guideline. It recommends that if the CML patient achieves CCR within 12 - 18 months, then   continue with same dosage of Gleevec unless there is loss of response (1log increase in PCR). See link below, pages CML-4, CML-5, and CML-A:
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf

The other things you could ask the Onc to do would be to perform a Kinase Domain Mutation Test to test for possible Gleevec resistance (which   would be a very conservative approach). Also, some leading Oncs are becoming more likely to switch to other drugs faster than in the past,   including Dr Neil Shah who discussed this at the L&LS CML Education   Series session in December. But that is not the prevailing recommended   approach, and increasing Gleevec dosage is a reasonable approach.

There are 3 approved CML drugs: Gleevec, Sprycel (Dasatinib), and Tasigna (Nilotinib).

There are clinical trials on other experimental drugs that are not yet approved for prescription. Your Onc could possibly suggest a clinical   trial, if current drugs do not work.

Here is a more complete listing of CML levels of response:
Complete hematologic response (CHR): Normal full blood count and white cell differential count
Minimal cytogenetic response: 66%–95% Ph-positive metaphases*
Minor cytogenetic response: 36%–65% Ph-positive metaphases*
Major cytogenetic response (MCR): 1%–35% Ph-positive metaphases*
Complete cytogenetic response (CCR): 0% Ph-positive metaphases*
Major molecular response (MMR): 3-log reduction of BCR-ABL by PCR
Complete molecular response (CMR): Negativity by PCR

*Measured by BMB Cytogenetics or FISH testing

There are more reasons than just kinase mutations for losing response:

http://mct.aacrjournals.org/cgi/content/full/2/3/225
http://asheducationbook.hematologylibrary.org/cgi/content/full/2006/1/219
http://esciencenews.com/articles/2008/06/25/activation.lyn.kinase.associated.with.imatinib.resistance.cml.patients

Here are several good lectures by Dr Druker and others (see CML section and click on "text" button):
http://www.leukemia-lymphoma.org/all_page?item_id=161418#CML

The   issue of how long Gleevec is keeping CML patients in a status of good   response is being studied right now by the European Leukemia Network   (ELN). Their work started July 2008:
http://www.leukemia-net.org/content/leukemias/cml/registry/imatinib_failure/

From   what has been seen, the rate of Gleevec failure is highest in the  first  year or two. After that the rate of failure appears to drop to a  low  level. The IRIS Trials (the first large Gleevec study) showed that  the  risk of CML progression among those patients dropped to nearly zero   after the first few years. So from what has been seen, Gleevec failure   after several years is fairly rare. And the deeper the response, the   more rare it becomes. I realize that if someone is one of the small   number who fail Gleevec after several years, the statistics don't make   it seem any better.

Sometimes Gleevec resistance is not associated with a kinase mutation. But Sprycel or Tasigna can still work most of the time.

Here is information showing how the second line drugs usually work well even if Gleevec stops working:
http://www.ufscc.ufl.edu/Patient/cancernews.aspx?section=cancernews&id=37344
http://professional.cancerconsultants.com/news.aspx?id=41090

It is believed that quick response indicates that resistance is unlikely to occur. But no one can say "never" occurs.

A zero PCR (PCRU, or CMR) does not mean zero leukemia. Some people with PCRU/CMR are barely undetectable, while others are deeply undetectable.   But there is no way to know which is which. If someone is barely undetectable, it is more likely that they could be detectable again on   future PCRs.


Resistence and Relapse

If  resistence (drug therapy failure) is going to happen, it is most likely  in the first year or so after diagnosis. For those failing Gleevec, this is generally the case, with rare exceptions.  The stats on Gleevec  effectiveness are still very impressive.

Mutations in the BCR-ABL (kinase mutation) can prevent CML drugs from working.  This is different than chromosome mutations.

Resistence  due to kinase mutations is most likely in the first year or so after  diagnosis, then the probability of having one occur decreases  significantly, although it can still happen. Those failing Gleevec generally do so within a year or so of starting drug therapy.  Current thinking suggests that the mutation may be there from the beginning, and  that it shows up over time (first year or so).  The stats on Gleevec effectiveness are still very impressive.  And either Tasigna or Sprycel  work against most kinase mutations.  There are currently over 100 forms of kinase mutations.  And lab tests for kinase mutations are not as  accurate as one would hope.

If  a person stops responding to Gleevec, a BCR-ABL Kinase Mutation test  should be done to see if there is a resistance to CML. Kinase mutations  (not the same as chromosome mutations) are a leading cause of loss of  drug therapy response, especially for Gleevec. This test can be done by  Genzyme, MolecularMD, ARUP and others:
http://www.molecularmd.com/clinTestsBCRABLMutat.php

It  is important to continue to show progress in reduction of leukemic  cells. Data shows that CML patients who have achieved at least CCR  (cytogenetics and/or FISH are zero) have a high probability of no  resistence or relapse. See the following information from the link  below:

At  12 months patients with CCR can be classified according to their  molecular response into those with a reduction of BCR-ABL transcripts by  at least 3-log (MMR) and less than 3-log....PFS [survival without  relapse] for patients with CCR and 3-log reduction was 98%, compared to  90% for patients with CCR but less than 3-log reduction of transcripts,  and 75% for patients without CCR.

http://asheducationbook.hematologylibrary.org/cgi/content/full/2005/1/174

BCR-ABL  Kinase Mutations are not the only reason for loss of response to drug  therapy.  A second major reason for loss of response is LYN Kinase  over-expression by leukemic cells.  Sprycel seems to be best equipped to  handle this form of loss of response to drug therapy, but the data is  still inconclusive.

http://www.sciencedaily.com/releases/2008/06/080624174903.htm

http://bloodjournal.hematologylibrary.org/cgi/reprint/101/2/690.pdf

Here is some info about the success of using Sprycel after Gleevec resistance:
http://ash.confex.com/ash/2008/webprogram/Paper12511.html

Signs  of possible disease progression may include increased PCR number (1 log  or greater increase), blast count, increased basophils and/or  monocytes, marrow fibrosis, and maybe additional chromosome changes. You  might want to ask your Onc if any of the other issues are showing up.  The BMB will be helpful.

T315i  is a kinase mutation in BCR-ABL, which is the leukemic protein that  causes out-of-control leukemic cell proliferation. Our CML drugs can  block the BCR-ABL and shut it down (which also leads to leukemic cell  death), except when mutations occur in the BCR-ABL. Gleevec is most  susceptible to mutation blocking, and Sprycel and Tasigna overcome most  of those mutation blocks. But none of the 3 can overcome the T315i  mutation block, so they cannot work against it. Several new drugs are in  development that show promise in working against T315i, so a clinical  trial might be an option to look into.

There  is no evidence that taking breaks from Gleevec will increase the  potential for Gleevec resistance. The roots of resistance seem most  likely determined from the beginning of the CML and how the original  leukemia forms, but no one has a good answer on what actually causes it.  But there is no reason to believe that Gleevec breaks make someone more  likely to become resistant.

Regarding  the KD Mutation test, the results should tell you if you have a  mutation that is interfering with Gleevec effectiveness, and if so, you  would need to switch drugs; and make sure the Onc tells you the actual  mutation nomenclature since there are many of them (such as Y253, E255,  etc). Some are better targeted by Sprycel, and others by Tasigna.

http://www.communityoncology.net/journal/articles/0308519.pdf

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