Hi all, a very ocasional póster here but avid reader of the many highly informed contributors that make this site what it is.
I was diagnosed with stage ‘A’ CLL in 2021 and continue to be on W & W. I have many of the classic symptoms but not severe enough to warrant treatment - yet!
I’ve recently been told by my specialist that I am IgHV unmutated and have more or less come to terms with the diagnosis without any great sense of anxiety. Unfortunately I read the report in greater detail when I returned home and thus discovered that I am IgHV unmutated subset 6.
I’ve made the mistake of consulting Dr Google and from what I can glean the prognosis of those in this subset is not great, for example greater likelihood of 17p deletion, Richter’s transformation, shorter periods of remission, etc.
This has caused something of a ‘wobble’ in my anxiety levels vis-a-vis my CLL outlook. Could anyone of you geniuses out there possibly inform me / direct me to a more detailed breakdown of what being in this subset entails as unusually, I can find precious little online.
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It would help if you shared the paper that gave you a wobble, because the first paper from 2010, which I've referenced below, and published in ASH, a generally reputable journal for CLL research, reports a good outcome - and this was from before we had the breakthrough in targeted therapy treatments!
Unmutated IGHV1-69/D3-16/J3 Stereotyped HCDR3 Rearrangements (Subset 6) Are Associated with Indolent Disease Course and Have Outcome Independent of Mutational Status In Early Stage CLL (Rai 0) (My emphasis)
our analysis documents and confirms that unmutated status of IGHV, and not stereotypy, is a relevant prognosticator of outcome (TTFT) in CLL. In the IGHV1-69 CLL it exclude a role of IGHV gene use for CLL progression. However, the good prognosis of Rai 0 U-CLL assigned to subset 6 suggests a differential clinical benign course of this particular subset, irrelevant of unmutated status. One possibility is that the IGHV1-69/D3-16/J3 rearrangements of subset 6 produce a tumor-specific BCR with stereotypic HCDR3 patterns that are anergized by antigen while circulating in the peripheral blood in early stage (Rai 0) CLL."
Then we have a mini-review from 2021 Distinctive Signaling Profiles With Distinct Biological and Clinical Implications in Aggressive CLL Subsets With Stereotyped B-Cell Receptor Immunoglobulin
Which begins "Subset #6 is another well-characterized clinically aggressive CLL subgroup (0.8% of all CLL), concerning cases bearing unmutated BcR IG (25)."
then concludes:-
"Regarding the genetic landscape, CLL cases assigned to stereotyped #6 display low frequency of TP53 mutations (4%), low-to-intermediate frequency of SF3B1 mutations (13%) and, in contrast, high frequency of NOTCH1 mutations (22%) which, interestingly, was not accompanied by trisomy 12 in almost none of the cases (41). Moreover, there is a strong evidence for selection by a common antigen in subset #6: in fact, it has been conclusively demonstrated that subset #6 BcR IG recognizes non-muscle myosin heavy chain IIA (MYHIIA), which appears on the surface of cells undergoing stress or apoptosis, with this recognition driving CLL cell survival and proliferation (59)."
From the last sentence,, subset 6 is behaving more like mutated IGHV than unmutated IGHV, perhaps explaining the better outcome independent of IGHV mutation status.
Of note, the risk of Richter's isn't mentioned for subset 6, despite the higher (22%) occurrence of NOTCH1 mutations , but it is for subset 8 in the same paper.
You might decide to have testing for NOTCH1 and trisomy 12 to get a better idea of your risk, but bear in mind my observation from approaching 14 years of reading these papers, that the conclusions from studies with small populations (~0.8%) in this case, can be highly influenced by other unreported factors in the study group. I've seen totally contrary results reported for people with the same studied markers, from different study groups. CLL is a very heterogeneous illness with some degree of familial influence after all.
Hi Neil, what would we do without you? Thank-you so much not only for your good counsel on this matter but for all you brilliantly informed contributions over the years. I haven’t missed one since I was diagnosed.
Im almost embarrassed to say it but the information came from ChatGPT and Google’s Bard. All my CLL specialist’s letter said about the testing was that I was IgHV unmutated, subset 6. Idiot that I am I simply typed in “prognosis for CLL subset 6 CLL” and both AI chat boxes came up with quite a lengthy and unremittingly bleak prognosis. I simply couldn’t find any abstracts which dealt with the issue.
Thanks as ever to you and the collective wisdom of all the contributors for allaying my fears. Generally speaking I’ve heeded the advice of you and others vis-a-vis undertaking internet searches, I naively thought that AI my be more accurate and up to date, now I realise its a potted version of whats already out there on the internet.
You have successfully un-wobbled me and for that me deepest thanks and appreciation.
Thanks for sharing your personal experience with ChatGPT! Six months ago, I mentioned this danger that these generative AI models "hallucinate" answers, in my reply to this post, concerning an upgraded version
"But it certainly still does make things up, scoring between 65% and 80% accuracy on those factuality tests, implying that in these tests, 20-35% of all the facts it asserts are still garbage. This will continue to improve, but that itself presents an interesting problem: the more factually correct an AI service becomes, the more people will learn to trust and rely on it, and thus, the greater the consequences of errors will become."
It's nice to know that I'm not about to be replaced just yet by artificial intelligence
Yes, the Generative Pre-Trained Transformer (GPT) AI models basically work by "mining the cloud" to find what has been publicly shared up to a few years ago. So they will share what they find irrespective of accuracy.
Not having seen AussieNeil 's excellent post, I prepared a post meant to help lessen your wobble. I’ll go ahead and post it even though I’m sure by now you are feeling quite stable having digested Neil’s post!
The figure accompanying this post is an edited version of Table 2 in the paper cited below. I’ve cut out the data for stereotypical subgroups 1, 2, 3, 4, 5, 7 & 8 to decrease the size of the figure. The data in the right most column “Heterogeneous CLL” is data from CLLers whose BCRs do not fit into a stereotypical subgroup.
Several things to notice about the data. As Neil pointed out not all individuals in Subset 6 have the recurrent, meaning common, CLL mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and/or cytogenetic aberrations that were scored in this study, in fact in this study 47% of subset 6 individuals didn’t have ANY cytogenetic aberrations.
Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
Thanks gardening-girl for helping to assuage my fears. If you look at my post to Neil (above) you will comprehend the vast stupidity which induced the ‘wobble’ in the first instance: - I never seem to learn! After a good couple of years of being symptomatic though not sufficient to warrant treatment I’ve been largely anxiety free due to the wealth of informed comment on here. In a weak moment I very stupidly thought that the latest AI advances could supply the accurate information I required without the need to bother you guys. WRONG.
Thanks very much for the research, reassurance & info and for un-wobbling me.
A great big thanks for rationalising, you’re right of course but I needed a booster from you lovely, informed lot, to tell me what a bloody idiot I’ve been. Have a look at my post to Neil which will add to the collective knowledge on this site of what NOT to do when seeking information about CLL (and how typical of me to be the one that has done it)!
I had been told that I was unmutated but Zap70 negative, with 13q deletion, so it seemed my disease features were anticorrelated, and I felt pretty optimistic once dietary changes seemed to be helping my swollen lymph glands and high lymphocyte counts decrease. Later I learned that in fact I was highly Zap70 positive, and at first I saw myself starting to cry and to fall apart. And I was bothered. Because I remembered the road runner cartoon that I had always watched as a kid. I thought about how the characters would be running on air and going along unexpectedly well, but then suddenly, aware that they were in the air, they looked down. And then they would get a look of panic, and plummet.
So I decided not to let myself stress out. Stress is an illness inducer. I decided that whenever I started to worry I would just keep going forward without looking down. Obviously I do my best to stay well in all other respects. I am still lucky to be improving rather than worsening, and I have not yet needed treatment for the CLL, only for infections, etc.
As you have been watch and wait for some time, there is reason to hope that your disease course will be equally benign. If not, keep in mind the many friends you find here, still alive and thriving due to their courage and to the many breakthrough treatments discovered during the past decade. I know this does not answer your question, exactly, but I related to your upset and wanted to reach out and wish you the best.
Thanks so much for your very supportive comments. It’s true that this site and the people on it are a tower of strength for us all. I think I’ve been successfully tolerating the W&W because it’s been reasonably benign, but of late, as I’ve said, the infections have been unremitting & strangely diverse ears, chest, urinary, rash. I think that has taken both a physical and psychological toll and I must now learn to ‘reset’ myself to accept that I’ve been very lucky until recently and perhaps this frequent infection thing is the start of a ‘new normal’ phase.
So thanks to you all for your invaluable collective wisdom.
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