James Armitage: Hello. I’m Jim Armitage from the University of Nebraska Medical Center. I want to welcome you to The ASCO Post Video Roundtable Series featuring Appropriate Management of Challenging Cases in Myeloma and Lymphoma. Now in this installment we are going to focus on the best treatment approach for patients with relapsed and refractory Hodgkin lymphoma, and I want you to note that we did not just forget the role of CAR T-cell therapy, as is going to be discussed here; it will be in a separate installment in this series. Now, I am joined today by two of my friends and colleagues who are experts in their various fields. You will have a chance to hear both of them if you watch these different presentations, and I will let them introduce themselves.
Matthew Lunning: Hi. I am Matt Lunning, associate professor at the University of Nebraska Medical Center. I specialize in lymphoma and cellular therapy.
Sarah Holstein: Hi. I am Sarah Holstein. I am an associate professor at the University of Nebraska Medical Center, and I specialize in multiple myeloma and related plasma cell dyscrasias.
Dr. Armitage: Alright. So, at this time we’re talking about patients with relapsed or refractory Hodgkin lymphoma, and I’m going to present a case to Matt, and he is going to tell us what to do about it and then we will ask him some questions. Okay, Matt, you got a 25-year-old guy with nodular sclerosing Hodgkin lymphoma stage IIIA. He achieved a complete remission when treated with ABVD both on the PET-2 and then post-treatment PET and was well. But when he came in to see you a year after the last treatment, you felt a node in his neck and did a PET scan, which showed that no node was bigger than 2 cm, but they were present both above and below the diaphragm. The SUV maximum was 8. The lymph node biopsy just showed recurrent lymphoma. What do you tell him?
Dr. Lunning: I think that’s a difficult situation because of the relapse rate at a year. You know, I have been really thinking about how to employ brentuximab vedotin in the new era, if you will, in the management of Hodgkin’s lymphoma because of the ability to now potentially use it I think in second line as a bridge to transplant and then, based on upon the AETHERA data, use it in transplant maintenance fashion. There have been several clinical trials that have used both brentuximab vedotin followed by combination chemotherapy, as well as brentuximab vedotin in combination with chemotherapy, namely bendamustine.
So in this case, I choose to look at the eligibility part of AETHERA study, which was the maintenance study of brentuximab vedotin following autologous stem cell transplant. So those patients received second-line therapy, were chemo sensitive, had a transplant, and then were randomized to receive brentuximab vedotin as a maintenance therapy or active surveillance looking for recurrence. Now the unique thing about that study was that they had to have certain characteristics in order to be eligible. This was not all comers who were relapsed Hodgkin’s lymphoma. It included some patients who were primary refractory. So as you alluded to, the patient had a PET-2, which was negative, and we didn’t calculate the IPS score, but they were advanced stage, but still, regardless of the IPS score, I think what we know is that PET-2 is pretty predictive for those patients who are going to likely have a good outcome. This patient did not have a good outcome to the first-line therapy because they recurred and the PET-2 is negative. So in my mind using that history, had the patient been PET-2 positive, now, okay, this may be a little more straightforward, but this patient with PET-2 negative, continued to get ABVD, which I think is a reasonable standard therapy, in the pre-ECHELON as more of a discussion in the ECHELON-1 data, but that is not a discussion for today, but had a PET-6, it was in CR. Now they have this kind of recurrence within one year so. I often will ask them, “so did you feel this lymph node?” Because I don’t see them every day, so if they had felt this lymph node three months earlier and felt that it was just coming and going and they were going to bring it to my attention, what’s the pace of this lymph node growing, but at that one year cutoff was another relative criteria to being in the AETHERA study, and then also extranodal sites of disease. I didn’t hear that he had any extranodal sites of disease. I would probably, with the intent in a 25 year old, do a bone marrow biopsy just to confirm that there was no extranodal disease involvement from that standpoint. Being that it was right around a year and the caveat still all of the history you gave as part of initial therapy, I would actually try and get the best second-line therapy that I think is out there, and I think that that does include brentuximab vedotin potentially in the second line.
Now how do you give it? We participated in the brentuximab vedotin/bendamustine clinical trial, as well as many other sites, and I think that that’s a regimen that you could employ in this situation. I don’t think it would be wrong to give ICE and have the discussion about brentuximab vedotin maintenance or discuss both and say, “look, there’s probably not going to be a survival advantage but there is a PFS advantage and we can use the brentuximab vedotin if you recur again.” However, given this history, I think that we’re putting a lot of eggs into this basket if we’re trying to go towards transplant. I have used brentuximab vedotin/bendamustine on and off clinical trials. I typically would give it for two cycles. Now there is a caveat around that: there was some infusion-related reactions seen in the clinical trials, and I think in practice where you’re combining the two, it seems like separately they do not do this, but together you have to add steroids to reduce the risk of not only the prevalence or the incidence of this occurring but also the severity. And interestingly, it seems to happen with cycle 2, not necessarily cycle 1, from that standpoint.
So we’d give two cycles and then repeat a PET scan, and I think that if that patient is in a CR, then proceeding towards transplant with the intent to give brentuximab vedotin single-agent maintenance after transplant is a reasonable approach. Now the way the study was was to give the number of cycles that led you to transplant plus whatever that number would be to get to 16. Now that’s assuming that they don’t have other adverse events along the way. For patients that are in a partial remission—that’s based upon the PET-CT criteria—and I think I’d have a discussion with them and you have to learn what their history is and know that you still have -- what the size of the lymph nodes went down to, what the SUV, the delta or the change in the SUV was. I don’t think all PRs are created equal in the Deauville scheme. And using their history, this may be the opportunity to take them to transplant. I don’t know when you are using brentuximab vedotin this early, that the days of applying using G and D as a third line to get them into the CR still apply; that’s data that we need to sort out. So in this situation, I’d be talking to them about second-line therapy going towards the transplant with maintenance brentuximab vedotin.
Dr. Armitage: And when you say transplant, you mean essentially always an autotransplant?
Dr. Lunning: Yeah, so I’m not comfortable right now in the second-line setting introducing allotransplant, even in the era of primary refractory Hodgkin’s lymphoma when you have checkpoint inhibitors, whether it’s nivolumab or pembrolizumab, from that standpoint if you have the caveats of what those drugs would do if this came back again, maybe even talk about moving those drugs up first line or second line, which I think is still in the trial arena. But taking a Hodgkin’s patient to an allotransplant is a big discussion because there is data, but I don’t know that you always had the intent-to-transplant data in Hodgkin’s lymphoma because there are certainly patients that we would want to take to an allotransplant that can’t get to an allotransplant mainly because of disease response or insurance. This is a population of patients that don’t always have private insurance that allows them to go towards an allotransplant, and depending upon the region of the country that you are in, that can be a barrier to an allotransplant.
Dr. Armitage: Two quick things: is a PET-negative CR ever good enough that you would not transplant somebody in this situation? And secondly, do you incorporate radiotherapy sometimes, always, never into this situation?
Dr. Lunning: So, I haven’t been in the situation where I have had an individual that has been on a PET CR after second-line therapy that has not went on to high-dose therapy and autologous stem cell rescue. Can I imagine the situation of a borderline six-decade type of an individual that then gets bendamustine and rituximab just to say a regimen because I was concerned about them getting ICE and you know they did well through that regimen and they said no to me for transplant? I think that that would be a situation where then I would probably try and complete the series because not everybody in that study went on to transplant, and they completed I believe six further cycles of bendamustine and BV and then subsequent brentuximab vedotin maintenance. The curves in the article on those patients actually looked pretty decent, so I think it’s a discussion for a clinical trial if we’re going to go down that road, but I still think the curative intent portion of that likely still in my opinion includes the transplant. On the radiation side of things, I really am looking for sites of bulk, so how you determine that, what size, but I think the location is also important for post-transplant radiation. If it’s in the inguinal region or in the axilla, I’m going to be more inclined to discuss with the radiotherapist and the patient about post-transplant radiation and the timing of such, especially if you’re getting into the brentuximab vedotin maintenance discussion because I do not know there is a significant amount of literature and experience on that, and also depends upon if they have had radiation before as part of their primary line of therapy.
Dr. Armitage: Well, when you say bulk, if they had a 10-cm mass, you’d be more likely to do it than in this person with a small mass. And what about if the Deauville score is right at the liver in one spot and not the others? Do you radiate that?
Dr. Lunning: Yeah, so more times than not when I have either a close Deauville 3 or 4, I’m dialing the nuclear medicine number and discussing or even going down there and really looking at, because I think you have to look at where they were before at the last PET to where they’ve gone, because this is a continuum, and if you did a PET a month from now, would it have helped? Would it have changed? We’ll, you don’t always have the luxury of that short-interval PET to help guide you. If I am concerned based upon the SUV going down but the size staying the same and it’s in a reasonable area, I may choose to radiate that solitary site.
Dr. Armitage: But the goal, if I heard you correctly, is that every time, every patient you see in this setting, your intention is to try to cure them?
Dr. Lunning: I tell them that and I document that, that the intent is to cure, to take this away and never have this come back. Understanding that “never” is a word that we often cautiously use in oncology.
Dr. Armitage: It is a dangerous word for us.
Dr. Lunning: Yes.
Dr. Armitage: I certainly enjoyed this, and I hope you all watching us today did too. Stay tuned for more installments of The ASCO Post Video Roundtable Series. I will be talking about a couple of types of lymphoma and another problem with myeloma in upcoming presentations. Thank you.