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The Current Unmet Needs in PTCL Treatment and Prospects

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



Transcript: 

Stephen Ansell, MD, PhD: Yeah. So I think that, the ECHELON-2 trial is very exciting for the CD30-positive patients. The challenge is there’s a sizable percentage of patients who are CD30-negative, and so the benefit for those patients has not been realized. In fact, what was interesting at the ASH [American Society of Hematology] meeting, there were 2 other trials that were negative trials just showing us that we’ve got a lot of work to do. So there was a clinical trial incorporating a CD52, or alemtuzumab combination, that did not show a significant benefit over the standard CHOP [cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone] chemotherapy. And there was a second trial utilizing lenalidomide, which is an immune-modulating agent, in combination with CHOP chemotherapy, which again did not show an improvement. So I think the excitement is in the progress now being made in the CD30-positive patients. The challenge lies in the CD30-negative population where we still really haven’t made the progress we would like, even with using some of these other new agents in those patients where the results have not been so good.

So I think there are 1 to 2 trials that came now in the relapsed and refractory setting. And the reason I think these are important, is because, as we mentioned earlier, brentuximab vedotin was successful in relapsed/refractory patients and now has progressed into frontline therapy. So the key question is, what else is out there that’s looking good in the relapsed/refractory setting that potentially could be a future game-changer in frontline?

So 2 trials that I thought were very interesting. Both of them were combination approaches. Romidepsin is an HDAC [histone deacetylase] inhibitor that is approved for T-cell lymphoma, and there was one trial compared, now adding to it a PI3-kinase inhibitor, and a second trial adding it to an azacitidine, which is again a DNA methylation modulator. And both of those had really high response rates, looking quite promising. Small studies. Clearly we’ve seen responses in the past and that haven’t translated into frontline therapies, but I think those are combinations to watch.

Then finally there was an anti-KER antibody. So that is an inhibitory receptor that is mainly seen on NK [natural killer] cells, and that was an antibody that showed, again, a very promising response in patients, with relapsed and refractory patients. So my hope is that these agents that are looking promising in refractory patients may, in the future, be useful in frontline combinations.

So I think the biggest challenge now is to really ask what’s the next main question, particularly for the CD30-negative patients. There are lots of discussions about is it simply just trying to give more chemotherapy? So, in other words, what’s the role of autologous stem cell transplant? Many people will do that because it just feels like it’s a good strategy to give more. But it’s not clear that that really is the best way to go, so really questioning where autologous transplant fits in is a good question that still needs to be answered. And then, as I mentioned, trying to find new agents that are well tolerated, so that they can be combined with standard therapy, is really where we need to go next. A lot of people have tried that. A lot of agents have been tested. Unfortunately, we’re still quite challenged in the CD30-negative population of PTCL [peripheral T-cell lymphoma] to see the real results translate into benefit for patients.

Again, that depends very much on the center. At Mayo Clinic where I work, in general I would say the majority of patients are eligible. We will typically do transplants for patients into their 70s. We have taken the view that in, particularly, the CD30-negative patients, we need to do everything we can because really your first opportunity is probably your best opportunity for a durable benefit. So we will typically do an autologous transplant in first remission. And I would say if you take the entire population, more than 50% of patients will progress to a transplant. The biggest challenge is there’s never been the randomized study that has clearly shown that autologous transplant in first remission is the way to go, so that remains somewhat controversial.

Transcript Edited for Clarity
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Transcript: 

Stephen Ansell, MD, PhD: Yeah. So I think that, the ECHELON-2 trial is very exciting for the CD30-positive patients. The challenge is there’s a sizable percentage of patients who are CD30-negative, and so the benefit for those patients has not been realized. In fact, what was interesting at the ASH [American Society of Hematology] meeting, there were 2 other trials that were negative trials just showing us that we’ve got a lot of work to do. So there was a clinical trial incorporating a CD52, or alemtuzumab combination, that did not show a significant benefit over the standard CHOP [cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone] chemotherapy. And there was a second trial utilizing lenalidomide, which is an immune-modulating agent, in combination with CHOP chemotherapy, which again did not show an improvement. So I think the excitement is in the progress now being made in the CD30-positive patients. The challenge lies in the CD30-negative population where we still really haven’t made the progress we would like, even with using some of these other new agents in those patients where the results have not been so good.

So I think there are 1 to 2 trials that came now in the relapsed and refractory setting. And the reason I think these are important, is because, as we mentioned earlier, brentuximab vedotin was successful in relapsed/refractory patients and now has progressed into frontline therapy. So the key question is, what else is out there that’s looking good in the relapsed/refractory setting that potentially could be a future game-changer in frontline?

So 2 trials that I thought were very interesting. Both of them were combination approaches. Romidepsin is an HDAC [histone deacetylase] inhibitor that is approved for T-cell lymphoma, and there was one trial compared, now adding to it a PI3-kinase inhibitor, and a second trial adding it to an azacitidine, which is again a DNA methylation modulator. And both of those had really high response rates, looking quite promising. Small studies. Clearly we’ve seen responses in the past and that haven’t translated into frontline therapies, but I think those are combinations to watch.

Then finally there was an anti-KER antibody. So that is an inhibitory receptor that is mainly seen on NK [natural killer] cells, and that was an antibody that showed, again, a very promising response in patients, with relapsed and refractory patients. So my hope is that these agents that are looking promising in refractory patients may, in the future, be useful in frontline combinations.

So I think the biggest challenge now is to really ask what’s the next main question, particularly for the CD30-negative patients. There are lots of discussions about is it simply just trying to give more chemotherapy? So, in other words, what’s the role of autologous stem cell transplant? Many people will do that because it just feels like it’s a good strategy to give more. But it’s not clear that that really is the best way to go, so really questioning where autologous transplant fits in is a good question that still needs to be answered. And then, as I mentioned, trying to find new agents that are well tolerated, so that they can be combined with standard therapy, is really where we need to go next. A lot of people have tried that. A lot of agents have been tested. Unfortunately, we’re still quite challenged in the CD30-negative population of PTCL [peripheral T-cell lymphoma] to see the real results translate into benefit for patients.

Again, that depends very much on the center. At Mayo Clinic where I work, in general I would say the majority of patients are eligible. We will typically do transplants for patients into their 70s. We have taken the view that in, particularly, the CD30-negative patients, we need to do everything we can because really your first opportunity is probably your best opportunity for a durable benefit. So we will typically do an autologous transplant in first remission. And I would say if you take the entire population, more than 50% of patients will progress to a transplant. The biggest challenge is there’s never been the randomized study that has clearly shown that autologous transplant in first remission is the way to go, so that remains somewhat controversial.

Transcript Edited for Clarity
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