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Prognostic Factors and the Impact of New Therapies

Panelists:Alessandra Ferrajoli, MD, The University of Texas MD Anderson Cancer Center; Richard R. Furman, MD, Weill Cornell Medical College; Thomas J. Kipps, MD, PhD, UC San Diego Moores Cancer Center; Shuo Ma, MD, PhD, Northwestern University Feinberg School of Medicine, Susan M. O’Brien, MD, UC Irvine Health; William G. Wierda, MD, PhD, University of Texas MD Anderson Cancer Center
Published: Tuesday, Jan 19, 2016


Transcript:

William G. Wierda, MD, PhD:
Hello, and thank you for joining this OncLive TV Peer Exchange. The availability of new monoclonal antibodies and novel targeted therapies for chronic lymphocytic leukemia has greatly increased the complexity of treating symptomatic patients. For this discussion, my colleagues and I will shed some light on the latest data coming out of ASH 2015, and how this new information will affect how we treat our patients with CLL.

I'm Dr. William Wierda, professor of medicine at the University of Texas, MD Anderson Cancer Center. Joining me today for this discussion are:

Alessandra Ferrajoli, professor of medicine, also at the University of Texas, MD Anderson Cancer Center. Dr. Rick Furman, associate professor of medicine and director of the CLL Research Center at Weill Cornell Medicine College. Dr. Thomas Kipps, professor of medicine, deputy director of research operations, UC San Diego at the Moores Cancer Center. Shuo Ma, associate professor of medicine at the Northwestern University and Robert H. Lurie Comprehensive Cancer Center. Dr. Susan O'Brien, associate director for clinical science for the Chao Family Comprehensive Cancer Center at UC Irvine Health. Thank you all for joining us today. Let's get started.

The first topic we're going to talk about is prognostic factors and evaluating patients with chronic lymphocytic leukemia. Let's start with Dr. Ma. And, there's an abstract that's being presented here by the German CLL Study Group, which is an international prognostic index for patients with CLL. I wonder if you could give us a little bit of insight into this and how it's useful in evaluating our patients.

Shuo Ma, MD, PhD: Right. So in this abstract they have reported the international prognostic index for patients with CLL, the CLL IPI, which is the international meta-analysis. Here, they pulled 8 randomized CLL studies that include over 3,000 patients, where they analyzed over 26 different kind of prognostic factors. And after the analysis they had found 5 independent prognostic factors including age, the clinical stage of the CLL, the presence of 17p deletion, and/or P53 mutation, and IGHV muted status. And lastly, the beta-2 microglobulin.

And based on the presence of these five prognostic factors, they divided patients into four different groups—either low risk, intermediate risk, high risk, or very high risk. And the 5-year overall survival of this four group of patients ranged from over 90% in the low risk patients to about 20% in the very high risk patients.

William G. Wierda, MD, PhD: So this has not yet been published, but it's been updated here at this meeting.

Shuo Ma, MD, PhD: Right.

William G. Wierda, MD, PhD: And it's useful in terms of predicting for time to first therapy, as well as overall survival?

Shuo Ma, MD, PhD: This is primarily for overall survival.

Thomas J. Kipps, MD, PhD: And one of the problems of this index, that I see, is that it was based on data that was collected in what's called the CLL8 Study. These patients received FCR (fludarabine, cyclophosphamide, and rituximab) chemoimmunotherapy versus FC chemotherapy. Also, data were collected from the Mayo Clinic where patients were followed.

So it was an amalgamation of patients who were followed, without therapy, versus patients also being treated with chemoimmunotherapy. I think with the advances that we currently have, it's calling into question some of the prognostic indicators that we have used in the past to stratify our patients. I think we have to be very careful about applying a metric such as the IPI to patients currently because it really doesn't take into account the newer therapies of ibrutinib or idelalisib, or obinutuzumab for that matter. So I think this is going to need to be adjusted.

Some of the prognostic factors in the IPI are very similar to what has already been known. I know that, Bill, you've put together a nomogram that has put together things such as beta-2 microglobulin, adverse cytogenetics, the mutation status of the antibody genes. These are all very important, and they're incorporated in the IPI. I don't think we're going to dispense with those, but I think we have to be very careful going forward with an algorithm that really is structured on today and yesterday's treatments. I think we're going to have to change that.

William G. Wierda, MD, PhD: So your opinion, then, is that these models may be relevant for more historical treatments, but may not be as relevant now for the small molecule inhibitors that we have, and we should be cautious about their clinical implementation and how they're used today.

Thomas J. Kipps, MD, PhD: Absolutely. I think that we still may have features, such as complex cytogenetics or the deletion of the short arm of chromosome 17, having potentially an adverse indication for some of the newer therapies such as ibrutinib or even idelalisib.

However, I think it really needs to be borne in mind that this is a moving target. We're talking about a game that's being played now. Patients are living longer and better. And I think to apply a metric that suggests that you're going to live only a certain number of years, it's clearly not going to be appropriate for today's treatments.

William G. Wierda, MD, PhD: Definitely I would agree. I think we all realize that many of our patients can be observed for many, many years, and some of them don't even need treatment. I think it's important to keep that in mind and to have an appreciation of the prognostic factors. Yet, we should not really use them to assess patients when they need to start treatment, or use them to initiate treatment, but more, again, for informational purposes and to give us an idea about the biology at this point.

Thomas J. Kipps, MD, PhD: And I must say, it was called the International Prognostic Index because they had more than two people from different countries, that's the reason.

Alessandra Ferrajoli, MD: But I think we need to wait. This was an ASCO abstract that we reviewed. The paper is going to come up soon. We will be able to apply it, prospectively, and see whether it's a valid index or not, at least at this meeting they're going to give an update of the relevance to these index in terms of patients with early disease. So we will see in the discussion how people feel about the utility of this CLL IPI.

Richard R. Furman, MD: I can't agree enough with Dr. Kipps in the importance of being able to use in clinical practice helpful measures for our patients. And no matter what new prognostic factors we develop, and of course, CLL doesn't really need any more prognostic factors, it's really going to be dependent upon those classic criteria from the original IWCLL or NCI working groups, based upon progression of disease, Rai stage, and all those factors that are just clinically apparent that are going to determine when you're going to initiate therapy.

And fortunately, with these new agents, the novel agents, the prognostic markers really don't become relevant in terms of response to treatment. Where I really think the majority of effort needs to be in this day and age is going to be identifying those patients who are unlikely to be basically maintained on a BCR antagonist long-term.

There are some patients with 17p deletion or some other genetic abnormalities that might have or are likely to have progression on a BCR antagonist. And those are the prognostic markers that we need to identify because they're the ones that are going to tell us that ibrutinib by itself is not going to be long-term the best option for this patient.

And I think likewise looking at the gene family 4-39 or notch 1 mutations, things that predict for Richter's Transformation, which is often a mode of escape from the BCR antagonists, really become increasingly important. Because those are the things that really may indicate to us that we have to change our treatment strategy.

Alessandra Ferrajoli, MD: But I think predictive factor is what you're asking for. Yes, usually predictive factor will follow the prognostic factor evaluation. So maybe we'll move there soon.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity


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Transcript:

William G. Wierda, MD, PhD:
Hello, and thank you for joining this OncLive TV Peer Exchange. The availability of new monoclonal antibodies and novel targeted therapies for chronic lymphocytic leukemia has greatly increased the complexity of treating symptomatic patients. For this discussion, my colleagues and I will shed some light on the latest data coming out of ASH 2015, and how this new information will affect how we treat our patients with CLL.

I'm Dr. William Wierda, professor of medicine at the University of Texas, MD Anderson Cancer Center. Joining me today for this discussion are:

Alessandra Ferrajoli, professor of medicine, also at the University of Texas, MD Anderson Cancer Center. Dr. Rick Furman, associate professor of medicine and director of the CLL Research Center at Weill Cornell Medicine College. Dr. Thomas Kipps, professor of medicine, deputy director of research operations, UC San Diego at the Moores Cancer Center. Shuo Ma, associate professor of medicine at the Northwestern University and Robert H. Lurie Comprehensive Cancer Center. Dr. Susan O'Brien, associate director for clinical science for the Chao Family Comprehensive Cancer Center at UC Irvine Health. Thank you all for joining us today. Let's get started.

The first topic we're going to talk about is prognostic factors and evaluating patients with chronic lymphocytic leukemia. Let's start with Dr. Ma. And, there's an abstract that's being presented here by the German CLL Study Group, which is an international prognostic index for patients with CLL. I wonder if you could give us a little bit of insight into this and how it's useful in evaluating our patients.

Shuo Ma, MD, PhD: Right. So in this abstract they have reported the international prognostic index for patients with CLL, the CLL IPI, which is the international meta-analysis. Here, they pulled 8 randomized CLL studies that include over 3,000 patients, where they analyzed over 26 different kind of prognostic factors. And after the analysis they had found 5 independent prognostic factors including age, the clinical stage of the CLL, the presence of 17p deletion, and/or P53 mutation, and IGHV muted status. And lastly, the beta-2 microglobulin.

And based on the presence of these five prognostic factors, they divided patients into four different groups—either low risk, intermediate risk, high risk, or very high risk. And the 5-year overall survival of this four group of patients ranged from over 90% in the low risk patients to about 20% in the very high risk patients.

William G. Wierda, MD, PhD: So this has not yet been published, but it's been updated here at this meeting.

Shuo Ma, MD, PhD: Right.

William G. Wierda, MD, PhD: And it's useful in terms of predicting for time to first therapy, as well as overall survival?

Shuo Ma, MD, PhD: This is primarily for overall survival.

Thomas J. Kipps, MD, PhD: And one of the problems of this index, that I see, is that it was based on data that was collected in what's called the CLL8 Study. These patients received FCR (fludarabine, cyclophosphamide, and rituximab) chemoimmunotherapy versus FC chemotherapy. Also, data were collected from the Mayo Clinic where patients were followed.

So it was an amalgamation of patients who were followed, without therapy, versus patients also being treated with chemoimmunotherapy. I think with the advances that we currently have, it's calling into question some of the prognostic indicators that we have used in the past to stratify our patients. I think we have to be very careful about applying a metric such as the IPI to patients currently because it really doesn't take into account the newer therapies of ibrutinib or idelalisib, or obinutuzumab for that matter. So I think this is going to need to be adjusted.

Some of the prognostic factors in the IPI are very similar to what has already been known. I know that, Bill, you've put together a nomogram that has put together things such as beta-2 microglobulin, adverse cytogenetics, the mutation status of the antibody genes. These are all very important, and they're incorporated in the IPI. I don't think we're going to dispense with those, but I think we have to be very careful going forward with an algorithm that really is structured on today and yesterday's treatments. I think we're going to have to change that.

William G. Wierda, MD, PhD: So your opinion, then, is that these models may be relevant for more historical treatments, but may not be as relevant now for the small molecule inhibitors that we have, and we should be cautious about their clinical implementation and how they're used today.

Thomas J. Kipps, MD, PhD: Absolutely. I think that we still may have features, such as complex cytogenetics or the deletion of the short arm of chromosome 17, having potentially an adverse indication for some of the newer therapies such as ibrutinib or even idelalisib.

However, I think it really needs to be borne in mind that this is a moving target. We're talking about a game that's being played now. Patients are living longer and better. And I think to apply a metric that suggests that you're going to live only a certain number of years, it's clearly not going to be appropriate for today's treatments.

William G. Wierda, MD, PhD: Definitely I would agree. I think we all realize that many of our patients can be observed for many, many years, and some of them don't even need treatment. I think it's important to keep that in mind and to have an appreciation of the prognostic factors. Yet, we should not really use them to assess patients when they need to start treatment, or use them to initiate treatment, but more, again, for informational purposes and to give us an idea about the biology at this point.

Thomas J. Kipps, MD, PhD: And I must say, it was called the International Prognostic Index because they had more than two people from different countries, that's the reason.

Alessandra Ferrajoli, MD: But I think we need to wait. This was an ASCO abstract that we reviewed. The paper is going to come up soon. We will be able to apply it, prospectively, and see whether it's a valid index or not, at least at this meeting they're going to give an update of the relevance to these index in terms of patients with early disease. So we will see in the discussion how people feel about the utility of this CLL IPI.

Richard R. Furman, MD: I can't agree enough with Dr. Kipps in the importance of being able to use in clinical practice helpful measures for our patients. And no matter what new prognostic factors we develop, and of course, CLL doesn't really need any more prognostic factors, it's really going to be dependent upon those classic criteria from the original IWCLL or NCI working groups, based upon progression of disease, Rai stage, and all those factors that are just clinically apparent that are going to determine when you're going to initiate therapy.

And fortunately, with these new agents, the novel agents, the prognostic markers really don't become relevant in terms of response to treatment. Where I really think the majority of effort needs to be in this day and age is going to be identifying those patients who are unlikely to be basically maintained on a BCR antagonist long-term.

There are some patients with 17p deletion or some other genetic abnormalities that might have or are likely to have progression on a BCR antagonist. And those are the prognostic markers that we need to identify because they're the ones that are going to tell us that ibrutinib by itself is not going to be long-term the best option for this patient.

And I think likewise looking at the gene family 4-39 or notch 1 mutations, things that predict for Richter's Transformation, which is often a mode of escape from the BCR antagonists, really become increasingly important. Because those are the things that really may indicate to us that we have to change our treatment strategy.

Alessandra Ferrajoli, MD: But I think predictive factor is what you're asking for. Yes, usually predictive factor will follow the prognostic factor evaluation. So maybe we'll move there soon.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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