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Practical Advice on the Future Management of MCL

Panelists: Ian W. Flinn, MD, PhD, Sarah Cannon Research Institute; Matthew S. Davids, MD, MMSc, Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute; Brad Kahl, MD, Washington University School of Medicine; John Pagel, MD, PhD, Swedish Cancer Institute
Published: Thursday, Aug 22, 2019



Transcript: 

Ian W. Flinn, MD, PhD: Brad, are there prognostic factors from the Mantle Cell Lymphoma International Prognostic Index [MIPI] to help you guide what therapy you use? Is it a Ki-67 or P53 mutation, as John was alluding to? Is there anything that helps you figure out what therapy to use and what you should be doing differently between patients?

Brad Kahl, MD: I wish they were helpful. I think the TP53 mutation is a very important baseline parameter. It’s more useful in telling me what not to do than what to do. We know now from some large, mature data sets that to take a patient through intensive chemotherapy and an autologous stem-cell transplant if they’re P53 mutated is not a good strategy. You should try something different. What that something different should be is less clear. I think you could make an argument for some strategy that doesn’t involve DNA-damaging agents to rely on your cell kill. BTK inhibition or lenalidomide, and then considering allogeneic stem cell transplant or CAR [chimeric antigen receptor] T-cell therapy, if you can find the right study, would be a better strategy. You’d need a fundamentally different approach from our traditional approaches if you have somebody who’s P53 mutated.

Regarding the MIPI, it’s often not helpful in telling you how to manage a patient. Sometimes, you’re on the fence. You might have a 65-year-old patient, and you’re trying to decide whether he should be intensive. Maybe he has some comorbidities, and you’re trying to decide whether to be nonintensive because of those comorbidities. If they were more favorable in their MIPI, you might lean toward the nonintensive approach. If they were less favorable, you might lean toward the intensive approach. I do find that there are some patients for whom I’m struggling to decide how aggressive to be with their treatment. Sometimes, I’ll use the MIPI to help break the tie.

Ian W. Flinn, MD, PhD: With the blastoid and polymorphic variants, I find it tremendously difficult to know what to do. Unfortunately, you can say, “Well, you shouldn’t do this,” but in reality, the alternatives are not all that attractive. What do you think, Matt?

Matthew S. Davids, MD, MMSc: Yes. This is fortunately a pretty rare group of mantle cell patients, but we do see them, and it’s very challenging to treat. They may have a transient initial response to these regimens that we talked about, but they almost always recur fairly quickly. For those patients, if you have a center that you refer to and there’s a clinical trial available, I think exploring these novel regimens is the best thing for the patient.

Ian W. Flinn, MD, PhD: The average community oncologist probably doesn’t see that many cases of mantle cell lymphoma a year, let alone in their career. Brad, what advice do you have for the community oncologist when they see someone with mantle cell lymphoma?
Brad Kahl, MD: If it’s a young patient who would be considered a candidate for an intensive strategy, send them in early so we can assess their fitness for stem cell transplantation. We can start working through the insurance approvals and all the issues related to that, so it’s better to see them early. We like to see them, so we can consider them for clinical trials. There’s still lots of room for improvement in mantle cell lymphoma.

To the extent that we can find appropriate trials for patients, we’d like to have that opportunity. I think most community oncologists are comfortable with the bendamustine-rituximab regimen, and that’s a perfectly reasonable thing to do for an older mantle cell patient. I would encourage community physicians to check around and see if there’s an appropriate clinical trial when they have a mantle cell patient, whether they are frontline or relapsed. Even though outcomes have improved tremendously— you said that earlier, and you’re absolutely right—there is still lots of room from improvement in mantle cell lymphoma.

Ian W. Flinn, MD, PhD: We want you to talk about CLL [chronic lymphocytic lymphoma]. We’re moving these targeted, novel agents to the frontline and getting away from the cytotoxic chemotherapy. Do you think it’s just a matter of time before we get away from bendamustine or the cytarabine-containing regimens and transplant, or do you see it differently?

Brad Kahl, MD: It could happen. Luhua (Michael) Wang, MD, at The University of Texas MD Anderson Cancer Center is studying some of these innovative approaches through a window study where he’s starting with novel targeted agents and then trying to truncate the amount of intensive chemotherapy that is given to patients. He’s shown that response rates to the targeted agents are very high. We don’t know what the long-term outcomes are yet. I would encourage people not to rush to those kind of strategies until some of the data that are currently being generated are mature, and we know that they’re a good strategy. I would love to get away from chemotherapy as much as anybody else, but the fact is, our strategies are working fairly well in mantle cell, so you don’t want to subtract what’s working until you know that what’s coming along is at least as good if not better.

Ian W. Flinn, MD, PhD: It’s not an easy question to get to. You have to be pretty sure of your therapy before you pull away from what we’ve done. There are trials though that are looking at BTK inhibition with venetoclax and other things frontline. John, do you have similar thoughts on this?

John Pagel, MD, PhD: I do. It’s very important to make sure that we’re not burning a drug too soon. In other words, we need to keep something in our back pocket, especially for those high-risk patients. I’m not sure that it’s going to play out to have BTK inhibition as part of the frontline regimen. If it does, I think it will be with chemotherapy for the immediate future. We’ll see if it allows us to give less chemotherapy. I think that might be appealing.

If we’re going to do that, we need to be able to stop treatment, too, and not just continue the BTK inhibitor indefinitely in mantle cell as we’re hoping to do in CLL.

Transcript Edited for Clarity

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Transcript: 

Ian W. Flinn, MD, PhD: Brad, are there prognostic factors from the Mantle Cell Lymphoma International Prognostic Index [MIPI] to help you guide what therapy you use? Is it a Ki-67 or P53 mutation, as John was alluding to? Is there anything that helps you figure out what therapy to use and what you should be doing differently between patients?

Brad Kahl, MD: I wish they were helpful. I think the TP53 mutation is a very important baseline parameter. It’s more useful in telling me what not to do than what to do. We know now from some large, mature data sets that to take a patient through intensive chemotherapy and an autologous stem-cell transplant if they’re P53 mutated is not a good strategy. You should try something different. What that something different should be is less clear. I think you could make an argument for some strategy that doesn’t involve DNA-damaging agents to rely on your cell kill. BTK inhibition or lenalidomide, and then considering allogeneic stem cell transplant or CAR [chimeric antigen receptor] T-cell therapy, if you can find the right study, would be a better strategy. You’d need a fundamentally different approach from our traditional approaches if you have somebody who’s P53 mutated.

Regarding the MIPI, it’s often not helpful in telling you how to manage a patient. Sometimes, you’re on the fence. You might have a 65-year-old patient, and you’re trying to decide whether he should be intensive. Maybe he has some comorbidities, and you’re trying to decide whether to be nonintensive because of those comorbidities. If they were more favorable in their MIPI, you might lean toward the nonintensive approach. If they were less favorable, you might lean toward the intensive approach. I do find that there are some patients for whom I’m struggling to decide how aggressive to be with their treatment. Sometimes, I’ll use the MIPI to help break the tie.

Ian W. Flinn, MD, PhD: With the blastoid and polymorphic variants, I find it tremendously difficult to know what to do. Unfortunately, you can say, “Well, you shouldn’t do this,” but in reality, the alternatives are not all that attractive. What do you think, Matt?

Matthew S. Davids, MD, MMSc: Yes. This is fortunately a pretty rare group of mantle cell patients, but we do see them, and it’s very challenging to treat. They may have a transient initial response to these regimens that we talked about, but they almost always recur fairly quickly. For those patients, if you have a center that you refer to and there’s a clinical trial available, I think exploring these novel regimens is the best thing for the patient.

Ian W. Flinn, MD, PhD: The average community oncologist probably doesn’t see that many cases of mantle cell lymphoma a year, let alone in their career. Brad, what advice do you have for the community oncologist when they see someone with mantle cell lymphoma?
Brad Kahl, MD: If it’s a young patient who would be considered a candidate for an intensive strategy, send them in early so we can assess their fitness for stem cell transplantation. We can start working through the insurance approvals and all the issues related to that, so it’s better to see them early. We like to see them, so we can consider them for clinical trials. There’s still lots of room for improvement in mantle cell lymphoma.

To the extent that we can find appropriate trials for patients, we’d like to have that opportunity. I think most community oncologists are comfortable with the bendamustine-rituximab regimen, and that’s a perfectly reasonable thing to do for an older mantle cell patient. I would encourage community physicians to check around and see if there’s an appropriate clinical trial when they have a mantle cell patient, whether they are frontline or relapsed. Even though outcomes have improved tremendously— you said that earlier, and you’re absolutely right—there is still lots of room from improvement in mantle cell lymphoma.

Ian W. Flinn, MD, PhD: We want you to talk about CLL [chronic lymphocytic lymphoma]. We’re moving these targeted, novel agents to the frontline and getting away from the cytotoxic chemotherapy. Do you think it’s just a matter of time before we get away from bendamustine or the cytarabine-containing regimens and transplant, or do you see it differently?

Brad Kahl, MD: It could happen. Luhua (Michael) Wang, MD, at The University of Texas MD Anderson Cancer Center is studying some of these innovative approaches through a window study where he’s starting with novel targeted agents and then trying to truncate the amount of intensive chemotherapy that is given to patients. He’s shown that response rates to the targeted agents are very high. We don’t know what the long-term outcomes are yet. I would encourage people not to rush to those kind of strategies until some of the data that are currently being generated are mature, and we know that they’re a good strategy. I would love to get away from chemotherapy as much as anybody else, but the fact is, our strategies are working fairly well in mantle cell, so you don’t want to subtract what’s working until you know that what’s coming along is at least as good if not better.

Ian W. Flinn, MD, PhD: It’s not an easy question to get to. You have to be pretty sure of your therapy before you pull away from what we’ve done. There are trials though that are looking at BTK inhibition with venetoclax and other things frontline. John, do you have similar thoughts on this?

John Pagel, MD, PhD: I do. It’s very important to make sure that we’re not burning a drug too soon. In other words, we need to keep something in our back pocket, especially for those high-risk patients. I’m not sure that it’s going to play out to have BTK inhibition as part of the frontline regimen. If it does, I think it will be with chemotherapy for the immediate future. We’ll see if it allows us to give less chemotherapy. I think that might be appealing.

If we’re going to do that, we need to be able to stop treatment, too, and not just continue the BTK inhibitor indefinitely in mantle cell as we’re hoping to do in CLL.

Transcript Edited for Clarity
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