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Strategies for Therapeutic Sequencing Agents

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Peter Martin, MD, MS, Weill Cornell Medicine; Loretta J. Nastoupil, MD, University of Texas MD Anderson Cancer Center; Grzegorz S. Nowakowski, MD, Mayo Clinic; Anas Younes, MD, Memorial Sloan Kettering Cancer Center
Published: Thursday, Feb 07, 2019



Transcript: 

Ian W. Flinn, MD, PhD: Let’s talk about how you sequence all these things. I know that the world would, like us, sort of have a cookie-cutter approach: You do this, you do that, you do that. But unfortunately, the world is not that simple. Ajay, let’s start with you. Do you have an overall approach of how you sequence all these things? And maybe we’ve talked a little about the first and second line, but beyond that, where it starts to get harder, I think, the data are less clear.

Ajay K. Gopal, MD, FACP: Right. This is a very challenging area, and I don’t think any of us are probably going to give you a pathway. We have challenges to sort out on what our internal pathways would be in these settings because there are a lot of factors to consider, as Nathan mentioned. What was your prior remission duration? What are your comorbidities? What’s your goal? What are you trying to get to with this therapy? Typically, if I’m treating a patient who has serial palliation and we are not getting to an allotransplant or to a CAR [chimeric antigen receptor] T-cell or some potentially curative therapy, which is really limited to a small number of patients you can offer that to, then I typically try to, in general, go with the least toxic approach that will relieve the problem that I’m treating.

I explained to patients that it’s really a chess match. Your first move makes a difference in what your tenth move is going to be, and you try to think about that as a life strategy in terms of managing this disease over the long term. And then for 80% of patients, it’s really about management and it’s probably not going to affect survival. You want to get them to a normal life span with the least toxicity. Now, that’s a very general statement. The good thing is we have so many options in our armamentarium now, and let’s not forget about radioimmunotherapy, which also has similar results as the [PI3K] inhibitors, so about a 60% response rate. It’s about a year PFS [progression-free survival], so that’s another option on the list.

Ian W. Flinn, MD, PhD: Do you think about using that earlier or later in terms of the need for good hematopoietic reserve, that kind of thing? How does that sequence?

Ajay K. Gopal, MD, FACP: Right, yes. I think there are cutoffs for platelets of like 100,000, neutrophil cutoffs, and marrow involvement. So that does—if you wait until very late line, that’s probably not going to be an option. Whereas, with the other drugs that are continuous therapy, you can always hold the dose or adjust the dose if you get toxicity.

Ian W. Flinn, MD, PhD: Nathan, I think a lot of us have referral bias for patients who are young, right? So Ajay has just taken us through all the issues like it’s a chess game. You’re working not the first, second, or third, but it’s the long term. There are really some challenges with the younger patients with follicular lymphoma in playing this chess game.

Nathan H. Fowler, MD: Yeah. Chronic therapy is an issue. I have a patient in his early 20s who just found out he has follicular lymphoma. So clearly, as Ajay mentioned, I’m not thinking about the next month or the next several months; I’m actually thinking about the next several years. And so how do we try to minimize the impact on his life with this disease. And I think, not to be overly optimistic, but I think we will have options that will lead to high levels of cure. And some of these, I think, are probably already in development. And so especially in these younger patients, I’m looking for something that’s going to minimize the impact in the patient’s life and, hopefully, not lead to any significant myelosuppression. And I think in the very near future, we’re going to have options for these young patients that are going to cure them. I’m really looking at how I can minimally impact their life and allow them to get exposure to these next-generation treatments.

Ian W. Flinn, MD, PhD: Scott, do you think about these same challenges? Is it a similar thought process? Anything you’d like to add about your approach?

Scott Huntington, MD, MPH, MSc: Yeah. So outside the rapid progressors, where we’re trying our best with the immediate with what we have on hand—clinical trials, PI3K inhibitors—for the folks, the 80% who are going to be in remission for many years—5, 10 years of frontline therapy—we’re going to be giving second-line, which will probably be very different at that point. And so we want to make sure that we minimize toxicity and get the vast majority of people that will do well, regardless of what we give in the frontline setting or second-line setting, the best chance. It’s really those rapid progressors that we need to work hard on as a group, and I think novel therapies, immunotherapies, and CAR T are likely going to change the outcomes in that subgroup.


Transcript Edited for Clarity



 

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Transcript: 

Ian W. Flinn, MD, PhD: Let’s talk about how you sequence all these things. I know that the world would, like us, sort of have a cookie-cutter approach: You do this, you do that, you do that. But unfortunately, the world is not that simple. Ajay, let’s start with you. Do you have an overall approach of how you sequence all these things? And maybe we’ve talked a little about the first and second line, but beyond that, where it starts to get harder, I think, the data are less clear.

Ajay K. Gopal, MD, FACP: Right. This is a very challenging area, and I don’t think any of us are probably going to give you a pathway. We have challenges to sort out on what our internal pathways would be in these settings because there are a lot of factors to consider, as Nathan mentioned. What was your prior remission duration? What are your comorbidities? What’s your goal? What are you trying to get to with this therapy? Typically, if I’m treating a patient who has serial palliation and we are not getting to an allotransplant or to a CAR [chimeric antigen receptor] T-cell or some potentially curative therapy, which is really limited to a small number of patients you can offer that to, then I typically try to, in general, go with the least toxic approach that will relieve the problem that I’m treating.

I explained to patients that it’s really a chess match. Your first move makes a difference in what your tenth move is going to be, and you try to think about that as a life strategy in terms of managing this disease over the long term. And then for 80% of patients, it’s really about management and it’s probably not going to affect survival. You want to get them to a normal life span with the least toxicity. Now, that’s a very general statement. The good thing is we have so many options in our armamentarium now, and let’s not forget about radioimmunotherapy, which also has similar results as the [PI3K] inhibitors, so about a 60% response rate. It’s about a year PFS [progression-free survival], so that’s another option on the list.

Ian W. Flinn, MD, PhD: Do you think about using that earlier or later in terms of the need for good hematopoietic reserve, that kind of thing? How does that sequence?

Ajay K. Gopal, MD, FACP: Right, yes. I think there are cutoffs for platelets of like 100,000, neutrophil cutoffs, and marrow involvement. So that does—if you wait until very late line, that’s probably not going to be an option. Whereas, with the other drugs that are continuous therapy, you can always hold the dose or adjust the dose if you get toxicity.

Ian W. Flinn, MD, PhD: Nathan, I think a lot of us have referral bias for patients who are young, right? So Ajay has just taken us through all the issues like it’s a chess game. You’re working not the first, second, or third, but it’s the long term. There are really some challenges with the younger patients with follicular lymphoma in playing this chess game.

Nathan H. Fowler, MD: Yeah. Chronic therapy is an issue. I have a patient in his early 20s who just found out he has follicular lymphoma. So clearly, as Ajay mentioned, I’m not thinking about the next month or the next several months; I’m actually thinking about the next several years. And so how do we try to minimize the impact on his life with this disease. And I think, not to be overly optimistic, but I think we will have options that will lead to high levels of cure. And some of these, I think, are probably already in development. And so especially in these younger patients, I’m looking for something that’s going to minimize the impact in the patient’s life and, hopefully, not lead to any significant myelosuppression. And I think in the very near future, we’re going to have options for these young patients that are going to cure them. I’m really looking at how I can minimally impact their life and allow them to get exposure to these next-generation treatments.

Ian W. Flinn, MD, PhD: Scott, do you think about these same challenges? Is it a similar thought process? Anything you’d like to add about your approach?

Scott Huntington, MD, MPH, MSc: Yeah. So outside the rapid progressors, where we’re trying our best with the immediate with what we have on hand—clinical trials, PI3K inhibitors—for the folks, the 80% who are going to be in remission for many years—5, 10 years of frontline therapy—we’re going to be giving second-line, which will probably be very different at that point. And so we want to make sure that we minimize toxicity and get the vast majority of people that will do well, regardless of what we give in the frontline setting or second-line setting, the best chance. It’s really those rapid progressors that we need to work hard on as a group, and I think novel therapies, immunotherapies, and CAR T are likely going to change the outcomes in that subgroup.


Transcript Edited for Clarity



 
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