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R/R MCL: Synchronizing Older and Newer Therapeutic Strategies

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, what do you think? What new therapies are you thinking about in mantle cell lymphoma? We have zanubrutinib, and we talked a little about it in CLL [chronic lymphocytic leukemia]. Do you see that being used in mantle cell lymphoma? Is there any reason to go for that versus the others?

Brad Kahl, MD: It’s hard to say right now. There are a bit of data for zanubrutinib in mantle cell lymphoma. It looks roughly comparable to acalabrutinib and ibrutinib. Whether it has some therapeutic advantage over the earlier BTK inhibitors, I honestly can’t tell yet. I’m glad to see zanubrutinib developed. It’ll be great to see larger, more mature data sets, and it’s always good to have options. I’ll never complain about having too many choices. As Matt mentioned, the real problem is the development of BTK resistance in mantle cell. Combination studies are very logical. The venetoclax–BTK inhibitors are a very good combination to study, and there’s a bit of experience there.

I’ve seen studies combining CDK inhibitors with BTK inhibitors, or proteasome inhibitors with BTK inhibitors, and these are all important studies that are currently underway. We’ll probably have results in the next year or 2 to help us know if doublets or triplets of novel targeted agents are better than just single BTK inhibition.

Ian W. Flinn, MD, PhD: We skipped over some of the older agents, right? We didn’t talk about bortezomib; we didn’t talk about lenalidomide. Where are you using those agents? Are you still using them?

Brad Kahl, MD: Lenalidomide is very useful in mantle cell lymphoma. It’s a very interesting drug. The response rates are not terribly high. The single-agent lenalidomide responses are in the 30%-to-40% range, but if you combine it with rituximab, you can bump that up into the 50%-to-60% range, and some of those responses can be quite durable. I do find lenalidomide to be a very useful option for relapsed mantle cell lymphoma.

Bortezomib is another pretty good option. It’s not quite as attractive as lenalidomide or BTK inhibition, because the response rates aren’t quite as high and the durability isn’t quite as good. There’s also the whole issue of peripheral neuropathy. However, it is another good tool to have in your toolbox. With mantle cell lymphoma and the way patients start to become resistant to therapies, you know you can burn through your options fairly quickly. There still is a huge unmet need in mantle cell lymphoma for more and better options for the relapsed-refractory patient.

Ian W. Flinn, MD, PhD: What about the frontline patients, John? There were data published in the New England Journal of Medicine a number of years ago about a group of patients who were treated with lenalidomide and rituximab in the frontline setting in mantle cell lymphoma. I don’t think of it as being the most standard approach, but there’s probably a subset of patients who have more indolent disease, and maybe they are the right people.

John Pagel, MD, PhD: Right. I think that R2, or Revlimid [lenalidomide] and rituximab, in the frontline setting—particularly for older patients, who were subjects in the study you’re alluding to—is a quite impressive option. If you take patients with mantle cell who are above age 65 who aren’t good candidates for chemoimmunotherapy, I think R2 [lenalidomide, rituximab] is a very appealing approach. The response rates there were quite good, although they were treatment-naïve patients. The CR [complete response] rates were quite good as well.

You could argue that over time, it might become the preferred regimen for all patients in the frontline. We don’t have data for that, clearly. We need to see more of that. I’m excited about R2 [lenalidomide, rituximab] in the frontline for the right patients.

One of the things we haven’t mentioned is that we’ve got to figure out a better way to treat patients with TP53 mutations in mantle cell. If you have a frontline patient with 1 of those mutations, it’s a whole different story. Those are people for whom I’m starting to think about CAR [chimeric antigen receptor] T-cell treatments, which is another new approach that we have to keep in mind. There are emerging data that show that CAR T cells can provide significant long-term survival advantage for very aggressive relapsed mantle cell patients. I like R2 [lenalidomide, rituximab] in the frontline in the right patients. I like the idea of BTK inhibition, as well, in relapsed patients. I think that in subsets of patients, and in particular, those with TP53 mutations, we have to consider more aggressive cellular therapies.

Ian W. Flinn, MD, PhD: You outlined a nice sequence about the potential for cellular therapies, perhaps as third line, for patients who need it.

Transcript Edited for Clarity

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Transcript: 

Ian W. Flinn, MD, PhD: Brad, what do you think? What new therapies are you thinking about in mantle cell lymphoma? We have zanubrutinib, and we talked a little about it in CLL [chronic lymphocytic leukemia]. Do you see that being used in mantle cell lymphoma? Is there any reason to go for that versus the others?

Brad Kahl, MD: It’s hard to say right now. There are a bit of data for zanubrutinib in mantle cell lymphoma. It looks roughly comparable to acalabrutinib and ibrutinib. Whether it has some therapeutic advantage over the earlier BTK inhibitors, I honestly can’t tell yet. I’m glad to see zanubrutinib developed. It’ll be great to see larger, more mature data sets, and it’s always good to have options. I’ll never complain about having too many choices. As Matt mentioned, the real problem is the development of BTK resistance in mantle cell. Combination studies are very logical. The venetoclax–BTK inhibitors are a very good combination to study, and there’s a bit of experience there.

I’ve seen studies combining CDK inhibitors with BTK inhibitors, or proteasome inhibitors with BTK inhibitors, and these are all important studies that are currently underway. We’ll probably have results in the next year or 2 to help us know if doublets or triplets of novel targeted agents are better than just single BTK inhibition.

Ian W. Flinn, MD, PhD: We skipped over some of the older agents, right? We didn’t talk about bortezomib; we didn’t talk about lenalidomide. Where are you using those agents? Are you still using them?

Brad Kahl, MD: Lenalidomide is very useful in mantle cell lymphoma. It’s a very interesting drug. The response rates are not terribly high. The single-agent lenalidomide responses are in the 30%-to-40% range, but if you combine it with rituximab, you can bump that up into the 50%-to-60% range, and some of those responses can be quite durable. I do find lenalidomide to be a very useful option for relapsed mantle cell lymphoma.

Bortezomib is another pretty good option. It’s not quite as attractive as lenalidomide or BTK inhibition, because the response rates aren’t quite as high and the durability isn’t quite as good. There’s also the whole issue of peripheral neuropathy. However, it is another good tool to have in your toolbox. With mantle cell lymphoma and the way patients start to become resistant to therapies, you know you can burn through your options fairly quickly. There still is a huge unmet need in mantle cell lymphoma for more and better options for the relapsed-refractory patient.

Ian W. Flinn, MD, PhD: What about the frontline patients, John? There were data published in the New England Journal of Medicine a number of years ago about a group of patients who were treated with lenalidomide and rituximab in the frontline setting in mantle cell lymphoma. I don’t think of it as being the most standard approach, but there’s probably a subset of patients who have more indolent disease, and maybe they are the right people.

John Pagel, MD, PhD: Right. I think that R2, or Revlimid [lenalidomide] and rituximab, in the frontline setting—particularly for older patients, who were subjects in the study you’re alluding to—is a quite impressive option. If you take patients with mantle cell who are above age 65 who aren’t good candidates for chemoimmunotherapy, I think R2 [lenalidomide, rituximab] is a very appealing approach. The response rates there were quite good, although they were treatment-naïve patients. The CR [complete response] rates were quite good as well.

You could argue that over time, it might become the preferred regimen for all patients in the frontline. We don’t have data for that, clearly. We need to see more of that. I’m excited about R2 [lenalidomide, rituximab] in the frontline for the right patients.

One of the things we haven’t mentioned is that we’ve got to figure out a better way to treat patients with TP53 mutations in mantle cell. If you have a frontline patient with 1 of those mutations, it’s a whole different story. Those are people for whom I’m starting to think about CAR [chimeric antigen receptor] T-cell treatments, which is another new approach that we have to keep in mind. There are emerging data that show that CAR T cells can provide significant long-term survival advantage for very aggressive relapsed mantle cell patients. I like R2 [lenalidomide, rituximab] in the frontline in the right patients. I like the idea of BTK inhibition, as well, in relapsed patients. I think that in subsets of patients, and in particular, those with TP53 mutations, we have to consider more aggressive cellular therapies.

Ian W. Flinn, MD, PhD: You outlined a nice sequence about the potential for cellular therapies, perhaps as third line, for patients who need it.

Transcript Edited for Clarity
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