This study reinforces others regarding mutations that predict a short time to first treatment. I think those of us that are 11qdel are aware of the association of 11qdel with mutated ATM and unmutated IGHV status.
By determining the relationship between a set of somatic mutations and established prognostic clinical features with time-to-first treatment (TTFT), study researchers identified potential early drivers of disease among treatment-naive chronic lymphocytic leukemia (TN CLL) patients. The study findings were recently published in the British Journal of Haematology.
“In a comprehensive analysis of all known clinical prognostic factors and 29 gene mutations in patients with TN CLL, mutated ATM and unmutated IGHV were the strongest predictors of TTFT,” the study authors wrote. “These results suggest that these two abnormalities are the most robust drivers of early CLL disease and progression.”
High‐risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.
I guess, Jackie, like many cancers, the closer the cancer cell is to resembling the parent (stem) cell the poorer the prognosis. Undoubtedly with many variations on that theme.
TTFT bothers me a little - because most, many in any case, me for sure, the CLL was active years before diagnosis.I can't understand how TTFT can be a reliable measure of progression rate. I know my CLL accelerated towards my treatment. 13q mutated.
TTFT is used a lot as a measure in low grade haematology disease. I guess it's about when the CLL becomes clinically significant enough to be diagnosed but that doesn't account for the incidental finding of CLL, which happens fairly often.
However, mostly there is a significantly long difference between those with these adverse markers (11q, unmutated) and those lucky enough to have 'better' markers and also be mutated to deduce cause and effect.
Hi Jackie, Many thanks again for this post - interesting as always when you post sth
Based on one of your recent posts, I had a conversation about additional markers with my professor here in France end August, but I do t think I had focused on “ATM” back then already.
As it is not really explained in the paper below, would you be able to give a short explanation “for dummies” about what the ATM market is?
The ATM gene maps to chromosome 11q22-q23 and several data indicate that 11q deletion results in ATM gene inactivation (deletion).
The ATM protein produced by this gene protects the integrity of the genome by preventing the processing of damaged DNA and by activating DNA-repair pathways. It induces apoptosis if the DNA damage cannot be repaired.
ATM mutations may also be present in the absence of 11qdel22-q23.
The majority of patients with ATM mutations show other poor prognostic biological features, i.e. unmutated IGHV, and positive for ZAP-70 and CD38 expression.
It's unusual for 11qdel CLL patients to have both copies chromosome 11 to have the deletion which mitigates its effect a little but these CLL patients typically have a short time to first treatment, do not have lengthy remissions following chemotherapy and have bulky abdominal nodal disease.
The good news is that Ibrutinib doesn't care if you've got 11qdel or if you're unmutated and almost all these patients do spectacularly well
My TTFT was exactly average at 2 years and really I waited too long, should have started 6 months earlier whilst I felt well, as my wellbeing suddenly fell off a cliff.
Ibrutinib has been good for me though and I’m very grateful 😊
Okay so they (ATM and unmutated IGHV) are the strongest predictors of TTFT (time to first treatment). Does that mean there should be no “watch and wait” for those people with that mutation?
Does that mean your overall survival is worse? They didn’t say that. And now with the new drugs like Ibrutinib and Venetoclax, those with those defects may respond better.
The article just raises more questions for me as that is my profile.
I was diagnosed in April 2019 and MD Anderson started my treatment of G plus V less than 60 days from diagnosis due to multiple and severe skin infections both viral and bacterial.
My specialist said he would get me “normal life span” and it would be 4-5 years before I relapsed (for a doctor to admit that so early on in treatment is great). My labs are normal right now except for slightly low H/H and increased IgG, A and E. I feel just a little more tired. Week 6 of Venetoclax.
The article didn’t mention treatment or overall survival.
It’s just one more piece in the puzzle of 11q. But the paper makes “watch and wait” seem obsolete for that ATM mutation especially with the new targeted therapies, in my opinion.
Really it’s “fast acting” CLL but it may be more treatable. Some survival curves with 11q and IB are 100% so far. So we are lucky we have these meds and nobody knows what is going to happen as not enough time has passed to examine all the data for say ten to fifteen years post treatment.
I believe Watch and Wait to be a relative term, and early treatment should be significantly influenced by the individual patients perspective on how it may improve their quality of life. Of coarse the perspective should first be influenced by credible medical consultation.
By relative I mean that when applying the Rai staging/Iwcll standards; A person with good pronostic markers may need to be treated at 3 month post diagnosis, whereas another who has less favorable markers may not need to be treated for 10 years post diagnosis. However not the norm, we actually see examples of such cases.
With regard to watch and wait, I think that the consensus with the medical community is shifting from being weighted for (waiting as long one can tolerate it) to a (wait until we determine what is the effort providing the greatest desirable outcome).
There is at least one trial in USA that I know of that is giving Ibrutinib to patients who do not need treatment according to conventional guidelines. It's aim is "to learn if providing earlier treatment for CLL or SLL with ibrutinib in patients who do not have symptoms will be more effective than waiting until symptoms develop". Here's the link: clinicaltrials.gov/ct2/show...
For me it was very true. I was 0% un-mutated, (0%-2% is un-mutated, 2% and above is mutated). I had been checked 6 months prior to CLL dx for different procedure and did not have CLL at that time. Went from 15 WBC to 197 WBC in 14 months. I was 13q deleted originally, now 13q normal. My ALC was doubling every 2.5 months and never even slowed down.
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