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:
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.
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:
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:
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:
Here are several good lectures by Dr Druker and others (see CML section and click on "text" button):
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:
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:
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:
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.
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.
Here is some info about the success of using Sprycel after Gleevec resistance:
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.