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Chronic Lymphocytic Leukemia; Initiating Therapy

Panelists: Krishna V. Komanduri, MD, Sylvester Comprehensive Cancer Center; Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center; John Byrd, MD, Ohio State University; Michael Keating, MB, BS, University of Texas MD Anderson Cancer Center; John Leonard, MD, New York-Presbyterian Hospital
Published: Wednesday, Feb 01, 2017



Transcript:

Krishna V. Komanduri, MD:
The next segment that we’re going to talk about today is really about what’s new in chronic lymphocytic leukemia (CLL), which is really an exciting area where we’ve seen a lot of progress and new drug development. I actually want to turn to Michael first. Just as with indolent lymphomas, there’s always a question in patients who are diagnosed with CLL when they present and they’re often alarmed that their white blood cell counts are elevated, when do we tell a patient that they should be treated? How do we make that decision?

Michael J. Keating, MB, BS: I think the answer is pretty much the same as it was 10 years ago in that the patients that didn’t have bulky disease and didn’t have marrow failure, during observation, didn’t have rapidly progressive disease. They didn’t double their white blood cell count in a year, for example. These are the criteria that have held up to the test of time. As Leo said, they’re pretty good guides, but if you have a lymph node in a particular area, you’re going to make different decisions based on that. And we have to say that the guidelines are guidelines. They’re not absolutes, and you just have to use your common sense. Even in the patients that we worry about a lot at the present time, the FISH (fluorescence in situ hybridization) will have a 17p deletion, but not all 17p’s behave the same.

And in an unusual thing in MD Anderson history, we actually collaborated with the Mayo Clinic and found out that patients were early stage disease with 17p deletion. Many of these patients would not progress for long, long periods of time and even some of them with extended follow-up, the 17p disappears. So, I think there’s still the indication if the 17p is going to be a bad actor, you would be able to find that out fairly quickly. And I think one of the things that’s happening, at the present time, is that we’re just changing the 17p population that we’re treating because we’re treating them immediately and disregarding all the other characteristics.

So, the worst part about saying that you’re going to consider this patient when you’re talking to them is being in “watch and wait.” They hate the term. The patient has already defined that they call it “watch and worry,” and I think that at the present time, we’re in a “watch and investigate” because we didn’t do very much workup in the patients that just had a little bit of CLL a long time ago. But, now we’re able to look at the genetic parameters with a lot more sophistication. There are studies that are already ongoing in the traditional “watch and wait”, where ibrutinib doesn’t cause the DNA damage and the immune suppression that fludarabine and alkylating agents cause. These are being actively studied to see if we can get the patients free of disease and what the consequences of that are. But, it’s way too early for us to consider.

I think the NCI guidelines, which are now the IWCLL (International Workshop on Chronic Lymphocytic Leukemia) criteria, are presently being re-evaluated, and there’s virtually no change in the indications for treatment in the next iteration coming along. So, the question that then comes up is, what are the treatments that you offer to different subsets of patients? And, as you’re aware, the FDA and the European agencies have accepted that the FCR program with fludarabine/cyclophosphamide/rituximab is the standard for young, fit adults. There’s some discussion as to whether 65 is the right age or whether it should be 70. But, one of the big holes that we have is that there’s nothing that’s being approved really for patients that over the age of 70. The average age of diagnosis of CLL is 72, so we can be like the alchemist that says, “Let’s concentrate on the doughnut and not the hole,” but the hole is very big in what the approved indications are.

We’re now at the situation where we have an approved drug, ibrutinib, for all stages of CLL. So, the temptation is to say to the patients, “Well, we’ll give you this oral medication that’s very well tolerated, etc.”, and go blissfully forward. But, many patients that are coming in to see us, at tertiary centers at least, are asking, “Should I be doing that?” because the FCR program in the patients that are mutated—immunoglobulin heavy chain sequence—two-thirds of those patients will probably be disease free out to 12 to 18 years, and won’t have to be on treatment all the time. And while we’re being very happy that we have such wonderful results early in all of our targeted therapies, the long-term consequences are now becoming more of a chore and more aggravating to the patients. We might say, “Well, they have aches and pains.” Everyone has aches and pains, that’s not a big deal, but it’s a big deal if you’re expected to be on treatment for the rest of your life and you have the aches and pains all the rest of your life. So, there are a lot of clinical criteria that we have to look at and find out what we want to achieve with treatment, and listen very carefully to what the patients themselves want to achieve with their therapy.

Krishna V. Komanduri, MD: That’s a good point. I think philosophically it’s interesting to me, as someone who doesn’t primarily manage CLL, that there are a group of patients with FCR who have a better molecular phenotype and who really do very, very well. I think that that’s actually interesting and suggests how we may need to use risk factors in really trying to integrate with clinical factors how we make decisions.

Transcript Edited for Clarity

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Transcript:

Krishna V. Komanduri, MD:
The next segment that we’re going to talk about today is really about what’s new in chronic lymphocytic leukemia (CLL), which is really an exciting area where we’ve seen a lot of progress and new drug development. I actually want to turn to Michael first. Just as with indolent lymphomas, there’s always a question in patients who are diagnosed with CLL when they present and they’re often alarmed that their white blood cell counts are elevated, when do we tell a patient that they should be treated? How do we make that decision?

Michael J. Keating, MB, BS: I think the answer is pretty much the same as it was 10 years ago in that the patients that didn’t have bulky disease and didn’t have marrow failure, during observation, didn’t have rapidly progressive disease. They didn’t double their white blood cell count in a year, for example. These are the criteria that have held up to the test of time. As Leo said, they’re pretty good guides, but if you have a lymph node in a particular area, you’re going to make different decisions based on that. And we have to say that the guidelines are guidelines. They’re not absolutes, and you just have to use your common sense. Even in the patients that we worry about a lot at the present time, the FISH (fluorescence in situ hybridization) will have a 17p deletion, but not all 17p’s behave the same.

And in an unusual thing in MD Anderson history, we actually collaborated with the Mayo Clinic and found out that patients were early stage disease with 17p deletion. Many of these patients would not progress for long, long periods of time and even some of them with extended follow-up, the 17p disappears. So, I think there’s still the indication if the 17p is going to be a bad actor, you would be able to find that out fairly quickly. And I think one of the things that’s happening, at the present time, is that we’re just changing the 17p population that we’re treating because we’re treating them immediately and disregarding all the other characteristics.

So, the worst part about saying that you’re going to consider this patient when you’re talking to them is being in “watch and wait.” They hate the term. The patient has already defined that they call it “watch and worry,” and I think that at the present time, we’re in a “watch and investigate” because we didn’t do very much workup in the patients that just had a little bit of CLL a long time ago. But, now we’re able to look at the genetic parameters with a lot more sophistication. There are studies that are already ongoing in the traditional “watch and wait”, where ibrutinib doesn’t cause the DNA damage and the immune suppression that fludarabine and alkylating agents cause. These are being actively studied to see if we can get the patients free of disease and what the consequences of that are. But, it’s way too early for us to consider.

I think the NCI guidelines, which are now the IWCLL (International Workshop on Chronic Lymphocytic Leukemia) criteria, are presently being re-evaluated, and there’s virtually no change in the indications for treatment in the next iteration coming along. So, the question that then comes up is, what are the treatments that you offer to different subsets of patients? And, as you’re aware, the FDA and the European agencies have accepted that the FCR program with fludarabine/cyclophosphamide/rituximab is the standard for young, fit adults. There’s some discussion as to whether 65 is the right age or whether it should be 70. But, one of the big holes that we have is that there’s nothing that’s being approved really for patients that over the age of 70. The average age of diagnosis of CLL is 72, so we can be like the alchemist that says, “Let’s concentrate on the doughnut and not the hole,” but the hole is very big in what the approved indications are.

We’re now at the situation where we have an approved drug, ibrutinib, for all stages of CLL. So, the temptation is to say to the patients, “Well, we’ll give you this oral medication that’s very well tolerated, etc.”, and go blissfully forward. But, many patients that are coming in to see us, at tertiary centers at least, are asking, “Should I be doing that?” because the FCR program in the patients that are mutated—immunoglobulin heavy chain sequence—two-thirds of those patients will probably be disease free out to 12 to 18 years, and won’t have to be on treatment all the time. And while we’re being very happy that we have such wonderful results early in all of our targeted therapies, the long-term consequences are now becoming more of a chore and more aggravating to the patients. We might say, “Well, they have aches and pains.” Everyone has aches and pains, that’s not a big deal, but it’s a big deal if you’re expected to be on treatment for the rest of your life and you have the aches and pains all the rest of your life. So, there are a lot of clinical criteria that we have to look at and find out what we want to achieve with treatment, and listen very carefully to what the patients themselves want to achieve with their therapy.

Krishna V. Komanduri, MD: That’s a good point. I think philosophically it’s interesting to me, as someone who doesn’t primarily manage CLL, that there are a group of patients with FCR who have a better molecular phenotype and who really do very, very well. I think that that’s actually interesting and suggests how we may need to use risk factors in really trying to integrate with clinical factors how we make decisions.

Transcript Edited for Clarity
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