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Dr. Alison Moskowitz:
Welcome to the ASCO Post round table 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 who I'll allow to introduce themselves.
Dr. Ann LaCasce:
Hi, I'm Dr. Ann LaCasce. I'm an associate professor at Dana-Farber Cancer Institute.
Dr. Andrew Evens:
Hi, I'm Andrew Evens, associate director at the Rutgers cancer Institute of New Jersey.
Today, we will be discussing recent updates in Hodgkin lymphoma and integrating these new developments to four patient case studies. Our third installment will focus on Hodgkin lymphoma in older patients. So, I will start with the case. So, this is a case of a 65-year-old man who presented with body aches, night sweats, and back pain. He underwent a CAT scan which showed generalized lymphadenopathy. He had a left inguinal lymph node excisional biopsy that showed classical Hodgkin lymphoma. His PET scan showed FDG uptake within generalized lymphadenopathy as well as within his bones. Overall, he had stage IV disease and IPS score of 4 based upon his stage, age, male sex, and albumin. So when I'm thinking about a patient who is 60 years or older with Hodgkin lymphoma, I'm immediately thinking about Dr. Evens' data, and so, I would love to hear about his thoughts about how he initially approaches a patient like this and how maybe that has changed over time.
Sure. Well, this is really an emblematic case, and I say that for a couple reasons, one its advanced stage, and we know of course, Hodgkin lymphoma having the very unique age-based bimodal age distribution with that second peak really peaking in the 70s and 80s, and with that said, those are relative curves, but about 20% of patients in the United States and Western world will be over age 60, and when you look at that older Hodgkin lymphoma saying over age 60 years, majority of them have advanced stage disease. You'll see a lot more mixed cellularity, Epstein-Barr within the tumor, and of course are older with more comorbidities. I think what's interesting is I think when you look at almost any cancer, usually older age compared to somebody in their 20s or 30s will be a negative prognostic factor. What's maybe a little extra unique is just extra disparity in outcomes.
Meaning 40-50 percentage points worse when you use a cut point of less than age 60 or greater than age 60. We had looked back at the most recent advanced stage study in North America, the ABVD Stanford V study, and we looked at about 50 patients who were older, and we saw exactly that. But then, of course the question is, why is that? And the answer is many different reasons, but probably the top two is of course, tolerability. It's really critical. We think of ABVD or AVD etc., As being relatively well tolerated in younger patients, but in that older patient population, it just is tougher to tolerate every two weeks of course with bleomycin. You can get away with bleomycin, but we know the number 1, 2, and 3 risk factor for bleomycin lung toxicity is age, and there has to be great caution there.
And with that said, I think there probably is some real difference in biology, and even if you take away tolerability, probably worse prognosis, just in terms of comparative to that younger patient population. So we have to do a better job, and I would say the good news is over the last 5 and definitely 10 years, there's been greater attention to this in the United States and internationally. We had published a phase 2 study. It was a multicenter phase 2 study. Paul Hamlin was at MSK, the senior author on this. We had actually designed this before ECHELON-1. So we didn't have that as a benchmark, and we knew we had brentuximab vedotin, it was a novel agent, first in class. We wanted to incorporate it, and the study design was really predicated on tolerability. In other words, we didn't give it concurrently for that reason. We decided to do it sequentially.
So, for an older patient population, we started with two cycles of brentuximab vedotin. It also gave us an interesting window look to single-agent brentuximab vedotin, which showed by the way the response rate to just two cycles for mostly advanced stage older Hodgkin lymphoma patients was almost 80% with about a third CR rate. Patients then went on to receive six cycles of AVD. We just dropped the bleomycin a priori, said the risks outweighed the benefits, and then went on, you could call it, to sequential or consolidative brentuximab vedotin for four cycles.
In retrospect, it's pretty long therapy, and maybe if I had to do it again, we would give less chemotherapy, especially to early responders. And I should add, you should never feel forced to give all of this regimen. There are plenty of patients, if they aren't tolerating the AVD, you might cut it short at four or five cycles before moving on to the four brentuximab vedotin, but the bottom line is we were pretty impressed with the results, albeit in a phase two study, seeing two-year event-free and progression-free survival over 80%.
But one really important caveat I want to highlight in this and all older Hodgkin lymphoma studies is the fitness of a patient. And we did do geriatric assessments in this study, we looked mainly at activities of daily living and CIRS-G comorbidity score. In this study, we found the cut point to be important of 10 on the comorbidity score, and for patients who were fit, meaning they had all intact activities of daily living and a CIRS-G below 10, that PFS and OS was actually north of 90%. Whereas maybe not surprisingly, they did much worse, and it really was a tolerability standpoint if they were not fit. There were no frail patients on this study.
And so that's obviously an important consideration, maybe not just in Hodgkin lymphoma, but all older patients is that geriatric assessment and working with geriatric oncology or other colleagues to help do that. And so how do we treat those patients? Well, there have been also studies looking at this. Whether, we call it palliative therapy or just other non-aggressive therapy for this patient population, there was a progressive phase 2 study that started with brentuximab vedotin alone, then added bendamustine which was closed in these older patients due to toxicity, BV plus dacarbazine, and then most recently BV plus nivolumab. And so I think we have to, it always is important to not have therapeutic nihilism, and if there is an older patient, especially if they're fit, the goal should be cure, but if you truly have an unfit or frail patient, then I think any of these regimens, whether BV dacarbazine or now BV nivolumab, is an option.
And then just one last point I'll highlight is on the ECHELON-1 study is there were older patients allowed on it, partly because there was no BEACOPP, and we know BEACOPP should never be given even baseline version to older patients. And we look back at 186 patients treated, and it was fairly similar in terms of outcomes, maybe a little bit better, non-statistically significant. In terms of PFS, we'll have to see the overall survival in that subset of patients at the upcoming ASCO meeting, but not surprisingly, it was not tolerated as well when given concurrently, BV and AVD in particular, febrile neutropenia comparing older to younger patients, 37% to 17% and grade 3 peripheral neuropathy, which remember, grade 3 peripheral neuropathy means it affects your core ADLs - bathing, dressing, eating, etc., was 18% versus 3%. So, if you are going to use ECHELON-1 and concurrent BV, AVD for older patients, really need to have a very close eye on neuropathy.
Thank you. That was a really nice comprehensive review of management of patients who are 60 years or older. Ann, I'm curious what your thoughts are with regard to which patients might be eligible for less aggressive therapy, how do you select patients who really should not be receiving combined chemotherapy?
I'll just say that I completely agree with everything that Andy has said, and I use a lot of the Evan's regimen. I think it's really nice because sometimes you have patients who don't look so great and are very symptomatic from their Hodgkin and you give them the two cycles of BV and they really perk up. And then I would try to get some anthracycline in, unless someone had significant frailty or cardiomyopathy or other comorbidity that really would preclude their getting combined chemotherapy. But I think as we've learned with elderly NHL patients where we often give our mini-CHOP, I think it is important to try to give people the benefit of the doubt because, what looks like, there was a prior study with BV-nivo which would probably be the regimen I would reach for, that didn't look so favorable.
So, as Andy pointed out, you can truncate the number of cycles of AVD if patients are PET-negative early on, then I might give four or try to give as much as possible. Sometimes you can't give those four consolidated doses of BV for neuropathy, but it is a well-tolerated regimen, and I agree I never give bleomycin over 60. I think this is a really nice regimen. And if you have someone who's younger, I have a patient right now who has lupus, bad lupus, was on significant immunosuppression, and I really felt nervous about giving her, she had stage IV disease, BV, AVD. So we've done this sequential approach and she's responded really well and tolerated it quite well.
Yeah. I completely agree with that. I have found that this regimen is really well tolerated as well and it's really the one I go to. I agree, even someone who might be younger, who you're worried about how they're going to tolerate the combination, I just want to mention the patient that I presented actually was on the clinical trial and is in remission many years out from therapy and did quite well. And so I have been very impressed by the regimen and use it regularly for patients who are over 60. One thing that we didn't really touch upon because it doesn't come out with this case is what we do for someone who has early-stage disease, who's over 60. I would say that I tend to have a little different approach because we can get away with a shorter course of chemo and we're not as worried about the long-term effects of radiation for those patients. And so, Andy, I'm curious how you approach those patients.
Alison, I think you hit the nail on the head. Is that number one? Yes. You can use similar regimens to younger patients but really think about what's bigger risk in terms of acute and later toxicity is probably the chemotherapy, and so really using radiation much more than I would in the younger patients, almost in lieu of multi-agent chemotherapy. So if someone, which is not common, happened to have favorable early stage, yeah, that would be two cycles of ABVD or maybe drop the bleomycin. Although usually two cycles you can get away with if you run into bleo trouble, it tends to be a little later, cycles 3, 4, and 5, unfavorable early stage, probably RATHL. And again, maybe never using any bleomycin, just dropping it a priori that might be 4 to 6 cycles of AVD in that patient population.
I think I'll wrap this up with some clinical takeaways. So as Andy had mentioned, we see less favorable outcomes for patients who are 60 years and older with Hodgkin lymphoma, primarily due to treatment-related toxicity, but also somewhat related to the underlying biology of their disease. There is data indicating that single-agent brentuximab or brentuximab in combination with either dacarbazine or nivolumab can be effective, but this is more reasonable for our patients who we feel like cannot tolerate multi-agent chemotherapy, where the goal of therapy might be more palliative. We are all very impressed by the data and the tolerability of sequential therapy with BV and AVD and, in particular, I just want to highlight the data from ECHELON-1 which showed that when giving these drugs in combination, we really didn't see as much of a benefit for the patients who are over 60 and that's potentially because of the added toxicity.
And so, it seems to be much better tolerated when we give these drugs sequentially starting with BV and then switching to AVD. And then finally one thing that we touched upon towards the end is that patients who have early-stage disease, we really should be considering incorporating radiation therapy for these patients, because we're not worried about the long-term effects of that.
So that brings us to the end of this case. Please see other segments for further discussion about the latest data in Hodgkin lymphoma or visit ascopost.com.