The immunoglobulin heavy chain gene (IgHV) mutation status correlates with the clinical outcome of patients with CLL treated with chemoimmunotherapy. Why the survival rate of patients with unmutated IgHV is worse than that of patients with mutated IgHV is unknown.
A low IgHV mutation rate is found in rapidly dividing cells whereas a high mutation rate is typically found in slowly dividing cells. Thus, the proliferation rate of CLL cells determines the IgHV muta-tion status and patients’ clinical outcome. A cutoff of 2% deviation or 98% sequence identity to germline in the IgHV sequence has been routinely used as a prognostic marker.
A retrospective analysis of the survival and progression-free survival of 535 CLL patients treated with chemoimmunotherapy showed that the percent deviation of the immunoglobulin heavy chain gene variable region sequence from the germline sequence (IgHV%) is a continuous variable. CLL patients’ survival correlated with a continuous increase of IgHV% deviation. The higher the percent deviation, the better was the treatment outcome, suggesting that IgHV% is a continuous and not a dichotomized prognostic variable.
Very interesting read. Since the basis for the terms “mutated” and “unmutated” appears to have been proven false, I wonder if those terms will go away and just be replaced with “proliferation rate.”
I've been wondering about this for years now. I'm right at 2%. What does that mean. Would I respond more like a mutated or an unmutated chemoimmunotherapy patient? I know it doesn't make that much difference anymore but I still thought it was funny that I was right on the cutoff and considered unmutated.
A very interesting read. I have to wonder if or why some of the author's points have not been made previously, so I started look at them.
The idea that IGHV mutated vs unmutated as being a continuum, and not the binary status it has long been considered by many of us was also pointed out in reference [11], a paper also from 2018:
The absolute percent deviation of IGHV mutation rather than a 98% cut-off predicts survival of chronic lymphocytic leukaemia patients treated with fludarabine, cyclophosphamide and rituximab
So I think that idea may be gaining steam as the idea sails. That reference paper
How did the binary status get established in the first place? I think it was a statistical thing to try to organize groups of patients to explain why some never needed treatment at all. The binary was originally perhaps "treatment required vs. probably not", because those who never need treatment can take care of themselves if and when they get over the shock of the C-word. I'm sure that most hemo/oncologists know these nuances. I'm sure they also know of IGHV mutated patients (M-CLL) that do require treatment, and some IGHV unmutated (U-CLL) patients who have managed to avoid treatment for a decade or more.
But having a test result in hand with a binary positive/negative is needlessly upsetting, I think. It all too easily becomes a proxy for "life vs. death" in the minds of many patient, when in fact it should be "how long might my life be?" or "how much trouble might my last years be?" or "shouldn't I actually be asking my cardiologist or endocrinologist how long my life might be, because this CLL thing is just a complicating nuisance for me?"That's an attitude that I have failed to master myself after 8 years of W&W and no treatment. I am T12+, mutated IGHV.
So I think patients want answers to questions the tests cannot provide. Perhaps looking at IGHV mutations as a continuum, along with some other factors, we might approach getting good answers "how much trouble might my last years be?", and the answer might still be "roll the dice thrice", or "look at what killed your ancestors", or "ask a different specialist".
Back to the original paper, though. The real reason the authors wrote it was to try to explain WHY the IGHV measurement is a prognostic factor at all. So it goes into the microbiology of somatic hypermutation, and draws on papers that are 8 to 20 years old. Stuff that has been out there. It's beyond my mental pay grade to assess the quality of it all. But it sure is interesting.
I now hear better that all these cells appear to be post germinational - they've left the marrow, and gone to a lymph node or the spleen to learn what microbes to fight. I wonder what determines each surface marker that leads the microbiologists to conclude they are post-germinational. I suspect that B-cells can meet a pathogen in the dark alley on the way to the germinal center, and transform into their super-hero, hypermutated role there. Some of them may appear to be post-germinational, but have their finger in their jacket pocket, so you think they have a gun.
I'm so grateful for the time to even ponder such things.
I always think that we can define a CLL by this and that genetic profile etc etc but in the end the Dr deals with the clinical signs and symptoms they are presented with. Nothing more, nothing less.
Wow! good read. Too much to digest in three thanksgiving meals. I may come back for some dessert when my brain swell is less.
Here is what I believe I learned in the small portion that I chose to consume for the importance of mutational status to a patient in choosing therapy.
Summarized analytic perspective to article Re: contradiction with current standards.
Prognostic value of mutational status with regard to FCR. - unchanged.
Prognostic measure for mutational status 2% deviation or 98% ... - unchanged
Mutated vs unmutated cell (unmutated do not complete mutation). - unchanged
Mutational status does not change over time with any measurable significance. - unchanged
Theory determining mutational status. - changed
Change = Proliferation rate of post germinal CLL cells when catalyzed by AID
- that CLL patients’ survival correlated with a continuous increase of IgHV% deviation
- that the IgHV mutation status does not directly affect the disease course or treatment outcome; it rather depends on the proliferation rate of CLL cells.
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