When someone is diagnosed with CLL they have at least one clone of B lymphocytes that are growing faster than they should and/or dying less than they should. As a result we are diagnosed with cancer. But the illness may be slow growing, not even needing treatment initially, but may develop to a point where treatment is needed, and can become more resistant to treatment and grow more aggressively.
As we have learnt more about the genetics of the disease scientists have realised that there are 'sub clones' where different cells within the mass of B lymphocytes may have different genetic markers. In other word like my photo of the sheep not all CLL cells in the same individual look alike.
UPDATE: One of the comments below suggested a great video that explains clonal evolution very well. I do recommend you watch it: youtube.com/watch?v=9bUuMA_...
The data in the next bit of this post comes from the following article:
See ncbi.nlm.nih.gov/pmc/articl...
For example TP53 mutations (which have a similar effect to 17p deletions) were present in 10.6% of patients, but only 6.4% counted as clonal i.e were dominant in a large part of the population of cells, 4.2% were "subclonal" and might have been missed in the past with less sensitive measurement.
Certain mutations strongly predicted a shorter time to first treatment and/or overall survival whereas in some cases only clonal and not sub clonal mutations had an affect. This suggests the effect of mutations are complicated.
Interestingly TP53 mutations which we know predict lack of response to treatment didn't in this sample predict a shorter time to needing first treatment. They did however predict length of overall survival presumably due to conferring lack of response to certain treatments. This survival difference may well disappear as new treatments are used which work even in the presence of TP53 mutations or 17p deletions.
All survival data we have at the moment look back at the past when we didn't have many of the treatments as we do now. Even FCR is rather new when it comes to considering long-term survival.
In the case of mutations of IVHV, the presence of a mutation makes it LESS likely a patient will proceed quickly to treatment.
Immediately then it seems clear that if you want some idea of your prognosis or how your particular illness is likely to develop you should ask for deletion and mutation analysis at diagnosis. The more specialist your CLL centre the more likely you will be to be able to get this. However, bear in mind that some people with good markers will progress more quickly than expected and some people with poor markers will progress more slowly than expected.
As always in CLL things are not as simple as we first think. Over time even with no treatment CLL cells can acquire new mutations. In the study we are looking at 24% of patients who were tested at the onset of disease and then again before they were treated had acquired a new mutation.
If you only have the option to have a single mutation and deletion analysis then, you should wait till just before treatment since the first reading shouldn't be relied on as being accurate at the time of treatment, especially as mutation / deletion status has a significant influence on treatment choice In the UK and most other countries a TP53 mutation or 17p deletion will allow you first line access to ibrutinib, and in some other countries being non mutated in IVGH will also allow you to avoid chemo.
Following treatment in the study we are looking at there was an increase in the incidence of mutations, and the percentage of cells carrying the mutations also often increased after treatment (or indeed they sometimes had already increased at the point that treatment was required).
Treatment is associated with especially the TP53 clones growing and becoming more prominent. Has that been caused by treatment or is it a mark of the disease progressing? And if treatment causes it how does it cause it? Is it a direct effect of a certain treatment or simply caused by lots of cells being killed and the more aggressive / resistant ones growing as a result (clonal evolution)?
The UK guidelines suggest that it is important to be influenced by the presence of ANY TP53 deletions in your choice of treatment as they believe if you use FCR which doesn't kill those cells, they will simply grow and replace the other cells your treatment will kill off onlinelibrary.wiley.com/doi...
Imagine if we had a poison that could kill only the white sheep in the photo attached to this post. Pretty soon we would see no white sheep but the black ones would have just carried on growing and indeed as they didn't have to fight for food with the white sheep they may even grow faster than they were when there was lots of white sheep about.
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FCR
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The effect of treatment was examined in the patients who were treated in the crucial CLL8 trial in Germany which showed that FCR was superior to FC. It is a very important study and it surely suggests that a combination approach is probably going to prove to be better not just with traditional chemo but also in the future with new agents.
The study looking at clonal evolution in FCR and FC treated patients can be seen here ncbi.nlm.nih.gov/pmc/articl... and the next few points are all summary and reflection on reading that article.
The study had 103 patients that had been studied in a systematic way in the study. What was clearly seen was that although 19% of patients had seen clonal evolution prior to starting treatment compared to old samples (similar to the study we looked at previously) double this number experienced it following treatment if they then relapsed. In other words 40% of people who relapsed after receiving FCR or FC had experienced clonal evolution compared to their pre-treatment sample.
Is this being caused by the chemo causing new mutations? Or is it simply the fact that cells are being killed off and so therefore there is an evolutionary pressure favouring the survival and hence growth of pre-existing treatment resistant clones?
The answer seems to be the latter. FCR was shown to be more effective than FC. R is not chemotherapy and does not damage DND. And yet despite the fact that it was more effective at killing the cells and hence prolonging patient survival, or perhaps BECAUSE of this fact, very much more clonal evolution happened in the FCR treated patients than in those given just FC. Other factors such as IGVH mutation status and whether or not patients showed an initial response did not predict whether or not you would develop clonal evolution.
The paper concluded "Collectively, these results suggest that clonal evolution is accelerated by therapy, and might be even more so by chemo(immuno)therapy capable of inducing profound remissions."
So despite the fact that FCR causes a better overall survival of the patient group as a whole it does lead to an increase in the expression of TP53 and the group that gets that do experience worse survival. These cells are of course resistant to FCR so perhaps all we are saying is that if you treat patients with FCR some of them will become resistant to it.
Therefore it would seem we have a bit of a trade off here. If you kill the cells aggressively you will prolong life of the patient group as a whole but in some individuals will induce more growth of treatment resistant cells which were probably there all along but treatment gave them the opportunity to grow.
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IBRUTINIB
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What then of treatment with a 'slower' agent that doesn't kill CLL cells so quickly, Ibrutinib? Will we see clonal evolution and treatment resistance emerging at a similar rate in Ibrutinib patients?
First of all, there is no evidence that ibrutnib fails to kill cells with TP53 mutations or 17p deletion. So we wouldn't expect to see clonal evolution increasing the numbers of cells exhibiting that particular mutation. If we apply a poison that kills all sheep to the sheep we see in our photograph the numbers of black sheep wouldn't increase.
We do, however, see resistance to ibrutnib emerge in a small number of patients (and this number could rise with longer treatment durations). This appears to be possibly de to new mutations (or it conceivably be due to a few patients having this mutation already in a few cells that then get the chance to grow in a similar way). This is discussed in more detail in the following paper: ncbi.nlm.nih.gov/pmc/articl... Interestingly patients with unstable or high risk genetic markers including 17p deletion may be more likely to experience this.
In another follow up study of 308 patients treated with ibrutinib with a median follow up of less than two years (most of whom it should be noted were relatively high risk patients) 10% discontinued due to disease progression see jamanetwork.com/journals/ja...
Of those who progressed in the above study about half of them had a RIchters Transformation. Similar to the above report it seems that poor genetic markers also predict treatment failure with ibrutinib.
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VENETOCLAX
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Of course we also have another treatment option emerging Venetoclax in combination with either rituximab or ibrutinib. It kills CLL cells very quickly. Will it induce clonal evolution and treatment resistance? It turns out again that there are some patients who develop mutation based resistance to venetoclax nature.com/articles/s41467-...
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CONCLUSION
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Clearly we do not have very long term follow up with ANY of these treatments, even FCR.
Perhaps we just need to take the view that none of these treatments are likely to induce a complete cure in anyone and we should be prepared for the fact that if the disease does come back with any of these treatments it may be resistant to the treatment patients have had so far.
But of course if patients have a VERY long remission with any of these medications and the resistance rate is low then perhaps this is more of a theoretical risk except in the case of FCR where it seems everyone is in agreement that FCR should not be used in patients who have any detectable TP53 mutations or 17p deletions because of the risk of treatment resistance and clonal evolution being quite significant in that case.
Also the issue of clonal evolution and resistance would seem to suggest that combination treatments may be better as to get resistant to two different treatments the cells would need to develop two mutations at once. So in our illustration if a black sheep had a resistant gene to poison A (say ibrutinib) and a grey sheep had a resistant gene to poison B (say venetoclax) and you poisoned all the sheep with both poisons you wouldn't get any resistance would be there theory.
It is also possible that killing CLL cells quickly may accelerate the clonal evolution process, and this does seem to be the case with FCR compared to FC when it comes to TP53 mutations.
When it comes to choice of first line treatment when you are definitely not already TP53 mutated (even at a low level) I am not sure if the current state of clonal evolution can really give us enough information to help us guide treatment but as we know most about FCR and TP53/17pdel effects it is tempting to see this as a strike against FCR as a first line option.
So what have I missed about clonal evolution? Did I get anything wrong? Are there any important publications I haven't seen? Remember this is just my interpretation on the data and should not be used to form the basis of medical decisions for individual patients who should discuss these and other matters with their doctor.
This is an unlocked post as it is more of a scientific discussion than a call for personal experience and so you are advised not to share personal medical information in the discussion section of this post.
Bi clonal CLL
Mode of Progression After Frontline Treatment Predicts Clinical Outcomes in Patients With CLL
