In this post I will discuss why there are such wide variations in TKI drug response among CML patients, and the major causes of drug resistance and failure. I have promised to do this for some time, but the subject is difficult and the answers are not necessarily satisfying, to me or to you. There is still much which needs to be discovered.
Drug response rate is probably the most important and dramatic difference among patients and the number one cause for concern. But the answers to the question "why?" are not necessarily simple. CML patients experience significant variations in response to CML TKI drugs, with some responding quickly, others slow but steady, some with a steadily declining test results, some with ups and downs in results, some respond for only a short time, some with long plateaus in results, some respond much better to one specific drug, and some have issues with severe drug resistance and drug failure on specific or multiple drugs. Patients respond at vastly different rates as measured by PCR log reductions, FISH testing, and BMB cytogenetics. Drug resistance can take the form of some level of limited response (suboptimal and/or very slow) or outright failure when the results are clearly unacceptable with little or no response.
But why such variations, some of which are extreme? Response variations can be from several causes, including:
Drug side effects leading to drug intolerance
Drug metabolism and uptake
Drug discharge from the cell and plasma
Differences among TKI drugs (pharmacokinetics)
Cellular variations among patients
Other patient specific issues
Failure to take the drug (adherence)
I will deal with each of these now in more detail.
Drug side effects/intolerance:
Sometimes a patient will respond well enough to a drug but may not be able to withstand the side effects of it, or may not be able to take a large enough dosage due to side effects such as low blood counts. This is called drug "intolerance", not drug failure. Failure means it won't work, while intolerance means the patient cannot remain on the drug long enough at therapeutic dosages to adequately control the disease. Drug breaks are often required to allow the side effect to subside, and lower dosage is also commonly necessary. For some patients a therapeutic dosage is higher than others due to individual patient factors discussed in the paragraphs below. The most common side effect which causes drug intolerance is perpetual low blood counts. This can be low WBC, low RBC, low PLT, or a combination of these. Other intolerable side effects can be whatever the patient is unable or unwilling to endure. So the first thing to understand is the difference between drug intolerance and drug failure, even though both can lead to poor response.
One issue worth addressing related to drug intolerance is that some patients only require small dosages of a drug, and standard dosages create intolerance issues. In this case the patient would do well to take less drug since they can have an adequate response while avoiding side effects which would lead to intolerance of the excess dosage.
Drug metabolism and uptake:
CML TKI drugs only do their work controlling CML while inside leukemic cells which are capable of dividing. They do not accomplish their task in the GI tract, or in the blood plasma, or inside non-blood cells, or inside normal (non-leukemic) blood cells. So the TKI drug must go from pill form in the stomach to the drug inside leukemic blood cells if there is to be any benefit. This occurs in two stages, and if either of the two uptake stages are deficient, drug response will be degraded. First, the drug must break down in the alimentary canal and get into the blood plasma. This first level of drug uptake occurs primarily through the stomach and duodenum. This uptake occurs best in an acidic environment, which is the normal state in these organs. If the normal acidic processes are disrupted (antacids, PPI drugs, etc) drug uptake can be reduced. If binding agents (calcium pills, etc) are present at the same time, some of the drug may bind to those agents. Drug uptake is generally not much of an issue unless the patient does something to limit that uptake, although it could be an issue for a small set of patients. The level of drug uptake can be assessed through a blood plasma test, although this test may be hard to find because the US FDA virtually shut down the process at one point over a disagreement with one of the TKI drug makers.
Once the TKI drug has been absorbed from the GI tract into the plasma the second level of drug uptake is from plasma into the leukemic blood cells. This process is not the same for each drug, and is not fullly understood. Gleevec is taken into blood cells via the cellular OCT1 pump, while Sprycel and Tasigna do not use OCT1 but rather appear to be taken up more passively. There is little information about the other TKI drugs. Some people have low OCT1 activity, so Gleevec often does not work as well for those patients, but other drugs could work better. This is just one reason why a simple drug switch can produce dramatic results.
Although not an uptake issue, if the body clears the drug too quickly from the plasma, there can be reduced effectiveness. Less is known about what might cause excessive drug clearance to occur. But other drugs and some herbals might be a cause of accelerated TKI drug removal from the plasma.
This issue often affects dosage required to gain the same level of response. Some patients can do as well on half or quarter the dosage another patient requires. Leukemic cells usually have more than one BCR-ABL messenger protein (ATP binding site) which must be shut down by the TKI drug, so it is not enough to have just one molecule enter the leukemic cell. It is mainly a matter of getting the drug into the leukemic cells, and sometimes a leukemic cell may require more than others.
TKI Activity Inside the Leukemic Cell:
Once the TKI drug is inside the leukemic cell it must bind to multiple BCR-ABL messenger proteins (ATP binding site) to shut down the cell replication signaling process. I say "multiple" since there are more than one in most leukemic cells, so there must be multiple inhibitions of the BCR-ABL ATP binding sites in each cell. So to shut down a leukemic cell there must first be adequate drug inside that cell. After all BCR-ABL ATP binding sites have been shut down by the TKI drug the leukemic cell cannot reproduce, so it either self-destructs or lives out its remaining life as a neuter. This is the goal of a TKI drug, to stop leukemic cell replication and thereby prevent future generations of leukemic cells from being created. When enough leukemic cells have been "neutered" by the TKI drug only the highest level leukemic cells remain, which are much harder to neuter and/or kill off. To learn more about the genetics of CML read my paper on the issue:
If there is sufficient drug inside the leukemic cell but the cell continues to divide, then the drug is not doing its work for one of several reasons. The reasons could include mutations in the BCR-ABL messenger protein (kinase mutations), BCR-ABL gene amplification, variations in the type of BCR-ABL the patient has, and unknown reasons. There is still much to learn about the issue.
Drug Discharge Rate from Cells:
Just as drug uptake into leukemic cells is important for drug response, keeping the drug inside leukemic cells in sufficient quantity is also important. Recent studies have shown that for some patients the TKI drugs (especially Gleevec) can cause increased activity in the enzyme ABCB1 which expels drugs and other things from the cells. This higher level of this enzyme called "ABCB1 drug efflux transporter" (a type of cellular garbage man) might cause drug expulsion and decrease TKI levels inside the leukemic cells. Since the drug only works inside leukemic cells, this more rapid drug expulsion from the cells could decrease drug response. Recall that there are multiple BCR-ABL signaling enzymes inside each leukemic cell, so it takes numerous molecules of the TKI drug to effectively inhibit each leukemic cell and shut it down.
Kinase mutations are changes in the BCR-ABL messenger protein (ABL portion) structure at the location where the TKI drug must bind to shut down the leukemic cell replication process. If this "docking site" for the drug mutates and changes structure, the drug attachment may be weakened (reduced drug response) or made impossible (drug failure). There are over 100 known ABL kinase mutations, although possibly 33 can cause some level of TKI drug resistance for Gleevec, and only a few of these 33 can cause resistance for Tasigna, Sprycel, or Bosutinib. Ponatinib does not have any known kinase mutation resistance issues. These kinase mutations have names such as Y253H, E355, F255K, T315i and others. While kinase mutations can be a major cause of Gleevec resistance, slower response, or even drug failure it is not a major cause of resistance in the other drugs, although it can happen occasionally. This leaves the cause of most TKI drug resistance to other issues, even though Oncs are often quick to blame kinase mutations. Kinase mutations cause possibly 1/3 of drug resistance/failure for Gleevec, but only about 5% of non-Gleevec resistance/failures.
TKI kinase mutations probably do not develop over time, but more likely are there from the beginning of the disease. Often Gleevec will appear to work well for a time, but then be reduced or fail. This may be due to Gleevec handling the non-mutated leukemic cells but as time goes by the mutated cells are not shut down and therefore continue to expand so the response is lost. Supporting this theory is the fact that kinase mutations almost always appear within the first 2 years of diagnosis. If a patient can get past 2 years, then kinase mutations rarely appear. For the very few exceptions these could have been recessive or could have developed over time, but that is unknown. We have learned that low dosage is not an inducer of kinase mutations, although that was initially a concern.
Differences among TKI drugs (Pharmacokinetics):
Each TKI drug is different, making it function differently. Each binds in a different pocket of the ABL kinase, otherwise there would be patent violations. A good overall comparison of the various TKI drug "pharmacokinetics" (methods of drug action) can be found here:
Because each TKI drug works slightly differently, these various drugs are able to defeat certain aspects of the disease to better or lesser degrees. Each drug has its strengths and weaknesses. Gleevec has not been outdated by the later TKI drugs.
Some drugs are said to be "stronger" than Gleevec. That is not an accurate statement, although second generation TKIs may work better for some patients. But those difference can come at a cost, which is inhibition of more off-target kinases which do not affect the course of the disease and may cause side effects.
Alternate Signaling Pathways in Leukemic Cells:
Although CML is highly dependent on the BCR-ABL signaling process, it is not solely dependent on it. Higher level leukemic stem cells have multiple pathways to ensure survival, which makes them difficult for TKI drugs to kill off. This is why TKI drugs are not thought to provide a cure. It is possible that lower level leukemic cells can acquire this alternate pathway survival mechanism in some patients. This is why there has been much research on this subject, and we see other pathways such as STAT, LCK, HEDGEHOG, LYN, CRKL and others being targeted. In fact, Sprycel and Bosutinib are effective in some patients because they target the alternate pathway SRC in addition to BCR-ABL.
There can be drug-to-drug interaction which decreases efficacy. They appear to be rare but little is known about the issue. I would not assume that if an interaction checker says the drug is OK to use with a TKI that this is absolute. If there is lack of adequate response I would experiment with changing the other drugs if possible.
We do not all have the same type of CML. 95% have either b2a2 (e13a2) or b3a2 (e14a2) or both. A few have e1a2, and some have very rare other breakpoint types. Some patients have a der 9 deletion (ASS deletion) (maybe 10%). Some have three or four way translocations of the Philadelphia Chromosome, or other secondary chromosome mutations (trisomy 8, monosomy 7, or others) or even secondary translocations (all of these can only be found by a BMB).
So not all CML is the same. Some leukemic cells have alternate splicing. Most CML has a rather "normal" Philadelphia Chromosome rearrangement whereby the chromosomes 9 and 22 break at the normal spots and then rearrange in the expected fashion on the new chromosome 22. Although the b2a2 (e13a2) and b3a2 (e14a2) are the most common, statistically the b2a2 responds more quickly than b3a2. Also, within both b2a2 and b3a2 there can be alternate splicing whereby certain micro-genetic material is deleted during the translocation, changing the nature of their BCR-ABL signals slightly. While the Philadelphia Chromosome (chromosome 22) is the cause of the BCR-ABL signals which cause CML, the chromosome 9 called der(9) may form in a way which puts out its own signals, although for most the der(9) is benign. But this is less of an issue than it was in the days before TKI drugs.
Some patients can have an amplified Philadelphia Chromosome, meaning it puts out stronger signalling. This is because there are two copies of the BCR-ABL gene on the Philadelphia Chromosome, so it sends out twice the BCR-ABL signals. Whether this can be seen during a BMB I am not sure, but it would be somewhat longer than the standard Philadelphia Chromosome.
The Phase at diagnosis is important when it comes to drug response. I want to warn patients that not all definitions of Advanced and Blast Phase CML are properly diagnosed, so get an expert opinion. The later the Phase, the more the CML has gained certain advantages. And it is not just that there are 3 phases, but also late Chronic Phase can react differently for some than early Chronic Phase. Gleevec should not be used for advanced phase CML, so Sprycel may be the best available drug option. Blast Phase diagnosis means the patient may respond to TKI drugs for a while (maybe a year or so), but the probability percentages for long term good response are not favourable due to the morphed genetics which are irreversible once they happen. A very few Blast Phase patients may be able to have a long term stable response using TKI drugs, but most would be well advised to consider bone marrow transplant, or at least try to find a matched donor just in case. For Advanced Phase CML the TKI drug will normally work, but I would advise more careful monitoring than Chronic Phase patients may require. Remember my warning to get an expert opinion about the Blast Phase diagnosis since it can be misdiagnosed.
Patient Specific Issues:
Some patients have other conditions which can impact drug response. These could include diabetes or other conditions.
Much is known about CML and the TKI drugs, but even more is unknown. These drugs are still cutting edge, and there is much more to learn about them. Hard as it may be to understand or accept, the major cause of TKI resistance and lack of response will often be unknown to the patient.
Some patients do not take the drugs as prescribed. I put this last because this is less often the case with drugs that are clearly life savers. Of course, Oncs suspect this first, not last. But if a person is interested enough to be reading this, then they likely do not have this problem.
What level of response is good enough?
While there is no clear answer, it appears that a stable CCyR is "good enough" for long term survival, so stable CCyR should not be considered a poor response in the sense of survival. Below average or suboptimal response is not drug failure as long as the response trend line is stable or downward. And some can overcome this lackluster response with higher dosage, or by switching drugs, so if someone is stable CCyR and wants to switch drugs to get a better response, that is understandable and is what I would do in that situation. Stats show that approximately 40% of patients move to a second line drug, but many of those are not actual failure or suboptimal response but intolerance of certain side effects. Stable MMR has been shown to have nearly 100% survival rate (I must add here this assumes continued taking the drug, not MMR in cessation where there is no real data). Anything better than MMR such as PCRU is just "more better".
But Oncs and patients have set the standard for good response very high, which leads to more questioning about why a patient is so slow in responding. While it may not help much, today's "slow" was called "unbelievable" just 15 years ago. And many Oncs improperly compare patient responses to each other instead of to NCCN treatment guidelines, causing patients to look at failure to achieve MMR in 1 year as unsatisfactory. Such "expectation inflation" is unprofessional and a disservice to patients.
Good Initial Response Followed by Loss of Response:
If the patient has a good initial response followed by loss of that response, normally within the first 2 years after diagnosis, it can be assumed there is not an issue of the two stages of drug uptake, unless something has changed such as taking other drugs. Drug resistance due to kinase mutations occurs most often during the first 2 years after diagnosis, and after that it does not normally appear. Other causes of loss of initial good response are likely due to rapidly killing off the leukemic cells the drug can handle, then the harder to handle leukemic cells come to the forefront and the response is lost. If the patient makes it through 2 years and has a good response, that good response will probably continue over the longer term. The first 2 years are the critical time for potential loss of response.
Multi-TKI Drug Failure:
Here is an article about how to proceed after multiple TKI drug failures, and there is no reason for me to try to summarize what it says:
At this point you may say: "That does not tell me why I have a poor drug response".
Probably true. I do not know, and neither does anyone else. If your response is truly unacceptable (no sustained CCyR), the best you can do is change drugs until you find one that has the best response with the fewest side effects, or else increase dosage of the present drug. If you have severe side effects no matter the drug, then the best you can do is take as much of the drug as is tolerable and deal with the side effects as best you can. If you are sustained MMR and want to complain, changing drugs is a reasonable option just to see what happens -- these drugs are not best friends, just tools to use. But if you are sustained MMR and just want to complain that it is resistance and sucks, tell someone else. At this point you may say "That's not fair". Of course it isn't. Then at this point you may say "Is that the best you have to offer?". Yes, it is. But as more is learned I will edit and add to this post.
Reading Room for Overachievers:
Dynamics of TKI Response
Edited by Trey, 22 August 2016 - 12:50 PM.