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Moderated by: Stephen Ansell, MD, PhD1
Discussants: Craig Moskowitz, MD2; Catherine Diefenbach, MD3; Andrew M. Evens, DO, MSc4
From Mayo Clinic, Rochester, MN1; Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY2; NYU School of Medicine and NYU Perlmutter Cancer Center, New York, NY3; Tufts University School of Medicine and Tufts Medical Center, Boston, MA4
Address for correspondence: Stephen Ansell, MD, PhD, Mayo Clinic, 200 First Street SW #W10, Rochester, MN 55905
E-mail: ansell.stephen@mayo.edu
Biographical sketch:
From Weill Medical College of Cornell University:
Dr. Moskowitz serves as principal investigator and co-investigator for a number of clinical trials aimed at improving the care of patients with lymphoma. His research has focused on improving the outcome of patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). This effort has been conducted along two tracks. One effort is focused on improving therapy for patients with disease that has returned or is not responding to standard therapy (refractory disease), through the use of high-dose therapy and autologous stem cell transplantation as well as new agents that can be incorporated into such "salvage" therapy. The second is aimed at developing risk-adapted strategies to optimize the treatment of newly diagnosed DLBCL by using what we have learned in the relapsed and refractory setting.
Dr. Moskowitz has been recognized for his research on a national level through multiple awards. He has lectured worldwide on lymphoma and stem cell transplantation. In addition, he is a member of the research council at MSKCC, and on the steering committees for the bi-annual international lymphoma conference in Lugano and international Hodgkin lymphoma conference in Cologne.
From NYU School of Medicine and NYU Perlmutter Cancer Center:
An alumna of the University of Pennsylvania School of Medicine, Dr. Diefenbach completed her internship and residency at the Johns Hopkins Hospital and her oncology fellowship at Memorial Sloan-Kettering Cancer Center, where she spent an additional year focusing on translational immunology.
Her scientific research focuses on the relationship between lymphoma and immunity; on developing novel and immune based treatment strategies for patients with relapsed lymphoma; and on biomarker discovery. She is currently leading a national clinical trial for relapsed Hodgkin lymphoma investigating the combination of the antibody drug conjugate brentuximab with the immune activating agents ipilimumab and nivolumab.
Dr. Diefenbach directs the lymphoma clinical research within the Hematology/ Oncology Division at the Perlmutter Cancer Center. She is a member of the ECOG Lymphoma Committee, the NCI Lymphoma Steering Committee Clinical Trials Planning Meeting, and the Editorial Board of Clinical Cancer Research. Her research is supported by the Lymphoma Research Foundation, the American Cancer Society and the National Cancer Institute (NCI).
From Tufts University School of Medicine and Tufts Medical Center:
DR. ANSELL: My name is Stephen Ansell, from Mayo Clinic, Rochester, Minnesota. I’m joined by Drs. Craig Moskowitz, Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Medical College of Cornell University, Catherine Diefenbach, Assistant Professor of Medicine at the NYU School of Medicine and the NYU Perlmutter Cancer Center, and Andy Evens, Professor of Medicine at Tufts University School of Medicine, and Faculty Member at Tufts Medical Center in Boston.
Welcome to all of you and thank you for participating in this medical roundtable discussion. The focus today is going to be on practical management of Hodgkin lymphoma. This is a very experienced group of roundtable participants whom I hope will give us valuable insights into some of the questions relating to managing Hodgkin lymphoma.
Let’s talk about patients with early stage Hodgkin lymphoma and discuss what we feel the standard management might be and how we would use positron emission tomographic (PET) scans to direct therapy. Craig, I’m going to ask you to start. Please discuss what your standard management of early stage Hodgkin lymphoma is and how you use PET scans to direct your treatment.
DR. MOSKOWITZ: I divide Hodgkin lymphoma, early stage, into three groups; favorable early stage, unfavorable early stage without tumor bulk, and stage two disease with tumor bulk. The standard management is well borne out these days from the German Hodgkin Lymphoma Study Group.1,2 For early stage favorable Hodgkin lymphoma I treat men and women quite differently.
For men with stage IA or IIA, non-bulky disease, I tend to use standard treatment, which is short course combined modality therapy with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and involved-field radiation. I do not use PET imaging in that setting. For women, however, as you know, the median age is young in this patient population. I’ve adopted a RAPID approach for these folks. I give 3 months of chemotherapy and then repeat the PET scan and if the PET scan is negative I stop treatment. If the PET scan is positive, I treat the patient as per that study, which was one more cycle of chemotherapy and radiation. But unfavorable early-stage disease without tumor bulk, once again, the issue is, should patients get chemotherapy alone or should they get combined modality therapy?
If I’m giving combined modality therapy, I do not use PET imaging. If I’m using chemotherapy alone and if this is a patient eligible for a RAPID approach I treat as above. If the patient was not eligible for RAPID because they had stage IIB disease, I usually give full course chemotherapy and I do not use PET imaging.
For patients with bulky stage II disease, I treat based upon the randomized cooperative group study, which is four to six cycles of chemotherapy followed by radiation. I do not use PET imaging in that setting.
DR. ANSELL: Craig, thanks. Andy, do you actually escalate therapy at any time based on PET results, or deescalate therapy? We heard from Craig that he follows some of the RAPID guidelines. Give us your perspective.
DR. EVENS: I think they’re all good questions. In a way, it’s not one size fits all. I think it has to be a very individualized patient-by-patient treatment decision. In other words, I might approach a 19-year-old woman with a bulky mediastinal mass differently than a 45-year-old man with a right cervical lymph node. This is one important point to convey. In terms of PET-adapted, I think it is evolving. The question is, is there any actionable evidence to go on?
In terms of where there are more data, which is in early negativity in terms of PET-2 negativity, there have been a couple publications alluded to—RAPID and the European Organisation for Research and Treatment of Cancer (EORTC)3—and I’m not sure those data changed the opinion if we didn’t have an early negative PET scan. We know, without an early negative PET scan, that patients who do not receive consolidative radiation have a small improvement in progression-free survival (PFS) and no difference in overall survival (OS).
What both of those studies showed is that basically persists. That margin of difference might be a little less—instead of 6%–8% difference in PFS, it might now be 4%–6%, but both studies proved to be not noninferior, so I’m not quite sure that has changed how I treat someone. In other words, an early negative PET scan. For PET positivity, the data are really evolving. I think, before the Lugano meeting this past June I would have said no.
I just saw a very recent second opinion on a younger patient in her mid-20s who had a bulky mediastinal mass, and then after two cycles was definitely better, but still PET positive, defined as it was a smidge greater than the liver, and the data that emanated from Lugano on early PET positive showed not only a PFS advantage, but a borderline OS, and that, of course, would be a game changer if PET-adapted therapy is pointing toward an OS advantage.
DR. ANSELL: Catherine, what’s your sense of the role of radiation therapy in early stage Hodgkin lymphoma?
DR. DIEFENBACH: As Andy said, the role of PET to stratify early stage patients is evolving. Another study that was reported in Lugano was the Response-adjusted Therapy for Hodgkin Lymphoma (RATHL) study4 where it appeared that for patients who had an early PET negative, the bleomycin could be omitted and the patients ended up with a PFS that was equivalent to patients who did not have bleomycin omitted. The decision of combined modality therapy vs standard therapy—I think Andy and Craig put it really well—will have to be individualized to the patient’s situation: specifically, to their age, sex, bulk of disease, and response after early disease assessment.
DR. MOSKOWITZ: That’s why it’s so hard to study this patient population. You have three folks on the phone and we’re all treating patients differently with an individualized approach. It’s almost impossible to come up with a clinical trial that everybody would be comfortable with in this patient population, which is why we have difficulty in writing one, which is disappointing.
DR. ANSELL: Craig, I wanted to circle back to you. The German Hodgkin Lymphoma Study Group has shown that if you omit bleomycin there is a slight decrease in outcome;5 however, the RATHL trial would suggest maybe not.6 Has that impacted your practice at all? Do you omit bleomycin in your regimens or do you use it standardly?
DR. MOSKOWITZ: Well, RATHL is for advanced stage disease and I’ve already stopped giving bleomycin to patients who are PET negative after 2 months of ABVD based on that approach; but I do not omit bleomycin for an early stage disease based upon the results from the German Hodgkin Lymphoma Study Group. We’re not giving full course chemotherapy in the early stage setting, so I’m willing to give the appropriate number of cycles, at least for now.
DR. ANSELL: Thanks for your perspectives. I think as it was pointed out, there’s a lot of individualization here and we still have an evolving role of PET scanning. Also, there are multiple new agents we’ll begin to talk about later in the program that may impact things further. So, I think this remains an area where it’s quite challenging to determine the optimal approach.
I want to turn our attention to talk about patients with advanced stage disease—predominantly stage III and IV disease. Catherine, how do you treat patients with advanced stage disease? What’s your approach, and as new agents are coming along, agents like brentuximab vedotin, where do you think they fit into your approach?
DR. DIEFENBACH: Just as Craig said, there isn’t really a one-size-fits-all approach to advanced-stage patients either. Just as early-stage patients are divided into at least three groups, we look at advanced-stage patients as a very heterogeneous population. One of the ways we stratify advanced-stage patients is based on what we call their risk score.
Traditionally, we’ve used the Hasenclever risk score—or the International Prognostic Score (IPS)7—which looks at seven clinical factors to get a sense of how these advanced-stage patients are going to do in terms of their PFS and OS.7 More recently, we have a manuscript where we’re looking in the modern era at using a streamlined score with only three of these factors instead of seven factors8 and the group from British Columbia has showed that, while this Hasenclever risk score is still relevant,9 it looks in the modern era with modern chemotherapy that it may be less helpful than it previously was, because the patients who did much worse are doing better, so the curves are narrowed.
Nonetheless, biologically and clinically, there’s a big difference between advanced-stage patients who have zero to two risk factors and advanced-stage patients who have five, six, or seven risk factors. The standard of care for treatment for advanced-stage patients both in the US and internationally has been either the chemotherapy regimen of ABVD or the chemotherapy regimen of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).10,11 There has been a controversy between those who prefer escalated BEACOPP and those who prefer ABVD. Escalated BEACOPP has a superior PFS to ABVD, which didn’t necessarily translate into an OS benefit, and patients who fail ABVD may be salvaged with stem cell transplant and second line chemotherapy and stem cell transplant.
Patients with escalated BEACOPP also have substantial therapy-related toxicity that patients with ABVD do not have, such as infertility and myelosuppression, higher rates of neutropenic fever, and higher rates of secondary leukemia, so there’s a cost associated with being treated with escalated BEACOPP that’s not associated with ABVD. With both regimens, the cure rate is approximately 75%–80%, so those who favor ABVD—I would consider myself one of them—would argue that you spare a certain number of patients who are salvaged with ABVD and who are cured unnecessary toxicity with the escalated BEACOPP. Those who are in favor of escalated BEACOPP for all patients would probably argue that an increased PFS should translate into an increased OS, and there have in fact been meta-analyses that show improved OS in some older trials with BEACOPP compared to ABVD, but this is a meta-analysis across many different trials.
More recently, brentuximab vedotin—an antibody drug conjugate, against CD30, which is expressed on the Hodgkin Reed-Sternberg (HRS) cell—combined with auristatin—a taxane-like cytotoxic chemotherapy—which acts like a Trojan horse, is delivered to the HRS cell, taken up by the HRS cell and then blows up the HRS cell while sparing, to a large extent, the microenvironment, has been incorporated into upfront therapy with ABVD.
Brentuximab was approved by the Food and Drug Administration (FDA) to treat relapsed Hodgkin lymphoma based on the pivotal study, which had an overall response rate of approximately 75% for relapsed patients.12 Based on this it was incorporated into upfront therapy. There was a phase I study which I think, Steve, you actually led, which combined ABVD with brentuximab vedotin.13 This, however, resulted in excessive pulmonary toxicity secondary to bleomycin, so bleomycin was then omitted. The data were reported at the American Society of Hematology (ASH) meeting and showed a 3-year failure free survival of 96% and OS of 100%, which is extremely impressive in this population. The Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma (ECHELON) [NCT01712490] is currently underway and should complete accrual this year.
I think that these data will certainly help to answer the question of whether incorporating brentuximab into the upfront regimen of ABVD can improve both PFS and OS for these patients and perhaps put BEACOPP, finally, to rest.
DR. ANSELL: Andy, do you have a place in your practice where you think escalated BEACOPP has a role?
DR. EVENS: The quick answer is yes, but that sliver of practice is extremely small, and as time is going on, it’s getting smaller. I think in the pre-response adapted era—5 to 10 years ago when BEACOPP was first published—it did show an OS advantage, but many people would argue the comparator or COPP/ABVD arm isn’t equivalent, so to speak, to contemporary ABVD.
I was using it mainly in patients with high IPS—patients who had a five, six, or seven. That, frankly, is not a large percent of the patient population. Now, in the PET-adapted, we don’t quite have that actionable evidence, as much has accumulated quite yet, as early stage disease. Even in the patients now with high IPS, I have to admit, I’m really starting with ABVD in everyone and only considering escalating in patients who have a positive PET scan, which I guess in my practice is somewhat lower than the clinical trial data.
The clinical trial data in advanced-stage disease would say that’s 15%–20% of the patients.14 I tend to find it’s closer in the 5% range. I think part of that is viewing the PET-adapted part we keep talking about—it can’t be viewed in a vacuum, meaning you shouldn’t review a report. You should sit side-by-side with your radiologist and try to review that scan, and while doing that, have a clear meaning of what defines PET positive and PET negative, because almost every study we talked about has it slightly different. Where’s the cut point? Is it at the liver—meaning a Deauville score of four or five—or is it less in the liver, etc? So, I think those types of things are very important to understand and appreciate when treating the patients.
DR. DIEFENBACH: Andy, I completely agree with you and I also would have a role for BEACOPP in a patient who was not responding to ABVD with interim scans. I also, at that time, if the patient was by PET/computed tomography unequivocally refractory, I would consider clinical trial probably in the same vein as the escalated BEACOPP. So, I agree with Andy that I have a sliver of patients for whom I do consider escalated BEACOPP, but that is a very small sliver.
DR. ANSELL: Craig, what’s your comment about modifications that are happening, even to escalated BEACOPP? The BrECADD regimen is incorporating new agents like brentuximab vedotin.15 What’s your thinking about that regimen?
DR. MOSKOWITZ: I don’t treat patients off protocol with protocol based treatment, so my familiarity with it is low. Just to digress for one second, I think that I have definitely changed my practice and I would say that I used to give BEACOPP quite a bit for patients with four to seven risk factors, which is about 20% of the patient population. I think, based upon two fairly large studies that will have about 1700 patients on, the RATHL study and the intergroup study in the United States—it’s fairly clear—to me at least—that one can start with ABVD chemotherapy.
Since 80% of the patients have a negative interim PET scan, despite the number of pre-treatment risk factors they have, you’re really limiting the number of patients who get crossed over to a more complicated program, so I’ve been using that approach. I’m very comfortable with it.
The issue of giving brentuximab vedotin with AVD as part of primary therapy is, once again, investigational, and I have many concerns about the cost of that treatment program and it’s applicability worldwide even if the study is positive.
DR. ANSELL: I think that’s a good point. One of the things I find very interesting as we talk about the escalated BEACOPP vs. ABVD comparison is that as brentuximab vedotin has been mixed into those two regimens, it’s almost as if those two regimens are coming toward each other. ABVD is being somewhat escalated in intensity and escalated BEACOPP being modified down. I think at the end of the day, we’re going to come to a combined approach that suits people on both sides of the intensity debate. Cost, however, is going to be an issue to make this an internationally usable regimen, so I think that’s a real challenge.
I want to pick up, Craig, on the point you made about risks of relapse and so on. When and if patients relapse, what do you use in your practice as the optimal salvage regimen? Also, I know you’re a big advocate for your patients to attain a complete remission before going to transplant, would you like to explain why?
DR. MOSKOWITZ: Once again my opinion about this has evolved over the years, but I think that I’m fairly comfortable right now that almost all these salvage regimens are quite similar. They have variable toxicity profiles, but if the treatment is given correctly and you look at the published literature, somewhere between 60% and 80% of the patients will likely be in remission after salvage chemotherapy. As defined as a negative PET, based upon standard criteria, those patients have a marked survival advantage, looking at published literature thus far.
As I’m maturing, I’ve been trying to treat patients with less aggressive salvage therapy to try to get them into remission. For example, in patients with early stage disease who relapse with non-bulky and non-widespread disease, I’d be more inclined to give an outpatient chemotherapy regimen. Patients with widespread, extranodal involvement, I’d be more inclined to give inpatient treatment off study. On clinical trials, that’s a different story, but we’ve published now, multiple times, that overwhelmingly a complete response (CR) prior to a stem cell transplant abrogates almost all the other prognostic factors.
DR. ANSELL: Right. Andy, if a patient had a response, but not a CR, or maybe only a modest improvement, would you say that’s a deal breaker for moving onto something like an autologous transplant?
DR. EVENS: I would say for the majority of patients, yes. There might be that patient who, depending on what they’ve received in the past—particularly if they have already received brentuximab vedotin—might be someone we still take to an autologous transplant.
There’s a significant minority you can still cure who are chemo-resistant, but I think I completely agree with Craig. In the era of novel therapeutics, that’s becoming less and less. As more options come on the table, I think if you really have somebody who’s chemotherapy resistant—that can be defined, I guess, as a positive PET, although I do think there are some gray zones in defining positive PET—I think it would be someone I would really look toward a novel therapeutic.
DR. ANSELL: Catherine, there have been some recent data about maintenance therapy after an autologous stem cell transplant. What’s your take on that?
DR. DIEFENBACH: I think the most recent data on maintenance therapy post autologous stem cell transplant comes from the AETHERA study,16 which Craig was the lead author on, and this investigated the question of whether using brentuximab vedotin as a consolidative therapy after transplant—as a maintenance therapy—improved PFS in this patient population.
The patients in this study who had relapsed disease were randomized between receiving brentuximab vedotin or being observed. Patients were treated for 16 cycles, which is approximately one year with this therapy, given every 3 weeks. Data from this study were in favor of brentuximab vedotin. The group that received brentuximab vedotin as opposed to being observed had a PFS of 42.9 months vs a PFS of approximately 24 months in the group that wasn’t treated with brentuximab vedotin.
This says a few interesting things. This demonstrates that most patients who are going into transplant are not doing so with optimal disease control. If all patients were going into transplant in a CR with only micrometastatic disease, there would not be such a stark difference between these arms. I think this study very nicely demonstrates that patients who benefit most strongly from the maintenance therapy are the patients who are considered to be the highest risk.
These are the patients with refractory disease who go into transplant with a high degree of tumor bulk, or patients who relapse within a short time—less than 12 months after their initial therapy—suggesting they didn’t really obtain optimal disease control with their therapy, or they had extranodal disease or disease outside of the lymph nodes affecting vital organs or bone marrow. These high-risk patients, based on these criteria, appear to be the ones who benefit the most from brentuximab maintenance. I think it gets a little tricky, however, because none of these patients receive brentuximab in their upfront therapy. So, going forward, it’s going to be an even harder question to ask—how are high-risk patients who receive brentuximab initially going to benefit from receiving a therapy that they relapsed from after receiving?
Getting brentuximab was not a free ride. There was a significantly higher amount of both sensory neuropathy, and about 20% of patients had motor neuropathy in the brentuximab group vs the non-brentuximab treated patients.
Finally, there was no difference yet—and this will still mature—in OS between the groups because the patients who didn’t get brentuximab were able to cross over and get it. This goes back to the old question with rituximab when rituximab maintenance was looked at. Is it better to receive brentuximab vedotin maintenance after transplant or is it better to receive it if you relapse after transplant? I think we won’t know the answer to that question for a few more years when we really see if the PFS translates into durable survival in the brentuximab treated group vs the non-brentuximab treated group. As Craig has alluded to with regard to the cost with respect to upfront therapy, I think this adds substantial costs subsequent to stem cell transplant. If we are going to use this therapy, I think we’ll have to be very clever in how we risk assess the patients who proceed to transplant, both prior to transplant and in terms of deciding whether they receive therapy.
There are actually efforts underway right now—internationally—to use better risk discrimination criteria for relapsed Hodgkin lymphoma to define a higher population of patients who are truly high risk, you might have the highest likelihood of benefiting from this sort of consolidative strategy.
DR. ANSELL: Craig, please comment. Catherine mentioned that the addition of brentuximab wasn’t without financial cost, and that there is also a toxicity cost. You led the study, what are your comments on the side effects of a year’s worth of brentuximab vedotin?
DR. MOSKOWITZ: I think, shockingly, the median number of doses that patients received on the study was 15, so almost a year or full course. In general, neuropathy is similar to every other single study that’s been looked at with single agent brentuximab. Peripheral neuropathy is real. For me, if a patient gets a dose reduction and the neuropathy does not improve, I would just stop the treatment. That’s how I practice.
I think the question Catherine raises is an extremely good one about patients who had a brentuximab vedotin pretransplant. Should they get brentuximab vedotin post-transplant? That’s something that’s clearly going to evolve, and the number of doses that a patient will receive post-transplant is going to evolve, but I think for the audience listening, this is here to stay for the next couple of years.
The FDA approved this August 17, so transplant physicians are going to initiate brentuximab vedotin therapy prior to the patient returning to their medical oncologist. It’s the medical oncologist who’s going to decide how many more cycles of brentuximab should be administered, because these folks would already have received three cycles by then.
Transplant physicians have to report 90-day efficacy data. In general, therefore, transplanters will see the patients up to around day 90. Brentuximab is administered between days 30 and 45 post-transplant, so by definition, the Hodgkin lymphoma patients who have met the criteria of the study are going to receive it. Medical oncologists need to decide what to do after that time point.
DR. DIEFENBACH: Craig, my question to you is given what the study showed—that the patients with the highest risk receive the most benefit—would you recommend giving this to everyone who undergoes a transplant, or really to the patients per the study who are considered to have at least one of these three risk factors?
DR. MOSKOWITZ: I only treat patients with maintenance who were potentially eligible for the AETHERA study. That means remission duration of less than one year, primary refractory disease, or extranodal involvement. If they did not meet those criteria, I do not recommend maintenance.
DR. ANSELL: Most of what we’ve discussed to far, with all of our therapeutic options, have been most likely to be utilized in younger patients—patients who can tolerate the intensive regimens, patients who can receive salvage therapy and can get a transplant. Elderly patients are a real challenge to treat. Andy, you’re an expert in this area—how do you manage a 70-year-old who presents with Hodgkin lymphoma? Are there some new options we should bear in mind as we think about these patients?
DR. EVENS: Yes, it’s definitely a challenging patient population. A recurring theme is there’s not a one-size-fits-all. Age 70 might fall right in the middle, but the definition of elderly, for better or for worse, has been greater than age 60 in most clinical studies and other analyses, but again, that 60-year-old vs the 85-year-old in a wheelchair will be approached differently.
Let’s say we take that sweet spot of someone in their early 70s who is still performing all their activities of daily living and most of their instrumental activities of daily living with a performance status of one—the quick answer off of a clinical study is I’d probably use AVD (AVBD without the bleomycin). We, and others, have reported the incidence of bleomycin lung toxicity and the number one risk factor is age. That’s part and parcel related to the renal clearance of bleomycin and knowing that that is a risk factor.
Are there other risk factors, such as preexisting lung disease, etc? Yes. We recently looked at what we called the contemporary era, meaning post 2000, when I was at Northwestern in Chicago—we collected close to 100 patients.17 It was more of a real-world population, it was whether or not you were on a clinical study, and a third of patients in that analysis had developed bleomycin lung toxicity. The mortality rate, if you developed bleomycin lung toxicity, was 30%.
If anyone’s ever had a patient die from that, they know it’s quite significant. We corroborated those data when we took a subset analyses out from E2406, the phase III randomized study of Stanford V vs ABVD. The rate of bleomycin lung was not quite as high. This again was a clinical study—probably a healthier population—but it was just under 30% with a mortality rate of just under 20%. To me it’s just too slippery of a slope. It’s hard, besides age, to predict who’s going to develop it. I think we’ve already mentioned some of the data. If we had to say which is the weakest link or the least potent of the ABVD, it would be the B.
That’s all for the clinical trial. Thankfully there are, now, clinical trials specifically carved out for this patient population of untreated older patients with Hodgkin lymphoma. We’re participating in a clinical trial with Paul Hamlin at Memorial Sloan Kettering and other sites where we’re utilizing a sequential approach integrating brentuximab vedotin. We rationalized that concurrent therapy would likely be too tough for these patients, so it’s designed in more of a window study where we start with two cycles of brentuximab vedotin given every 3 weeks, followed by chemotherapy, AVD, and then followed by consolidation therapy.
The study is not done yet. We have reported interim results at the recent Lugano meeting that was alluded to,18 and we showed yes, there’s still some toxicity, including to the brentuximab vedotin. But the disease related outcomes were phenomenal in the early report, upwards of 95%, which again is another theme in elderly Hodgkin that I didn’t talk about. One is the tolerability of therapy, and second is a strong sentiment—if not scientific hypothesis—that it’s a different disease biology, in other words, more aggressive. You see more mixalarity, Epstein Barr Virus related. Those are a couple of considerations. There are also studies out there that are looking—and especially the frail patients, maybe that 85 year old or so—what about single-agent novel therapeutics such as brentuximab vedotin or I’ve even heard through the grapevine now PD-1 inhibitors being tested as single agents in this patient population.
DR. ANSELL: Right, I think these are exciting times and there are data to be watched for in elderly patients. I want to talk about patients that have failed an autologous transplant. In the past, the typical next modality of therapy was an allogeneic (ALLO) transplant. Seeing as Craig is a guy that’s done a lot of transplants in the past—what do you see as the role of ALLO stem cell transplants? There are a lot of data now for new drugs in post-autologous failure patients, including brentuximab vedotin and PD-1 blockade. So, I guess the question is, has ALLO stem cell transplant for Hodgkin lymphoma gone away?
DR. MOSKOWITZ: Well, I see it as a slow, painful death to be perfectly honest.
DR. EVENS: No pun intended.
DR. MOSKOWITZ: No pun intended. We’ve been studying the checkpoint inhibitors as have you, Steve, for about 2 and a half years, and I will say that during this time, I have sent one patient to an ALLO stem cell transplant and that was a patient who really had a fairly poor response to nivolumab.
I find it very hard to pull the trigger, so to speak, to send a patient for an ALLO transplant now when the patients are receiving modern checkpoint inhibition and tolerating it so well with stable Hodgkin lymphoma that is not affecting their day-to-day life.
This, to me, is the most difficult question you’ve addressed so far on this teleconference. For someone who’s been doing this for a long time, I’m not sure at the present time who should get an ALLO transplant for Hodgkin lymphoma. I think it’s a difficult area. It’s unclear to me how to study it.
DR. ANSELL: Catherine, you’ve also done a lot of work with immune checkpoint inhibitors and combination studies. Give us your perspective on when to use brentuximab vedotin, when to use PD-1 inhibition, and when to use combinations.
DR. DIEFENBACH: I think most of these, Steve, are still research questions to a certain extent. Of these novel agents, the only one that is FDA approved for use in a relapse patient is brentuximab vedotin, which is approved for patients who have failed two or more chemotherapy regimens.
In practice, brentuximab is used much more commonly. If I have a patient who doesn’t have a huge amount of bulky relapse and is for some reason not a trial candidate I might well consider second line therapy with brentuximab as opposed to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy. There are data both out of City of Hope and Sloan Kettering showing that the efficacy for brentuximab vedotin in second line is at least equivalent to the data we saw in later line with respect both to the CR rate and the overall response rate, if not better.19,20
I think there’s an established role for brentuximab vedotin. There are other agents which are being used in the community that are not approved but are certainly looked at in combination or being used off-label, such as bendamustine, which also has published phase II data showing that it is also effective in relapsed Hodgkin lymphoma.21 I think really, with regard to second line, the goal is to get to a CR, and anything that can get you to a good CR to make autologous transplantation more effective is probably a good way to go. But I think the more interesting question is really how are we, in the future, going to design therapeutic strategies and therapeutic platforms that are really biologically based and relevant to Hodgkin lymphoma biology, rather than just taking something from column A and something from column B off the shelf?
I think the checkpoint inhibitors particularly speak to Hodgkin lymphoma biology, because what they’re doing—you have the PDL-1, which is expressed on the Hodgkin tumor cell (the HRS cell), and the PD-1 is actually on the T cells of the Hodgkin lymphoma microenvironment, and by blocking the ability of the T cells to interact with the Hodgkin lymphoma cells, you’re not actually directly killing anything.
What you’re doing is actually taking the activated T cells, which are switched off, and turning them back on the way you’d turn a light on and saying go do your job, go kill the HRS cells. We actually have a trial that’s open right now in which we’re combining brentuximab vedotin with a checkpoint inhibitor, ipilimumab, trying to do just that. We are trying to use the brentuximab to kill the HRS cells in bulk and release antigen and stimulate the T cells and we’re going to combine this with the PD-1 inhibitor nivolumab as well, and we’re planning to look at the triplet combination of dual checkpoint inhibition with ipilimumab and nivolumab with brentuximab and that study is open [Ipilimumab, Nivolumab, and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma; NCT01896999].
There are other studies ongoing, looking at brentuximab and nivolumab in combination as well. I think there’s a study planned, as Andy alluded to, in the elderly population as well as another study that is planned by pharmaceutical companies.
I think with regard to immune agents, we’ve only really scratched the surface, and everyone is very excited right now about these checkpoint inhibitors, but the immune microenvironment is composed of more than just some CD-4 cells that are sitting around in a switched off state. We have macrophages and dendritic cells and natural killer cells and I think there a lot of other exciting immunologic agents that are both being used right now in solid tumors and are being used pre-clinically that may have very exciting applicability for Hodgkin lymphoma.
Finally, there are the signaling agents—not to ignore them—like, the JAK/STAT inhibitors which is a pathway that’s highly upregulated in Hodgkin lymphoma cells and other agents, such as epigenetic agents, and I think going forward, the rational platforms are really going to combine these agents in intelligent ways and try to target the Hodgkin lymphoma in a way that can really obviate the need for ALLO transplant. I, as Craig, have the same issue with my patients who are on PD-1 inhibitor therapy. It’s very hard to see them doing so well and to really pull the trigger on referring them for an ALLO transplant.
DR. ANSELL: I’d like to summarize our roundtable discussion by saying These are exciting times. There are lots of changes in Hodgkin lymphoma that are developing as we watch, and the exciting thing is to see how we can optimize early stage therapy to minimize toxicity and maintain benefit., optimize advanced stage initial treatment to get the best results, again with the least toxicity, and then how to integrate these new agents with great promise into frontline therapies and salvage therapies so that, hopefully, down the line, we see more and more patients that are cured of their disease right away with initial treatment.
I want to thank Craig Moskowitz, Catherine Diefenbach, and Andy Evens for their participation.
References
1 Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640–652.
2 Eich HT, Diehl V, Görgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199–4206.
3 Raemaekers JM, André MP, Federico M, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;32(12):1188–1194.
4 Barrington SF, O’Doherty MJ, Roberts TH, et al. PET-CT for staging and early response—results from the Response Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) study. Hematol Oncol. 2013;31(Suppl. I):96–150. Abstract 18.
5 Behringer K, Goergen H, Hitz F, et al. for the German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015;385(9976):1418–1427.
6 Johnson PMW, et al. Response-adapted therapy based on interim FDG-PET scans in advanced Hodgkin lymphoma: 1st analysis of the safety of de-escalation & efficacy of escalation in the international RATHL study CRUK/07/033. Plenary Session: 13th International Conference on Malignant Lymphoma; June 17–20, 2015; Lugano, Switzerland.
7 Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506–1514.
8 Diefenbach CS, Li H, Hong F, et al. Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era. Br J Haematol. 2015. doi: 10.1111/bjh.13634. [Epub ahead of print]
9 Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era. J Clin Oncol. 2012;30(27):3383–3388.
10 Diehl V, Franklin J, Pfreundschuh M, et al. for the German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003;348(24):2386–2395.
11 Viviani S, Zinzani PL, Rambaldi A, et al for the Michelangelo Foundtaion; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203–212.
12 Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183–2189.
13 Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348–1356.
14 Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684–691.
15 Borchmann P, Eichenauer DA, Plütschow A, et al. Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: interim results of a randomized phase II study. Blood. 2013;122(21)4344.
16 Moskowitz CH, Nadamanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2015;385(9980):1853–1862.
17 Evens AM, Helenowski I, Ramsdale E, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood. 2012;119(3):692–695.
18 Evens AM, et al. Sequential brentuximab vedotin and AVD for older Hodgkin lymphoma patients: initial results from a phase 2 multicentre study. In: Hematological Oncology – Special Issue: 13-ICML, 13th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano (Switzerland), 17–20 June, 2015. Abstract 89.
19 Chen RW, Palmer J, Siddiqi T, et al. Brentuximab vedotin as first line salvage therapy in relapsed/refractory HL. Poster presented at: 54th ASH Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.
20 Moskowitz AJ, Schoder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015;16(3):284–292.
21 Moskowitz AJ, Hamlin PA, Jr, Perales MA, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31(4):456–460.
Moderated by: Stephen Ansell, MD, PhD1
Discussants: Craig Moskowitz, MD2; Catherine Diefenbach, MD3; Andrew M. Evens, DO, MSc4
From Mayo Clinic, Rochester, MN1; Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY2; NYU School of Medicine and NYU Perlmutter Cancer Center, New York, NY3; Tufts University School of Medicine and Tufts Medical Center, Boston, MA4
Address for correspondence: Stephen Ansell, MD, PhD, Mayo Clinic, 200 First Street SW #W10, Rochester, MN 55905
E-mail: ansell.stephen@mayo.edu
Biographical sketch:
From Weill Medical College of Cornell University:
Dr. Moskowitz serves as principal investigator and co-investigator for a number of clinical trials aimed at improving the care of patients with lymphoma. His research has focused on improving the outcome of patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). This effort has been conducted along two tracks. One effort is focused on improving therapy for patients with disease that has returned or is not responding to standard therapy (refractory disease), through the use of high-dose therapy and autologous stem cell transplantation as well as new agents that can be incorporated into such "salvage" therapy. The second is aimed at developing risk-adapted strategies to optimize the treatment of newly diagnosed DLBCL by using what we have learned in the relapsed and refractory setting.
Dr. Moskowitz has been recognized for his research on a national level through multiple awards. He has lectured worldwide on lymphoma and stem cell transplantation. In addition, he is a member of the research council at MSKCC, and on the steering committees for the bi-annual international lymphoma conference in Lugano and international Hodgkin lymphoma conference in Cologne.
From NYU School of Medicine and NYU Perlmutter Cancer Center:
An alumna of the University of Pennsylvania School of Medicine, Dr. Diefenbach completed her internship and residency at the Johns Hopkins Hospital and her oncology fellowship at Memorial Sloan-Kettering Cancer Center, where she spent an additional year focusing on translational immunology.
Her scientific research focuses on the relationship between lymphoma and immunity; on developing novel and immune based treatment strategies for patients with relapsed lymphoma; and on biomarker discovery. She is currently leading a national clinical trial for relapsed Hodgkin lymphoma investigating the combination of the antibody drug conjugate brentuximab with the immune activating agents ipilimumab and nivolumab.
Dr. Diefenbach directs the lymphoma clinical research within the Hematology/ Oncology Division at the Perlmutter Cancer Center. She is a member of the ECOG Lymphoma Committee, the NCI Lymphoma Steering Committee Clinical Trials Planning Meeting, and the Editorial Board of Clinical Cancer Research. Her research is supported by the Lymphoma Research Foundation, the American Cancer Society and the National Cancer Institute (NCI).
From Tufts University School of Medicine and Tufts Medical Center:
DR. ANSELL: My name is Stephen Ansell, from Mayo Clinic, Rochester, Minnesota. I’m joined by Drs. Craig Moskowitz, Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Medical College of Cornell University, Catherine Diefenbach, Assistant Professor of Medicine at the NYU School of Medicine and the NYU Perlmutter Cancer Center, and Andy Evens, Professor of Medicine at Tufts University School of Medicine, and Faculty Member at Tufts Medical Center in Boston.
Welcome to all of you and thank you for participating in this medical roundtable discussion. The focus today is going to be on practical management of Hodgkin lymphoma. This is a very experienced group of roundtable participants whom I hope will give us valuable insights into some of the questions relating to managing Hodgkin lymphoma.
Let’s talk about patients with early stage Hodgkin lymphoma and discuss what we feel the standard management might be and how we would use positron emission tomographic (PET) scans to direct therapy. Craig, I’m going to ask you to start. Please discuss what your standard management of early stage Hodgkin lymphoma is and how you use PET scans to direct your treatment.
DR. MOSKOWITZ: I divide Hodgkin lymphoma, early stage, into three groups; favorable early stage, unfavorable early stage without tumor bulk, and stage two disease with tumor bulk. The standard management is well borne out these days from the German Hodgkin Lymphoma Study Group.1,2 For early stage favorable Hodgkin lymphoma I treat men and women quite differently.
For men with stage IA or IIA, non-bulky disease, I tend to use standard treatment, which is short course combined modality therapy with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and involved-field radiation. I do not use PET imaging in that setting. For women, however, as you know, the median age is young in this patient population. I’ve adopted a RAPID approach for these folks. I give 3 months of chemotherapy and then repeat the PET scan and if the PET scan is negative I stop treatment. If the PET scan is positive, I treat the patient as per that study, which was one more cycle of chemotherapy and radiation. But unfavorable early-stage disease without tumor bulk, once again, the issue is, should patients get chemotherapy alone or should they get combined modality therapy?
If I’m giving combined modality therapy, I do not use PET imaging. If I’m using chemotherapy alone and if this is a patient eligible for a RAPID approach I treat as above. If the patient was not eligible for RAPID because they had stage IIB disease, I usually give full course chemotherapy and I do not use PET imaging.
For patients with bulky stage II disease, I treat based upon the randomized cooperative group study, which is four to six cycles of chemotherapy followed by radiation. I do not use PET imaging in that setting.
DR. ANSELL: Craig, thanks. Andy, do you actually escalate therapy at any time based on PET results, or deescalate therapy? We heard from Craig that he follows some of the RAPID guidelines. Give us your perspective.
DR. EVENS: I think they’re all good questions. In a way, it’s not one size fits all. I think it has to be a very individualized patient-by-patient treatment decision. In other words, I might approach a 19-year-old woman with a bulky mediastinal mass differently than a 45-year-old man with a right cervical lymph node. This is one important point to convey. In terms of PET-adapted, I think it is evolving. The question is, is there any actionable evidence to go on?
In terms of where there are more data, which is in early negativity in terms of PET-2 negativity, there have been a couple publications alluded to—RAPID and the European Organisation for Research and Treatment of Cancer (EORTC)3—and I’m not sure those data changed the opinion if we didn’t have an early negative PET scan. We know, without an early negative PET scan, that patients who do not receive consolidative radiation have a small improvement in progression-free survival (PFS) and no difference in overall survival (OS).
What both of those studies showed is that basically persists. That margin of difference might be a little less—instead of 6%–8% difference in PFS, it might now be 4%–6%, but both studies proved to be not noninferior, so I’m not quite sure that has changed how I treat someone. In other words, an early negative PET scan. For PET positivity, the data are really evolving. I think, before the Lugano meeting this past June I would have said no.
I just saw a very recent second opinion on a younger patient in her mid-20s who had a bulky mediastinal mass, and then after two cycles was definitely better, but still PET positive, defined as it was a smidge greater than the liver, and the data that emanated from Lugano on early PET positive showed not only a PFS advantage, but a borderline OS, and that, of course, would be a game changer if PET-adapted therapy is pointing toward an OS advantage.
DR. ANSELL: Catherine, what’s your sense of the role of radiation therapy in early stage Hodgkin lymphoma?
DR. DIEFENBACH: As Andy said, the role of PET to stratify early stage patients is evolving. Another study that was reported in Lugano was the Response-adjusted Therapy for Hodgkin Lymphoma (RATHL) study4 where it appeared that for patients who had an early PET negative, the bleomycin could be omitted and the patients ended up with a PFS that was equivalent to patients who did not have bleomycin omitted. The decision of combined modality therapy vs standard therapy—I think Andy and Craig put it really well—will have to be individualized to the patient’s situation: specifically, to their age, sex, bulk of disease, and response after early disease assessment.
DR. MOSKOWITZ: That’s why it’s so hard to study this patient population. You have three folks on the phone and we’re all treating patients differently with an individualized approach. It’s almost impossible to come up with a clinical trial that everybody would be comfortable with in this patient population, which is why we have difficulty in writing one, which is disappointing.
DR. ANSELL: Craig, I wanted to circle back to you. The German Hodgkin Lymphoma Study Group has shown that if you omit bleomycin there is a slight decrease in outcome;5 however, the RATHL trial would suggest maybe not.6 Has that impacted your practice at all? Do you omit bleomycin in your regimens or do you use it standardly?
DR. MOSKOWITZ: Well, RATHL is for advanced stage disease and I’ve already stopped giving bleomycin to patients who are PET negative after 2 months of ABVD based on that approach; but I do not omit bleomycin for an early stage disease based upon the results from the German Hodgkin Lymphoma Study Group. We’re not giving full course chemotherapy in the early stage setting, so I’m willing to give the appropriate number of cycles, at least for now.
DR. ANSELL: Thanks for your perspectives. I think as it was pointed out, there’s a lot of individualization here and we still have an evolving role of PET scanning. Also, there are multiple new agents we’ll begin to talk about later in the program that may impact things further. So, I think this remains an area where it’s quite challenging to determine the optimal approach.
I want to turn our attention to talk about patients with advanced stage disease—predominantly stage III and IV disease. Catherine, how do you treat patients with advanced stage disease? What’s your approach, and as new agents are coming along, agents like brentuximab vedotin, where do you think they fit into your approach?
DR. DIEFENBACH: Just as Craig said, there isn’t really a one-size-fits-all approach to advanced-stage patients either. Just as early-stage patients are divided into at least three groups, we look at advanced-stage patients as a very heterogeneous population. One of the ways we stratify advanced-stage patients is based on what we call their risk score.
Traditionally, we’ve used the Hasenclever risk score—or the International Prognostic Score (IPS)7—which looks at seven clinical factors to get a sense of how these advanced-stage patients are going to do in terms of their PFS and OS.7 More recently, we have a manuscript where we’re looking in the modern era at using a streamlined score with only three of these factors instead of seven factors8 and the group from British Columbia has showed that, while this Hasenclever risk score is still relevant,9 it looks in the modern era with modern chemotherapy that it may be less helpful than it previously was, because the patients who did much worse are doing better, so the curves are narrowed.
Nonetheless, biologically and clinically, there’s a big difference between advanced-stage patients who have zero to two risk factors and advanced-stage patients who have five, six, or seven risk factors. The standard of care for treatment for advanced-stage patients both in the US and internationally has been either the chemotherapy regimen of ABVD or the chemotherapy regimen of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).10,11 There has been a controversy between those who prefer escalated BEACOPP and those who prefer ABVD. Escalated BEACOPP has a superior PFS to ABVD, which didn’t necessarily translate into an OS benefit, and patients who fail ABVD may be salvaged with stem cell transplant and second line chemotherapy and stem cell transplant.
Patients with escalated BEACOPP also have substantial therapy-related toxicity that patients with ABVD do not have, such as infertility and myelosuppression, higher rates of neutropenic fever, and higher rates of secondary leukemia, so there’s a cost associated with being treated with escalated BEACOPP that’s not associated with ABVD. With both regimens, the cure rate is approximately 75%–80%, so those who favor ABVD—I would consider myself one of them—would argue that you spare a certain number of patients who are salvaged with ABVD and who are cured unnecessary toxicity with the escalated BEACOPP. Those who are in favor of escalated BEACOPP for all patients would probably argue that an increased PFS should translate into an increased OS, and there have in fact been meta-analyses that show improved OS in some older trials with BEACOPP compared to ABVD, but this is a meta-analysis across many different trials.
More recently, brentuximab vedotin—an antibody drug conjugate, against CD30, which is expressed on the Hodgkin Reed-Sternberg (HRS) cell—combined with auristatin—a taxane-like cytotoxic chemotherapy—which acts like a Trojan horse, is delivered to the HRS cell, taken up by the HRS cell and then blows up the HRS cell while sparing, to a large extent, the microenvironment, has been incorporated into upfront therapy with ABVD.
Brentuximab was approved by the Food and Drug Administration (FDA) to treat relapsed Hodgkin lymphoma based on the pivotal study, which had an overall response rate of approximately 75% for relapsed patients.12 Based on this it was incorporated into upfront therapy. There was a phase I study which I think, Steve, you actually led, which combined ABVD with brentuximab vedotin.13 This, however, resulted in excessive pulmonary toxicity secondary to bleomycin, so bleomycin was then omitted. The data were reported at the American Society of Hematology (ASH) meeting and showed a 3-year failure free survival of 96% and OS of 100%, which is extremely impressive in this population. The Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma (ECHELON) [NCT01712490] is currently underway and should complete accrual this year.
I think that these data will certainly help to answer the question of whether incorporating brentuximab into the upfront regimen of ABVD can improve both PFS and OS for these patients and perhaps put BEACOPP, finally, to rest.
DR. ANSELL: Andy, do you have a place in your practice where you think escalated BEACOPP has a role?
DR. EVENS: The quick answer is yes, but that sliver of practice is extremely small, and as time is going on, it’s getting smaller. I think in the pre-response adapted era—5 to 10 years ago when BEACOPP was first published—it did show an OS advantage, but many people would argue the comparator or COPP/ABVD arm isn’t equivalent, so to speak, to contemporary ABVD.
I was using it mainly in patients with high IPS—patients who had a five, six, or seven. That, frankly, is not a large percent of the patient population. Now, in the PET-adapted, we don’t quite have that actionable evidence, as much has accumulated quite yet, as early stage disease. Even in the patients now with high IPS, I have to admit, I’m really starting with ABVD in everyone and only considering escalating in patients who have a positive PET scan, which I guess in my practice is somewhat lower than the clinical trial data.
The clinical trial data in advanced-stage disease would say that’s 15%–20% of the patients.14 I tend to find it’s closer in the 5% range. I think part of that is viewing the PET-adapted part we keep talking about—it can’t be viewed in a vacuum, meaning you shouldn’t review a report. You should sit side-by-side with your radiologist and try to review that scan, and while doing that, have a clear meaning of what defines PET positive and PET negative, because almost every study we talked about has it slightly different. Where’s the cut point? Is it at the liver—meaning a Deauville score of four or five—or is it less in the liver, etc? So, I think those types of things are very important to understand and appreciate when treating the patients.
DR. DIEFENBACH: Andy, I completely agree with you and I also would have a role for BEACOPP in a patient who was not responding to ABVD with interim scans. I also, at that time, if the patient was by PET/computed tomography unequivocally refractory, I would consider clinical trial probably in the same vein as the escalated BEACOPP. So, I agree with Andy that I have a sliver of patients for whom I do consider escalated BEACOPP, but that is a very small sliver.
DR. ANSELL: Craig, what’s your comment about modifications that are happening, even to escalated BEACOPP? The BrECADD regimen is incorporating new agents like brentuximab vedotin.15 What’s your thinking about that regimen?
DR. MOSKOWITZ: I don’t treat patients off protocol with protocol based treatment, so my familiarity with it is low. Just to digress for one second, I think that I have definitely changed my practice and I would say that I used to give BEACOPP quite a bit for patients with four to seven risk factors, which is about 20% of the patient population. I think, based upon two fairly large studies that will have about 1700 patients on, the RATHL study and the intergroup study in the United States—it’s fairly clear—to me at least—that one can start with ABVD chemotherapy.
Since 80% of the patients have a negative interim PET scan, despite the number of pre-treatment risk factors they have, you’re really limiting the number of patients who get crossed over to a more complicated program, so I’ve been using that approach. I’m very comfortable with it.
The issue of giving brentuximab vedotin with AVD as part of primary therapy is, once again, investigational, and I have many concerns about the cost of that treatment program and it’s applicability worldwide even if the study is positive.
DR. ANSELL: I think that’s a good point. One of the things I find very interesting as we talk about the escalated BEACOPP vs. ABVD comparison is that as brentuximab vedotin has been mixed into those two regimens, it’s almost as if those two regimens are coming toward each other. ABVD is being somewhat escalated in intensity and escalated BEACOPP being modified down. I think at the end of the day, we’re going to come to a combined approach that suits people on both sides of the intensity debate. Cost, however, is going to be an issue to make this an internationally usable regimen, so I think that’s a real challenge.
I want to pick up, Craig, on the point you made about risks of relapse and so on. When and if patients relapse, what do you use in your practice as the optimal salvage regimen? Also, I know you’re a big advocate for your patients to attain a complete remission before going to transplant, would you like to explain why?
DR. MOSKOWITZ: Once again my opinion about this has evolved over the years, but I think that I’m fairly comfortable right now that almost all these salvage regimens are quite similar. They have variable toxicity profiles, but if the treatment is given correctly and you look at the published literature, somewhere between 60% and 80% of the patients will likely be in remission after salvage chemotherapy. As defined as a negative PET, based upon standard criteria, those patients have a marked survival advantage, looking at published literature thus far.
As I’m maturing, I’ve been trying to treat patients with less aggressive salvage therapy to try to get them into remission. For example, in patients with early stage disease who relapse with non-bulky and non-widespread disease, I’d be more inclined to give an outpatient chemotherapy regimen. Patients with widespread, extranodal involvement, I’d be more inclined to give inpatient treatment off study. On clinical trials, that’s a different story, but we’ve published now, multiple times, that overwhelmingly a complete response (CR) prior to a stem cell transplant abrogates almost all the other prognostic factors.
DR. ANSELL: Right. Andy, if a patient had a response, but not a CR, or maybe only a modest improvement, would you say that’s a deal breaker for moving onto something like an autologous transplant?
DR. EVENS: I would say for the majority of patients, yes. There might be that patient who, depending on what they’ve received in the past—particularly if they have already received brentuximab vedotin—might be someone we still take to an autologous transplant.
There’s a significant minority you can still cure who are chemo-resistant, but I think I completely agree with Craig. In the era of novel therapeutics, that’s becoming less and less. As more options come on the table, I think if you really have somebody who’s chemotherapy resistant—that can be defined, I guess, as a positive PET, although I do think there are some gray zones in defining positive PET—I think it would be someone I would really look toward a novel therapeutic.
DR. ANSELL: Catherine, there have been some recent data about maintenance therapy after an autologous stem cell transplant. What’s your take on that?
DR. DIEFENBACH: I think the most recent data on maintenance therapy post autologous stem cell transplant comes from the AETHERA study,16 which Craig was the lead author on, and this investigated the question of whether using brentuximab vedotin as a consolidative therapy after transplant—as a maintenance therapy—improved PFS in this patient population.
The patients in this study who had relapsed disease were randomized between receiving brentuximab vedotin or being observed. Patients were treated for 16 cycles, which is approximately one year with this therapy, given every 3 weeks. Data from this study were in favor of brentuximab vedotin. The group that received brentuximab vedotin as opposed to being observed had a PFS of 42.9 months vs a PFS of approximately 24 months in the group that wasn’t treated with brentuximab vedotin.
This says a few interesting things. This demonstrates that most patients who are going into transplant are not doing so with optimal disease control. If all patients were going into transplant in a CR with only micrometastatic disease, there would not be such a stark difference between these arms. I think this study very nicely demonstrates that patients who benefit most strongly from the maintenance therapy are the patients who are considered to be the highest risk.
These are the patients with refractory disease who go into transplant with a high degree of tumor bulk, or patients who relapse within a short time—less than 12 months after their initial therapy—suggesting they didn’t really obtain optimal disease control with their therapy, or they had extranodal disease or disease outside of the lymph nodes affecting vital organs or bone marrow. These high-risk patients, based on these criteria, appear to be the ones who benefit the most from brentuximab maintenance. I think it gets a little tricky, however, because none of these patients receive brentuximab in their upfront therapy. So, going forward, it’s going to be an even harder question to ask—how are high-risk patients who receive brentuximab initially going to benefit from receiving a therapy that they relapsed from after receiving?
Getting brentuximab was not a free ride. There was a significantly higher amount of both sensory neuropathy, and about 20% of patients had motor neuropathy in the brentuximab group vs the non-brentuximab treated patients.
Finally, there was no difference yet—and this will still mature—in OS between the groups because the patients who didn’t get brentuximab were able to cross over and get it. This goes back to the old question with rituximab when rituximab maintenance was looked at. Is it better to receive brentuximab vedotin maintenance after transplant or is it better to receive it if you relapse after transplant? I think we won’t know the answer to that question for a few more years when we really see if the PFS translates into durable survival in the brentuximab treated group vs the non-brentuximab treated group. As Craig has alluded to with regard to the cost with respect to upfront therapy, I think this adds substantial costs subsequent to stem cell transplant. If we are going to use this therapy, I think we’ll have to be very clever in how we risk assess the patients who proceed to transplant, both prior to transplant and in terms of deciding whether they receive therapy.
There are actually efforts underway right now—internationally—to use better risk discrimination criteria for relapsed Hodgkin lymphoma to define a higher population of patients who are truly high risk, you might have the highest likelihood of benefiting from this sort of consolidative strategy.
DR. ANSELL: Craig, please comment. Catherine mentioned that the addition of brentuximab wasn’t without financial cost, and that there is also a toxicity cost. You led the study, what are your comments on the side effects of a year’s worth of brentuximab vedotin?
DR. MOSKOWITZ: I think, shockingly, the median number of doses that patients received on the study was 15, so almost a year or full course. In general, neuropathy is similar to every other single study that’s been looked at with single agent brentuximab. Peripheral neuropathy is real. For me, if a patient gets a dose reduction and the neuropathy does not improve, I would just stop the treatment. That’s how I practice.
I think the question Catherine raises is an extremely good one about patients who had a brentuximab vedotin pretransplant. Should they get brentuximab vedotin post-transplant? That’s something that’s clearly going to evolve, and the number of doses that a patient will receive post-transplant is going to evolve, but I think for the audience listening, this is here to stay for the next couple of years.
The FDA approved this August 17, so transplant physicians are going to initiate brentuximab vedotin therapy prior to the patient returning to their medical oncologist. It’s the medical oncologist who’s going to decide how many more cycles of brentuximab should be administered, because these folks would already have received three cycles by then.
Transplant physicians have to report 90-day efficacy data. In general, therefore, transplanters will see the patients up to around day 90. Brentuximab is administered between days 30 and 45 post-transplant, so by definition, the Hodgkin lymphoma patients who have met the criteria of the study are going to receive it. Medical oncologists need to decide what to do after that time point.
DR. DIEFENBACH: Craig, my question to you is given what the study showed—that the patients with the highest risk receive the most benefit—would you recommend giving this to everyone who undergoes a transplant, or really to the patients per the study who are considered to have at least one of these three risk factors?
DR. MOSKOWITZ: I only treat patients with maintenance who were potentially eligible for the AETHERA study. That means remission duration of less than one year, primary refractory disease, or extranodal involvement. If they did not meet those criteria, I do not recommend maintenance.
DR. ANSELL: Most of what we’ve discussed to far, with all of our therapeutic options, have been most likely to be utilized in younger patients—patients who can tolerate the intensive regimens, patients who can receive salvage therapy and can get a transplant. Elderly patients are a real challenge to treat. Andy, you’re an expert in this area—how do you manage a 70-year-old who presents with Hodgkin lymphoma? Are there some new options we should bear in mind as we think about these patients?
DR. EVENS: Yes, it’s definitely a challenging patient population. A recurring theme is there’s not a one-size-fits-all. Age 70 might fall right in the middle, but the definition of elderly, for better or for worse, has been greater than age 60 in most clinical studies and other analyses, but again, that 60-year-old vs the 85-year-old in a wheelchair will be approached differently.
Let’s say we take that sweet spot of someone in their early 70s who is still performing all their activities of daily living and most of their instrumental activities of daily living with a performance status of one—the quick answer off of a clinical study is I’d probably use AVD (AVBD without the bleomycin). We, and others, have reported the incidence of bleomycin lung toxicity and the number one risk factor is age. That’s part and parcel related to the renal clearance of bleomycin and knowing that that is a risk factor.
Are there other risk factors, such as preexisting lung disease, etc? Yes. We recently looked at what we called the contemporary era, meaning post 2000, when I was at Northwestern in Chicago—we collected close to 100 patients.17 It was more of a real-world population, it was whether or not you were on a clinical study, and a third of patients in that analysis had developed bleomycin lung toxicity. The mortality rate, if you developed bleomycin lung toxicity, was 30%.
If anyone’s ever had a patient die from that, they know it’s quite significant. We corroborated those data when we took a subset analyses out from E2406, the phase III randomized study of Stanford V vs ABVD. The rate of bleomycin lung was not quite as high. This again was a clinical study—probably a healthier population—but it was just under 30% with a mortality rate of just under 20%. To me it’s just too slippery of a slope. It’s hard, besides age, to predict who’s going to develop it. I think we’ve already mentioned some of the data. If we had to say which is the weakest link or the least potent of the ABVD, it would be the B.
That’s all for the clinical trial. Thankfully there are, now, clinical trials specifically carved out for this patient population of untreated older patients with Hodgkin lymphoma. We’re participating in a clinical trial with Paul Hamlin at Memorial Sloan Kettering and other sites where we’re utilizing a sequential approach integrating brentuximab vedotin. We rationalized that concurrent therapy would likely be too tough for these patients, so it’s designed in more of a window study where we start with two cycles of brentuximab vedotin given every 3 weeks, followed by chemotherapy, AVD, and then followed by consolidation therapy.
The study is not done yet. We have reported interim results at the recent Lugano meeting that was alluded to,18 and we showed yes, there’s still some toxicity, including to the brentuximab vedotin. But the disease related outcomes were phenomenal in the early report, upwards of 95%, which again is another theme in elderly Hodgkin that I didn’t talk about. One is the tolerability of therapy, and second is a strong sentiment—if not scientific hypothesis—that it’s a different disease biology, in other words, more aggressive. You see more mixalarity, Epstein Barr Virus related. Those are a couple of considerations. There are also studies out there that are looking—and especially the frail patients, maybe that 85 year old or so—what about single-agent novel therapeutics such as brentuximab vedotin or I’ve even heard through the grapevine now PD-1 inhibitors being tested as single agents in this patient population.
DR. ANSELL: Right, I think these are exciting times and there are data to be watched for in elderly patients. I want to talk about patients that have failed an autologous transplant. In the past, the typical next modality of therapy was an allogeneic (ALLO) transplant. Seeing as Craig is a guy that’s done a lot of transplants in the past—what do you see as the role of ALLO stem cell transplants? There are a lot of data now for new drugs in post-autologous failure patients, including brentuximab vedotin and PD-1 blockade. So, I guess the question is, has ALLO stem cell transplant for Hodgkin lymphoma gone away?
DR. MOSKOWITZ: Well, I see it as a slow, painful death to be perfectly honest.
DR. EVENS: No pun intended.
DR. MOSKOWITZ: No pun intended. We’ve been studying the checkpoint inhibitors as have you, Steve, for about 2 and a half years, and I will say that during this time, I have sent one patient to an ALLO stem cell transplant and that was a patient who really had a fairly poor response to nivolumab.
I find it very hard to pull the trigger, so to speak, to send a patient for an ALLO transplant now when the patients are receiving modern checkpoint inhibition and tolerating it so well with stable Hodgkin lymphoma that is not affecting their day-to-day life.
This, to me, is the most difficult question you’ve addressed so far on this teleconference. For someone who’s been doing this for a long time, I’m not sure at the present time who should get an ALLO transplant for Hodgkin lymphoma. I think it’s a difficult area. It’s unclear to me how to study it.
DR. ANSELL: Catherine, you’ve also done a lot of work with immune checkpoint inhibitors and combination studies. Give us your perspective on when to use brentuximab vedotin, when to use PD-1 inhibition, and when to use combinations.
DR. DIEFENBACH: I think most of these, Steve, are still research questions to a certain extent. Of these novel agents, the only one that is FDA approved for use in a relapse patient is brentuximab vedotin, which is approved for patients who have failed two or more chemotherapy regimens.
In practice, brentuximab is used much more commonly. If I have a patient who doesn’t have a huge amount of bulky relapse and is for some reason not a trial candidate I might well consider second line therapy with brentuximab as opposed to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy. There are data both out of City of Hope and Sloan Kettering showing that the efficacy for brentuximab vedotin in second line is at least equivalent to the data we saw in later line with respect both to the CR rate and the overall response rate, if not better.19,20
I think there’s an established role for brentuximab vedotin. There are other agents which are being used in the community that are not approved but are certainly looked at in combination or being used off-label, such as bendamustine, which also has published phase II data showing that it is also effective in relapsed Hodgkin lymphoma.21 I think really, with regard to second line, the goal is to get to a CR, and anything that can get you to a good CR to make autologous transplantation more effective is probably a good way to go. But I think the more interesting question is really how are we, in the future, going to design therapeutic strategies and therapeutic platforms that are really biologically based and relevant to Hodgkin lymphoma biology, rather than just taking something from column A and something from column B off the shelf?
I think the checkpoint inhibitors particularly speak to Hodgkin lymphoma biology, because what they’re doing—you have the PDL-1, which is expressed on the Hodgkin tumor cell (the HRS cell), and the PD-1 is actually on the T cells of the Hodgkin lymphoma microenvironment, and by blocking the ability of the T cells to interact with the Hodgkin lymphoma cells, you’re not actually directly killing anything.
What you’re doing is actually taking the activated T cells, which are switched off, and turning them back on the way you’d turn a light on and saying go do your job, go kill the HRS cells. We actually have a trial that’s open right now in which we’re combining brentuximab vedotin with a checkpoint inhibitor, ipilimumab, trying to do just that. We are trying to use the brentuximab to kill the HRS cells in bulk and release antigen and stimulate the T cells and we’re going to combine this with the PD-1 inhibitor nivolumab as well, and we’re planning to look at the triplet combination of dual checkpoint inhibition with ipilimumab and nivolumab with brentuximab and that study is open [Ipilimumab, Nivolumab, and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma; NCT01896999].
There are other studies ongoing, looking at brentuximab and nivolumab in combination as well. I think there’s a study planned, as Andy alluded to, in the elderly population as well as another study that is planned by pharmaceutical companies.
I think with regard to immune agents, we’ve only really scratched the surface, and everyone is very excited right now about these checkpoint inhibitors, but the immune microenvironment is composed of more than just some CD-4 cells that are sitting around in a switched off state. We have macrophages and dendritic cells and natural killer cells and I think there a lot of other exciting immunologic agents that are both being used right now in solid tumors and are being used pre-clinically that may have very exciting applicability for Hodgkin lymphoma.
Finally, there are the signaling agents—not to ignore them—like, the JAK/STAT inhibitors which is a pathway that’s highly upregulated in Hodgkin lymphoma cells and other agents, such as epigenetic agents, and I think going forward, the rational platforms are really going to combine these agents in intelligent ways and try to target the Hodgkin lymphoma in a way that can really obviate the need for ALLO transplant. I, as Craig, have the same issue with my patients who are on PD-1 inhibitor therapy. It’s very hard to see them doing so well and to really pull the trigger on referring them for an ALLO transplant.
DR. ANSELL: I’d like to summarize our roundtable discussion by saying These are exciting times. There are lots of changes in Hodgkin lymphoma that are developing as we watch, and the exciting thing is to see how we can optimize early stage therapy to minimize toxicity and maintain benefit., optimize advanced stage initial treatment to get the best results, again with the least toxicity, and then how to integrate these new agents with great promise into frontline therapies and salvage therapies so that, hopefully, down the line, we see more and more patients that are cured of their disease right away with initial treatment.
I want to thank Craig Moskowitz, Catherine Diefenbach, and Andy Evens for their participation.
References
1 Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363(7):640–652.
2 Eich HT, Diehl V, Görgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199–4206.
3 Raemaekers JM, André MP, Federico M, et al. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014;32(12):1188–1194.
4 Barrington SF, O’Doherty MJ, Roberts TH, et al. PET-CT for staging and early response—results from the Response Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) study. Hematol Oncol. 2013;31(Suppl. I):96–150. Abstract 18.
5 Behringer K, Goergen H, Hitz F, et al. for the German Hodgkin Study Group; Swiss Group for Clinical Cancer Research; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet. 2015;385(9976):1418–1427.
6 Johnson PMW, et al. Response-adapted therapy based on interim FDG-PET scans in advanced Hodgkin lymphoma: 1st analysis of the safety of de-escalation & efficacy of escalation in the international RATHL study CRUK/07/033. Plenary Session: 13th International Conference on Malignant Lymphoma; June 17–20, 2015; Lugano, Switzerland.
7 Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506–1514.
8 Diefenbach CS, Li H, Hong F, et al. Evaluation of the International Prognostic Score (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era. Br J Haematol. 2015. doi: 10.1111/bjh.13634. [Epub ahead of print]
9 Moccia AA, Donaldson J, Chhanabhai M, et al. International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era. J Clin Oncol. 2012;30(27):3383–3388.
10 Diehl V, Franklin J, Pfreundschuh M, et al. for the German Hodgkin's Lymphoma Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med. 2003;348(24):2386–2395.
11 Viviani S, Zinzani PL, Rambaldi A, et al for the Michelangelo Foundtaion; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203–212.
12 Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183–2189.
13 Younes A, Connors JM, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol. 2013;14(13):1348–1356.
14 Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684–691.
15 Borchmann P, Eichenauer DA, Plütschow A, et al. Targeted BEACOPP variants in patients with newly diagnosed advanced stage classical Hodgkin lymphoma: interim results of a randomized phase II study. Blood. 2013;122(21)4344.
16 Moskowitz CH, Nadamanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2015;385(9980):1853–1862.
17 Evens AM, Helenowski I, Ramsdale E, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood. 2012;119(3):692–695.
18 Evens AM, et al. Sequential brentuximab vedotin and AVD for older Hodgkin lymphoma patients: initial results from a phase 2 multicentre study. In: Hematological Oncology – Special Issue: 13-ICML, 13th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano (Switzerland), 17–20 June, 2015. Abstract 89.
19 Chen RW, Palmer J, Siddiqi T, et al. Brentuximab vedotin as first line salvage therapy in relapsed/refractory HL. Poster presented at: 54th ASH Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA.
20 Moskowitz AJ, Schoder H, Yahalom J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015;16(3):284–292.
21 Moskowitz AJ, Hamlin PA, Jr, Perales MA, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31(4):456–460.
Moderated by: Stephen Ansell, MD, PhD1
Discussants: Craig Moskowitz, MD2; Catherine Diefenbach, MD3; Andrew M. Evens, DO, MSc4
From Mayo Clinic, Rochester, MN1; Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY2; NYU School of Medicine and NYU Perlmutter Cancer Center, New York, NY3; Tufts University School of Medicine and Tufts Medical Center, Boston, MA4
Address for correspondence: Stephen Ansell, MD, PhD, Mayo Clinic, 200 First Street SW #W10, Rochester, MN 55905
E-mail: ansell.stephen@mayo.edu
Biographical sketch:
From Weill Medical College of Cornell University:
Dr. Moskowitz serves as principal investigator and co-investigator for a number of clinical trials aimed at improving the care of patients with lymphoma. His research has focused on improving the outcome of patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). This effort has been conducted along two tracks. One effort is focused on improving therapy for patients with disease that has returned or is not responding to standard therapy (refractory disease), through the use of high-dose therapy and autologous stem cell transplantation as well as new agents that can be incorporated into such "salvage" therapy. The second is aimed at developing risk-adapted strategies to optimize the treatment of newly diagnosed DLBCL by using what we have learned in the relapsed and refractory setting.
Dr. Moskowitz has been recognized for his research on a national level through multiple awards. He has lectured worldwide on lymphoma and stem cell transplantation. In addition, he is a member of the research council at MSKCC, and on the steering committees for the bi-annual international lymphoma conference in Lugano and international Hodgkin lymphoma conference in Cologne.
From NYU School of Medicine and NYU Perlmutter Cancer Center:
An alumna of the University of Pennsylvania School of Medicine, Dr. Diefenbach completed her internship and residency at the Johns Hopkins Hospital and her oncology fellowship at Memorial Sloan-Kettering Cancer Center, where she spent an additional year focusing on translational immunology.
Her scientific research focuses on the relationship between lymphoma and immunity; on developing novel and immune based treatment strategies for patients with relapsed lymphoma; and on biomarker discovery. She is currently leading a national clinical trial for relapsed Hodgkin lymphoma investigating the combination of the antibody drug conjugate brentuximab with the immune activating agents ipilimumab and nivolumab.
Dr. Diefenbach directs the lymphoma clinical research within the Hematology/ Oncology Division at the Perlmutter Cancer Center. She is a member of the ECOG Lymphoma Committee, the NCI Lymphoma Steering Committee Clinical Trials Planning Meeting, and the Editorial Board of Clinical Cancer Research. Her research is supported by the Lymphoma Research Foundation, the American Cancer Society and the National Cancer Institute (NCI).
From Tufts University School of Medicine and Tufts Medical Center:
DR. ANSELL: My name is Stephen Ansell, from Mayo Clinic, Rochester, Minnesota. I’m joined by Drs. Craig Moskowitz, Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Medical College of Cornell University, Catherine Diefenbach, Assistant Professor of Medicine at the NYU School of Medicine and the NYU Perlmutter Cancer Center, and Andy Evens, Professor of Medicine at Tufts University School of Medicine, and Faculty Member at Tufts Medical Center in Boston.
Welcome to all of you and thank you for participating in this medical roundtable discussion. The focus today is going to be on practical management of Hodgkin lymphoma. This is a very experienced group of roundtable participants whom I hope will give us valuable insights into some of the questions relating to managing Hodgkin lymphoma.
Let’s talk about patients with early stage Hodgkin lymphoma and discuss what we feel the standard management might be and how we would use positron emission tomographic (PET) scans to direct therapy. Craig, I’m going to ask you to start. Please discuss what your standard management of early stage Hodgkin lymphoma is and how you use PET scans to direct your treatment.
DR. MOSKOWITZ: I divide Hodgkin lymphoma, early stage, into three groups; favorable early stage, unfavorable early stage without tumor bulk, and stage two disease with tumor bulk. The standard management is well borne out these days from the German Hodgkin Lymphoma Study Group.1,2 For early stage favorable Hodgkin lymphoma I treat men and women quite differently.
For men with stage IA or IIA, non-bulky disease, I tend to use standard treatment, which is short course combined modality therapy with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and involved-field radiation. I do not use PET imaging in that setting. For women, however, as you know, the median age is young in this patient population. I’ve adopted a RAPID approach for these folks. I give 3 months of chemotherapy and then repeat the PET scan and if the PET scan is negative I stop treatment. If the PET scan is positive, I treat the patient as per that study, which was one more cycle of chemotherapy and radiation. But unfavorable early-stage disease without tumor bulk, once again, the issue is, should patients get chemotherapy alone or should they get combined modality therapy?
If I’m giving combined modality therapy, I do not use PET imaging. If I’m using chemotherapy alone and if this is a patient eligible for a RAPID approach I treat as above. If the patient was not eligible for RAPID because they had stage IIB disease, I usually give full course chemotherapy and I do not use PET imaging.
For patients with bulky stage II disease, I treat based upon the randomized cooperative group study, which is four to six cycles of chemotherapy followed by radiation. I do not use PET imaging in that setting.
DR. ANSELL: Craig, thanks. Andy, do you actually escalate therapy at any time based on PET results, or deescalate therapy? We heard from Craig that he follows some of the RAPID guidelines. Give us your perspective.
DR. EVENS: I think they’re all good questions. In a way, it’s not one size fits all. I think it has to be a very individualized patient-by-patient treatment decision. In other words, I might approach a 19-year-old woman with a bulky mediastinal mass differently than a 45-year-old man with a right cervical lymph node. This is one important point to convey. In terms of PET-adapted, I think it is evolving. The question is, is there any actionable evidence to go on?
In terms of where there are more data, which is in early negativity in terms of PET-2 negativity, there have been a couple publications alluded to—RAPID and the European Organisation for Research and Treatment of Cancer (EORTC)3—and I’m not sure those data changed the opinion if we didn’t have an early negative PET scan. We know, without an early negative PET scan, that patients who do not receive consolidative radiation have a small improvement in progression-free survival (PFS) and no difference in overall survival (OS).
What both of those studies showed is that basically persists. That margin of difference might be a little less—instead of 6%–8% difference in PFS, it might now be 4%–6%, but both studies proved to be not noninferior, so I’m not quite sure that has changed how I treat someone. In other words, an early negative PET scan. For PET positivity, the data are really evolving. I think, before the Lugano meeting this past June I would have said no.
I just saw a very recent second opinion on a younger patient in her mid-20s who had a bulky mediastinal mass, and then after two cycles was definitely better, but still PET positive, defined as it was a smidge greater than the liver, and the data that emanated from Lugano on early PET positive showed not only a PFS advantage, but a borderline OS, and that, of course, would be a game changer if PET-adapted therapy is pointing toward an OS advantage.
DR. ANSELL: Catherine, what’s your sense of the role of radiation therapy in early stage Hodgkin lymphoma?
DR. DIEFENBACH: As Andy said, the role of PET to stratify early stage patients is evolving. Another study that was reported in Lugano was the Response-adjusted Therapy for Hodgkin Lymphoma (RATHL) study4 where it appeared that for patients who had an early PET negative, the bleomycin could be omitted and the patients ended up with a PFS that was equivalent to patients who did not have bleomycin omitted. The decision of combined modality therapy vs standard therapy—I think Andy and Craig put it really well—will have to be individualized to the patient’s situation: specifically, to their age, sex, bulk of disease, and response after early disease assessment.
DR. MOSKOWITZ: That’s why it’s so hard to study this patient population. You have three folks on the phone and we’re all treating patients differently with an individualized approach. It’s almost impossible to come up with a clinical trial that everybody would be comfortable with in this patient population, which is why we have difficulty in writing one, which is disappointing.
DR. ANSELL: Craig, I wanted to circle back to you. The German Hodgkin Lymphoma Study Group has shown that if you omit bleomycin there is a slight decrease in outcome;5 however, the RATHL trial would suggest maybe not.6 Has that impacted your practice at all? Do you omit bleomycin in your regimens or do you use it standardly?
DR. MOSKOWITZ: Well, RATHL is for advanced stage disease and I’ve already stopped giving bleomycin to patients who are PET negative after 2 months of ABVD based on that approach; but I do not omit bleomycin for an early stage disease based upon the results from the German Hodgkin Lymphoma Study Group. We’re not giving full course chemotherapy in the early stage setting, so I’m willing to give the appropriate number of cycles, at least for now.
DR. ANSELL: Thanks for your perspectives. I think as it was pointed out, there’s a lot of individualization here and we still have an evolving role of PET scanning. Also, there are multiple new agents we’ll begin to talk about later in the program that may impact things further. So, I think this remains an area where it’s quite challenging to determine the optimal approach.
I want to turn our attention to talk about patients with advanced stage disease—predominantly stage III and IV disease. Catherine, how do you treat patients with advanced stage disease? What’s your approach, and as new agents are coming along, agents like brentuximab vedotin, where do you think they fit into your approach?
DR. DIEFENBACH: Just as Craig said, there isn’t really a one-size-fits-all approach to advanced-stage patients either. Just as early-stage patients are divided into at least three groups, we look at advanced-stage patients as a very heterogeneous population. One of the ways we stratify advanced-stage patients is based on what we call their risk score.
Traditionally, we’ve used the Hasenclever risk score—or the International Prognostic Score (IPS)7—which looks at seven clinical factors to get a sense of how these advanced-stage patients are going to do in terms of their PFS and OS.7 More recently, we have a manuscript where we’re looking in the modern era at using a streamlined score with only three of these factors instead of seven factors8 and the group from British Columbia has showed that, while this Hasenclever risk score is still relevant,9 it looks in the modern era with modern chemotherapy that it may be less helpful than it previously was, because the patients who did much worse are doing better, so the curves are narrowed.
Nonetheless, biologically and clinically, there’s a big difference between advanced-stage patients who have zero to two risk factors and advanced-stage patients who have five, six, or seven risk factors. The standard of care for treatment for advanced-stage patients both in the US and internationally has been either the chemotherapy regimen of ABVD or the chemotherapy regimen of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).10,11 There has been a controversy between those who prefer escalated BEACOPP and those who prefer ABVD. Escalated BEACOPP has a superior PFS to ABVD, which didn’t necessarily translate into an OS benefit, and patients who fail ABVD may be salvaged with stem cell transplant and second line chemotherapy and stem cell transplant.
Patients with escalated BEACOPP also have substantial therapy-related toxicity that patients with ABVD do not have, such as infertility and myelosuppression, higher rates of neutropenic fever, and higher rates of secondary leukemia, so there’s a cost associated with being treated with escalated BEACOPP that’s not associated with ABVD. With both regimens, the cure rate is approximately 75%–80%, so those who favor ABVD—I would consider myself one of them—would argue that you spare a certain number of patients who are salvaged with ABVD and who are cured unnecessary toxicity with the escalated BEACOPP. Those who are in favor of escalated BEACOPP for all patients would probably argue that an increased PFS should translate into an increased OS, and there have in fact been meta-analyses that show improved OS in some older trials with BEACOPP compared to ABVD, but this is a meta-analysis across many different trials.
More recently, brentuximab vedotin—an antibody drug conjugate, against CD30, which is expressed on the Hodgkin Reed-Sternberg (HRS) cell—combined with auristatin—a taxane-like cytotoxic chemotherapy—which acts like a Trojan horse, is delivered to the HRS cell, taken up by the HRS cell and then blows up the HRS cell while sparing, to a large extent, the microenvironment, has been incorporated into upfront therapy with ABVD.
Brentuximab was approved by the Food and Drug Administration (FDA) to treat relapsed Hodgkin lymphoma based on the pivotal study, which had an overall response rate of approximately 75% for relapsed patients.12 Based on this it was incorporated into upfront therapy. There was a phase I study which I think, Steve, you actually led, which combined ABVD with brentuximab vedotin.13 This, however, resulted in excessive pulmonary toxicity secondary to bleomycin, so bleomycin was then omitted. The data were reported at the American Society of Hematology (ASH) meeting and showed a 3-year failure free survival of 96% and OS of 100%, which is extremely impressive in this population. The Phase 3 Frontline Therapy Trial in Patients With Advanced Classical Hodgkin Lymphoma (ECHELON) [NCT01712490] is currently underway and should complete accrual this year.
I think that these data will certainly help to answer the question of whether incorporating brentuximab into the upfront regimen of ABVD can improve both PFS and OS for these patients and perhaps put BEACOPP, finally, to rest.
DR. ANSELL: Andy, do you have a place in your practice where you think escalated BEACOPP has a role?
DR. EVENS: The quick answer is yes, but that sliver of practice is extremely small, and as time is going on, it’s getting smaller. I think in the pre-response adapted era—5 to 10 years ago when BEACOPP was first published—it did show an OS advantage, but many people would argue the comparator or COPP/ABVD arm isn’t equivalent, so to speak, to contemporary ABVD.
I was using it mainly in patients with high IPS—patients who had a five, six, or seven. That, frankly, is not a large percent of the patient population. Now, in the PET-adapted, we don’t quite have that actionable evidence, as much has accumulated quite yet, as early stage disease. Even in the patients now with high IPS, I have to admit, I’m really starting with ABVD in everyone and only considering escalating in patients who have a positive PET scan, which I guess in my practice is somewhat lower than the clinical trial data.
The clinical trial data in advanced-stage disease would say that’s 15%–20% of the patients.14 I tend to find it’s closer in the 5% range. I think part of that is viewing the PET-adapted part we keep talking about—it can’t be viewed in a vacuum, meaning you shouldn’t review a report. You should sit side-by-side with your radiologist and try to review that scan, and while doing that, have a clear meaning of what defines PET positive and PET negative, because almost every study we talked about has it slightly different. Where’s the cut point? Is it at the liver—meaning a Deauville score of four or five—or is it less in the liver, etc? So, I think those types of things are very important to understand and appreciate when treating the patients.
DR. DIEFENBACH: Andy, I completely agree with you and I also would have a role for BEACOPP in a patient who was not responding to ABVD with interim scans. I also, at that time, if the patient was by PET/computed tomography unequivocally refractory, I would consider clinical trial probably in the same vein as the escalated BEACOPP. So, I agree with Andy that I have a sliver of patients for whom I do consider escalated BEACOPP, but that is a very small sliver.
DR. ANSELL: Craig, what’s your comment about modifications that are happening, even to escalated BEACOPP? The BrECADD regimen is incorporating new agents like brentuximab vedotin.15 What’s your thinking about that regimen?
DR. MOSKOWITZ: I don’t treat patients off protocol with protocol based treatment, so my familiarity with it is low. Just to digress for one second, I think that I have definitely changed my practice and I would say that I used to give BEACOPP quite a bit for patients with four to seven risk factors, which is about 20% of the patient population. I think, based upon two fairly large studies that will have about 1700 patients on, the RATHL study and the intergroup study in the United States—it’s fairly clear—to me at least—that one can start with ABVD chemotherapy.
Since 80% of the patients have a negative interim PET scan, despite the number of pre-treatment risk factors they have, you’re really limiting the number of patients who get crossed over to a more complicated program, so I’ve been using that approach. I’m very comfortable with it.
The issue of giving brentuximab vedotin with AVD as part of primary therapy is, once again, investigational, and I have many concerns about the cost of that treatment program and it’s applicability worldwide even if the study is positive.
DR. ANSELL: I think that’s a good point. One of the things I find very interesting as we talk about the escalated BEACOPP vs. ABVD comparison is that as brentuximab vedotin has been mixed into those two regimens, it’s almost as if those two regimens are coming toward each other. ABVD is being somewhat escalated in intensity and escalated BEACOPP being modified down. I think at the end of the day, we’re going to come to a combined approach that suits people on both sides of the intensity debate. Cost, however, is going to be an issue to make this an internationally usable regimen, so I think that’s a real challenge.
I want to pick up, Craig, on the point you made about risks of relapse and so on. When and if patients relapse, what do you use in your practice as the optimal salvage regimen? Also, I know you’re a big advocate for your patients to attain a complete remission before going to transplant, would you like to explain why?
DR. MOSKOWITZ: Once again my opinion about this has evolved over the years, but I think that I’m fairly comfortable right now that almost all these salvage regimens are quite similar. They have variable toxicity profiles, but if the treatment is given correctly and you look at the published literature, somewhere between 60% and 80% of the patients will likely be in remission after salvage chemotherapy. As defined as a negative PET, based upon standard criteria, those patients have a marked survival advantage, looking at published literature thus far.
As I’m maturing, I’ve been trying to treat patients with less aggressive salvage therapy to try to get them into remission. For example, in patients with early stage disease who relapse with non-bulky and non-widespread disease, I’d be more inclined to give an outpatient chemotherapy regimen. Patients with widespread, extranodal involvement, I’d be more inclined to give inpatient treatment off study. On clinical trials, that’s a different story, but we’ve published now, multiple times, that overwhelmingly a complete response (CR) prior to a stem cell transplant abrogates almost all the other prognostic factors.
DR. ANSELL: Right. Andy, if a patient had a response, but not a CR, or maybe only a modest improvement, would you say that’s a deal breaker for moving onto something like an autologous transplant?
DR. EVENS: I would say for the majority of patients, yes. There might be that patient who, depending on what they’ve received in the past—particularly if they have already received brentuximab vedotin—might be someone we still take to an autologous transplant.
There’s a significant minority you can still cure who are chemo-resistant, but I think I completely agree with Craig. In the era of novel therapeutics, that’s becoming less and less. As more options come on the table, I think if you really have somebody who’s chemotherapy resistant—that can be defined, I guess, as a positive PET, although I do think there are some gray zones in defining positive PET—I think it would be someone I would really look toward a novel therapeutic.
DR. ANSELL: Catherine, there have been some recent data about maintenance therapy after an autologous stem cell transplant. What’s your take on that?
DR. DIEFENBACH: I think the most recent data on maintenance therapy post autologous stem cell transplant comes from the AETHERA study,16 which Craig was the lead author on, and this investigated the question of whether using brentuximab vedotin as a consolidative therapy after transplant—as a maintenance therapy—improved PFS in this patient population.
The patients in this study who had relapsed disease were randomized between receiving brentuximab vedotin or being observed. Patients were treated for 16 cycles, which is approximately one year with this therapy, given every 3 weeks. Data from this study were in favor of brentuximab vedotin. The group that received brentuximab vedotin as opposed to being observed had a PFS of 42.9 months vs a PFS of approximately 24 months in the group that wasn’t treated with brentuximab vedotin.
This says a few interesting things. This demonstrates that most patients who are going into transplant are not doing so with optimal disease control. If all patients were going into transplant in a CR with only micrometastatic disease, there would not be such a stark difference between these arms. I think this study very nicely demonstrates that patients who benefit most strongly from the maintenance therapy are the patients who are considered to be the highest risk.
These are the patients with refractory disease who go into transplant with a high degree of tumor bulk, or patients who relapse within a short time—less than 12 months after their initial therapy—suggesting they didn’t really obtain optimal disease control with their therapy, or they had extranodal disease or disease outside of the lymph nodes affecting vital organs or bone marrow. These high-risk patients, based on these criteria, appear to be the ones who benefit the most from brentuximab maintenance. I think it gets a little tricky, however, because none of these patients receive brentuximab in their upfront therapy. So, going forward, it’s going to be an even harder question to ask—how are high-risk patients who receive brentuximab initially going to benefit from receiving a therapy that they relapsed from after receiving?
Getting brentuximab was not a free ride. There was a significantly higher amount of both sensory neuropathy, and about 20% of patients had motor neuropathy in the brentuximab group vs the non-brentuximab treated patients.
Finally, there was no difference yet—and this will still mature—in OS between the groups because the patients who didn’t get brentuximab were able to cross over and get it. This goes back to the old question with rituximab when rituximab maintenance was looked at. Is it better to receive brentuximab vedotin maintenance after transplant or is it better to receive it if you relapse after transplant? I think we won’t know the answer to that question for a few more years when we really see if the PFS translates into durable survival in the brentuximab treated group vs the non-brentuximab treated group. As Craig has alluded to with regard to the cost with respect to upfront therapy, I think this adds substantial costs subsequent to stem cell transplant. If we are going to use this therapy, I think we’ll have to be very clever in how we risk assess the patients who proceed to transplant, both prior to transplant and in terms of deciding whether they receive therapy.
There are actually efforts underway right now—internationally—to use better risk discrimination criteria for relapsed Hodgkin lymphoma to define a higher population of patients who are truly high risk, you might have the highest likelihood of benefiting from this sort of consolidative strategy.
DR. ANSELL: Craig, please comment. Catherine mentioned that the addition of brentuximab wasn’t without financial cost, and that there is also a toxicity cost. You led the study, what are your comments on the side effects of a year’s worth of brentuximab vedotin?
DR. MOSKOWITZ: I think, shockingly, the median number of doses that patients received on the study was 15, so almost a year or full course. In general, neuropathy is similar to every other single study that’s been looked at with single agent brentuximab. Peripheral neuropathy is real. For me, if a patient gets a dose reduction and the neuropathy does not improve, I would just stop the treatment. That’s how I practice.
I think the question Catherine raises is an extremely good one about patients who had a brentuximab vedotin pretransplant. Should they get brentuximab vedotin post-transplant? That’s something that’s clearly going to evolve, and the number of doses that a patient will receive post-transplant is going to evolve, but I think for the audience listening, this is here to stay for the next couple of years.
The FDA approved this August 17, so transplant physicians are going to initiate brentuximab vedotin therapy prior to the patient returning to their medical oncologist. It’s the medical oncologist who’s going to decide how many more cycles of brentuximab should be administered, because these folks would already have received three cycles by then.
Transplant physicians have to report 90-day efficacy data. In general, therefore, transplanters will see the patients up to around day 90. Brentuximab is administered between days 30 and 45 post-transplant, so by definition, the Hodgkin lymphoma patients who have met the criteria of the study are going to receive it. Medical oncologists need to decide what to do after that time point.
DR. DIEFENBACH: Craig, my question to you is given what the study showed—that the patients with the highest risk receive the most benefit—would you recommend giving this to everyone who undergoes a transplant, or really to the patients per the study who are considered to have at least one of these three risk factors?
DR. MOSKOWITZ: I only treat patients with maintenance who were potentially eligible for the AETHERA study. That means remission duration of less than one year, primary refractory disease, or extranodal involvement. If they did not meet those criteria, I do not recommend maintenance.
DR. ANSELL: Most of what we’ve discussed to far, with all of our therapeutic options, have been most likely to be utilized in younger patients—patients who can tolerate the intensive regimens, patients who can receive salvage therapy and can get a transplant. Elderly patients are a real challenge to treat. Andy, you’re an expert in this area—how do you manage a 70-year-old who presents with Hodgkin lymphoma? Are there some new options we should bear in mind as we think about these patients?
DR. EVENS: Yes, it’s definitely a challenging patient population. A recurring theme is there’s not a one-size-fits-all. Age 70 might fall right in the middle, but the definition of elderly, for better or for worse, has been greater than age 60 in most clinical studies and other analyses, but again, that 60-year-old vs the 85-year-old in a wheelchair will be approached differently.
Let’s say we take that sweet spot of someone in their early 70s who is still performing all their activities of daily living and most of their instrumental activities of daily living with a performance status of one—the quick answer off of a clinical study is I’d probably use AVD (AVBD without the bleomycin). We, and others, have reported the incidence of bleomycin lung toxicity and the number one risk factor is age. That’s part and parcel related to the renal clearance of bleomycin and knowing that that is a risk factor.
Are there other risk factors, such as preexisting lung disease, etc? Yes. We recently looked at what we called the contemporary era, meaning post 2000, when I was at Northwestern in Chicago—we collected close to 100 patients.17 It was more of a real-world population, it was whether or not you were on a clinical study, and a third of patients in that analysis had developed bleomycin lung toxicity. The mortality rate, if you developed bleomycin lung toxicity, was 30%.
If anyone’s ever had a patient die from that, they know it’s quite significant. We corroborated those data when we took a subset analyses out from E2406, the phase III randomized study of Stanford V vs ABVD. The rate of bleomycin lung was not quite as high. This again was a clinical study—probably a healthier population—but it was just under 30% with a mortality rate of just under 20%. To me it’s just too slippery of a slope. It’s hard, besides age, to predict who’s going to develop it. I think we’ve already mentioned some of the data. If we had to say which is the weakest link or the least potent of the ABVD, it would be the B.
That’s all for the clinical trial. Thankfully there are, now, clinical trials specifically carved out for this patient population of untreated older patients with Hodgkin lymphoma. We’re participating in a clinical trial with Paul Hamlin at Memorial Sloan Kettering and other sites where we’re utilizing a sequential approach integrating brentuximab vedotin. We rationalized that concurrent therapy would likely be too tough for these patients, so it’s designed in more of a window study where we start with two cycles of brentuximab vedotin given every 3 weeks, followed by chemotherapy, AVD, and then followed by consolidation therapy.
The study is not done yet. We have reported interim results at the recent Lugano meeting that was alluded to,18 and we showed yes, there’s still some toxicity, including to the brentuximab vedotin. But the disease related outcomes were phenomenal in the early report, upwards of 95%, which again is another theme in elderly Hodgkin that I didn’t talk about. One is the tolerability of therapy, and second is a strong sentiment—if not scientific hypothesis—that it’s a different disease biology, in other words, more aggressive. You see more mixalarity, Epstein Barr Virus related. Those are a couple of considerations. There are also studies out there that are looking—and especially the frail patients, maybe that 85 year old or so—what about single-agent novel therapeutics such as brentuximab vedotin or I’ve even heard through the grapevine now PD-1 inhibitors being tested as single agents in this patient population.
DR. ANSELL: Right, I think these are exciting times and there are data to be watched for in elderly patients. I want to talk about patients that have failed an autologous transplant. In the past, the typical next modality of therapy was an allogeneic (ALLO) transplant. Seeing as Craig is a guy that’s done a lot of transplants in the past—what do you see as the role of ALLO stem cell transplants? There are a lot of data now for new drugs in post-autologous failure patients, including brentuximab vedotin and PD-1 blockade. So, I guess the question is, has ALLO stem cell transplant for Hodgkin lymphoma gone away?
DR. MOSKOWITZ: Well, I see it as a slow, painful death to be perfectly honest.
DR. EVENS: No pun intended.
DR. MOSKOWITZ: No pun intended. We’ve been studying the checkpoint inhibitors as have you, Steve, for about 2 and a half years, and I will say that during this time, I have sent one patient to an ALLO stem cell transplant and that was a patient who really had a fairly poor response to nivolumab.
I find it very hard to pull the trigger, so to speak, to send a patient for an ALLO transplant now when the patients are receiving modern checkpoint inhibition and tolerating it so well with stable Hodgkin lymphoma that is not affecting their day-to-day life.
This, to me, is the most difficult question you’ve addressed so far on this teleconference. For someone who’s been doing this for a long time, I’m not sure at the present time who should get an ALLO transplant for Hodgkin lymphoma. I think it’s a difficult area. It’s unclear to me how to study it.
DR. ANSELL: Catherine, you’ve also done a lot of work with immune checkpoint inhibitors and combination studies. Give us your perspective on when to use brentuximab vedotin, when to use PD-1 inhibition, and when to use combinations.
DR. DIEFENBACH: I think most of these, Steve, are still research questions to a certain extent. Of these novel agents, the only one that is FDA approved for use in a relapse patient is brentuximab vedotin, which is approved for patients who have failed two or more chemotherapy regimens.
In practice, brentuximab is used much more commonly. If I have a patient who doesn’t have a huge amount of bulky relapse and is for some reason not a trial candidate I might well consider second line therapy with brentuximab as opposed to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy. There are data both out of City of Hope and Sloan Kettering showing that the efficacy for brentuximab vedotin in second line is at least equivalent to the data we saw in later line with respect both to the CR rate and the overall response rate, if not better.19,20
I think there’s an established role for brentuximab vedotin. There are other agents which are being used in the community that are not approved but are certainly looked at in combination or being used off-label, such as bendamustine, which also has published phase II data showing that it is also effective in relapsed Hodgkin lymphoma.21 I think really, with regard to second line, the goal is to get to a CR, and anything that can get you to a good CR to make autologous transplantation more effective is probably a good way to go. But I think the more interesting question is really how are we, in the future, going to design therapeutic strategies and therapeutic platforms that are really biologically based and relevant to Hodgkin lymphoma biology, rather than just taking something from column A and something from column B off the shelf?
I think the checkpoint inhibitors particularly speak to Hodgkin lymphoma biology, because what they’re doing—you have the PDL-1, which is expressed on the Hodgkin tumor cell (the HRS cell), and the PD-1 is actually on the T cells of the Hodgkin lymphoma microenvironment, and by blocking the ability of the T cells to interact with the Hodgkin lymphoma cells, you’re not actually directly killing anything.
What you’re doing is actually taking the activated T cells, which are switched off, and turning them back on the way you’d turn a light on and saying go do your job, go kill the HRS cells. We actually have a trial that’s open right now in which we’re combining brentuximab vedotin with a checkpoint inhibitor, ipilimumab, trying to do just that. We are trying to use the brentuximab to kill the HRS cells in bulk and release antigen and stimulate the T cells and we’re going to combine this with the PD-1 inhibitor nivolumab as well, and we’re planning to look at the triplet combination of dual checkpoint inhibition with ipilimumab and nivolumab with brentuximab and that study is open [Ipilimumab, Nivolumab, and Brentuximab Vedotin in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma; NCT01896999].
There are other studies ongoing, looking at brentuximab and nivolumab in combination as well. I think there’s a study planned, as Andy alluded to, in the elderly population as well as another study that is planned by pharmaceutical companies.
I think with regard to immune agents, we’ve only really scratched the surface, and everyone is very excited right now about these checkpoint inhibitors, but the immune microenvironment is composed of more than just some CD-4 cells that are sitting around in a switched off state. We have macrophages and dendritic cells and natural killer cells and I think there a lot of other exciting immunologic agents that are both being used right now in solid tumors and are being used pre-clinically that may have very exciting applicability for Hodgkin lymphoma.
Finally, there are the signaling agents—not to ignore them—like, the JAK/STAT inhibitors which is a pathway that’s highly upregulated in Hodgkin lymphoma cells and other agents, such as epigenetic agents, and I think going forward, the rational platforms are really going to combine these agents in intelligent ways and try to target the Hodgkin lymphoma in a way that can really obviate the need for ALLO transplant. I, as Craig, have the same issue with my patients who are on PD-1 inhibitor therapy. It’s very hard to see them doing so well and to really pull the trigger on referring them for an ALLO transplant.
DR. ANSELL: I’d like to summarize our roundtable discussion by saying These are exciting times. There are lots of changes in Hodgkin lymphoma that are developing as we watch, and the exciting thing is to see how we can optimize early stage therapy to minimize toxicity and maintain benefit., optimize advanced stage initial treatment to get the best results, again with the least toxicity, and then how to integrate these new agents with great promise into frontline therapies and salvage therapies so that, hopefully, down the line, we see more and more patients that are cured of their disease right away with initial treatment.
I want to thank Craig Moskowitz, Catherine Diefenbach, and Andy Evens for their participation.
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