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 blood cancer 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.
Blood Cancer for Dummies
- Introducing Blood Cancer for dummies
- Cell biology and blood cancer for dummies
- Fish testing and chromosomes for dummies
- Mutated and unmutated CLL for dummies
- Viruses for dummies – blood vancer / corona edition
- Covid for dummies – part deux
- Ibrutinib and BTK inhibitors for dummies
- Antibodies (immunoglobulins) for dummies
- Monoclonal antibodies for dummies
- Clonal evolution for dummies
In CLL cells that proliferated at a high rate, a high-utility repair mechanism is engaged; as a result, the IgHV mutation level is low (or “unmutated”). Conversely, in CLL cells that proliferated at a low rate, a low-utility repair mechanism is engaged; as a result, the IgHV mutation level is high (or “mutated”).What is the most common CLL mutation? ›
Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Deletion 13q14 is the most frequent genetic lesion of CLL occurring in 50% to 60% of cases.What is the prognosis for unmutated IGHV CLL? ›
Cases with mutated IGHV (mCLL) had a better prognosis, as seen above the survival probability in cases of mCLL is 0.50 in 150 months and continues to remain the same, unlike unmutated CLL in which the survival probability falls to 0.50 in 50 months reaching almost Zero in 180 months.What mutation is CLL cancer? ›
In most cases of CLL, a change can be found in at least one of these chromosomes. Most often this change is a deletion − that is, loss of part of a chromosome. The loss of part of chromosome 13 is the most common deletion, but other chromosomes such as 11 and 17 can also be affected.Which is better mutated or unmutated CLL? ›
Patients with chronic lymphocytic leukemia (CLL) whose leukemic clone uses a mutated immunoglobulin heavy variable (IGHV) gene (M-CLL) typically have less aggressive disease than patients with CLL that use an unmutated IGHV gene (U-CLL) (1, 2).What does mutation mean in leukemia? ›
Gene mutations that “turn on” oncogenes or “turn off” tumor suppressor genes can cause bone marrow cells, particularly immature WBCs, to grow out of control. As these unhealthy cells continue to divide and grow, they develop into acute leukemia.What is the most aggressive form of CLL? ›
A small number of people with chronic lymphocytic leukemia may develop a more aggressive form of cancer called diffuse large B-cell lymphoma. Doctors sometimes refer to this as Richter's syndrome.Which has worse prognosis in CLL? ›
Four CLL subgroups were defined for prediction of overall survival: (1) TP53 and/or BIRC3 abnormalities with the poorest overall survival with a 10-year overall survival of 29% only, (2) intermediate-risk with NOTCH1 and/or SF3B1 and/or del(11q), (3) low-risk harboring trisomy 12 and/or normal genetics, and (4) very- ...Which gene mutation predicts poor prognosis in CLL? ›
In a variety of different CLL trials, genomic aberrations, particularly 17p deletion and mutation status for TP532-7 had the strongest relation to clinical outcome. Their assessment before institution of therapy has therefore been recommended for every CLL patient.What are poor prognostic markers in CLL? ›
At presentation, WBC count and ALC > 100 × 109/L are poor prognostic markers. Patients who received chemotherapy had a longer median survival. It is recommended that full blood count is done for all patients for earlier detection of CLL, which may affect survival.
- a low blood level of beta-2-microglobulin.
- a low number of CLL cells have the proteins CD38 (cluster of differentiation 38) or ZAP-70 (zeta-associated protein 70)
Lymphocyte doubling time (LDT), serum beta2-microglobulin (s-β2M), serum thymidine kinase (s-TK) and lactic dehydrogenase (LDH) are the most common conventional serum markers in CLL and predict poor outcomes. LDT has been used as a prognostic parameter for more than 30 years.What is mutated CLL? ›
In CLL, these genes are either mutated or unmutated. Mutated IGHV is often associated with a favorable outlook, whereas unmutated IGHV genes can mean that your CLL is higher risk and may not respond as well to certain treatments. 1,3. More than 1 in 2 people (56%) with CLL have the unmutated IGHV gene .How bad is CLL cancer? ›
Around 87% of people with chronic lymphocytic leukemia (CLL) live for 5 or more years following diagnosis. Although doctors cannot often cure the disease, a person can live with this form of leukemia for many years. CLL accounts for around one-quarter of new leukemia cases.Can CLL turn into brain cancer? ›
According to a report published in Clinical Lymphoma, Myeloma, & Leukemia, a large autopsy study found brain involvement in 20 percent of CLL cases. CLL that spreads to the brain can occur anytime during the disease, notes the Cureus study.What are the recurrent mutations in CLL? ›
Over the last 10 years, whole-exome and/or whole-genome sequencing studies have dissected the genomic landscape of CLL, demonstrating that only a few recurrent gene mutations are present in more than 5–10% of cases (ATM, NOTCH1, SF3B1, TP53), while the majority are seen in a minor proportion of cases (<1–5%) [20, 21, ...What is the IgVH mutation in CLL? ›
The IgVH gene mutation status is one of the discriminators of clinical outcome in patients with CLL. The mutational status of the immunoglobulin genes expressed by CLL cells can be used to segregate patients into two subsets that have significantly different tendencies for disease progression.