Who is Getting the IGHV (formerly known as IgVH) Mutational Status Tests in UK?

[jibs60]

Hello all,

I recently got my FISH results back and had for some reason assumed that I would also get IGHV mutationial status tested along with that as part of pre-treatment diagnostics. However, my consultant pointed that was not done as routine at my (non CLL specialist centre) hospital.

My CD38 was marked simply as NEGATIVE on my flow cytometry report taken on diagnosis, so the assumption would be be that I am likely mutated using that as as a surrogate test. Searching back through the archives I found this from Chris in a recent thread healthunlocked.com/cllsuppo...

"There is a direct test for IGHV mutation status and gene driver number, but it is extremely expensive and is rarely done outside major CLL research centers...However, we have a cheap test, called Flow Cytometry, that every CLL patient has had done at diagnosis. A cell surface protein, called CD38, is a good indicator of IGHV mutation status... so clinically CD38 is used... as a prognostic marker.

If your CD38 is under 30% your IGHV gene is likely mutated. If the percent is over 30% the gene is likely unmutated. This CD38 is called a marker and is about 70% correct. Further, the percent changes over time, but rarely goes over or under the 30% mark."

I know that some specialists, the late Terry Hamblin included, felt that the surrogate test provided by CD38 was unreliable due to its tendency to change over time, whereas IGHV remains constant.

As IGHV mutational status is acknowledged to be a good indicator of likely response to FCR treatment, including potential clonal evolution, I'd quite like to have the test done now as I approach treatment.

It would be useful though to get an idea of what is going on at other hospitals in relation to this test prior to treatment and outside of trials. I gather the test is not cheap, and want to make an informed decision about whether I should be requesting it based on the experiences of others in a similar situation here in the UK.

I'd be really grateful if people could briefly let me know of any useful experiences or views on this subject.

Thank you!

J xxx

[Mikey47]

Hi Jules, I have always believed that I am Unmutated by virtue of my 11q deletion. Michael Keating says that almost everyone with the 11q is Unmutated and that 11q is the only FISH type that is strongly correlated with mutation status. I haven't been told otherwise.

Now, from tests at Bournemouth I found that my CD38+ is only 1% which was encouraging.

I would expect to get my IGVH status clarified at some point on my trial.

Mikey

[Cllcanada Top Poster CURE Hero]

Well since I have had a Richter's transformation there is a 68% chance that I'm IGHV4-39, type 8...

Absolutely nothing could change it...you play the cards you were given...

[HAIRBEAR_UK Founder Admin]

The Cardiff group published a definitive prognostics paper last year that was the result of a very large UK study. The conclusions were drawn from data collected from a very large group of patients this explains the significance and current thinking as well as recommendations. How these will be taken up I don’t know?

If they have clearly identified and confirmed that this test has prognostic significance in early CLL is there another paper that provides clarification of the significance of this test to guide therapy? The conclusion in the abstract below suggests that this was not the recommendation at the time of the study. But has more data now come to light that could affect this?

Defining the prognosis of early stage chronic lymphocytic leukaemia patients.

ncbi.nlm.nih.gov/pubmed/221...

Excerpt from abstract;

” IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.”

The paper has been discussed by Chaya at CLL topics where the significance of IGHV is also focused upon.

updates.clltopics.org/4336-...

From a patient perspective I can understand thoughts ahead of treatment with FCR if recent data published at ASH by Anderson are suggesting that those who gain best results are mutated??

[jibs60 in reply to HAIRBEAR_UK]

Hi Nick,

Hope all is okay with you?

Thank you - yes, you are spot on with my reasons for wanting to know my status.

I agree with Chris that we play the cards we are dealt, and there is nothing we can do to change the deal. Playing 'blind' though makes it very hard to plan strategically for an increasingly complex treatment future. Knowing which mutational status card I hold could have an impact on my decision about whether to go with FCR now or to try and wait for a chance at ibrutinib next year...

Of course, I could get run over by something proverbial in the meantime, mutated or otherwise...

Thanks to all for your considered and thoughtful responses - really useful in helping me to think about this - Paula, I didn't see your initial post before you deleted it, but I'm sorry I didn't get to see your perspective...thanks for shedding light on my sudden name-change mid conversation though..I was a bit confused

Love and good weekends to all xxxx

[HAIRBEAR_UK Founder Admin]

Hi Paula

I think we have to be careful how this is worded. It appears that those who are still in remission after 9 years following FCR may be more likely to be mutated however good strong responses are gained by those who are not too. FCR is the proven standard of care and until personalized medicine becomes a reality there is still a catch all aspect to how CLL is treated.

The hope is for the future advancing testing capabilities will direct therapy choice . Today there are few tests translated for clinical use yet and the treatment options that may benifit from this are still experimental within clinical trial. that resource is going to become increasingly important to treating clinicians in the face of the current financial climate and price caps setting approvals by Guidance regulatory bodies like NICE.

Here is the recent patient Power broadcast:

this adds much hope for those feeling trapped with FCR treatment. As CD38 is a good if not perfect surrogate for IGHV mutational status knowing you may be mutated must be very encouraging ahead of treatment. as the talk is that remissions can be achieved that may be close to the C word? cure

here is the video clip by Andrew of Dr Wierda sharing his thoughts from IWCLL where the long term FCR treatment data was recently discussed following work by MD Anderson. this showed just how successful FCR is and with an average remission six and a half years. the suggestion is that those with even longer remissions may be IGHV mutated.

. MRD negative status at the close of treatment is important in establishing the stronger remission it seems that IGHV mutated and +12 patients gain stroger MRD and are more likely to gain the deepest remission. this raises the question for this group if MRD testing can be introduced during therapy will it reduce the number of cycles of FCR this group requires? I know researchers in the UK are exploring this. Dr samir Agrawal and team at Bart's discussed this at our London CLLSA meeting last year.

youtube.com/watch?v=Tk_j2hY...(Not working as expected?)

Is Long-Term CLL Remission with FCR a Cure?” - “This is the first time in CLL the word "cure" has been discussed in relation to a chemo-based regimen.” patientpower.info/video/is-...

Yes it is very confusing and a good reason why today with the increasing complexity of CLL treatment options coming available in trial a consultant with a special interest in CLL should be on your care team either as part of the MDT (multidisciplinary team) macmillan.org.uk/Cancerinfo... or as your consultant.

nick

.

[PaulaS Volunteer]

Hi J,

I had written a reply to you earlier this morning, (which you may or may not have read ), but having seen Nick's response above, I realise that things are much more complicated than I had thought, so I deleted it. (I'm writing this to explain why that post is addressed to me). It was helpful to be reminded that good responses to FCR are also gained by those who have not got mutated status, even if mutated tend to do even better.

Very confusing business, all this...

Thinking of you,

Paula

[cllgirl]

Hi! I am sorry for your situation- we all want to know as much as possible as we fight our CLL battle. This may not be comforting to you, but I will advise you that when I was diagnosed 4 years ago (under an Ibrutinib clinical trial for 6 months now), I , too, was CD 38 negative. The bad news is that I was IGVH unmutated. I know we are all different with various CD markers, but obviously a CD38 negative finding is not definitive when it comes to IGVH mutation status. If you can have the IVGH status tested and verified, you will have more information to go on and hopefully better prepared to make decisions as to your treatment. Wishing y.ou the best and peace

[jibs60]

Thank you CLL girl,

This is exactly why I wanted to make a case for having the test - given the decision I have to make about having FCR now or trying to hang on for ibrutinib later...I'd feel much happier sitting down at the chemo cocktail bar if I knew I was at least in the best place genetically to do as well as possible...as far as we can ever know...

I see you are treated at MD Anderson, so things will be different in terms of which diagnostic tests you are offered etc., being in the US Did you have your IVGH as part of your trial?

Glad to hear you got on an ibrutinib trial, and hope it is all going well for you.

Thanks so much for taking the time to respond.

J xx

[louise66]

Hi,

After I was diagnosed and had been busy finding out all I could on CLL, I asked my consultant for the test to find my mutational status. My consultant went over what the results could mean and that I fully understood what I was going to find out.

My test results came back that I have the Unmutated gene, not what I'd wanted to hear! I have found this result really hard to come to terms with, but I felt I needed to know so I could understand my CLL better.

Although I'm glad I know, I think it makes me worry more.

Take care all,

Louise

[eric91]

hello everybody,

It seems that cd38 echoes IGHV mutation but is only about 70% accurate. Is it due to the cut off value (30%). By exemple are we sure that cd38=1% means mutation?

eric

[Cllcanada Top Poster CURE Hero in reply to eric91]

Both CD38 and ZAP70 done in a research lab, echo IGHV gene mutation, however there is about 30% discordancy... which means that each isn't correct... or don't agree with one another.

Nothing is certain in CLL , but for CD38, below a level of 30% you are mutated, above 30% you are unmutated. the lower the percent the better, in other words.

CD38 does change, but it rarely cross the 30% cut-off from mutated to unmutated.

To be perfectly accurate you need a direct IGHV test, but they are expensive and not done routinely outside of clinical trials. If you are going to that extent, then also get subtyping done, because it REALLY matters which of the family of IGHV genes is driving your CLL...

Check out the late Dr. Hamblin's website... he co-discouvered this gene

mutated-unmuated.blogspot.c...

[eric91]

thank you for this link, i've read with interest this link but it's not clear for me if a very low cd38 means "mutated" with certainty

[Ernest2]

Thanks everyone for the updates on IgHv

From things I learned last week, have updated my comments on end of post:

healthunlocked.com/cllsuppo...

Thanks,

Ernest

[Prudie]

Good morning,

I was wondering if you ever did find out your mutational status or not?

Best Wishes

Debbie