Saw my CLL specialist yesterday and he had the results of the IgHV testing he requested. It seems I am unmutated status which isn't great news. At the time of starting treatment, we were in 1st year of pandemic and Acalabrutinib was offered. As he said normally I would have been offered FCR because I had P53 and no 17p del which at the time was great news. The reality would have been that I wouldn't have stayed in remission very long on FCR. The pandemic did me a big favour - not something you would hear many people say.
I realise that this puts me in the high risk category but he did show me journals where patients on 1st line treatment with Acalabrutinib did just as well as mutated. Due to pandemic and unable to get my reading glasses changed I couldn't read his screen all too well!!
Can anyone on here point me in the direction of any publications, journals, articles etc that would increase my knowledge of my unmutated status. I guess I'm on a (another) new learning journey.
The other thing we discussed was the fact that my father died of multiple myeloma. He said thats another B cell leukaemia and we do tend to see genetic factors at play. So now I have to worry about passing this on to the kids! Just something to add to my worry machine.
Kate
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Eucalyptus22
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I am unmutated and about 50% of CLLers are unmutated. 50% are mutated. I did B+R treatment and my CLL Specialist told me my remission would be about 3-3.5 years and 5 years if mutated. I was in remission 3.5 almost 4 years. To many unknown factors play a role in length of remission regardless of IgVH status. Also, your percent of mutation has a bearing on your outcome. I was 0% which means unmutated. 0% to 2% is unmutated and 2% to 98% is mutated. There should be a wealth of information on IgVH testing as it has been around for some time. Blessings.
My first remission of about 4 years was from 6 months of bendamustine + rituximab. Then in Sept 7th of 2022 I started V&O and finished up Nov of 2023, but have been in remission one month after starting V&O. Since I was able to finish both of my treatments without becoming intolerant, I can repeat either one. My bloods are not perfect, but acceptable.
Hi Kate,Your specialist is right that with familial CLL, there is a higher risk of other blood cancers as well as a higher risk of CLL. The absolute risk is still quite low, just more than that in the rest of the population.
With respect to your desire to learn about unmutated CLL, you'll be able to find some specialists/consultants arguing that mutated and unmutated IGHV CLL are different diseases. There still isn't agreement on what causes the IGHV mutational difference. The classic argument is that it represents a difference in when the CLL arose in the maturation path of B cells. Mutated CLL is understood as arising in CLL which has gone through the somatic hypermutation process. This is when there is an internal rearrangement in the IGHV gene, which holds the instructions for the production of the B cell Receptor (BCR) part of the B cell. This is guided by helper T cells (hence the name) in node germinal centres and is how B cells can detect invading viruses, bacteria, etc through their matching BCR locking onto an epitope in a protein of the invader. Those accepting this explanation argue that it fits the pattern observed in that the more mature a B cell is when it becomes cancerous, the more chronic the B cell cancer.
The newer theory, is that the difference in the IGHV region of CLL cells from that in other body cells (i.e. that which was inherented) reflects the cell's ability to correct DNA damage arising during cloning. There is always some damage; uncoiled human DNA is about 2 metres long and the DNA is duplicated in a few hours during cell division. Unmutated CLL isn't very good at correcting damage, so you get a faster progression rate in your CLL from the less stable genome. Mutated CLL is quite good at fixing damage, but doesn't always incorporate the correct nucleotide base. (The bases used in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T).) So the slight differences in CLL DNA in the IGHV gene arose from this.
Sorry, I don't have any references to hand, but I've underlined some key words you can use in your searches for the same. Or you can forget all about it, because nowadays in countries like the UK, where targeted therapies are available, the outcome from these treatments isn't much different for mutated and unmutated CLL. In countries where the older "chemo" treatments like BR and FCR are all that is available, those with unmutated CLL are statistically more likely to progress sooner after treatment than mutated folk; they have shorter remissions on average.
Thanks Neil for your very clear analysis of the differences. It just goes to underline the wonders of the human body and if we were just bystanders to this disease we would continually be in awe. Prior to my father getting multiple myeloma no family members had leukaemia or even cancer, so I could easily speculate as to what brought about the changes in his cells that I then possibly inherited. On reading about MM I can see the similarities to CLL.
For the sake of the family, I shall continue in my journey to understand my new status but I will hold on to the big 'take-away" from yesterday which was thanks goodness I didn't get FCR.
As a parent of adults I wonder if it is their fate or can they influence in any way the genetics they may/may not have inherited. Does lifestyle choices make a difference? Who knows?
In the meantime, thank you for the time you have taken to construct your reply.
In this recent video, Nitin Jain MD from M D Anderson adds some more detail to our understanding of the implications for IGHV unmutated patients in the context of fixed duration, targeted therapy.
He says IGHV status is still important in the era of targeted therapies, especially in the context of time limited therapy and gives the example of those on fixed duration Venetoclax plus Obinutuzumab (V+O) who are IGHV unmutated. He notes that, if you stop therapy at just one year, those patients tend to have a higher rate of relapse, even if they achieve a negative MRD (minimal/measurable residual disease) remission.
This article from October last year, which reported on a debate held at SOHO 2021, has more to say about the longer term data that’s starting to show a role for IGHV status in the era of targeted therapies.
“In the context of venetoclax therapy, IGHV mutations may, in fact, become a useful marker,”
“More data are needed to determine if IGHV mutation status has prognostic value in light of fixed-duration therapy ”
“We are starting to see separation between [patients with] mutated and unmutated [IGHV with fixed-duration treatment] in distinction to continuous BTK [treatment] where mutational status doesn’t seem to make a difference and both groups of patients continue to benefit equally as they stay on therapy.”
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