Dr. Alison Moskowitz:
Welcome to the ASCO Post Roundtable Series on updates in lymphoma. I'm Dr. Alison Moskowitz associate attending from the lymphoma service at Memorial Sloan Kettering Cancer Center. Joining me are two of my colleagues who will introduce themselves.
Dr. Ann LaCasce:
Hi, good morning. I'm Dr. Ann LaCasce from Dana-Farber Cancer Institute. I'm an associate professor of medicine.
Dr. Andy Evens:
Hi, 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 second installment will focus on bulky early-stage Hodgkin lymphoma. I'm going to present a case. This is a 23 year old woman who presents with significant neck swelling, fever, shortness of breath, and cough. Because of these symptoms, she was admitted for expedited workup. She had a CAT scan that showed enlarged cervical and mediastinal lymphadenopathy, including deviation of her trachea and compression of her SVC. A left cervical lymph node core biopsy was performed and showed classical Hodgkin lymphoma. Her PET showed bilateral cervical and mediastinal lymphadenopathy with the mass measuring over 13 centimeters. She also had a pleural effusion that felt to be likely due to compression from the mass. I'd like to start with Anne to talk to us about this case, because I know when I'm thinking about bulky Hodgkin lymphoma, I'm really looking at the data that she recently presented. And so I'd love to hear her thoughts about this particular case.
Dr. LaCasce:
Thanks Alison. So, I think with bulky disease, particularly in a patient this young, we would love to omit the radiotherapy because we're really thinking about late complications, including risk of breast cancer in a woman under 30 and cardiovascular disease. We had a hint from the RATHL study; there were some patients with bulky stage II disease there who did not receive radiotherapy, almost 120 patients, and the outcome of those patients was quite favorable with the PFS of about 91%. So our Alliance study, which took a long time to accrue because it's a relatively rare patient population, started with two cycles of ABVD, and then was response-adapted using a PET Deauville 1-3, then got four additional cycles of ABVD without radiotherapy, and those who were PET-positive were escalated to BEACOPP for four cycles and then got radiation. This used the sort of standard definition of bulky disease—greater than 10 centimeters or one-third of the maximum intrathoracic diameter.
We found that patients actually did very similarly, very well. So the PET-2 negative patients, which was about 80% of patients, had a 93% PFS at 3 years. Interestingly, the patients who were PET-positive actually did quite well with four cycles of BEACOPP and radiation. We had done a similar study in the Alliance (David Straus') study where patients who were non-bulky got two cycles of escalated BEACOPP and radiotherapy and the PET-positive patients in that group didn't do as well. That was like 67%. So I think the additional cycles of chemotherapy, both in the PET-positive and the PET-negative arm here make a big difference. I think this is a very appealing approach to try to avoid radiotherapy in as many patients as we can. We don't use a lot of escalated BEACOPP in this country.
So, I think the question then becomes, what do we do with the patients who are PET-2 positive? I suspect most practitioners are probably not escalating to BEACOPP, given, not a lot of familiarity with the regimen. I think in that setting, if you do an additional two cycles and then repeat a PET scan, this is a group of patients I would absolutely incorporate radiotherapy because I think it's absolutely necessary, and we want to try to get them in long term remission with their upfront therapy. I think if they're continuing to respond, I would probably give the radiation and not escalate them, but the data looks good, so I think you can certainly say it would be reasonable to give four cycles of escalated BEACOPP. There's interesting data from Anita Kumar at MSK, where she incorporated brentuximab plus AVD in unfavorable patients. There were a fair number of bulky patients, both using a cutoff of 7 centimeters, which reflected some work she had done, where that seemed to be a cutoff using craniocaudal and transverse, and in that study patients who were PET2- and PET4-negative after BVAVD were treated in four cohorts with reducing doses of radiotherapy, and the last cohort did not get radiation. The outcome for those patients are very similar to this data. Those who did not get radiotherapy did as well as those who did. I think this is sort of where we're moving. The next study that I think is going to be really exciting is led by COG. It'll be a US inter-group study in combination with COG, starting with ABVD, and then randomizing patients who are PET-negative to continue with ABVD four cycles if they're unfavorable, two cycles if they're favorable, and then the control arm will be BV-nivo. In the PET-positive, they'll be randomized to BEACOPP plus radiation versus BV-nivo plus radiation. I think that will be a very large randomized study. It will include a lot of really important endpoints, including quality of life, 12-year overall survival, looking at quantitative PET imaging to see if we can really predict who needs these more intensive regimens as well as cell-free DNA. I think that's sort of where we're headed, but I think we now, between the RATHL study and this data and some data from Europe also, that we really don't need radiation in patients who are PET-2 negative, even with bulky disease.
Dr. Moskowitz:
Yeah. I think that's really helpful and Andy, do you do anything different with how you approach these patients or are you generally in agreement with Ann?
Dr. Evens:
No, I agree with everything Ann said, the Alliance 50801 data just really reinforces a lot of their previous data in a good way, with little bit of differences, whether you look at EORTC H10 data, the RATHL data, some of the data Gallamini has published, showing that a couple things that yes, using early PET to pick out the patients who would need intensification on one stretch. Then of course, critically, as Ann nicely alluded to- finding those patients, lower risk, who do not need radiation in consolidation, which we had done historically for these patients, really everybody... Where most patients had received consolidative radiotherapy, if you had bulk disease. I think this is a nice breakthrough, really for 80% or so of patients. It looks like we're able to avoid radiation.
I think of course one important component is the Deauville scoring. All of us have weekly lymphoma tumor boards and we're able to sit there and sift through every PET scan. I think sometimes that's harder in the community, but it's just so important to really, especially in these bulky disease patients who can really have some borderline, to really between that 3 or 4, to really sit down and go through that data. It's really important data. As Ann also nicely depicted, what's the next step and how do we incorporate novel therapeutic agents to not only continue to mitigate the risk of radiation, but also at the same time, to lower the amount of chemotherapy which we know can cause late effects, not just cardiac late effects, but many others. So, continuing towards novel therapeutics and less reliance on radiation and chemotherapy.
Dr. Moskowitz:
Ann, I'm wondering if it's okay if I put you on the spot, because I'm curious-with regard to the Alliance 50801 study, I am really impressed by how well the PET2-positive patients did by getting four cycles of the BEACOPP and radiation, but I'm regularly asked by the other physicians... The patient's had an excellent response, but they're PET2-positive, clearly a Deauville 4 response, maybe not one that's necessarily in the middle, but a clear Deauville 4 response, but a clear reduction in the size of the mass, and improvement in symptoms. Is it your practice to escalate a patient like that, to escalate BEACOPP, or do you tend to consider doing another two cycles of ABVD and rechecking?
Dr. LaCasce:
In all honesty, I tend to do another two cycles of ABVD. I don't tend to do fertility preservation up front in these patients. I think in someone who's primary refractory, I will often pause there to do fertility preservation, but here you've got to keep going, and it would really require thinking about that upfront, which may not be an issue in every patient, only in women of who desire that, but I tend to do two more ABVD and get another PET scan, and if they're continuing to respond, I may do six and radiation or... I really think by adding the radiation and hoping for the best, knowing that they may be more likely to relapse. Some of those patients aren't going to relapse and then we avoid having to do transplant.
I think that was before we actually had all this data back and I haven't had a patient who's been PET2-positive, and would I do it in the right situation? I think I probably would, but I think in the US, we're just a little more reticent to use this regimen just because we don't tend to use it, not because it's not a very good regimen.
Dr. Evens:
Allison, to your point, I think it's another way to say it. There's Deauville, 4, and then there's, Deauville, 4. That's maybe some of the issues with that. If you have a patient who, let's say the normal liver, even though it's a visual inspection, but let's use SUVs. The liver, let's say is 2.9 and a patient had very metabolic, over 30 and it's come down to 3.1 or 3.2, really close, versus that patient who still has one or two lesions, and that SUV is still 20 or 18. First you want to make sure they're not primary refractory, but that might be a patient that I would escalate to BEACOPP, as Ann said.
Another important point that Ann made, that I think really is a difference, is at least in this patient population, is the number of cycles of chemotherapy. We saw that come across in the EORTC H10 study where they receive six cycles. It seems to be, that probably is a difference, at least before we start to incorporate novel therapeutic agents. So in other words, if you're going to escalate or not, four cycles is probably not enough. You need six cycles probably across the board in unfavorable, early stage Hodgkin's lymphoma.
Dr. Moskowitz:
Just to clarify, just as, as long as we're not planning on consolidating with radiation therapy, is that correct?
Dr. Evens:
That's correct. Yes. That's part of the decision-making where if you're thinking of that consolidation where maybe you don't need it for PET2-negative. For PET2-positive, real PET2-positive, you're probably going to need to consolidate afterwards as well with radiation.
Dr. Moskowitz:
Yeah. I agree. I think, I'll tie this up, and just discuss some key takeaways from this case as Ann and Andy discussed, we define bulky disease as 10 centimeters, but as Ann mentioned, there's data indicating that maybe even 7 centimeters may be reasonable to define as bulk. Actually in my practice, I tend to use 7 centimeters as bulk and to define as bulk. In the past, we generally would've treated these patients with combined modality therapy, but we've really moved away from using radiation therapy, and we now have very nice data from the Alliance study that Ann led and also from Dr. Gallamini’s study, showing that we can get away with six cycles of ABVD and no radiation therapy, provided the patient has a negative PET response after two and six cycles of treatment.
Since we're treating these patients with six cycles of ABVD, typically we would treat these patients as per the RATHL study, where we drop the bleomycin after two cycles of ABVD.
This 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.
