Advances in Hematologic Malignancies at ASCO22

Dr. Stephen Ansell, of the Mayo Clinic in Minnesota, tells host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about ECHELON-1’s compelling overall survival analysis in newly diagnosed Hodgkin lymphoma and key advances in the SHINE, MOMENTUM, and ASCEMBL trials that were featured at the 2022 ASCO Annual Meeting.   TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for Clinical Affairs at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast.  My guest today is Dr. Stephen Ansell, a professor and chair of medicine at the Department of Hematology at the Mayo Clinic in Minnesota. Dr. Ansell shares his insights on key advances in hematologic malignancies that were featured at the 2022 ASCO Annual Meeting.  Our full disclosures are available in the show notes and disclosures of all guests on podcasts can be found on our transcripts at asco.org/podcasts.   Stephen, it's great to have you on the podcast today.  Dr. Stephen Ansell: Thanks so much for having me, John.  Dr. John Sweetenham: So, Stephen, I'd like to start with your thoughts on Abstract 7503, which of course is one that you authored, and this is a 6-year follow-up study of the ECHELON-1 trial. This includes a positive overall survival analysis for brentuximab vedotin in newly diagnosed advanced Hodgkin lymphoma. Can you tell us more about this?  Dr. Stephen Ansell: Yeah, sure, John. And you know, as you point out, the thing that’s really interesting and unique about this trial is we haven't had a lot of studies in Hodgkin lymphoma that show an overall survival advantage as you well know. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy has actually been quite difficult to beat when it's been an overall survival endpoint that one has been looking at.  There have been some other strategies in the past that have been looked at—the escalation of therapies such as escalator BEACOPP, and maybe modification of therapy to minimize toxicity, such as the RATHL trial where bleomycin is dropped out.  In all of these studies, there have been advantages for progression-free survival, but not clearly against ABVD as the standard and overall survival advantage. So, our listeners would probably know that ECHELON-1 was a comparison between brentuximab vedotin ABVD chemotherapy, and ABVD chemotherapy as the standard, showing an initially modified progression-free survival advantage and subsequently a progression-free survival advantage. But now with 6 years of follow-up, an overall survival advantage. And I think that's really what makes this quite unique.  Dr. John Sweetenham: One of the reasons I think many people, myself included, thought that it was going to be a very high bar to show an overall survival difference in this study was simply the fact that treatments to relapsed and refractory Hodgkin lymphoma, in general, have improved really quite substantially, both before and during the conduct of this trial.  Do you have any thoughts on that? Were you surprised? And any thoughts on why we're seeing this in the face of the rapidly evolving treatment landscape in the relapse setting?  Dr. Stephen Ansell: Yeah, I think that's an excellent point. And, John, I think there have been 2 schools of thought, as you know, those that have felt that the first shot was always the best one. And you should go hard right off the bat and others have said, you don't need to give everybody intensive treatment, because as you say, subsequent therapies can be very effective.  This would actually challenge that second position because when we looked at how patients were managed in both groups when they relapsed, the vast majority of relapsing patients in the group that got ABVD subsequently got brentuximab vedotin, as part of their regimen. Most patients—and it was balanced in both arms—got the standard kind of salvage treatment, autologous stem cell transplant approach, and some patients in both arms, got novel agents, including PD1 blockade, that was a minority, partly because of the timing of when the study was done.  But I think all of the things that we would normally do were done, and yet there's still a survival advantage. The one interesting thing I think that's worth taking away from this is when one looked at some of the influences on what might have made that overall survival difference, there were more patients progressing and dying from Hodgkin's in the ABVD arm suggesting that adding brentuximab vedotin does make a difference to the disease itself. But also interestingly, there were fewer patients in the brentuximab arm, who got a second lymphoma.  And interestingly, there were quite a substantial number of people in the ABVD arm when they relapsed to or subsequently got a different lymphoma, suggesting that the brentuximab vedotin, may actually target a precursor cell in a heme malignancies space and actually may have a benefit that way.  Dr. John Sweetenham: So, what's your overall conclusion from this study now that brentuximab vedotin plus ABVD is the standard of care for patients with newly diagnosed advanced Hodgkin lymphoma?  Dr. Stephen Ansell: I would say that if you have advanced-stage disease with classical Hodgkin lymphoma histology, it's very difficult not to say that this would be the standard of care to manage the patients.  I think we've learned that this study applied to older patients who are often difficult to treat. And so, hence, that's also a very valid treatment to give. And it's very difficult to argue against giving treatment that has an overall survival advantage for patients. So, in my practice, this has become the standard of care.  Dr. John Sweetenham: Okay, great. Thanks, Stephen. Let's move on and talk about LBA7502. This reported on the primary results of a double-blind placebo-controlled study known as SHINE, which looks at the use of ibrutinib in combination with bendamustine and rituximab followed by rituximab maintenance as a first-line treatment for older patients with mantle cell lymphoma. What are your thoughts and key takeaways from this study?  Dr. Stephen Ansell: Again, I think this is a very important study in older patients with mantle cell lymphoma. So, as you well know and many of our listening audience would know that we kind of has 2 strategies in mantle cell lymphoma. In younger patients, we may treat them with a more intense approach, sometimes with autologous stem cell transplant, often with a kind of alternating high-intensity therapies.  For patients who are older, bendamustine rituximab is really a standard therapy for patients with that demographic. And this now really pushes the field forward by showing that if you take bendamustine rituximab and add ibrutinib an effective therapy in the relapse setting, in the upfront setting, there is a substantial advantage for how patients do.  If one looks at the overall outcomes, it shows that progression-free survival is improved; we don't have overall survival benefit yet. But as we track these patients, it'll be interesting to see if that does transpire in time.  I will say again that I always like placebo-controlled arms because it helps us really get a handle on toxicities. And in general, in this population of patients, it was well tolerated. So, I think this, again, is a regimen that is going to be very useful in older patients.  Dr. John Sweetenham: I think that the lack of an overall survival benefit so far could of course be because there was a crossover in a study for those patients who progressed on the placebo-controlled arm.  But my other question about this, just to get your impression, is that there is a subgroup of elderly patients or older patients with a very slowly progressive disease where the management approach has been more of a watch-and-wait and observation-only approach until they become symptomatic. Do you think results like this, which start to show a progression-free survival benefit from upfront therapy, change that philosophy? Should we be thinking harder about whether anyone should be observed now?  Dr. Stephen Ansell: I think that's a good question. And to be frank, I will say that in my practice, I still have a spirit of, I'm happy to watch patients who have a very low burden of disease to just get a sense of the pace of the disease. Because as you say, you may be surprised by a subset of patients whom you may not need to treat for a year or even longer. And my view is that a year of no treatment is always better than a prolonged progression-free survival interval on treatment. So, I take the view that if you don't need to treat, that is still the best management.  Dr. John Sweetenham: Great, thank you! So, we're going to change gear for a moment and move out of lymphoid malignancy and talk a little about Myeloproliferative Syndrome. I’m interested to hear your thoughts on the MOMENTUM study. So, this was Abstract 7002, another phase 3 randomized study, in this case, looking at the use of momelotinib versus danazol in symptomatic and anemic patients with Myelofibrosis, who previously had a JAK inhibitor. What are your thoughts on this study?  Dr. Stephen Ansell: I think again, this is really good and very interesting data because those that treat Myelofibrosis will know these are challenging to treat. And many times, the symptoms they experience, the transfusion challenges they have, and the difficulty they have with very large spleens are all things that impact the quality of life quite profoundly. And therapies, in general, that would benefit those symptoms are always highly valuable.  So, I did find, again, I'm not as much of an expert in Myelofibrosis, but certainly, my colleagues who are were very satisfied with these results, basically showing improvement when compared to danazol, which again, I would anticipate as modest control with not particularly good efficacy, again, some of those symptoms I just spoke about, but momelotinib really showed a substantial benefit for the symptoms that this disease causes, and obviously transfusion requirements and improved spleen sizes and spleen symptoms.  So, I think in general, for managing patients for whom the quality of life is profoundly impacted, this is going to be a useful agent moving forward.  Dr. John Sweetenham: Okay, great. Thanks. And staying on the theme of Myeloid diseases, Abstract 7004 reported on the efficacy and safety, from the so-called ASCEMBL study, another phase 3 study, in this case, looking at the use of asciminib versus bosutinib in patients with Chronic Myeloid Leukemia (CML) who are in chronic phase, and who had already received 2 or more tyrosine kinase inhibitors. And this was an update at week 56 of the study. Why do you think this study should be on our radar?  Dr. Stephen Ansell: Well, I think again, we're always looking for agents that make a difference, particularly with subsequent lines of therapy in this disease. I think bosutinib is really regarded as a standard of care in this population of patients and an agent that comes along, ascitinib in this case, that shows a significant benefit, that really brings yet another tool for us to utilize in these patients.  I must say, again, as I looked at the results, comparing also looking for the major molecular responses, and the benefit and durability thereof, this was pretty impressive data. And so, I think it's very useful in this disease to have a plethora of tools that we can reach to be able to really impact the outcome of patients. So, I think, again, this is highly relevant data that we would use in the clinic in the not-distant future.  Dr. John Sweetenham: Do you think it's likely it’ll move into frontline treatment over time?  Dr. Stephen Ansell: So, I think that is a good question. I don't know the answer to that, except to say that these results are pretty impressive. And so, I do believe that that's going to need to be tested, but as has been done in CML over the decades and which is really to be applauded, there have been randomized trials, comparing head-to-head agents showing which agent really has the greatest benefit and efficacy. So, I’ll watch that space with a lot of interest.  Dr. John Sweetenham: Thanks! And finally, I'd like to return to lymphoid malignancy. In the 2020s, it would be almost impossible to review a meeting such as ASCO without saying something about CAR T-cell therapy, and this podcast is going to be no exception.  So, I wonder if I could get your thoughts on Abstract 7571. And this was an abstract, which reported real-world outcomes for axicabtagene ciloleucel, otherwise known as the Axi-Cel, for the treatment of large B-cell lymphoma. And it looked at the outcomes according to race and ethnicity. What are your thoughts on this study?  Dr. Stephen Ansell: Well, John, I smiled when you were said there's not a possible to really have a conversation without bringing in CAR T-cell somewhere along the way, but what I liked about this abstract, is it really was bringing in the real-world data, because many times and again, I have to stress that real-world data, when it comes to CAR T-cells is probably not the real world in the most real-world nature of things. And that is just you have to have access to certain centers to be able to get this therapy. And I think that's what this abstract actually points to.  It does look at almost 1,400 patients treated with Axi-Cel. And now that in large cell lymphoma, this is a standard of care where we either use a post-transplant and now even as a first relapse therapy, this is becoming highly relevant. And the question is just always seeing discrepancies between various population groups when we look at how outcomes transpire from this therapy.  And as it turns out, if one looks at Asian populations, those are really not adversely impacted, or Hispanic populations. But the African American population continues to have a less favorable outcome, even with this sophisticated therapy.  And that does suggest that possibly, when those patients, in general, can get access to this care, might actually be a little later in the disease, greater disease burden, possibly a little later line of therapy, resulting in not as favorable results.  I think this is whereas health care providers, we need to turn our attention in the future. And that is to say, how can we make care be equally good for all patients everywhere within our country, rather than there being nuggets where certain people benefit a lot and other areas where people benefit very little.  Dr. John Sweetenham: Yeah, thank you. There was good discussion after this study was presented and I think much of it focused around exactly what you've just said. Most of this difference is almost certainly not biological but it's really related to access to care and so on and that was an important take-home message. So, thanks for emphasizing that.  Stephen, thanks so much for sharing your insights with us today regarding the 2022 ASCO Annual Meeting on our podcast. I really appreciate your being willing to talk to us.  Dr. Stephen Ansell: John, thank you very much for having me.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts.    Disclosures:  Dr. John Sweetenham:  Consulting or Advisory Role: EMA Wellness  Dr. Stephen Ansell:  Honoraria: WebMD, Research to Practice  Research Funding (Inst.): Bristol-Myers Squibb, Seattle Genetics, Affimed Therapeutics, Regeneron, Trillium Therapeutics, AI Therapeutics, ADC Therapeutics  Disclaimer:  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.