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Treating Patients With CD30-Positive PTCL

Insights From: Stephen M. Ansell, MD, PhD, The Mayo Clinic
Published: Monday, Jan 28, 2019



Transcript: 

Stephen Ansell, MD, PhD: So CD30 is a tumor necrosis factor receptor that is expressed on T cells, typically activated T cells. And certain types of peripheral T-cell lymphoma—most notably the anaplastic large cell lymphoma subtype, but also a number of other peripheral T-cell lymphomas—can express this protein. That actually has given us a real opportunity to bring something new to the treatment of patients with peripheral T-cell lymphoma [PTCL], and that’s because the agent, brentuximab vedotin, targets CD30, binds to CD30. CD30 then gets internalized and the agent delivers the MMAE [monomethyl auristatin E] toxin or chemotherapy agent to the malignant cell. And that then induces cell death.

And in the relapsed and refractory setting, that’s been a very significant success, particularly in the patients with anaplastic large cell lymphoma, whether it be ALK-positive or ALK-negative. And now most recently in combination with the CHOP [cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone] backbone, just omitting the vincristine—that combination of brentuximab vedotin plus CHOP chemotherapy with no vincristine—has actually been very successful and has been shown to be superior to the CHOP combination in the recently published and presented ECHELON-2 clinical trial.

Again, because PTCL can be a variety of different histologies lumped into 1 thing, it’s important to talk about what exactly do you mean. So, if you’re talking about anaplastic large cell lymphoma, CD30 is almost universally expressed at very high levels in anaplastic large cell lymphoma that is both ALK-positive or ALK-negative. But if you take the peripheral T-cell lymphoma not otherwise specified—so that’s kind of a grab bag to lump kind of a lot of the other diseases that we don’t have good names for yet—about half of those may express CD30. In the clinical trial that was recently published, they set a bar at 10% to say that at least 10% of the malignant cells needed to express CD30 for that to be felt to be a positive disease. But, quite frankly, there’s probably some degree of positivity even in a larger percentage, but that’s less well studied.

I think the feeling was just that they needed to have at least a compelling amount of CD30 expressed on malignant cells. However, the same CD30 cut points are being tested in B-cell lymphoma, and responses were seen even with less than 1% of the cells expressing CD30. So the staining is typically done by immunohistochemistry, and it might be that actually it underestimates the amount of expression based on the fact that you can get responses even with very low levels of CD30 detected by immunohistochemistry.

I think the challenge is just CD30-positive peripheral T-cell lymphoma remains a disease that responds quite poorly to chemotherapy, particularly just typical CHOP chemotherapy. In contrast, the patients who have anaplastic large cell lymphoma, which is very positive for CD30, just standard CHOP chemotherapy in the ALK-positive fraction of those patients can actually result in pretty good results. Seventy percent of patients may have a good long-term outcome. The ones that are ALK-negative tend to land between those 2 groups, less good. And, again, genetic testing including looking for DUSP22 mutations or mutations of TP63 have helped to define that group to some degree. But all told, there’s quite a spectrum of how patients respond, and part of it is just our lack of understanding of exactly what diseases we’re treating. But if you were to say, in the summary, having new drugs to treat these diseases is really critical, because of the fact that notoriously over the years, we have been less successful in treating T-cell lymphomas than we have with treating B-cell lymphomas.

Transcript Edited for Clarity 
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Transcript: 

Stephen Ansell, MD, PhD: So CD30 is a tumor necrosis factor receptor that is expressed on T cells, typically activated T cells. And certain types of peripheral T-cell lymphoma—most notably the anaplastic large cell lymphoma subtype, but also a number of other peripheral T-cell lymphomas—can express this protein. That actually has given us a real opportunity to bring something new to the treatment of patients with peripheral T-cell lymphoma [PTCL], and that’s because the agent, brentuximab vedotin, targets CD30, binds to CD30. CD30 then gets internalized and the agent delivers the MMAE [monomethyl auristatin E] toxin or chemotherapy agent to the malignant cell. And that then induces cell death.

And in the relapsed and refractory setting, that’s been a very significant success, particularly in the patients with anaplastic large cell lymphoma, whether it be ALK-positive or ALK-negative. And now most recently in combination with the CHOP [cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone] backbone, just omitting the vincristine—that combination of brentuximab vedotin plus CHOP chemotherapy with no vincristine—has actually been very successful and has been shown to be superior to the CHOP combination in the recently published and presented ECHELON-2 clinical trial.

Again, because PTCL can be a variety of different histologies lumped into 1 thing, it’s important to talk about what exactly do you mean. So, if you’re talking about anaplastic large cell lymphoma, CD30 is almost universally expressed at very high levels in anaplastic large cell lymphoma that is both ALK-positive or ALK-negative. But if you take the peripheral T-cell lymphoma not otherwise specified—so that’s kind of a grab bag to lump kind of a lot of the other diseases that we don’t have good names for yet—about half of those may express CD30. In the clinical trial that was recently published, they set a bar at 10% to say that at least 10% of the malignant cells needed to express CD30 for that to be felt to be a positive disease. But, quite frankly, there’s probably some degree of positivity even in a larger percentage, but that’s less well studied.

I think the feeling was just that they needed to have at least a compelling amount of CD30 expressed on malignant cells. However, the same CD30 cut points are being tested in B-cell lymphoma, and responses were seen even with less than 1% of the cells expressing CD30. So the staining is typically done by immunohistochemistry, and it might be that actually it underestimates the amount of expression based on the fact that you can get responses even with very low levels of CD30 detected by immunohistochemistry.

I think the challenge is just CD30-positive peripheral T-cell lymphoma remains a disease that responds quite poorly to chemotherapy, particularly just typical CHOP chemotherapy. In contrast, the patients who have anaplastic large cell lymphoma, which is very positive for CD30, just standard CHOP chemotherapy in the ALK-positive fraction of those patients can actually result in pretty good results. Seventy percent of patients may have a good long-term outcome. The ones that are ALK-negative tend to land between those 2 groups, less good. And, again, genetic testing including looking for DUSP22 mutations or mutations of TP63 have helped to define that group to some degree. But all told, there’s quite a spectrum of how patients respond, and part of it is just our lack of understanding of exactly what diseases we’re treating. But if you were to say, in the summary, having new drugs to treat these diseases is really critical, because of the fact that notoriously over the years, we have been less successful in treating T-cell lymphomas than we have with treating B-cell lymphomas.

Transcript Edited for Clarity 
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