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Jul 10, 2020

In this episode, Dr. Catherine Diefenbach, Director of Hematology Translational Research and the Clinical Lymphoma Program at NYU Langone's Perlmutter Cancer Center, discusses clinical trials that address relapsed Hodgkin lymphoma and innovative methods using new or immune-based therapies to find new ways to control the disease.

 

Transcript

ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll. I'm delighted to welcome Dr. Catherine Diefenbach to the podcast today.

 

Dr. Diefenbach is Director of both Hematology, Translational Research, and the Clinical Lymphoma Program at NYU Langone's Perlmutter Cancer Center. She is also Associate Professor in the Department of Medicine at NYU Grossman School of Medicine. And she joins us today to discuss relapsed Hodgkin's lymphoma and innovative methods to control the disease.

 

Dr. Diefenbach serves in an advisory role for Seattle Genetics, Merck, and Bristol-Myers Squibb and receives funding from these organizations. Full disclosures are available on our episode pages. Dr. Diefenbach, it's great to have you on the podcast today.

 

Dr. Catherine Diefenbach: Geraldine, thank you so much for inviting me. I'm delighted to be on your podcast.

 

ASCO Daily News: You have presented data at several meetings highlighting different arms of your ongoing clinical trial combining checkpoint inhibitor with immunotherapy. And you are currently leading a national clinical trial for patients with relapsed Hodgkin's lymphoma. Can you tell us about this study?

 

Dr. Catherine Diefenbach: Yes, I'd be very happy to. So, back in 2013 when there was no immunotherapy in the lymphoma space, we hypothesized that activating the immune microenvironment in Hodgkin's lymphoma and combining this with a tumor-targeting agent, such as an antibody-drug conjugate, might be a way to overcome resistance for patients with relapsed Hodgkin's lymphoma.

 

We began this trial as a single-arm, phase I in the cooperative groups, combining the antibody-drug conjugate brentuximab vedotin with the immune checkpoint inhibitor ipilimumab. And, as nivolumab became incorporated into the CTEP portfolio, we expanded this into a three-arm, phase I trial to include an arm containing brentuximab and the checkpoint inhibitor nivolumab and then a triplet arm of brentuximab, ipilimumab, and nivolumab.

 

There's strong biologic rationale for doing this in Hodgkin's lymphoma because Hodgkin's lymphoma has a biology that's unlike any other lymphoma or really any other cancer. While most cancers, if you look at them under a microscope, have sheets of monomorphic cells, in Hodgkin's lymphoma, the microenvironment is composed of less than 1% of the tumor cells or the Hodgkin Reed-Sternberg cells and, instead, is made up primarily of the cells of the patient's own immune system, including dendritic cells, macrophages, monocytes, and T cells.

 

For this reason, we thought that the idea of priming the immune system to reject, rather than tolerate, tumor was one that had a strong scientific rationale in Hodgkin's lymphoma, even though it didn't have a high antigenic burden in the classic sense of being an immunologically hot tumor that was commonly understood in the solid tumor world.

 

So, beginning with the arm of brentuximab vedotin and ipilimumab, we enrolled patients sequentially into, initially, dose escalation and then a dose expansion for each cohort. So we enrolled brentuximab ipilimumab first, then brentuximab nivolumab, and then brentuximab, ipi, and nivolumab.

 

Both brentuximab and nivolumab have single-agent activity with very high overall response rates for relapsed patients, but the complete response rate for both single agents is quite low. For nivolumab, it's between 12% and 24%. And, for brentuximab, it's about 34%.

 

And the PFS test for brentuximab is about 5.4 months. The PFS for nivolumab is longer, but it's approximately 12 months. So we know that most patients do relapse on these therapies eventually.

 

Although, with both agents, there are some extremely long responders. There's been a subset of patients in the initial brentuximab vedotin pivotal trial who remain in remission for many years after brentuximab. This is a small subset of the CR patients. And remissions to checkpoint inhibitor are durable for a subset of patients, but none of the PFS lines seem to be plateauing with longer follow. So it was clear that more innovative strategies were needed for relapsed patients.

 

We saw that, for our arm of brentuximab and ipilimumab, we had a CR rate of 50%. For brentuximab and nivolumab, we had a CR rate of 65%. And, for the triplet combination of brentuximab, ipi, and nivolumab, the CR rate, the Complete Response rate, was over 80%. This included patients who had previously received brentuximab.

 

40% of our patients were already relapsed after autologous stem cell transplant or allogeneic stem cell transplant. And 57% of our patients were refractory or had not responded to their most recent therapy. So this basically showed us that patients with relapsed Hodgkin's lymphoma who were resistant to classic chemotherapy or had not responded to stem cell transplant could still obtain a complete response when you combined a tumor-targeting antibody-drug conjugate with an immune checkpoint inhibitor.

 

We have followed our patients now for more than two years in both doublet arms and for nearly two years in the triplet arm, which is the longest follow-up for patients treated with these agents. Additionally, as 40% of our patients were post-transplant, we have some indication for how patients who don't use this therapy as a bridge to transplant end up doing.

 

And we saw that the progression-free survival appears quite durable for patients on both nivolumab-containing arms. And, in fact, for patients on the triplet arm, the duration of response, at least at this point with about 18 months of follow-up, appears to be equivalent between patients going to transplant and not going to transplant.

 

We did see that toxicity was a little bit higher in the triplet arm compared to the doublet arm with more grade 3 toxicities and slightly more therapy discontinuations. However, most patients in all arms tolerated the therapy extremely well.

 

Many patients went off for a stem cell transplant and are doing very well with a post-transplant progression-free survival that is between 80% and 100%. And this compares extremely favorably to patients who use chemotherapy as a bridge to transplant where the post-transplant progression-free survival is closer to 55% or 60%.

 

So we're very excited and encouraged by these data, and they have actually formed the foundation of a national randomized phase II trial, which is currently ongoing throughout the [? ECTN, ?] comparing the doublet brentuximab and nivolumab to the triplet of brentuximab, ipilimumab, and nivolumab with a primary endpoint of complete response rate, but secondary endpoints of progression-free survival, tolerability, safety, and outcome of patients who do and do not go to transplant.

 

ASCO Daily News: Excellent, now, speaking more broadly, what are the different recommendations and treatment strategies for relapsed Hodgkin's lymphoma?

 

Dr. Catherine Diefenbach: Thank you. This is a very interesting question. I think, for a long time, autologous stem cell transplant has been the standard of care for patients with chemotherapy-sensitive relapse. So that includes patients who relapse more than six months after their initial chemotherapy or patients with primary refractory disease, which is defined as relapsing within six months of first-line chemotherapy who are able to obtain a second complete response or near complete response and good disease control with second- or third-line chemotherapy. And that's certainly the goal of a lot of investigational therapy to come up with better bridges to transplant because we know that, if you go to transplant in a complete response, you have a much better outcome than if you go into transplant with disease.

 

So our study can potentially be used as a bridge to transplant. And about 36% of our patients did use our therapy as a bridge to transplant. Other potential bridges to transplant include the combination of bendamustine and brentuximab vedotin, which has been recorded by Ann LaCasce and others. Other brentuximab combinations, the regimen ICE is still used, gemcitabine-containing regimens.

 

So I think what is really exciting is that there are many ways now to get patients to transplant. So the goal should really be, if you can obtain a remission, to go to transplant with the optimal disease control. If you obtain optimal disease control, autologous stem cell transplant is really the most widely used and safest methodology to obtain a cure for relapsed patients.

 

And we know that approximately 50% of patients who go to autologous stem cell transplant, at least if they're induced with traditional chemotherapy, are cured. So that means that we can salvage quite a large number of patients with autologous stem cell transplant.

 

And I did not encourage anybody on E4412 to defer or delay or not go to transplant when they asked me. I'm enjoying this treatment. I want to not go to transplant. I would tell them this is experimental. We don't know how this is going to work long term, and transplant has decades of data to show that it cures patients. So please go to transplant.

 

However, transplant does have significant toxicities with it including much higher rates of infertility compared to patients who get first-line chemotherapy or immunotherapy, as well as long-term potential damage to stem cells and a higher risk of MDS and hospitalization and other consequences for younger patients. For older patients, obviously, transplant is more toxic. And then you also have a subset of patients who have relapsed after autologous stem cell transplant, and their curative options are much more limited.

 

So, for those patients, I think we really need to be thinking of more innovative ways to offer patients long-term disease control and potential cure. And I think the question of whether immunotherapy and checkpoint combinations do this is something that we're going to need more data before we're able to really determine.

 

We have some early signals in our study that look like potential flattenings of plateaus around two years, but these are small numbers. It's hard to read too much into this. Most of the patients in the other brentuximab nivolumab study reported by Herrera went to transplant. So it's hard to know how the non-transplant patients did because these were all transplant-eligible patients.

 

When we compared our transplant patients who went and didn't go to transplant, it was also not a randomized comparison. So the patients who didn't go to transplant generally tended to be post-transplant and have more refractive disease and have been more heavily pretreated.

 

The question of whether anything can replace transplant is an important research question that's going to need to be looked at in a large-scale randomized clinical trial. And it's something that we're actually in the early planning stages of considering as a phase III trial to use immunotherapy brentuximab combinations to ask the question of whether patients in complete remission can defer stem cell transplantation.

 

But, outside of a research trial, the standard of care for patients with relapsed Hodgkin's lymphoma should be an autologous stem cell transplant after obtaining good disease control. And, for patients who are not able to do this or who are relapsed post-transplant or who are not fit for transplant, there are many chemotherapy options, as well as immunotherapy options and clinical trial options.

 

ASCO Daily News: Well, Hodgkin's lymphoma is primarily a cancer of the young. And, for many patients, it is curable. But, for about 30% of patients, the disease will come back or be unresponsive to chemotherapy. What are the different approaches to try to get to cure for these patients?

 

Dr. Catherine Diefenbach: So I think, Geraldine, we talked about for the patients whose disease comes back, but who are sensitive to chemotherapy and can go to an autologous stem cell transplant. But, for the other patients who cannot go to transplant or relapse after transplant, options for them include checkpoint inhibitor therapy, brentuximab vedotin if they haven't had it before, clinical trials, such as my trial or other trials looking at brentuximab in combination with chemotherapy or immunotherapy.

 

There are CAR T cell trials for Hodgkin's lymphoma that have been reported last year at ASH. Although, these are not as far along as they are for non-Hodgkin's lymphoma. There are other antibody-drug conjugates that are being looked at for relapsed Hodgkin's lymphoma.

 

So I would urge patients with relapsed Hodgkin's lymphoma who are relapsed post-autologous stem cell transplant who are old and unfit or who are not able to obtain adequate disease control to benefit from transplant to look for innovative clinical trials that would offer reasonable toxicity and high likelihood of potential disease control, either because they're combining two well-known agents with well-known spectrums of toxicity and known efficacy rates or because they have already established phase I data or because they're an innovative biological trial.

 

I think, however, that we still lose far too many patients every year with Hodgkin's lymphoma. And we need newer and better strategies to improve outcomes for patients, such as patients who relapse after checkpoint inhibitor therapy or who relapse after CAR T cell therapy. We need to have more options for these patients.

 

ASCO Daily News: You serve as the principal investigator for numerous clinical trials at NYU Langone Perlmutter Cancer Center, many of which are exploring innovative methods of combining new targeted or immune-based therapies to find new ways to control lymphoma. You also recently presented really interesting data that was published in the May 2020 issue of the British Journal of Haematology on the impact of immunotherapy on subsequent treatment for both Hodgkin and non-Hodgkin lymphoma. Can you tell us more about this?

 

Dr. Catherine Diefenbach: Yes, Geraldine, I'd be happy to. This is actually really interesting work that was led by my fellow, Nicole Carreau. And it involved centers across the United States in which we collaborated in a retrospective analysis, looking at the impact of immunotherapy, specifically checkpoint inhibitor therapy, on the subsequent treatment.

 

And we hypothesized that, potentially, giving immunotherapy might, in a sense, reset chemotherapy sensitivity in patients. And there was some early data from this coming out of the solid tumor world. So we wondered if we might see this in lymphoma patients.

 

And so we looked in both Hodgkin and non-Hodgkin lymphoma patients. And we saw that Hodgkin lymphoma patients who got treated with immunotherapy and then responded and then progressed seemed to, in fact, have an enhanced response to chemotherapy compared to their response to treatment before immunotherapy. And this is exciting, and this is interesting in terms of how to design future trials because it raises the question of whether-- there are questions regarding how to sequence immunotherapy and chemotherapy and how to combine these agents and how to sequence them.

 

So what was really interesting and exciting was our non-Hodgkin lymphoma data. So we sort of expected that, in patients who responded to checkpoint inhibitor therapy, this might impact their next line of treatment, but most non-Hodgkin lymphoma patients do not respond to checkpoint inhibitor therapy. They're not a group of patients that are sensitive to this. And, in fact, in our non-Hodgkin's lymphoma patient group, the response rate to checkpoint inhibitor therapy was quite low, as is typical.

 

However, we saw a striking improvement in their next line of treatment that they got after the checkpoint inhibitor therapy compared to their response from the treatment they got before the checkpoint inhibitor therapy, suggesting that patients did not need to have a response to the checkpoint inhibitor therapy to experience this treatment sensitization effect. And this occurred in patients throughout the multiple centers that participated. It wasn't only at one or two centers.

 

And it really appeared to be independent of the response to the checkpoint inhibitor. So, patients who had stable disease or who progressed, both appeared to have this sensitization effect. And this data will be shortly published in the British Journal of Haematology.

 

ASCO Daily News: All right, let's talk about toxicities, a couple of questions. Is transplant always going to be necessary for cure? Because it involves a lot of toxicities. And how do the toxicities from standard chemotherapy differ from those resulting from immunotherapy?

 

Dr. Catherine Diefenbach: Those are both very good questions, Geraldine. I think we would say that, right now, transplant remains the standard of care. It has the most data behind it. And it is a known curative modality. That being said, the caveats are that there are significant toxicities, including risk of neutropenic infections, infertility, not being able to work for many months, and, of course, a long-term risk of MDS.

 

So the question of, over the future, whether anything will displace transplant, I think whatever-- I think the questions are really going to be, can you identify a group of patients for whom the relapse risk is potentially lower, that transplant could be deferred or delayed? And are there any other treatments that have a curability, not just a response rate, but a long-term, disease-free, progression-free survival rate over 50% that could potentially replace transplant where you could say, well, this would be our second-line approach and then use chemotherapy to go to transplant in third line? And so push transplant then to third line and give patients then three passes at a cure, instead of two.

 

So I could envision that happening if immunotherapy with antibody-drug conjugate or dual immunotherapy antibody-drug conjugates or immuno-chemo combinations can demonstrate, in large randomized trials, that they are equivalent to and no more toxic than transplant. And I would say, actually, that the standard should be equivalent to in PFS and less toxic than transplant. But, if that were the case, I think then there might be a subset of patients for whom transplant could be deferred.

 

The toxicities with immunotherapy are quite different than the toxicities with standard chemotherapy. So standard chemotherapy causes lowering of the white blood cell count primarily, which can cause risk of infection, anemia, which can cause tiredness, nausea, the vinblastine and brentuximab vedotin as well can cause a peripheral neuropathy, pins and needles in the hands and feet.

 

Those are really the main toxicities of ABVD, which is the standard chemotherapy we give here, and brentuximab vedotin, which is now approved in the first line as well. The chemotherapy regimen given in Germany, the BEACOPP regimen, has a significantly higher toxicity rate, but it's not given very frequently in this country, but, basically, has intensely increased amounts of neutropenic fever and all the toxicities we talked about.

 

The toxicity with immunotherapy is less myelosuppression than toxicities related to autoimmune activation, so hypothyroidism, skin rashes, rare instances of diabetes or diarrhea from inflammatory colitis. You can have pancreatitis. You can have eye inflammation.

 

Most patients on immunotherapy don't have any of these side effects and do very well, but these were some of the rare side effects that we saw on our trial. Additionally, both brentuximab vedotin and nivolumab have a small risk of lung inflammation called pneumonitis, which is also a concern, particularly if a patient smokes.

 

ASCO Daily News: Well, I want to thank you, Dr. Diefenbach, for sharing your insights on the different approaches in the treatment of relapsed lymphoma and more. Thank you so much for joining us on the ASCO Daily News podcast today.

 

Dr. Catherine Diefenbach: Geraldine, it was a pleasure to join you. And thank you so much for inviting me to be a part of your podcast.

 

ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please rate and review us on Apple Podcasts.

 

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