Mutated vs. Unmutated CLL (2023)

I was surprised to realize that I have not posted on thedifference between “mutated” and “unmutated” CLL. This is such a basic characterization of CLLthat I assumed I had posted on it previously.

Credit belongs to the late “Terry Hamblin” whose labactually helped figure this out and created his own CLL blog“mutated/unmutated” that was a valuable source for CLL education prior to hisdeath. For many insightful articles on CLL I would direct readers to his blog.

Whether a case of CLL is referred to as “mutated” or not isa characterization of the B cell receptor (BCR). Remember that every B cell has its own uniqueBCR and it will only have that one BCR for the entire life of the B cell. When a B cell grows up to full maturity, theBCR becomes a secreted antibody. Youmake antibodies to fight off just about every infection out there. Each infection you can fight off representsthe success of a B cell to identify it, go through a bunch of rounds of celldivision, then mature to make antibodies.Each B cell has one and only one unique BCR.

The interaction between B cells and whatever they are tryingto fight off is a really important event in B cell biology. Keep in mind that diseases like lupus andrheumatoid arthritis are really just B cells getting confused between what isnormal in your body and what is an invading microorganism. It is super important that B cells stayproperly focused on things that are not you and leave the rest of you alone.

This is where T cells come into play. T cells are sort of like B cellchaperones. T cells help determine ifthe B cell that has received a “signal” through the BCR that is worth fighting offor not. If the T cell thinks the B cellis on the right track it provides “T cell help.” If the T cell thinks the B cell is misguided,it can kill the B cell.

When a B cell gets “T cell help,” the B cell goes through aprocess called “affinity maturation.”That is just a fancy phrase to describe a set of changes that aredesigned to “refine” the BCR of the engaged B cell into a more effectiveantibody. The B cell literally turns onmachinery that induces mutations into the BCR.Those that do a better job fighting the infection are selected to liveand those that do worse get eliminated from the body. Many of those mutations are in a veryspecific part of the BCR called the “variable region” aka. IgVH (for thevariable region of the heavy chain of the immunoglobulin).

This is where we get the terminology “mutated” BCR, or“mutated “IgVH” or even “mutated CLL.”So what is “unmutated” then.

Turns out, there are circumstances where a B cell can engagean invading germ and based upon the interaction, can go on to B cell maturitywithout T cell help. In these casesthere is no “affinity maturation” and no mutations are introduced into theIgVH. When CLL arises from such cellsthey are referred to as “unmutated.” If they go through T cell help they acquire BCR mutations. At least that is the main theory out there that is somewhat under challenge.

For discussion sake, it is probably fair to say that aparticular individual with CLL will have disease that is entirely “mutated” or“unmutated.” The way we measure this isto compare the genetic sequence of an individuals BCR and compare it to all theknown “templates” in the human body. Ifit is ≤ 98% identical, we call it mutated where more than that is non-mutated.

So why does it matter?

Turns out that cases with an unmutated IgVH / BCR typically have disease that grows more quickly.Quite frequently it is associated with other high risk markers likedeletion of chromosomes 11Q or 17P. Ifyou dig deeper than FISH, you also find that many of the high risk mutationssuch as BIRC3, SF3B1 and NOTCH are also more common in unmutated CLL and help determine prognosis. In short, it is often worse disease.

In fact, in our recent paper in the New England Journal ofMedicine looking at idelalisib in combination with rituximab, something like85% of the patients who needed treatment for relapsed disease had an unmutatedBCR. I think that is a fairly dramaticexample of who is likely to have problems with their disease and needtreatment. The patients with mutatedIgVH didn’t accrue nearly as frequently to the study because they don’t relapseas commonly (it is about a 50/50 split in new cases).

Stopping the discussion at mutated / unmutated also missessome really fascinating information on “stereotyped” B cell receptors which are common in CLL. I have a prior post onthe subject. In short, stereotypes canhappen in about a third of CLL cases and may have very specific prognostic /predictive information for patients that can be good or bad depending on thesubtype.

Mutated / unmutated also makes a difference with the newdrugs like ibrutinib and idelalisib.Since these drugs are inhibiting signaling through the B cell receptor,perhaps it is not surprising that there are differences in responses betweenthe two. In contrast to the generalthemes of who does better / worse with chemo, it would appear that patientswith unmutated BCR / IgVH actually respond more quickly and deeply to ibrutinib.

It makes mespeculate what will happen when we are finally ableto use these drugs in the front line setting.Would it make more sense to use 6 months of chemoimmunotherapy like FCR or Bendamustine / Rituximab in those patients with a mutated BCR because theyare likely to get durable disease control?Perhaps we would then use the newer drugs in those patients withunmutated IgVH where the long term benefit of chemotherapy is less? Maybe a test that allowed to us fully removeall the high risk patients with mutations or FISH abnormalities should be theones to get chemo? Perhaps taking a pillevery day is better even if it has to be taken for many years. I expect different patients will answer thatdifferently.

Anyhow, I frequently will test for the IgVH mutation statusat diagnosis because it gives me some ability to predict what the future mightlook like. I often follow those patientsa little more closely in the first year or two to make sure they don’t get intotrouble whereas I am a little more relaxed with the patients with a mutatedIgVH. Patients want to know how theirdisease is likely to behave, this is a test I commonly use.

A few disclaimers are important.

ZAP-70 is a test we used to use more commonly but for the most part it is merely a proxy for the status of the IgVH mutation status. Those cases that are unmutated (bad) tend tohave high ZAP-70 and vice versa. Unfortunatelytesting for ZAP-70 has a lot of technical difficulties and it isn’t nearly asreliable as sending for mutation analysis.I do not use ZAP-70 in my clinic though there are some selected labs whodo a good job (University of California San Diego) and I would trust theirresults.

Measuring CD38 is an attempt to classify how much the CLL isproliferating. This can be useful, butother data sets have shown that CLL cells are often dying at the same rate orhigher. Merely knowing the “birth rate”isn’t quite as useful since we don’t have a test to measure the “death rate.” I like to think of CD38 as “how fast is thetreadmill going.” While you may not begoing anywhere, it can be useful to know how quickly you are spinning yourwheels trying to get there (see prior posts on clonal evolution).

Finally, we designate mutated versus unmutated based uponthe percentage of sequence similarity to known genetic sequences. 2% is the magical number. If you are greater than 2% different you are“mutated” while those that are less than 2% are “unmutated.” Occasionally you get a case where you are at1.9% different. Once again, this isprobably humans trying to make a categorical variable out of continuousdata. Probably safe to say that the moremutated you are the better up to a point.

Anyhow, I hope that is a useful primer on why we get thistest. I always order this and FISH atdiagnosis. Others will argue that youdon’t need FISH until you are going to select therapy. Fine, good people can disagree – I won’targue that point but I want to know and I think informed patients want toknow. I am looking forward to being ableto test for the new molecular markers as well and I suppose it may be the samedebate there.

Thanks for reading


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 is mutated and unmutated in CLL? ›

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 percentage of CLL patients have unmutated IGHV? ›

CLL Prognostic Markers: IGHV

An unmutated status is associated with a poorer prognosis, and about 40% of all CLLs will be unmutated at diagnosis.

What is the prognosis for unmutated IGHV? ›

Unmutated IGHV gene is a molecular marker associated with poorer prognosis and shorter survival (mean OS = 95 months). Forty to 50 percent of patients will have the unmutated IGHV gene. The remainder are mutated; the prognosis is good and the mean overall survival is 293 months.

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.

What is the most important prognostic determinant of CLL? ›

TP53 mutation/deletion

TP53 aberrations (including del(17p) and TP53 mutations) are so far the most important prognostic factor in CLL.

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.

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 good prognostic markers for CLL? ›

ZAP-70, CD38 and CD49d are prognostic markers of CLL. They help in segregating those patients of CLL which will need treatment from those that can be placed in the “Wait and watch” group.

What type of mutation causes chronic lymphocytic leukemia? ›

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.

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