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Prognostic Factors and Predictive Markers for CLL

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Published on August 16, 2021

What Are the Prognostic Factors and Predictive Markers for CLL?

What can prognostic factors and predictive markers tell us at the time of diagnosis? Listen in as William Wierda, MD, PhD, from MD Anderson Cancer Center discusses the process of a diagnostic workup for chronic lymphocytic leukemia (CLL) with hosts Michele Nadeem-Baker and Jeff Folloder. They also explain how physicians use these markers to design effective treatment plans for their patients.

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Transcript | Prognostic Factors and Predictive Markers for CLL

Michele Nadeem-Baker: Dr. Wierda, what prognostic markers do you want to identify first when you have a patient come in, and you haven't met with them before?

Understanding Prognostic Factors and Predictive Markers

Dr. Wierda: So, the answer to that question is a little bit different than what the standard recommendation is. Because you don't need the prognostic factors for management initially. There are some prognostic factors that you need for management, but you don't need them at initial diagnosis if patients don't need treatment, because they don't change right now what we do for treatment initially in terms of watch and wait. If a patient has a high-risk feature, then that is not a reason to start them on treatment.

So, they're not required at initial diagnosis. I like to get them, and I always get them, because it gives me a better picture of a patient's disease, and I know what to, or I have an idea of what to, anticipate and what the future looks like. It allows me to have a better discussion and conversation with patients realizing that there are no hard fast rules. There are several prognostic factors that we have. For any individual patient, that patient may have some in the favorable category, and they have some in the unfavorable category.

And so we see a mixed picture often, and how that sorts out, and which prognostic factor might trump another, et cetera. It's a very complicated discussion. Again, we don't use these to determine when to start treatment, but we do use some of them in terms of how we manage patients. The prognostic factors that we routinely do with patients coming to Anderson, we do a diagnostic workup, which is flow cytometry. This is a method that allows us to look at the various proteins on the lymphocytes, and to distinguish a normal lymphocyte from an abnormal lymphocyte. An abnormal lymphocyte in this case being a CLL cell, which is a B cell that has certain proteins on the surface, and that constellation characterizes the cells as abnormal. There are proteins that are there that shouldn't be there in a normal B cell, and that's how we know a cell as a CLL cell.

So, we do a diagnostic workup with flow cytometry, and then we evaluate for specific chromosome abnormalities. The test that we use to do that is called FISH. And there are several chromosomal abnormalities that we look for that are prognostic, which all include 17p deletion, 11q deletion, trisomy 12, and 13q deletion. Those are the standard markers that we probe for. And those – we can talk about how those are helpful in terms of prognosis. And then we do the immunoglobulin heavy chain variable gene sequencing and sequence analysis to determine if that gene is mutated or unmutated. We can talk more about that in detail.

And then we have a panel right now of 163 genes that we sequence to determine if there are mutations in any of those genes. Now, this is a general panel that was developed for lymphoid diseases. Not all of the genes that we sequence are relevant to CLL. They may be relevant to other diseases. Nevertheless, we have one panel that we use for all the B cell malignancies. The most important gene on that panel is TP53, because we need to know whether or not TP53 is mutated. So, FISH, IGHV mutation status, and gene sequencing – particularly TP53. But it includes many others, some of which are relevant for CLL.

Jeff Folloder: All these tests that you do, the FISH, the flow, the TP53, the mutation status, all of these are are sort of like being able to look at things with a specific lens that can say: "This patient might fit within this statistical model, and might fit within this one, and may have attributes to the left and attributes to the right." So, they give you general indications, not n

What Can These Factors Tell Us at the Time of Diagnosis?

Dr. Wierda: Correct.

Jeff Folloder: Great. That was the point of clarification that I wanted to make. And I also want to make this slightly personal. Back when I was diagnosed 11 years ago, I was diagnosed with trisomy 12. And I was told by my doctor at the time that was an aggressive prognostic indicator. Of course, that scared the living daylights out of me. And now as we've moved on, trisomy 12, although it can be aggressive, it's not considered to be quite that aggressive anymore. So, how are things changing? And if you could very quickly, tell us why levels of aggression have moved up and down.

Dr. Wierda: Sure. Things are changing a lot lately because of the new treatments that we have. Because some of the high-risk features that we used to identify with chemotherapy-based treatment, for example, are no longer high-risk. And when we talk about the prognostic factors, we talk about various time points or end points during the course of the disease. For example, time from diagnosis to when somebody needs treatment. We can do models that predict for that. That is probably the model and the system that has changed least, because it hasn't been affected by treatment. The only thing really that affects that is bringing in new prognostic factors and determining how strong of predictors they are with that time point.

Other time points or end points are response to treatment, how long the treatment controls the disease, or how long a patient's in remission. And then overall survival, which is time from diagnosis to death. There are a lot of end points that we use these factors for in terms of predicting and prognosticating. And the newer treatments have really impacted on those end points significantly in those patients who need to be treated. For example, 11q deletion used to be a high-risk feature. With ibrutinib-based therapy, we have learned that it's really no longer a high-risk feature. We can control the disease very well, equally well, in patients who have an 11q deletion versus those who don't have an 11q deletion.

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