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Impact of Prognostic Factors on Clinical Decisions in CLL

Insights From: Michael Choi, MD, UC San Diego Medical Center; Matthew S. Davids, MD, Dana-Farber Cancer Institute; William Wierda, MD, PhD, MD Anderson Cancer Center
Published: Wednesday, Apr 11, 2018



Transcript: 

William Wierda, MD, PhD: The prognostic factors are very useful. We do all of the prognostic factor profiling on patients. One thing I didn’t mention was the sequencing of other genes, not just TP53. We have a panel of genes that we sequence routinely for those who come and see us as new patients, and we’re correlating that with outcomes. For example, one of the recent analyses we did showed that patients who have a mutated ATM gene tend to have more proliferative disease and have a shorter time between diagnosis and first treatment. So, we’re learning about these new factors. New factors that we’ll learn more about and make more correlations with in the near future will be these various genes that have been identified and are mutated in CLL. Which mutations correlate with which endpoints will be data that emerge over the next few years.

We do a profiling of prognostic factors for patients at MD Anderson when they come in as new patients, and that’s mostly to get a good idea of the patient characteristics and what to expect for the patient. It’s nice to have that information so as to have a good discussion with the patient so that they’re more informed about what they might expect from their disease. Although, there aren’t perfect correlations and there are patients who behave differently than what their prognostic factor or profile might indicate.

We do use a FISH panel. You really do need to know if a patient has 17p deletion or not, particularly for patients who need treatment. If a patient comes in and they don’t necessarily need treatment, you don’t have to have these prognostic factors. They’re helpful for discussion, they’re helpful for an understanding of what to expect, but none of them are essential in newly diagnosed patients who don’t need any treatment.

They become essential when you have a patient who has had progression of their disease and needs treatment. The one factor that you need to know is whether or not they have 17p deletion, and I would argue that you really need to know if they also have a mutated TP53. Those are patients you avoid chemoimmunotherapy with in favor of giving them a small molecule inhibitor, particularly a BTK inhibitor.

Mutation status is also very important, and that will help direct you in terms of a fit patient going to chemoimmunotherapy with FCR versus going toward a small molecule inhibitor, which is the approach that I take. If a patient has an unmutated V gene, for example, I know those patients are going to relapse. I tend to favor treating with a BTK inhibitor because things are evolving and changing so quickly in the field now that I think in a year or two, there will be something better coming along where we’ll be talking to that patient about getting them into a deep remission and getting them into a treatment-free interval. So, my preference is that approach over giving them chemotherapy, where you run the risk of exposure to the normal bone marrow and toxicities from the alkylating agents and risk for other problems like MDS and AML.

The key prognostic factors are the ones that I mentioned: FISH testing, particularly 17p deletion; mutations in TP53; and the V gene sequencing. Those are things that help direct treatment. They don’t necessarily dictate whether or not patients fall into these 3 categories that the German CLL Study Group has proposed: the “go-go,” “slow-go,” and “no-go.” Those features are more correlated with a patient’s age and their ability to tolerate the more toxic treatments like chemoimmunotherapy, where the “go-go” tends to be younger patients, patients younger than 65 who can tolerate FCR-type treatment. The “slow-go” are patients who can’t tolerate the FCR-based regimen, but might be able to tolerate other regimens, like bendamustine or rituximab or chlorambucil plus obinutuzumab. And the “no-go” are the ones who you don’t want to give chemotherapy to and for whom we reserve less toxic treatments, or the least toxic treatments, for those patients, such as CD20 antibodies, etc.

Comorbidities will also correlate with those 3 categories: the “go-go” patients being those who don’t really have much in the way of comorbidities and can tolerate treatment well. In contrast, at the other end of the spectrum would be the “no-go” patients who have a lot of comorbidities and limitations and would be much less likely to be able to tolerate the intensive treatments.

For first-line therapy, patients who have a 17p deletion, whether they’re “go-go” or “slow-go” or “no-go,” should be treated with a BTK inhibitor–based therapy. I would not recommend chemoimmunotherapy for those patients, regardless of the category that they fall in. Those categories are more useful for stratifying patients and directing for chemoimmunotherapy-based treatment, although you do see a bit more toxicity in patients who are older and have comorbidities with a BTK inhibitor. So, those would be patients for whom I would be more inclined to dose reduce the BTK inhibitor out of concern of having toxicities.

Transcript Edited for Clarity
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Transcript: 

William Wierda, MD, PhD: The prognostic factors are very useful. We do all of the prognostic factor profiling on patients. One thing I didn’t mention was the sequencing of other genes, not just TP53. We have a panel of genes that we sequence routinely for those who come and see us as new patients, and we’re correlating that with outcomes. For example, one of the recent analyses we did showed that patients who have a mutated ATM gene tend to have more proliferative disease and have a shorter time between diagnosis and first treatment. So, we’re learning about these new factors. New factors that we’ll learn more about and make more correlations with in the near future will be these various genes that have been identified and are mutated in CLL. Which mutations correlate with which endpoints will be data that emerge over the next few years.

We do a profiling of prognostic factors for patients at MD Anderson when they come in as new patients, and that’s mostly to get a good idea of the patient characteristics and what to expect for the patient. It’s nice to have that information so as to have a good discussion with the patient so that they’re more informed about what they might expect from their disease. Although, there aren’t perfect correlations and there are patients who behave differently than what their prognostic factor or profile might indicate.

We do use a FISH panel. You really do need to know if a patient has 17p deletion or not, particularly for patients who need treatment. If a patient comes in and they don’t necessarily need treatment, you don’t have to have these prognostic factors. They’re helpful for discussion, they’re helpful for an understanding of what to expect, but none of them are essential in newly diagnosed patients who don’t need any treatment.

They become essential when you have a patient who has had progression of their disease and needs treatment. The one factor that you need to know is whether or not they have 17p deletion, and I would argue that you really need to know if they also have a mutated TP53. Those are patients you avoid chemoimmunotherapy with in favor of giving them a small molecule inhibitor, particularly a BTK inhibitor.

Mutation status is also very important, and that will help direct you in terms of a fit patient going to chemoimmunotherapy with FCR versus going toward a small molecule inhibitor, which is the approach that I take. If a patient has an unmutated V gene, for example, I know those patients are going to relapse. I tend to favor treating with a BTK inhibitor because things are evolving and changing so quickly in the field now that I think in a year or two, there will be something better coming along where we’ll be talking to that patient about getting them into a deep remission and getting them into a treatment-free interval. So, my preference is that approach over giving them chemotherapy, where you run the risk of exposure to the normal bone marrow and toxicities from the alkylating agents and risk for other problems like MDS and AML.

The key prognostic factors are the ones that I mentioned: FISH testing, particularly 17p deletion; mutations in TP53; and the V gene sequencing. Those are things that help direct treatment. They don’t necessarily dictate whether or not patients fall into these 3 categories that the German CLL Study Group has proposed: the “go-go,” “slow-go,” and “no-go.” Those features are more correlated with a patient’s age and their ability to tolerate the more toxic treatments like chemoimmunotherapy, where the “go-go” tends to be younger patients, patients younger than 65 who can tolerate FCR-type treatment. The “slow-go” are patients who can’t tolerate the FCR-based regimen, but might be able to tolerate other regimens, like bendamustine or rituximab or chlorambucil plus obinutuzumab. And the “no-go” are the ones who you don’t want to give chemotherapy to and for whom we reserve less toxic treatments, or the least toxic treatments, for those patients, such as CD20 antibodies, etc.

Comorbidities will also correlate with those 3 categories: the “go-go” patients being those who don’t really have much in the way of comorbidities and can tolerate treatment well. In contrast, at the other end of the spectrum would be the “no-go” patients who have a lot of comorbidities and limitations and would be much less likely to be able to tolerate the intensive treatments.

For first-line therapy, patients who have a 17p deletion, whether they’re “go-go” or “slow-go” or “no-go,” should be treated with a BTK inhibitor–based therapy. I would not recommend chemoimmunotherapy for those patients, regardless of the category that they fall in. Those categories are more useful for stratifying patients and directing for chemoimmunotherapy-based treatment, although you do see a bit more toxicity in patients who are older and have comorbidities with a BTK inhibitor. So, those would be patients for whom I would be more inclined to dose reduce the BTK inhibitor out of concern of having toxicities.

Transcript Edited for Clarity
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