Dr. Alison Moskowitz:
Welcome to the ASCO Post Roundtable series on updates in lymphoma. I'm Dr. Alison Moskowitz. I'm an Associate Attending from the Lymphoma Service at Memorial Sloan Kettering Cancer Center. Joining me today are two of my colleagues.
Dr. Ann LaCasce:
So, I'm Dr. Ann LaCasce from Dana-Farber Cancer Institute. I'm an Associate Professor of Medicine.
Dr. Andy Evens:
Hi, my name is Dr. Andy Evens, Associate Director at the Rutgers Cancer Institute of New Jersey.
Dr. Moskowitz:
Today, we will be discussing recent updates in Hodgkin lymphoma and integrating these new developments into four patient case studies. Our first installment will focus on advanced stage Hodgkin lymphoma, and I will start with a case.
So, this is a case of a 35-year-old female who originally presented with cough. She presented to her primary doctor who performed some lab tests and found that her white count was elevated to 19,000. A CAT scan of the chest, abdomen, and pelvis showed widespread lymphadenopathy, including a lesion in her lung, as well as lesions in her liver. She had a left upper lung biopsy that showed classical Hodgkin lymphoma. Her International Prognostic Score was found to be 3 due to a low albumin, elevated white count, and stage IV disease. So, we have a patient here with advanced stage Hodgkin lymphoma. I'll start off with Andy as far as, how would you initially approach this patient, and has your practice changed at all over time?
Dr. Evens:
Sure. Yeah. And this is a pretty representative case, just in the fact that it falls in that first age peak in patients in their 20s and 30s. It's someone that, even though they come out as a Hasenclever-Diehl International Prognostic Score (IPS) of 3, to me, it seems a little higher risk, just given the extranodal disease. I know that's not a risk factor but just seems pretty widespread. So, of course, we also know the Hasenclever-Diehl is a fairly old score. It certainly was a seminal publication back in the 1990s, but there have been some subsequent analyses looking at more updated prognostication, and we look forward to some of that new data as it comes out.
But, in terms of treatment, of course, many of us have used ABVD for, not just years, but decades now. And, there have been a number of regimens to try to knock ABVD off the top of the totem pole. Escalated BEACOPP is one, and in some countries that has become a standard. But, I think in many places, especially in most of the United States, it has not. Yes, BEACOPP-based regimen showed a progression-free survival advantage. But, I think part of the issue was, certainly we know significant increased toxicity, not just acutely, but also post-acute, after treatment. And then, it never translated to an overall survival advantage. In terms of to the point, Dr. Moskowitz, of what has broken through, we of course have to talk about ECHELON-1, which was the international randomized study, adding brentuximab vedotin in lieu of bleomycin. So, in other words, brentuximab vedotin plus AVD versus ABVD. And that was done without PET adaptation even though early PETs were done.
And, the initial analysis, several years ago now at 2 years, showed a progression-free PFS advantage, which was approximately absolute benefit of 5%. Although, that was counterbalanced where there was increased toxicity we know during treatment. In particular, febrile neutropenia and neuropathy. I think there was maybe some slow uptake initially to that, even though it did garner FDA approval out of the gates. I think what's impressed me at least is just year over year, at 3 years, at 4 years, at 5 years. Not only has that PFS advantage stabilized, if anything, it's increased a little bit, number one. Number two, a lot of those toxicities, thankfully, that were increased in the brentuximab vedotin + AVD arm have really equaled out. In other words, the neuropathy compared to ABVD really looks to be quite similar. And then some other, I think, important data such as fertility, second malignancies, etc.
But, the big number three breakthrough that we look forward to at the upcoming ASCO meeting is the reported overall survival advantage to brentuximab vedotin + AVD. So, I think in a word or two words, that's a game changer. It's really not been seen in my academic generation or at least in the last 20 years showing an overall survival advantage compared to classic ABVD. So, certainly we need to see those details, and I had already been using more and more of this regimen, but I think it'll really, probably should become the standard of care after we see that data.
Dr. Moskowitz:
Yeah. I completely agree with that. And Ann, I'm curious what your thoughts are as far as whether your practice has shifted since the press release regarding the survival advantage of BVAVD.
Dr. LaCasce:
I think as Dr. Evens said, we had started to move towards giving BVAVD to the majority of our patients, younger patients. It's really not terribly well tolerated in patients over 60, which we'll get to later, but in a patient like this, I think that progression-free survival data in and of itself was enough to suggest that that's how we should be initiating therapy. The neuropathy can be problematic, particularly giving brentuximab plus vinblastine, but in our younger patients, most of them do recover. The data from Europe that I think is interesting is the LYSA data where they started with escalated BEACOPP and de-escalate based on PET negativity to ABVD. That data looks very, very good. But again, in a 35-year-old woman, I wouldn't be very enthusiastic about, particularly if she were interested in having kids, the infertility risk at that age with two cycles of BEACOPP might be significant.
I think now we need to see where we're going next with the big North American randomized study, comparing BVAVD with the nivolumab + AVD. And, I think that will be extremely interesting. And I think we need those correlatives to try to figure out who may benefit from which regimen given that checkpoint inhibitors also come with a risk of some rare but very significant toxicities which may be persistent over time. Fortunately, that study seems to be accruing ahead of schedule, so we really look forward to seeing that. But, I think the overall survival benefit just sort of clenches that this would clearly be how I would also manage this patient.
Dr. Moskowitz:
What do you think about changing therapy based upon interim PET? Should we still consider that or, do we need to move away from that now?
Dr. LaCasce:
I think the data, there was a benefit in the PET-positive patients who got BVAVD. The outcome of those patients, I think, is very suboptimal. The study obviously was not PET-directed, so we don't really know what the benefit of switching at that point would be, but I would like to see some PET adapted studies really trying to figure out, is that a patient group there that you would want to add a checkpoint inhibitor to? Or, think about going to upfront auto transplant because we know the outcomes are really not what we would like to see.
Dr. Evens:
Yeah, I totally agree. And, the couple ways I'll look at the data is exactly like Dr. LaCasce said is the PFS benefit. And, we'll see on the overall survival benefit, transcended whether you were PET2-negative or PET2-positive with BVAVD. But, not surprisingly, if you were PET2-positive, the outcomes were much worse. And so, yes, we know that this qualitative PET2-positive, regardless of treatment regimen, is a worse prognosis. I guess where I'm also thinking is, is that a real springboard? Is that enough? In other words, what about metabolic tumor burden? What about incorporating ctDNA? And, as Ann highlighted, that in our S1826 North American study, there's a lot of really cool correlative studies built in. And really, that's the hope of all of our treatments, whether it's BVAVD or nivolumab + AVD. Can we actually start to get to a point where we personalize and can identify whether based on a PET or ctDNA or some other important correlative, who should get what?
Dr. Moskowitz:
Talking a little bit more about personalizing therapy, are there any scenarios where you might consider treating as per the RATHL study or starting with escalated BEACOPP?
Dr. LaCasce:
I think if a patient had underlying neuropathy or was a little bit more frail but not over 60, where I would use a sequential approach that Dr. Evens has published, and we'll probably be discussing a little bit later. I would consider using the RATHL approach which is something that we did for some time, and the outcomes are good. They're not quite as good. It is appealing to incorporate some brentuximab in there. So, maybe I would actually do more of a sequential approach because that becomes much, much more tolerable when you're giving half as much brentuximab and doing it in a sequential way. But, I think if patients have a strong opinion, one way or the other, as well. They often don't because the data looks good, particularly now with the survival benefit.
Dr. Evens:
Yeah, I agree. It really maybe is that neuropathy patient who just cannot handle the brentuximab vedotin. But, I think the other issue with RATHL, it's great if you're PET2-negative because you can drop the bleomycin after two cycles. It's what do you do for PET2-positive, which are 15 to 20% of patients? Can that patient tolerate four to six cycles of escalated BEACOPP? So, a few patients here and there, but I think, right now, less and less in advanced stage Hodgkin's lymphoma.
Dr. Moskowitz:
That's great. So, I think I'm going to wrap this up. It sounds like we're all very much in agreement with the management for this patient. In general, with regard to the key clinical takeaways. For patients, at least younger patients, with advanced stage Hodgkin lymphoma, our preferred regimen, particularly based upon the recently reported survival benefit of BVAVD compared to ABVD from ECHELON-1, I'd say our preferred regimen these days is BVAVD. For a few patients, we might consider ABVD as per RATHL based upon baseline neuropathy. We look forward to the data that's going to be presented at ASCO and see some of the more details regarding this survival benefit with BVAVD cause it really is quite impressive that this has been reported as we haven't seen survival benefits of more aggressive therapies in the past in randomized studies and advanced stage disease.
But, it is important to note that there is some different toxicity profile with BVAVD compared to the standard ABVD. There's less pulmonary toxicity because we don't have bleomycin, but we do see higher rates of neuropathy which we need to monitor. And then, it's really important that patients receive growth factor due to the higher risk of febrile neutropenia with this regimen which we don't see as much with ABVD.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in Hodgkin lymphoma, or visit ASCOpost.com.
