When told I had chronic lymphocytic leukemia (cll) four years ago, all I heard was "leukemia". Google soon became my best friend and worst enemy. I just wanted to find out how long I had to live.
My travels on the learning curve of cll were slow with many wrong turns. I figured out chronic leukemia was better than acute, that was good. Then I learned about the FISH test, which put my cll in four buckets, if you will, based on chromosome mutations. 13q was the best bucket, 17p the worst, trisomy 12 and 11q in between, whatever those numbers and letters meant (see FISH test for dummies).
Somewhere along the way I kept reading about mutated and unmutated cll. What the heck? I thought all cll was mutated chromosomes. As it turns out there are two much bigger buckets we can be on that predict the course of our cll, the mutated bucket and the unmutated bucket. About half of us have mutated IGHV cll, the other half unmutated. As counter intuitive as it sounds, having mutated cll puts us in the good bucket.
But what exactly is mutated in mutated cll, another chromosome? Nope, what is mutated is a small part of a Y shaped antibody that is on the surface of our cll cell. IGHV is a fancy acronym for immunoglobulin heavy chain region. Immunoglobulin is another word for antibody. Think of an antibody as a person doing the YMCA dance on a cll cell, but someone throwing up four arms instead of two. The two outer arms are the heavy chain arms, the region that gets mutated in mutated cll.
Before we try to dumb that down, lets keep it as simple as we can now. Doctors can run an expensive test to look at the Y shaped antibody (immunoglobulin) on the surface of our cll. If one of the Y arms has gone under a mutation, we have mutated IGHV cll that carries a favorable prognosis. If the Y arm is unmutated, our prognosis is less favorable (or maybe not, more on that later). 17p and 11q cll are most often associated with unmutated IGHV.
Want to try to understand this on a deeper level? Read on, but it can be confusing and in trying to dumb it down, for me too, I have taken some liberties that might not be 100% scientifically correct.
We have to do a brief review of cll cell biology to get us ready. Cells are the building blocks of life. It is thought that the first life on earth was a one cell organism, humans are multi-celled organisms with trillions of cells. Our cells have an outer membrane and a nucleus. The nucleus is packed with chromosomes, dna and genes.
Each cell has a different function. The genes that sit on our chromosomes give cells the codes to tell them what to do. One gene might tell a red blood cell how to deliver oxygen, another tell the brain how to think. Cancer is cells gone bad. A corrupted gene or chromosome in a skin cell might cause skin cancer.
The cells that are corrupted with cll are lymphocyte cells, hence the name chronic lymphocytic leukemia. Lymphocytes are a type of white blood cell that helps our immune system fight viruses and such. How do lymphocytes do that? This is where it gets really cool. First a little more cll biology.
Cells have to communicate to work. If a brain cell wants your hand to pick up a fork, its sends a message through nerve and muscle cells. Cells have little receptors on the surface that allow chemical signals to cross the membrane. Different cells have different receptors. To work one cell has to have a plug that fits the receptor. Now we can go back to lymphocytes and antibodies and the cool part.
You go to work and your coworker sneezes near you, unaware she has the flu. A tiny droplet with the flu virus enters through your mouth or nose. A virus is an infectious agent that hijacks your good cells and does what viruses do best, multiply.
Enter lymphocytes. Once your body becomes aware of a virus invader, your body sends out navy seal type lymphocytes to fight the virus. How so? Well, lymphocytes size up the virus and create a specific type of antibody, a protein that can bind to a virus and neutralize it. Remember we said these antibodies (immunoglobulins) look like a Y on the surface or our cells? Well the tips of the Y arms on antibody are specifically created to bind to a particular virus. A measles antibody wont bind to a flu virus. If you get the flu, your body needs to create an antibody specific to that flu strain. That is why viruses can run their course, even if untreated. When we have functional immune systems, after a few days our newly made antibodies overwhelm and neutralize the cells hijacked by the virus. Wild, isn't it?
The antibodies hang around, that's why once you get the measles, you should not get them again. The antibodies are in place. Then why do we keep getting colds and flus? That is because each flu or cold we get is a slightly different virus, requiring our lymphocytes different to make new antibodies unique to the new invader virus.
So in explaining mutated IGHV, as a side benefit we now know how cll impairs our immune systems. Our cancerous lymphocytes do not work as they should and don't make enough antibodies. And now you know something about the "ig" numbers on our labs. Ig is an abbreviation for immunoglobulins, immunoglobulins are another word for antibodies. Antibodies are proteins on the surface of our lymphocytes that attack invaders. If we have low ig numbers on our labs, our bodies are not making enough antibodies to protect us from invaders like viruses, bacteria and even pollen.
So now we go back to mutated and unmutated cll. Cells have a life span, just like humans. An old cell is more mature than a new cell. The thought with mutated cll is that as a lymphocyte cell matures, the Y arms of the antibody on its surface go through a change, a mutation, in a way such that mutated cll cells have more cancer fighting ability. Since we have one cll cell that is the mother of all our cll cells, if the mother cell was more mature and had a mutated antibody on it when it went bad, so will all our cll cells forever after. If our mother cll was a young cell when she went bad, she will be unmutated as will all her children.
The cutoff for mutation status is 2%. Less than 2% is unmutated. More than 2% is mutated, the more mutated the better. Someone whose test shows they are 8% mutated is thought to have a better prognosis than someone 5% mutated. And it makes a difference what region of the heavy chain (the outer Y arm of your antibody) you are mutated. Those mutated at the V3-21 region have cll that acts unmutated.
Recently some scientists have come up with a much different theory why having mutated cll is better, a theory so different its almost like saying that up to now scientists have been completely wrong about why mutated cll is better, like finding out the earth is round, not flat.
I see no reason to try to dumb down this scientific debate. In the first place, its over my head. Secondly, for our purposes its not that important we know why mutated IgHV cll is better, only that it is.
Is it even important we know our mutation status in the first place? Is it just prognostic? As it tuns out, its not just prognostic. We know that on average people with unmutated cll will not do as well with chemotherapy treatments like fcr. So there is an argument mutation testing is important not just as a prognostic marker, but also to help inform our treatment choices for those considering chemo. In the UK and some other countries where chemo is used front line for unmutated cll as well, one might not have an argument for mutation status testing since it will not inform the treatment choice.
Now the good news. Mutation status might not be as important as a prognostic indicator going forward as it was in the past. While unmutated cll does not respond, on average, to chemo as well as mutated cll does, there does not seem to be the same difference with new drugs like ibrutinib and venetoclax. Put another way, people with unmutated cll starting out on ibrutinib and venetoclax as a first treatment are doing just as well as those with mutated cll. The old survival tables showing people, on average, living longer with mutated cll than unmutated cll are obsolete to the point they should be removed from google searches. Everyone diagnosed today with any flavor of cll, mutated or not, has a great chance to live a long and normal life.
And now you can figure out how vaccines work. They trick your body into creating antibodies. By giving someone a tiny bit of the measles, they can get the measles antibodies in gear. We cant have live vaccines because even the tiniest bit of a virus might overwhelm our weakened ability to create antibodies. And now you also know what it means when someone tests you for antibodies. They can tell if you had the measles as a child if you still carry measles antibodies.
Well I hope I have not thoroughly confused everyone. Its hard to even have a rudimentary understanding of mutated cll without knowing about antibodies and how they work. And now that we know a little more about how cells work, we can better understand how scientists are using this knowledge to create drugs that bind to our cll cells and override the corrupt instructions the cells are getting.
Make no mistake about it. Now that they have mapped all our genes and know what they do, new and better cancer treatments for all sorts of cancers are in the works. Now that they know what is keeping our cll cells from dying a normal death, they are figuring out ways to override that. When we start talking about how venetoclax and ibrutinib work, this background information on how cells work will hopefully make it more understandable.
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cajunjeff
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The only thing that I would say you said slightly wrong is this. Our CLL cells don’t make useful antibodies, the rest of our lymphocytes do but they become less and less able to function and less and less in number as CLL crowds them out and then treatments kill them too.
I would also perhaps add this.
When people talk about TP53 mutation or some other mutation this is not the same thing you have been discussing but instead represents a change in a gene. And in the case if this specific gene it is a bad thing for it to be mutated not a good thing like IGHV. So it’s almost a lazy thing to say “mutated CLL” tho everyone does because we should say WHAT is mutated.
Incidentally the TP53 mutation makes FCR and other chemo almost never work and it is essentially the same effect as a 17pdeletion which means losing part of the 17th chromosome which happens to be the same but where this TP53 gene exists. Like antibodies this gene codes for a protein and i this case if that protein is damaged or absent chemo can’t really work.
17pdel /TP53 mutations are much more important than IGHV mutations. And in fact some people who are IGHV UNmuated CAN do well wirh FCR after all. Just less of them then those who are IGHV mutated.
I was one of them. I am IGHV unmuated byt got to disease undetectable status after FCR.
Oh and it’s worth saying that all these mutations and deletions well have spoken about in this thread as well as things like 13q deletions etc are only talking about our CLL cells. The genes in our remaining healthy lymphocytes and the rest of our cells are not affected (which is why we can’t directly give our kids the same CLL clone we have).
Some of us will have what are called “somatic” mutations in other parts of rhe DNA in all our cells ie these are the variations in our DNA we inherit from our parents. We will all have at least some mutations somewhere in the DNA. And some of these might make it more likely for us to develop CLL but they are not the specific cause of CLL in the same way some genes can be for say breast cancer. There is no one gene you can pass to your kids that guarentees they will get CLL.
It is true that we are born with a kind of genetic loading made up of lots of genes that make us more or less likely to develop cancer. Our kids will never have exactly There same make up as we do since they will inherit some of the genes from the other parent. There may turn o it to be more than 100 genes involved in this.
Well I tried to be careful to write that those with unmutated Cll, “on average”, don’t do as well with chemo as do those with mutated Cll. Your case is a good example of where someone with unmutated Cll did better on chemo than some with mutated Cll.
And your case and my case are good examples of why we shouldn’t obsess over prognostic markers. I have mutated Cll which predicted an indolent course, but I treated early after a bad bout of hemolytic anemia. You have had a wonderful response to fcr.
Markers are no guarantee of anything. I think they are most important when they inform treatment choice. FISH informs treatment choice because 17 p contraindicates fcr.
I still think IGHV testing informs treatment choice as well. Despite your excellent results with fcr, I think eventually in the UK that ibrutinib or venetoclax will become the preferred choice of treatment for unmutated Cll.
Sequencing is another issue. We know people on fcr sequence well to ibrutinib. It has to be very encouraging for you to know that your mrd status predicts a long remission for you and you still have ibrutinib and venetoclax in your back pocket. It’s even money many more options will surface in the next five to ten years.
Having Cll sucks but we are lucky to be living in an era where we have so many legit options.
Along those lines, I am 13q mutated and had a very bad reaction to FCR, so you never know. I guess that Adrian and I are good examples of how they say that we are all different.
Thanks for the kind words. I reread my post and found it confusing and overly long. But I guess it’s just a complicated subject. It’s hard to explain without a lot of foundational information about cells and antibodies.
Yes re my being TP53/17p - mutated. Bad news in earlier years. Dr Terry Hamblin told me he was sorry to see that I had over 30% mutation, and there was talk of being in the BAD bucket on earlier discussion lists. However luckily very slow progression over the years; and fast forwarding to 2017 and BTK inhibitors, the picture has changed completely. Hallelujah.
I really enjoyed reading this! Thank you!!! I have two questions please: (1) can the FISH test results change over time? (2) what (if any) would be the best test/method to find out if after treatment with Ibrutinib we have been cured? [I know that cure is not typical, but I remain an optimist, lol]
1. The FISH test can change over time. CLL tends to start as a single clone of identical cells. But they can pick up new mutations over time. And presumably it must be possible at least in theory to catch CLL twice and have two separate clones.
Over time more mutations and deletions tend to arise and you have a mixed clone. If you then treat with any treatment the less aggressive sub clones with fewer deletions or mutations are killed more easily and leave space and resources for the more aggressive ones to take Over and so over time the disease often gets progressively
Faster and more aggressive and harder to treat.
2. Ibrutinib almost never cures anyone. In fact it almost never gets someone to MRD undetectable which is a stepping stone in the route to a “cure” or at least a remission so long that you don’t get sick again before you die or something else. The idea of Ibrutinib is to slow the disease down and reverse it rather than erradicate it. With long term treatment maybe 10% get to undetectable but it’s unlikely any of those are cured.
Venetoclax containing treatments or FCR chemo are the two options which gets lots of people to MRDU status. Then if you keep repeating the MRDU and it never begins to rise over time at some point it would be asked “are you cured?” But some people might relapse ten years or More later and show they werent cured at all.
Yes the FISH results can change and evolve over time maresba. It’s called clonal evolution and basically due to the survival of the strongest clones following treatment. Our IGHV status usually remains constant however.
The best way to ascertain MRD (minimal disease status) after treatment is by a BMB (bone marrow biopsy). These are done routinely on clinical trials but a flow cytometry is more often used outside of trials to look at the peripheral blood (alongside lab results of your full blood count of course).
Sometimes it feels like draining the ocean of all it’s fish but leaving a couple of tougher fish hiding in a rock. Over time they’ll multiply but be even stronger this time which is why it’s sometimes important to continue with treatment beyond MRD ‘success’. A friend has just reached UMRD on ibrutinib alone (by BMB testing) but she was one of the first on ibrutinib in the UK and has aggressive deletions).
Studebaker, I had to remove my reply to you when I realised this is an unlocked post as I don’t care to give treatment details on others without their permission.
Fixed that, I didn’t think to lock post. As a side question, my post doesn’t contain any confidential info about me that I care about. Is it better for me to lock the post so juts the community sees, or unlock so anyone researching Cll might find it.
I don’t have a personal preference. I haven’t given much thought to locking or unlocking my posts.
It’s entirely up to you Jeff and entirely reasonable to leave a post unlocked if you think it’s an important explanatory post that the wider net would appreciate and benefit from. Plus it attracts people to the site. It’s simply that the responses take their status from that and I didn’t want to discuss another person if it could distribute more widely.
Yes that’s fine Jeff. It’s why we advise people not to use actual names or photo avatars because they become visible when responding to unlocked posts. When discussing very personal matters, not everyone wants the neighbours or co-workers to hear about their constipation or site of rashes! 😉
Personally I’ve had CLL since 2005 and if someone wouldn’t have left their post unlocked I would’ve never found this site. And I would’ve never heard of it. I had never heard of Health unlocked until stumbling on that person‘s post.
Just as a side note, I remember back around 2003 when they were running the FCR trials down at M D Anderson, they weren't testing for mutation status because it was still quite new. At the time Dr. Terry Hamblin,( who first wrote about the significance of the mutation status), was on the ACOR CLL list. He would say if they tested the FCR patients for mutation status he would bet that the ones that were having the best results were mutated. I think he meant that it was there mutation status more than the FCR that was responsible for there good results. Anyway it turns out it was both.
One could also argue that as treatment get away from chemo the test won't be needed any more, but I think the jury's still out on if unmutated patients will do as well as mutated patients on the new treatments
Wow! I read this incredibly understandable explanation of mutated/unmutated and the description of CLL with a smile...wishing that that on that July 2012 day of my diagnosis I had access to this clear information about a cancer I was even sure how to spell. I had just retired from my profession as a librarian. My job was to seek out accurate and current information about a myriad of topics. Thank you so much for providing such clear accurate and current information about CLL for all of us but especially for the newly diagnosed who need clarification and information to help them breath again and prepare for what lies ahead. I am fortunate to be part of the Elevate trial taking acalabrutinib and obinutuzimab... I am almost at year four with only one node larger than the 1.5cm criteria for a complete remission..this was my first treatment....information is power and your words are surely empowering for all CLLers.
My only addition, related not to IGHV status but to normal IgG production, would be to point out that the process of hypermutation is thought to be a random one and is not guided by a specific pathogen/antigen. The B cells do not get a set of new instructions to fight a particular pathogen, rather only the B cells that by chance produce an immunoglobulin that binds to an antigen will survive, multiply, and develop into either IgG secreting plasma cells or memory B cells.
At any given time the number of different immunoglobulin gene sequences available for antigen selection is limited only by the number of B cells in the healthy human body (that excludes us CLLers). Some estimates are that at any given time 2×10 to the 12th different IgG gene sequences are available for selection, one per B cell. Most of these B cells live only a few weeks. Only those B cells that encounter a non-self antigen survive.
Good stuff gardening girl. You have a deeper understanding of these things than I do. I am guessing you have some sort of science background to be able to discuss things on such a high level.
I am fascinated by all the crazy things cells do in our bodies. I feel bad about killing so many brain cells during my college days now. In my defense, it was the sixties. 😛
Well Jeff, I somehow managed to make it through the 60s unscathed! I have no special medical knowledge but I had a 40 yr career in research and teaching as a cell and molecular biologist. Currently I am a gardening-girl trying desperately to keep up with the tremendous advances in cell and molecular biology! 😊
As I've told you before I love your wonderful communication skills!
A cell and molecular biologist?!? As Ricky Ricardo might say, that splains a lot, Lucy. 😛. It’s extra flattering that you think I got it remotely correct.
My azaleas, redbuds and camellias are in full bloom. My Japanese magnolia just dropped its blooms. I had a glorious mix of red coleus all over my yard last year and I want to try the blue and purple ones this year. But I got a puppy who eats everything in her path and the coleus might be toxic to pets, so I might go back to impatiens this year that do very well in my yard.
Your yard sounds beautiful. You should include some pictures with your posts! You are way ahead of us in Tennessee, although yesterday I did see some blossoms on one of our peach trees.
I added a picture of a backyard pot we planted with red coleus. I had them in a lot of my beds too. The reds are vibrant but I really want to try the blue ones.
Cll cells, and other cells, have a variety of molecules that reside on the cell surface. These molecules have much to do with the function of the cell.
To identify the different molecules, scientists assign names to them with letter initials and a number. CD stands for cluster of differentiation. 38 is the number given to that unique molecule.
To diagnosis Cll they give us a test called flow cytometry. Cll cells can be identified by having certain molecules on the surface like CD 5 and CD 20. These molecules act like fingerprints. If there are more molecules than expected, it’s called “over expressing”. Cll cells over express CD 5 and CD 20.
CD 38 is an enzyme found on some Cll cells, but not others. If more than 20% of our cells express CD 38, we are said to be CD 38 positive.
Statistically it appears that those of us who are CD 38 positive have, on average, more aggressive Cll. About two thirds of those who are CD 38 positive will also have unmutated IGVH Cll.
So CD 38 is just another marker they use to predict the course of our Cll. Unlike mutation status, our CD 38 status can change over time.
But it’s no guarantee of anything either way. One can be CD 38 negative and still have aggressive Cll, one can be CD 38 positive and have indolent Cll.
I hope that helps. More importantly, I hope it’s correct. Lol. I’m no doctor for sure.
Might be no Dr but excellent at explaining things- thanks I looked at my typing again and CD 38 low so guess that’s good news and 3 years since Dx still on watch &wait so feel a bit more positive now.
This is a 2 cups of Caffeine *read* - really *nailed it* & I so appreciate the responses from everyone’s playlist.
Thank you, #cajunjeff for acting as the DJ and adding music to our communal dance. You are brave, fearless & gifted with an ability to choreograph what can be a disheartening search into the journals.
I can’t get the YMCA out of my mind’s eye.
Adding music & dance will forever keep this explanation *alive and simplified*.
To the administrators & participants struggling with the complexity of this disease, thank you for the updates.
Question- *FLOW accuracy from Bone Marrow Aspiration vs venous draw* -
Is a BMA needed? Is there more chance to understand the clones, mutations & be able to choose a more suitable treatment plan (including changing course before a problem gets worse)?
Does it matter with current choices like Ibrutinib vs venetoclax or a newer BTK?
Does anyone know of a medical center using the new assay *clonoSEQ* which may replace the FLOW.
I have run into great resistance to get someone on my *team* to order this test.
It is FHA approved, Medicare pays ($2000), generous - (their words) patient assist on the copay- and replaces the often - as our disease progresses- inconclusive FLOW. & Now accepts 2 ml of venous blood (vs BMA) in a purple top tube. What’s not to love?
When my most trusted medical advisor (Cardiologist) suggested I trip up to see the east coast guru- Dr Anthony Mato - I realized - no one yet knows what to do with the results.
I’ve asked the company to send a link to a sample result sheet with the explanation and possible published study from a journal. If they comply with my request, I will post.
#cajunjeff - thank you. Can I nudge you to think about BMA vs Venous blood accuracy in defining the significance of our clones, mutations & treatment courses?
& many cheers to your gardening efforts.
Your flowers are perfect *eye candy* presented with music & dance from an alumni of The Age of Aquarius- wonderful memories! Thank you.
DB, I am not really sure I understand your question, but I will give it a shot. I take it you are asking about what tests we should undergo to inform out treatment choices.
The clonoseq test you describe, to my understanding is a more advanced sort of mrd testing that is more sensitive to finding any residual cancer cells in our marrow. I assume would be superior to mrd testing in our peripheral blood. I will use myself as an example. I am on ibrutinib and doing well. Should I push to undergo clonoseq testing on my bone marrow aspirate?
Keeping in mind that by basic fallback is that more information is better than less, I still think you have to balance that with the cost of the test, the invasiveness of the test, the timing of the test and what need you have for the information.
First of all, I am fairly certain I am not mrd negative, few people on ibrutinib alone are. If I wanted to know, I would do a blood test first. I dont want anyone digging in my spine with a needle and there is no need to look in my marrow if I am mrd positive in the blood. I know I will be mrd positive in the marrow as well.
I have no plans to quit ibrutinib, no reason to think I am mrd negative and therefore no reason to have my marrow tested. If my doctor had added venetoclax to my treatment plan in the hope of me stopping all drugs, and I got mrd negative in my blood, then the clonoseq would be of great meaning to me. I want the most clear picture of whether I have any residual cancer before I suspend my meds.
The tests I might push for before starting any treatment would be FISH, IGHV mutation test and next generation sequencing. All of these tests might inform my treatment choice. I think sequencing is rarely done, but it might reveal a btk or other existing mutation that would predict resistance to ibrutinib and have my doctor look at venetoclax option more.
I dont know if I answered your question, but I wold not push to have my bone marrow tested unless I was considering stopping my meds if I was mrd undetectable. Its an expensive test and involves a bone marrow procedure which is painful and carries a risk of infection.
Well done and easy to understand, even after a nice glass of red.
When diagnosed in 10/2013 my CLL was told, unmutated, no CD 38, Trisomie 12.
After 6 x FCR it was MRD neg im 4/2014. Since then, my blood work was excellent, all green.
The MRD changed over time to 0,1 up to 0.6 of all Leucos.
Then new messures of MRD UD, they told me in Cologne (Prof Hallek), under 0,7 is not detectable.
Then it was messured 0,01! Now, in Jan 2020 it is 0,1 again.
0,1 was already in late 2014.
Sometimes I doubted the mutated/unmutated status and read some abstracts from ASH, that it can sometimes be in between.
Anyway, thinking of the prognosis I got in 2013!!! I am still happy. Although my Prof in 2013 once told me not to be too worrysome and should not google too much, he said, in his opinion, all CLL patients seemes to have a normal lifespan, due to new agents available soon (2013!).
Thanks so much Jeff! If mutation is a continuous scale, with the higher the mutation % the better, why an arbitrary number of 2% was chosen? Seems to me that it should not be that binary.
Ben, from what I have gleaned from what I have read, I do not think the 2% is totally arbitrary. I think rather that 2 is the number where being mutated below that number doesn't confer any real benefit, and where being above two percent does, on average at least. I think case that fall close to the 2% range can act mutated or unmutated.
I do not see IGHV mutation status as some perfect prognostic indicator anyway, folks can be 0% mutated and still do well. I think on average though, 2% is the line where, on average, being mutated showed a benefit over being unmutated.
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