Ann LaCasce, MD, MMSc, discusses Hodgkin lymphoma and how to approach the different types of Hodgkin patients.
associate professor of medicine at Harvard Medical School and in the program director for the Dana Farber Farber Cancer Center um fellowship program and it's been a mentor to many of us. So I'm really glad that she to join and will present today on Hodgkin lymphoma. Great thanks so much Austin. Uh I hope everyone can see my slides here. We're good, good. Alright so here are my disclosures. So I'm going to break this up into really three main sections. The first I'm going to talk about the various modalities uh that we have to approach patients with Hodgkin and give a little overview of Hodgkin. And then we'll focus on early stage patients in advanced stage patients. And then actually 1/4 part with a little bit on patients with relapsed or refractory disease. So Hodgkin is actually quite an uncommon disease. As you know, you might forget that if you work at the farmer because we see a lot of Hodgkins, there's about 9000 new cases a year. Unfortunately the number of deaths is quite low at less than 1000. Uh This is a disease uh Most frequently diagnosed in the adolescent and young adult range. The median age is about 39 and you can see this big peak between 20 and 34. It's more common in the industrialized world where the nodule er sclerosis subtype predominates and its associated with a high standard of living uh in the developing world, the E. V. V. Associated subtypes, mixed singularity and lymphocyte depleted which is extremely rare and often associated with HIV are more common and you can see on the right the relative five year survival is very high and almost 90%. Uh And the demographics are there most common in whites but also seen in blacks and Hispanics very rare in asians pacific Islanders. So in terms of the history of the therapy of hodgkin is is really fascinating and really a success story in oncology. And it dates back to the 19 forties after there was an explosion in Bari during World War One with nitrogen mustard. And it was noted that both the civilians and the service men who were uh at autopsy were examined had um a play asia of their bone marrow and lymph node tissue. And this led to the hypothesis that perhaps we could use nitrogen mustard as a therapeutic agent in treating lymphoma. And this was done in the fifties uh and then mop was developed and then at the National Cancer Institute in 1970. Um DaVita and colleagues including George Cornell is shown here. We have to give a shout out to as the senior person in our group um cured uh patients with lymphoma for the first time. Uh A BVD was then introduced in the seventies, escalated via cop then came along and more recently we have Brent Taksim, a band, the checkpoint inhibitors and the overall survival of patients with Hodgkin's continues to improve and when you look at the chemotherapy in Hodgkin's mop was developed for drug regimen. Um With the idea that if you use multiple different agents with different mechanisms of action, you could overcome resistance. This was based on how tuberculosis was treated back in the day and 50% of patients were cured with mop, but it caused infertility and bone marrow stem cell damage leading to MDS or AML. Then a B. V. D. Was introduced and was initially tested as hybrid regimens alternating with mop and these were better than mop. And then a BVD became the standard of care. It is an effective regimen, has a very low risk of infertility and does not affect bone marrow stem cells. The one drug that we do worry about is the blue omission in particular with lung toxicity. But if you're cautious and some of our newer regimens drop it early based on response. Uh It's really a manageable drug and then escalated be a cop. Was introduced by the Germans who have really moved this field forward enormously. They do large randomized studies uh and can answer a question quickly escalated be a cop was facilitated by the development of growth factors so that the schedule and the intensity of the regiment could be um increased. It is however somewhat more like mop and its effect on the bone marrow stem cells and infertility and we'll talk more about being a cop as we move forward. In addition, not only has chemotherapy made remarkable strides over the past decades but radiation has also changed dramatically. You can see on the left the mantle field this was the standard of care and early stage patients and as we know, is associated with significant late toxicity then involved field radiotherapy came in limiting fields dramatically, but now we're using an involved site radiotherapy or even involved. Note if you have adequate imaging upfront, this uses very fancy um imaging techniques and the fields and dose and machinery have all changed so much over the past few decades that we hope to see significantly lower late effects related to radiation. As we move forward along with these developments, the understanding of the biology of Hodgkin lymphoma has also accelerated enormously over the past decade. For many years. It was not known what the reed Sternberg cell was, what the cell of origin was. But uh in the nineties, very elegant experiments where micro dissection of individual cells was done and the cells were analyzed and identified two B B cells with uh that could not make immunoglobulin. Uh and recently over the, you know, we now know that there are many different cell surface markers that are potentially target herbal in Hodgkin and that the reed Sternberg cell, which is about 1% of the cells in the nodal tissue is surrounded by all these other normal inflammatory and immune cells that secrete all these cytokines and chemokines that drive the growth and and uh and uh you know sustainability of the disease. Um and those include on the cell surface cd 30 and Pd L. One, which as we'll show and you know, has led to the development of very active drugs in Hodgkin lymphoma. So the first drug was Brent Taksim antidote in the antibody drug conjugate to Cd 30 with M. M. A. E. That prevents microbial uh function and causes cell apoptosis. You can see in the pivotal study the waterfall plot was really very dramatic with 75% of patients achieving a response about a third achieving a complete response in the relapse and refractory setting. These were highly refractory patients in many cases and you can see the progression free survival um correlates strongly with response. And for those patients who achieved a complete remission, even a subset of those patients went on to have durable remissions. Even in the absence of allergenic stem cell transplantation. And then the most recent addition to our armamentarium is the checkpoint inhibitors targeting PD one, Pemberley Lucy Mob and the volume of both of which are approved in Hodgkin's. They have overall response rates that are higher, perhaps than in any disease out there at, you know, in the 70 to 75% range. The complete remission rate with single agent therapy is relatively low. But these are very active drugs and the reason they are so active again is because of the biology of the reed Sternberg cell and work by Margaret ship and others has shown that um the reed Sternberg cell is characterized by copy gainer amplification of chromosome 92 4 which encodes for PD L. One and PD L. Two. And you can see in this amplified um image here this strong very strong staining of PD L. One on the reed Sternberg cells. We know the toxicity profile of um of these drugs and very few patients require discontinuation due to toxicity. So moving on to early stage Hodgkin's lymphoma. This is a 22 year old woman who presented with asymptomatic at Ganapathy in the neck largest node was about four centimeters biopsy show classical Hodgkin lymphoma. Um The cells express cd 30 and C. D. 15 as we would expect. Pet scan is shown here and actually this note is above the diaphragm. It's a little bit misleading in this image Baseline Laboratory Studies showed a set rate of 22 and she was diagnosed with stage two a disease. So when approaching a patient like this who's 22 has many years of life ahead, we really need to think about um the risk of relapse and curing the disease and balancing that with the risk of late toxicities. And this is work from Andrea in who's in our group who is a radio therapist who's really a leader in the field. And um when you look at the the likelihood of recurrence of classical hodgkin lymphoma really plateaus at 10 years in the vast majority of recurrences are very early in the first three years. But the rates of secondary malignancy and cardiac disease you can see continue to rise over time. So what are those radiotherapy related late effects? Secondary cancers? These have a very long latency uh and in Chris over time related to the dose and the field of radiation uh that was given uh breast cancer in women under 30 is very significant risk. Lung cancer is associated with smoking and we don't see that terribly often, but it can happen. Gi cancers, esophageal cancer can be seen as can soft tissue sarcoma and thyroid cancer as well as thyroid dysfunction related to radiation is extremely common. Cardiovascular disease is the other major complication of radiotherapy and can also be uh influenced by the the receipt of Adrian Mitchelson. Um We see a cardiac uh disease in multiple forms, coronary artery disease, valvular disease, pericardial and conduction abnormalities. All can happen in patients who have received radiotherapy. So this study was done some time ago published in 2012. But it's really a landmark study in that it tested the hypothesis of uh could we give chemotherapy alone to patients with early stage hodgkin's lymphoma and have good overall survival. So the primary outcome of this study was 12 year overall survival. So patients with stage one and two a non bulky Hodgkins were randomized to receive standard therapy, which at that time was sub total noted radiation 2 35 gray patients who are unfavorable. According to these risk factors listed also received two cycles of A. B. B. D. And the experimental arm was a BBB alone, patients got two cycles and then had a ct. If they had a complete remission by C. T. They got two additional cycles for a total of four. If a partial remission they got a total of six And again the primary outcome, 12 year overall survival. And as you can see from the left hand panel, the freedom from disease progression was better in the patients who received radiotherapy alone with a small difference compared to chemotherapy alone. But when looking at overall survival there was a benefit in the patients who did not receive radiotherapy. This study was closed early due to a change in the standard of care and radiation from sub total notable radiation to involve field in the midst of the study. So it was underpowered. Uh and there were some of the deaths on the radiotherapy arm that may not have been related to radiation. However this did show that patients getting a BBd alone, particularly those who received four cycles and had a ct cr could do very very well. So then along came pet scanning and we know that this is one of the prognostic indicators that we can use to help tailor therapy. And in this study, patients with early stage Hodgkin's lymphoma. 246 patients received standard treatment with chemo and radiation and the patients who were pet to negative had um significantly better outcomes as shown here. So it's important to think about what is a positive pet scan when you look at this data because it's not uniform across studies. I think there's no question that Dove 01 and two are considered negative. This is where the uptake is less than or equal to Media steinem double three is sometimes positive, sometimes negative. More recently. Uh It's typically considered to be negative. Uptake is greater than media steinem but less than or equal to liver. Four and five are positive. So this study the er Tch 10 study built upon the H. D. Six study and asked the question, could we treat patients with chemotherapy alone. So this divided patients into favorable and unfavorable groups based on the risk factors of having a large media standard mass Age over 50. Set rate over 50 without be symptoms or 30 with the symptoms or more than or equal to three or notable sites of disease involvement. So patients were randomized to standard treatment so favorable three cycles of Abdi plus radiotherapy regardless of the pet. Unfavorable four cycles. And those uh in the experimental arm were then randomized uh to risk to be treated according to the pet scan. So if they were pet to negative they got four cycles of a bBD. If they were pet to positive, they were escalated to two cycles of escalated via cop plus radiotherapy for the favorable patients In the unfavorable arm. The only difference was the pet negative patients got four cycles. So these are the results and you can see there was about a 9% difference in progression free survival in the favorable patients who got chemotherapy alone versus radiation. Uh In the unfavorable group there was really very small difference at 2% remembering that the unfavorable did get six cycles of a Bbd. Um And for the pet positive patients who were escalated to be a cop. This did result in a better five year progression free survival as shown on the bottom right. Uh And again the positive pet here was Dove il three through five and about 19% of patients were pet positive. So um this these are two additional pet directed studies. The first is the rapid study which was restricted to patients with without be symptoms stage one a and two. A patient's instead of having a pet after two cycles had a pet after three cycles. Those who were pet negative. Uh And this was again, Dove 01 and two were randomized to receive radiotherapy versus observation patients who were pet to pet three rather positive went on to receive an additional cycle of a Bbd and radiotherapy. And when you look at the pet negative patients here, sorry. The pet negative patients here you can see that there is a statistically significant difference in those who received radiotherapy compared to those who did not but they only received three cycles of a. B. D. D. And in the alliance study 50604. This was not a randomized study. This was a pet directed study. And this included all non bulky early stage patients after two cycles of a Bbd pet to negative. This was dove 01 through three got an additional two cycles of a Bbd. And those who were four or five were escalated to be a cop followed by radiotherapy. And here you can see um that the patients who were over one or two did very well with four cycles of a. B. D. D. With a three year progression free survival of 94%. Those who were double three, however did a little bit less well with the PFS of about 77%. And those who had four or five and were escalated didn't do all that well, 67% doesn't seem uh you know, optimal for early stage Hodgkin's lymphoma with aggressive treatment. So what about patients who are bulky? Uh And the same sort of approach was taken. The raffle study um was a very important study done in europe, where patients received two cycles of a Bbd and then again using pet if they were pet to negative double one through three. They got four cycles of a BVD versus A. B. D. And there was no difference between those two arms. I'll show some more data later patients who were positive went on to receive be a cop. This study included unfavorable patients with stage two B. Disease or stage two A. With bulk. And when you hone in on the patients who had bulky stage two disease, they did very well if they were pet too negative with six cycles of chemotherapy only and you can see their three year progression free survival was about 92%. We also did a bulky study parallel to the 50604 study in the alliance. And you can see this study here. Um The difference here is that the pet Two negative patients got six cycles of a BBD and patients who were pet to positive got four cycles of be a cop and you can see really favorable um three-year progression free survival of 90% in the pet positive and 93% in the pet negative patients. So that's a lot of data and this is an area of really intense debate. How do you really manage these patients? And for me for the adolescent and young adult group, I really try to prioritize omitting radiotherapy and older patients. It may be a more nuanced discussion and we discuss the pros and cons of radiation. There is a slightly higher risk of relapse generally with omission of radiation but no difference in overall survival. So for stage one and two A who are non bulky, I would do two cycles of a BbD. if their pet to negative and have double one or two. I would consider four cycles If double three. I would give a raffle approach and drop the belly omission and give four additional cycles of a. b. d. If their pet to positive. I would continue on with chemotherapy and restage after cycle four. You could escalate to be a cop. We tend not to do that in the US. I think radiotherapy is very important in patients who are pet to positive. Similar approach in station in patients with stage two B. Disease. Um I think that you know in europe these are often treated as advanced stage patients and they need more chemotherapy. And I would follow a raffle approach if their pet to negative if their pet to positive again would restage after cycle four bulky patients. As I just showed I think chemotherapy alone if your pet to negative is very reasonable. Based on our alliance study and based on the raffle study this is sort of where we're heading. This study was recently published and added Brent Taksim map to a. V. D. Patients who were pet negative after four cycles were then randomized not randomized rather but treated in four different cohorts with decreasing doses of radiotherapy with the goal of avoiding radiotherapy altogether. And you can see these patients did very well and there was no difference in any of the cohorts including the group of patients who did not receive any radiotherapy. So um what's next I think um testing uh PD one inhibitors in the up front setting. We're going to need very large randomized studies to show a benefit in these favorable group of patients because they generally do so well. And we will really need to take a look at adverse events, late effects, quality of life and financial toxicity. I'll just show you this schema here for an upcoming US intergroup study in early stage disease led by the Children's oncology group. Um This builds on what I've already shown patients will get. This will include all patients favorable and unfavorable with early stage disease. Is pet stratified after two cycles of A. B. B. D. Patients who are pet negative will be randomized to standard therapy with chemotherapy alone versus the experimental arm of B. B. Plus uh volume. After four cycles patients who are pet positive. The standard would be escalation to be a cop for two cycles plus radiotherapy. And we will test BB Nevo for four cycles with radiotherapy. So moving on to the advanced stage, sorry I missed this one. Here we go. 29 year old patient presents with uh here stage for a disease had neck pain. Um Had a chest cT which showed this distribution of Adan apathy in the chest had a biopsy that showed hodgkin lymphoma, pet show disease above and below the diaphragm with a pulmonary nodule disease within bone. His I. P. S. Score was a two for male and stage four disease. So how would we treat this patient? And the first thing I wanted to address was is there a benefit to escalate and be a cop? If this patient were treated in europe um he would get to be a cop. And you can see that When compared to a DVD across the board there is at least a 10% difference in progression free survival. 10-15%. But no difference in overall survival. We again reviewed the toxicity of escalated be a cop which has led to it's not really being used routinely in the us. This again is the raffle study. And you can see the majority of patients in this study had advanced stage disease. And for those who were pet to negative there was no difference with dropping leo Missin. Um The escalated be a cop arm. They were, there were two different regimens here escalated versus be a cop. 14 and escalated be a cop was better. And you can see the progression free survival did trend with age. I mean with stage rather with stage three patients um having a progression free survival to 83%. Stage for 80%. So um what about deescalating. Starting with escalated be a cop. And then de escalating to a B. V. D. And the pet uh to negative setting. And this was done as a strategy uh driven by the french lisa group and this data really looks very appealing patients. Start with escalated be a cop and if they remain pet two and four negative they finish out with four cycles of A. B. B. D. And they compared this to the standard arm of six cycles of A. B. B. D. And you can see hair. There was no significant difference in the five year progression free survival was very favorable uh At 86%. So this is the echelon one study which randomized patients with stage three or four disease to A. B. B. D. Uh times six versus Brent Taksim A. Plus A. B. D. And you can see when this was this was recently updated And the progression free survival is about 7% improved in the patients who received maximum plus a. v. D. And then there was this very unexpected press release that came up In early February which surprisingly showed a overall survival benefit with longer term follow up with a 41% reduction in the risk of death. So um I would say in our group we have tended now to use BVD Aivd and patients who are under 60 with advanced stage disease. The rates of persistent peripheral neuropathy are significant. You can see here at five years um much higher in the group who got BVD Aivd compared to A. B. V. D. Uh Though um most of the cases were low grade. So um moving on to where we're moving uh in the future. Uh Pemberley awesome ebb and the volume are being tested up front. This is a study that came out of Emory looking at adding pem bro running with pembroke for three cycles and then incorporating a. B. D. Uh and you can see here this was a group of patients with uh both early and advanced stage disease. But you can see that the progression free survival with relatively short follow up is 100%. So this is obviously very appealing. And what we have now in terms of ongoing studies are in the US and Canada were comparing Brent Taksim hapless aivd versus the volume at plus A. V. D. And patients with stage three and four disease. Uh This study is ahead of a cruel and we're hoping to get these results in the next few years uh in europe. They're looking at being a cop versus Brent Taksim map containing regimen and I think this will also be very important data uh once these studies are complete. So just a few words on the relapse and refractory setting, we know that about 10-30% of patients with Hodgkin's will ultimately relapse after initial therapy. This includes 10-20% of patients with early stage disease and about 25% of patients with advanced stage disease. Um fortunately the percentage of patients were primary refractory is relatively low at 10-15%. We'll highlight the importance of a biopsy particularly in someone who's relapsed um as opposed to primary refractory just to make sure that we're not seeing inflammation or a gray zone or even we know that these patients are at risk for developing subsequent non hodgkin lymphoma. So our standard of care remains to take patients to second line treatment. Uh and those who respond well, then go on to autologous stem cell transplant. This is based on two very small studies. You can see this one with 21 patients in one arm and 17 and the other patients got either second line chemotherapy uh whether uh decks a beam alone or then followed that up with a stem cell transplant and there was an improvement in progression free but not overall survival. So I just wanted to comment on on this slide, we've been looking at uh you know, outcome over time in patients who go to autologous stem cell transplant. And we know that the the pet response after salvage chemotherapy is a major driver of outcome. But now it appears that in patients who get checkpoint inhibitors as part of salvage chemotherapy, they also seem to be doing better than we would anticipate. And if you look at, you know, these sort of, this was a large retrospective analysis presented at ash and for patients who are getting older regimens of chemotherapy, uh you know, the outcomes are still quite good but for those getting checkpoint inhibitors. Uh the progression free survival looks significantly better and again, you know, the response at transplant seems to be a significant predictor of outcome. This study um uh looked at maintenance Brent Taksim a bob for five for one year following autologous stem cell transplant and high risk patients. Uh And with longer term follow up at five years, you can see that there is a significant benefit to maintenance Brent Taksim mob compared to uh placebo. How this is going to be impacted by the receipt of upfront Brent Taksim mob in advanced stage patients is yet to be seen. But for particularly for patients who are Brent Taksim of naive and go to auto transplant. We typically offer this though patients can very frequently develop significant peripheral neuropathy and it's rare that a patient actually makes it through an entire year, particularly if they've had any prior Brent Taksim oB frontline or salvage. So how do we manage patients with, you know, younger patients with relapsed and refractory disease who are transplant eligible uh salvage chemotherapy and you know, for those patients who are primary refractory or have relapsed early within a year, you know, we really do try to give checkpoint inhibitors uh and will incorporate Brent taxicab if they're naive, it appears that these patients do better with transplant for those patients who relapse later. Um we will often go to ice chemotherapy which has long been a standard therapy, but I will say, you know, within our group, we've been talking about this a lot. And given the activity of these BB can sorry, these checkpoint containing regiments like Vivi Nevo and Pemba losing mad plus G D. D. We really are sort of transitioning over to using those regiments even in patients who may have later relapses. We are still consolidating patients with auto transplant. We don't have enough data yet to say that we can omit transplant in patients who have complete remissions to checkpoint containing salvage regimens. That there are some studies coming up to look at that. We also use radiotherapy if patients relapse with localized disease because radiotherapy really is a very effective and important modality. And Hodgkin is just choosing the right patients at the right time in order to use it. And again we use Brent taxes maintenance for high risk patients. So in summary, I would uh say that short and long term risks and benefits of upfront therapy really needs to be balanced, particularly with regard to the use of radiotherapy and early stage patients, particularly young women with chest disease. Radiotherapy is certainly appropriate. Uh and a very good modality as I mentioned. But we will often use it for those patients who are pet to positive or those who are older or have disease in areas where the radiotherapy is less likely to be associated with late toxicity. Um, in patients with stage three or four disease, we use BVD AivD as our standard treatment at this point, I didn't show this data because I've already put in probably too much data in this talk but there is data from Andy Evans and colleagues doing a sequential approach with two doses of Brenton followed by a B. D. Chemo and following up with consolidation with Brent in patients over 60. Uh that has had very um has very good progression free survival and is an approach we often use in our patients who are over 60 and in whom we do not want to give liam ison, a stem cell transplant remains the standard of care for patients with relapsed and refractory disease and the role of Brent Taksim, a band. The PD one inhibitors continues to evolve uh and is moving further up into the up front setting in both advanced stage and maybe even in early stage patients. So more to come on that. So I have to show you very proud of this picture of my phenomenal are lymphoma group. Uh really just an amazing group of people to work with. So thank you. Thank you and so much for that uh tour through Hodgkin lymphoma which is often uh it's not easy to figure out what the right treatment is for for the patient. Just given all of the favorable unfavorable. So thank you for breaking that down. Um and uh I don't see any questions right now. Um So maybe we can move on to our last um talk and then we'll finish with the panel discussion. I'd like to introduce dr interior on who has come from us, the NIH, who.
