As I continue to educate myself it appears that mutated is better than unmutated. I have had both fish and flow tests and although I have just 13q deletion no signs of other deletions I am struggling to figure out if I am mutated versus unmutated (although I’m leaning towards unmutated) based on what I am reading. Can anyone provide me some direction how to determine that “what language or other measurements” would further help me figure that out.
Thx
Your Flow Cytometry results may include results for CD38 and ZAP-70 status. These tend to correlate with IGHV mutation status, with CD38 being a better indicator than ZAP-70. If you are CD38 negative and ZAP-70 negative, there's a reasonably good chance you are IGHV mutated and if positive for both, IGHV unmutated. The CD 38 and ZAP-70 markers are liable to change over time, whereas IGHV mutation status is unlikely to change.
Neil
AussieNeil, Many thanks! I have read that ZAP-70 is not always measured in standard IGVH testing and that they are using other markers now. Is that correct? Aren't there other means or criteria for detecting whether a person is mutated versus unmutated? I believe there are... Plese let me know... Best, G
There have been multiple attempts to find better markers than CD38 and ZAP-70 as an easier to perform surrogate test for IGVH testing, but I'm unaware of any that have been shown as better than these - or available outside of a research facility. Chris Cllcanada and Jackie Jm954 might know of some...
gene7591
There is direct IGHV gene mution testing available and there is a program current to certify labs to do it to a specific standard worldwide.
Its very time consuming and therefore expensive...
ZAP70 is a poorer surrogate, because it can be effected by handling.
CD38 is more accurate, but both are only correct 70% of the time...
~chris
Chris- Thanks very much. Yes, I have also heard that some of these "markers" are nowhere near 100% accurate- and as you mention, perhaps only accurate about 70% of the time. That means- I believe- that some material percentage of people identified with a certain "marker" are actually NOT in that category, correct? As someone with advanced scientific training (not a doctor, but I have undergraduate and graduate degrees in science), I know that test limitations are worth paying attention to- and that argues for follow-up testing to confirm any results. Best, G
Yes it is not unusual to have members state that they don't meet the expected IGHV mutation status given their CD38 and ZAP-70 markers. There were a couple of papers on this surrogate effort by MDA researchers and Hamblin et al, but I can't find them now. The original MDA paper included an analysis showing a useful correlation of IGVH with ZAP-70. The responding paper by Hamblin et al showed a far less clear correlation - different patient populations...
Figure 7 in this paper illustrates the challenge:
nature.com/articles/2403147...
Think about how well scatter plots from your lab experiments (I presume you did these as part of your training) align with a linear correlation predicted by theory and you'll appreciate the challenges.
Neil
I don't know of any either and neither are 100% reliable for predicting mutational status. I can't add anything to the excellent answer from Chris.
Hi Superdad,
This article usefully expands on what Neil has explained. The link to the source now seems to be broken but this content is very helpful;
CD 38 & ZAP 70
What is the significance of CD38 in CLL?
‘The presence of the antigen CD38 on B-CLL cells is a much discussed prognostic indicator in CLL. Whether it is a truly independent prognostic indicator or simply a reflection of IgVH gene mutational status, CD38 clearly seems to have some relevance in predicting whether a patient’s CLL is likely to have a favorable or unfavorable clinical course. CD38 is detected by flow cytometry, a diagnostic technique frequently used in confirming CLL.
Patients with less than 30 percent CD38+ B-CLL cells are likely to have a favorable clinical course requiring minimal or no therapy. Patients with equal to or greater than 30 percent CD38+ B-CLL cells are more likely to have an unfavorable clinical course requiring earlier and ongoing treatment. Significant differences in survival are also thought to exist between these two groups. CD38 expression remains stable over time in the majority of patients, but it is known to change in approximately 25 percent of cases. Its level of expression does not seem to be influenced by chemotherapy.
The connection between CD38 expression and IgVH gene mutational status is not well understood. It appears that patients with less that 30 percent CD38+ B-CLL cells are likely to have mutated IgVH genes while patients with greater than 30 percent+ B-CLL cells are more likely to have unmutated IgVH genes. While this is often the case, there is approximately a 30 percent discordance between assays for CD38 and IgVH mutational status (see also: What is the significance of IgVHgene mutational status in CLL?)
Both CD38 and IgVH gene mutation are thought to be useful prognostic indicators in B-CLL, but because of the relative ease of testing for CD38, it is a much more convenient test.
CD38 and IgVH mutational status are just two of a number of prognostic indicators in CLL. Others include, circulating levels of beta-2-microglobulin and soluble CD23, lymphocyte doubling time, serum thymidine kinase levels, bone marrow histology, and chromosome abnormalities.
What is the significance of ZAP-70 in CLL?
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70. This protein is a member of the protein-tyrosine kinase family and when expressed on B-CLL cells is surrogate marker for IgVH gene mutational status. The presence of ZAP-70 can be detected by flow-cytometric analysis, and the level of expression is thought to correlate with mutational status.
CLL patients with less than 20 percent ZAP-70 positive B-CLL cells are likely to have mutated immunoglobulin V genes, predictive of a more favorable clinical course, while patients with greater than 20 percent positive B-CLL cells are likely to have unmutated immunoglobulin V genes, predictive of a less favorable clinical course.’
Regards,
Newdawn
unfortunately the link has been removed and David's work has gone... 😔
New dawn,
Thank you for that information so I’m looking at a couple of different report on my venipuncture detail it says:
CD19/CD5+ Cell’s neg (<20%) for zap-70 then zeta associated protein,T-cells, 5.92% of CD19/CD15 unmutated is how gene status in B cells
On my flow panel it says B-cell population co-expressing CD5,CD11 and CD23 is present, CD38 expression not detected
My fish shows no evidence of trisomy12(12+), p53(17p13) and 11q22.3 which I believe is good. Only shows (13q14.3).
I can’t figure out if I am mutated or not and appreciate any help.
This sight has been so helpful and I have learned so much, can’t say enough how much it has helped me understand more about cll
Thank you so much
Given 'CD38 expression not detected' and 'Cell's neg (<20%) for zap-70)' it is quite likely that your CLL falls into the IGHV mutated category.
Neil
Thank you also Neil.
< 20% ZAP70 likely mutated...
When I go in for my next visit I feel more prepared to speak to my cll specialist. I had no idea what to ask or Understood any of these test was so out of it.
Thanks cllcanada
We have all been there, in fact they never had any of this in the CLL stone age when I was diagnosed... 😮
May notice we use 'likely' a lot... Nothing in CLL is certain...
CLLcanada,
I am hope someday I can look back at this time in my life as the stone age and we can be talking about how successful all these and other new treatments are in changing peoples lives with this and other cancers. Would be great if our kids and grandchildren to grow up where cancer is no so scary anymore.
Dear Superdad,
I'm hoping that in about say 4 to 5 years time genetic profiling will give us better answers. I guess there will still be some statistics in the answer and that may improve over time.
In the meantime I would celebrate your hopefully mutant status.
Best wishes,
Ernest
Ask for the specific test for mutational status.
I’d always understood that specific test for mutational status to be incredibly difficult to obtain with only a few centres carrying it out as a stand alone test. Certainly it’s rarely if ever done in the U.K. and my haematologist was unable to give me any indication from my flow cytometry test from 5.5 yrs ago. He said they didn’t capture the information then. However, even FISH testing isn’t routinely offered in the U.K. so I’m completely in the dark as to my biomarkers.
Seems to me that for the most part, it isn’t given the prominence it deserves as a guiding prognostic factor in many places despite this from Dr. Sharman;
Dr. Sharman recently said this on the subject (taken from a PP interview discussing treatment considerations);
'First of all, I think that the IgVH mutation analysis is poorly understood by most practicing providers. I think there is a significant misunderstanding and even amongst physicians I know first hand who are interested in hematology, there’s often at times, a lack of total awareness of what this means. To me, IGHV mutation analysis defines treatment intent.'
Regards,
Newdawn
For what it is worth, I have the same problem understanding test results. I have a FISH test that states:
"A 13q deletion indicates a favorable prognosis in chronic lymphocytic leukemia (CLL). The remaining probes do not differ from the normal controls."
I also had a phone conversation where the doctor said I was mutated but I am struggling to put the numbers together myself and was initially happily under the impression that the 13q deletion was mutated but this does not appear to be the case.
Obviously I will try to work with all the information provided above.
I will take a contrarian position to pkenn and agree with NewDawn, Neil & Chris.
Both Superdad and jbctx have all the preferred markers -13q and highly likely Mutated (that I wish I had), but digging deeper into statistics will NOT provide more worthwhile information. You both now need to determine where you fit on the -13q Mutated prognostic curves.
IMO - the only way to really personalize this further is to track your own blood results over months and years. (Anything else falls into the old saying "Lies, Damn Lies & Statistics")
Use this cllsupport.org.uk/cll-sll/s...
or this cllsociety.org/toolbox/keep...
Once you have 4-6 data points of how fast your own personal ALC is rising, plot the number of years it will take to fall between 100.000 and 200,000 and that will be a very rough estimate of when you MIGHT need treatment.
This is NOT exact, and does NOT work for everyone, but could be used like a wind sock to tell the general direction and how fast things MIGHT happen for someone -13q and Mutated.
Just my own personal brain storm ( & envy ) Len
We are not on opposite sides at all. I should have realized that mutational status is not often done in the UK. In a perfect world we would have all of the answers we would like to be able to predict the probable course of our CLL. I have never had my musational status tested. My CLL is so completely atypical that following my kidneys has been the way to follow my status. B2M for my case is useless. And it seems that when the markers are all done and analyzed, they can only tell us what might happen. No simple, black and white answers, no matter how much information one has.
Or use trend lines to predict when platelets may drop below 100 or haemoglobin may drop below 10. Also, an exponential curve is likely a better fit for lymphocyte growth - hence the measurement of 'doubling time'.
This maybe a dumb question. ALC should be between 1 - 3 which is the normal range. I'm at 10.6 at the moment. 13q unmutated. WBC 12k. I was wondering how high can the ALC go without treatment.
I believe Dr. Kipps had a patient with an absolute lymphocyte count [ALC] over 1400K.
This time last year, my ALC was at 450K or so and rising..., but both my Hgb and platelets were in free fall, so treatment was started.
Its the rate of rise that is the indication for treatment, and doubling in 6 months usually starts a treatment discussion. Counts are one indicator, how you feel and B sysmptoms play a role.. enlarged nodes, night sweats, fatigue, weight loss etc.
Its the whole patient the indicates time for treatment... not a single number.
Generally ALC counts under 30K are not a concern, but over that mark, doctors start to look for this 6 month doubling...
~chris
Chris - thank you that is wonderful news. I can sit back and relax a little now. One more question with my ALC is 10.6 the ALC% is 82%. When it's at 100% wouldn't these bad b-cells out crowd the Neutrophils and lower my defense system?
Hi Naka,
Your hypothetical premise of ALC rising to over 99% is what actually happens for many patients. When the CLL cells occupy most of your bone marrow your Red Blood components like Hemoglobin, hematocrit and platelets will start to decline often before the Neutrophils, and that will trigger treatment.
Some patients get a more significant decline in Neutrophils from treatment than before treatment.
When the Neuts go well below 1 then serious infections can occur, so the doctors will watch for that.
But even with a normal ANC, your immune system can be very weak. Low IGG IGA & IGM are common effects, as well as an ineffective immune system even with all numbers near to normal.
See Dr. Terry Hamblin’s blog on immunodeficiency
mutated-unmuated.blogspot.c...
Len
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