06 Aug 2019

Izveštaj ICML 2019

I ove godine je u Luganu, Švajcarska, po 15.-ti put održana međunarodna konferencija posvećena malignim limfomima ICML. Skoro 4000 eksperata iz oblasti hematologije razmenjivalo je svoja iskustva, a najzanimljivije prezentacije i dostignuća, možete pročitati u nastavku, kao transkript webinara na kome je izveštaj i predstavljen. Transkript prati prezentaciju, koju možete preuzeti ovde.

“Highlights of ICML 2019”

Dr Pavlovsky: Okay. Hello, everyone. I want to welcome all the audience and I want to welcome Dr. Kerry Savage for joining me for this presentation, this educational activity where we will discuss some of the abstracts presented in ICML 2019 just a few weeks ago in Lugano, Switzerland. This was a truly global meeting with almost 4,000 participants attending. Around 90 countries were represented by all the participants and we can see that every year or every three years we have this meeting with more and more participants from different areas of the world. It was difficult to choose the best abstract, so I decided just to choose those abstracts which are easily incorporated in every day clinical decisions. So, we will focus more on the results
of this kind of trial; and I will start with this. I found this a very interesting trial. It was an international from Nostich Call for early stage CLL to try to see which patients who have asymptomatic CLL have a higher risk group for time to next treatment. So, they looked at a retrospective trial and they divided their patients in three groups depending on whether they had or not this variables, whether they had un-mutated IGBH, palpable lymph nodes, or a lymphocyte count over 1,500; and with these very easy factors, we could divide the risk of our patients needing first line treatment in three different groups, a low risk group, where we see the patients who have none of these factors, have very low possibilities of needing treatment within the first year, and there’s a plateau after 10 years, intermediate risk, the green line, and the high risk. So, I think this can help us decide our approach to the follow up of our patients and how often we have to see them and the intensity of the different meetings we have to have with out patients. Going on with

Dr Savage: Astrid, can I interject and ask a question? So, in your own clinical practice in an asymptomatic patient with early stage CLL, are you standardly testing for the mutational status?

Dr Pavlovsky: Yes, we’re trying to do that. We have incorporated that in the last few years. Maybe in those older patients with very asymptomatic and absolutely no, showing no risk of progression, we might skip this test, but we’re trying to do, regularly have the IGBH, especially for those patient in whom we might probably use chemotherapy. Young patients in whom the IGBH status will help us decide whether patients need to have treatment with chemotherapy or other lines of therapy.

Dr Savage: Okay, thank you.

Dr Pavlovsky: How about you, Kerry? Do you regularly use this?

Dr Savage: We just recently have available IG status testing. We test for FSH, although it’s more commonly in patients who are going to make a decision about treatment as opposed to the asymptomatic. I guess we’ll talk about that later about intervening early in asymptomatic, but I think for the mutational, because the technology doesn’t change, I think, for me, this slide is very useful for how to follow a patient, rather than  making [Audio Not Clear] treatment. So, I think it’s worthwhile to have this information if the institution is testing for it.

Dr Pavlovsky: Absolutely. I think what we learned from this trial is how to follow our patient. This is not about starting treatment, but it’s just about the risk of needing a first line treatment, so it can help us follow up more regularly or less frequently. So, if we continue with CLL, we know they resonate two trials, which here we have the five year follow up for patients receiving Ibrutinib for first line treatment. As this was a randomized trial between Ibrutinib once daily versus Chlorambucil, and I think the importance of this trial is not the comparison, but what happens in a five year follow up of patients being with Ibrutinib. What we see is that at 60 months, 70% of the patients treated with Ibrutinib were progression free. So, they were still on treatment and we see the comparison. This is compared to a Chlorambucil where only 12% were progressionfree. So, I think this is maybe a weak comparison, but it’s nice to see that this curve is not dropping quickly
after five year follow up, so with Ibrutinib. Also resulted in an improved overall survival versus Chlorambucil, and what’s also important to see is this slide here where more than five years, there were 27% who were still on treatment at five years, and of the whole group of patients, 58% continued with Ibrutinib on the study. So, most patients were able to continue with the drug. 91% of the patients had to discontinue Ibrutinib due to adverse events, and 6% due to progressive disease. Two of these patients discontinued due to risk of transformation, which is known to be one of the main reasons for discontinuation due to progressive treatment. So, I think this is the longest follow up we have of first line treatment with Ibrutinib. And something else that we’re learning is that the longer the patients are in treatment with Ibrutinib, the higher the probability of obtaining a CR. When nine months, only 4% of the patients had obtained a CR, but as time goes by, this percentage is larger, so not only are they still on treatment with control of the disease, but also we have a higher probability of obtaining CR over time. So, I also think this is some good news, and we will go on the next one, and continue to speak about.

Dr Savage: I’m sorry. Before we go on to the next one, just with the last one, although that toxicity slide wasn’t shown, I think it’s interesting that you still see toxicity throughout the treatment, but one other thing to flag that doesn’t always come out in the clinical trials in the very rare risk of ventricular arrhythmia, atrial fibrillation are very well known class effect with Ibrutinib, but I’m always paying attention to sudden death in these trials because we reported a series, along with Jennifer Brown and Dana Farber of actual ventricular arrhythmias and sudden death. So, there are rare ventricular events and in that study that you just presented there were two cases where the cause of death was unknown. So, it’s something to keep in mind. I certainly think Ibrutinib has excellent efficacy, and obviously we don’t use prabucol anymore, so the comparative market is not relevant today, but it does show that people stay in remission a long time.

Dr Pavlovsky: Yes. I agree with you that doing a chemotherapy-free regimen doesn’t mean that we cannot expect adverse events. The adverse events are more frequent during the first year, but we have to keep in mind throughout the whole treatment, they can come, even adverse events, three, four, or five can come even after some years of continuous Ibrutinib, but still I think we are learning as we go through. Many of us already have patients treated with Ibrutinib and we are learning as the follow ups of the trials are presented. So, I think this is something that we didn’t know at the beginning that the more treatment we could have, the higher the rate of CR.

Dr Savage: Right. Agreed.

Dr Pavlovsky: This is also about CLL in first line. This is effect of fixed duration of Venetoclax plus Obinutuzumab on PFS and rates of duration of minimal residual disease in patients with comorbidity. So, something that we don’t like about Ibrutinib is the chronic treatments. With this new combination, we can talk about this fixed duration, only six months. So, this is one of the benefits of this combination. This was also a randomized trial. Patients with previously untreated CLL and comorbidities being a CRS more than six or a low creatinine level were randomized one to one, either to Venetoclax plus Obinutuzumab or to Chlorambucil plus Obinutuzumab, and this is only for six cycles. So, that is one of the good things about it. So, when we look at adverse events, these are the adverse events grade three or four. The most common adverse events for both groups were cytopenia or the neutropenia, thrombocytopenia, and anemia with a higher percentage of patients with neutropenia, and this, I’m not sure if it was a statistically significant, but both groups had these cytopenias. And when we look at the response to treatment we see that after six months of Venetoclax plus Obinutuzumab, 50% of the patients had complete response, 35 with partial response, and in the group with Chlorambucil plus Obinutuzumab, 23% had CR versus 48. So, these are very different CR rates, but I think this is a progression free survival, which is 88% at 24 months for the group with Venetoclax plus Obinutuzumab versus 64. So, we see a very statistically significant difference for both groups, and I think this is probably the most important curve where we only see one group of patients, one curve, which is really different from the rest, and these are patients who received Chlorambucil plus Obinutuzumab and had an un-mutated IGVH, and the rest of the groups, meaning that patients with mutated IGVH who
received either Venetoclax plus Obinutuzumab or Chlorambucil plus Obinutuzumab had the same PFS. So, the big difference is for this group, and that is why I think the IGVH is so important before we start treatment because it can decide which treatment will be most beneficial for this group of patients. So, only one curve stands out with a worse prognosis with patients with unmutated IGVH, and we can see, whoops, I’m sorry, there was no difference in overall survival for any of the groups. So, it think this is also clinically relevant to try to decide which group of patients will need this new drug, which we know are more expensive and might not be available for everyone. So, maybe we have different ways of choosing in which group of patients
Venetoclax plus Obinutuzumab is really more relevant for PFS. And we can conclude this for trial in CLL, that single agent Ibrutinib offers sustained PFS and overall survival benefit over Chlorambucil, that the depth of response to Ibrutinib improved over time, that with a follow up of 66 months, more than half of the patients remained on long term continuous Ibrutinib, and for Venetoclax and Obinutuzumab, can be applied safely to elderly patients with CLL, with relevant comorbidities, and provides a superior outcome compared to Chlorambucil plus Obinutuzumab, but there’s no difference in IGVH mutated without P-53 mutation. P-53 is also a very relevant prognostic factor, which patients who receive chemotherapy with P-53 mutation have a worse prognosis. There’s no difference in overall survival, and this combination achieves a higher rate of MRD negative responses so far observed in randomized prospective trials.

Dr Savage: So, I just have a couple of questions here. So, in your clinical practice, and your patients and using Venetoclax, which ones are you admitting into the hospital? So, just speaking to the feasibility and logistics of using this drug.

Dr Pavlovsky: Okay, so we are not using Venetoclax in first line for any patient. It is not authorized in our country. We were able to do it in second line, and I think this is very, the attractive of doing Venetoclax instead of Ibrutinib is the fixed duration, and as we all know, the toxicity, or the most relevant toxicity was, I’m saying was because now I think we have different elements to be able to have Tumor Lysis Syndrome. So, we are admitting to our hospital those patients with a higher probability of doing Tumor Lysis Syndrome and we are admitting them one day before they start their treatment with IV hydration and labs performed twice a day during the first days, and if everything is okay, and most of the times with this ramp up, starting with 20 milligrams and slowly giving higher doses, most patients do fine, and we haven’t had any patient with Tumor Lysis Syndrome so far.

Dr Savage: And if you had all of these drugs at your disposal, let’s put country funding aside and you have this diagnosed patient, what would you choose in this elderly population, both in the mutated and the unmutated category?

Dr Pavlovsky: Okay, so I think, as you say, there’s a big difference between mutated and un-mutated, and Chlorambucil plus Obinutuzumab or Rituximab, for elderly patients, and we do have some patients with Chlorambucil, I think this is a very easy treatment, and with patients with mutated IGVH, it offers quite a good prognosis. Clearly for patients with un-mutated IGVH or the P-53 mutation, we have to think of some of the new drugs. I think Venetoclax plus Rituximab, being that it’s a fixed duration, it’s very attractive. So, we haven’t had that authorized for such a long time, so we have more experience with Ibrutinib, but in the last, I would say, eight or 12 months, we have the possibility of offering Venetoclax plus Rituximab, the MURANO trial, and most of our patients are receiving this combination.

Dr Savage: So, you would use either. They’re kinda equal for you if you have them both in front of you.

Dr Pavlovsky: Yes. I like the fixed duration of Venetoclax. That’s definitely, but I also think the patient, that is definitely very important. Some patients don’t want to be admitted to the hospital, some patients don’t want IV, and also, the risk of atrial fibrillation and hypertension related to Ibrutinib has to be considered. Also, the risk of the anticoagulation plus Ibrutinib in many of these patients who are old and have comorbidities, that also has to be considered when deciding treatment.

Dr Savage: I just want one last question. Are you doing P-53 mutational status at your center?

Dr Pavlovsky: Yes, we’re doing… No, we’re doing FSH. We’re trying to start doing P-53 mutation, but we’re doing FSH for 17P, which is our different things. We’re missing some of the patients. We’re missing a percentage of the patients who do not have 17P by FSH, and could have P-53 mutations, but we’re working on that. We’re trying to have that in our center, and we’re deciding, we’re doing this test on patients who we think will need treatment, because this can change regarding IGVH mutation, which does not change throughout the follow up of the patients, but P-53 can change, so we’re doing that before we start treatment or before we decide treatment.

Dr Savage: Okay. I’d like to take the opportunity to encourage listeners to fire in their questions. We’d love to hear from you.

Dr Pavlovsky: Okay. So, we will go on. Now, we’re changing hematological disease. This is one trial of follicular lymphoma, and I also think this is one question I had on my every day clinical practice. This is a response or re-entered maintenance therapy in advanced follicular lymphoma. These are the results of the interim analysis of the 4-12 trial conducted by the FL Association, and this is, their aim or their big question was whether patients who achieve both complete metabolic remission and molecular response, would this group of patients be benefited by Rituximab maintenance? That was the big question, and this is the way they designed their trial. Their standard arm, the patients received either R-CHOP or RB. This is investigator’s decision, and patients who are in CR or PR which just go on to Rituximab maintenance every two months for two years, and we would talk about those patients who did have a response. For the experimental arm, after induction treatment, patients would have a PET done, and if PET was negative and if the patient had a molecular marker, they would do MRD analysis, and if PET was negative ad MRD was negative, they would not offer Rituximab maintenance. So, this is the big comparison, giving Rituximab maintenance to all the patients, or not giving Rituximab to those patients who are PET negative or MRD negative, and those patients who were PET negative or MRD positive would receive only four weekly doses of Rituximab, and the primary end point was PFS for this  group; and this is what we see. These are the two arms.

Dr Savage: Astrid? Astrid?

Dr Pavlovsky: Yes.

Dr Savage: Can you just go back to that flow for one second? Why do you think they decided to only give Rituximab weekly times four as their maintenance in the experimental arm instead of balancing up with what is standard?

Dr Pavlovsky: Because this is a subgroup of patients. These are all patients who are PET negative. So, theseare patients who are in CR, and they would divide them in those who were also MRD negative, but it’s PET negative plus MRD positive, so I think they decided that this group of patients were in a very good response, but maybe needed some little extra compared to this group of patients who were not evaluated for MRD and also included patients with PR. So, I think this is the difference and I think also we could learn here, this is not reported, but we could learn here whether for those patients who are PET negative and MRD positive, whether only four weekly doses of Rituximab would be enough.

Dr Savage: Yeah, although they would have needed a randomization for that. I personally would have preferred a design where the maintenance was the same on the standard and experimental. But yeah, we’ll come back.

Dr Pavlovsky: So, our patients who are PET positive will just go on over to more therapy, and these are the curves. This is like a summary of the whole presentation. These are the two important curves, which is arm A, which is either the standard arm where patients receive, patients who are in PR or in CR receive two years of Rituximab maintenance, but it’s PET and MRD driven treatment. So, we see that the PFS is different, being 84% for the standard arm and 69% for the response adapted maintenance arm. So, what can we say? We all know that a complete metabolic response is good, that a complete molecular response is good and offers better prognosis, but however, this is not enough, or at least this trial shows us that this is not enough to omit the two year Rituximab maintenance. Oops, I’m sorry. Here, we go on to diffuse large B-cell lymphoma. So, here we will talk about two different trials that were presented, one after the other. This is the robust trial, which is the first report of a phase three trial study of Lenalidomide plus R-CHOP versus placebo plus RCHOP in previously untreated A, B, C-type diffuse large B-cell lymphoma. So, we have had quite a few previous publications trying to improve R-CHOP, adding an X drug, adding different drugs, and we have seen that for the whole group of diffuse large B-cell lymphoma, nothing has shown to be more effective than RCHOP, but there’s this question about this A, B, C type, which have a different activation mechanism whether Lenalidomide is useful. So, this was a multi-centered international randomized double blind placebo control trial where I said before patients were in stage two to four diffuse large B-cell lymphoma, they were selected
by CP nano string. If patients were A, B, C type, they would be included in this trial and they were randomized one to one, either to R two, R-squared CHOP, and the dose of Lenalidomide was 15 milligrams day one through 14, and they completed six cycles of regular R-CHOP, versus placebo plus R-CHOP. The primary end points were PFS at 24 month. So, there was no difference in both groups. We see that the PFS rates at one and two year were no different for either including or not including Lenalidomide in first line treatment for A, B, C type diffuse large B-cell lymphoma. There were no difference in overall survival in CR, nor in PFS. So, this was disappointing. We were all wanting to see something more effective than R-CHOP for this group of
patients, and following this presentation, Dr. Nowakowsky showed their results from the additional also of Lenalidomide to R-CHOP in newly diagnosed diffuse large B-cell lymphoma. This is a phase two inter-group study. So, it’s the same treatment and we will look at the difference. Here, they’ve included all patients with diffuse large B-cell lymphoma. They will do the future predefined analysis in the A, B, C group, and they randomize one to one either to R-CHOP or R-square, and here the dose was 25 milligrams day one through 10. So, the dose was a little bit higher and the primary end points were PFS in all diffuse large B-cell lymphoma. And here, we see two different curves. We see that the one year PFS for R-square CHOP was 83% versus 73% for R-CHOP, and there’s also a difference in the two year PFS. So, this was a positive trial with a statistical P saying that R-CHOP was associated with at 34% reduction in the risk of progression or death favoring R two CHOP for this group of patients. So, this gave room for a big discussion about why these different results, and we can discuss this. I’m not sure if we can arrive to the correct answer, but why did we have these two different results where we know that the patient population the two trials was different. It was only the A, B, C group versus the whole diffuse large B-cell lymphoma. We don’t know whether the dose was something that made a difference. It was 15 milligrams day one and 14 versus 25 milligrams day one through two, and also the type of trial, phase two versus phase three. I think we’re all hoping for something better than R-CHOP, but I am not sure whether this is enough evidence to incorporate R-square as a new standard for diffuse large B-cell lymphoma. I think this is an open question still. What are your thoughts?

Dr Savage: Well, I think the more robust trial was the robust as phase three. The rationale is stacked and the A, B, C, subtype. I also wanted your comment on the design of the ECOG study and having a one-sided P value.

Dr Pavlovsky: Yes. I think we will look at this and I think maybe in the future this sub analysis will help us define whether this group of patients will be benefited. Also, they are using the immunized chemistry to do the Hans Algorithm. I think this will also help us to know how well we’re doing, those who will use the Hans Algorithm, but although the designs were different, I still don’t think there’s enough evidence to incorporate this in our clinical practice.

Dr Savage: No, I agree. My point was they used a one-sided P value. If you double it for a two-sided, it would be statistically significant. So, I thought that, as you indicated, these are slightly different populations, but the first study is more robust in that analysis of the question, in my mind, the right subgroup. There is a little bit of activity in Lenalidomide and [Audio Not Clear] but I don’t think it’s the subtype that we would wanna develop it. So unfortunately, this is yet another

Dr Pavlovsky: Negative trial.

Dr Savage: The list of diffuse large B-cell lymphoma. The other problem with all of these studies that always comes up is the selection bias because the patients have to be fit in order to get into the study.

Dr Pavlovsky: That’s right.

Dr Savage: Wait for the study things to happen. I personally like the designs where they actually allow one cycle of R-CHOP and that will bring in some more high risk patients, but I like to have it clean, but by cleaning it up, they narrow the population and it becomes very difficult to see those small differences. So, as the studies that are brewing right now, do you see any that you’re looking forward to seeing in the DLB?

Dr Pavlovsky: Well unfortunately, as you said before, I think we haven’t found anything better than R-CHOP. I think the question is whether patients with double hit benefit with a more intense regimen like a dose adjusted EPOC. I think we are all doing that, but there’s no clear evidence. We know that R-CHOP is insufficient, but we don’t know whether more intense therapy is clearly better or not. Yeah, I think the one I’m interested in the Polatuzumab study that’s now

Dr Pavlovsky: Oh, that’s right.

Dr Savage: Yeah, that’ll take a little bit to report, but the data in relapse setting is actually quite impressive, and then the addition of Venetoclax. There was one question that just floated here that I’m gonna give you you. It says, do you think Lenalidomide has any role in diffuse large B-cell lymphoma or in any group of patients?

Dr Pavlovsky: Well, we have with the trial with Lenalidomide maintenance in elderly patients, which show the difference in PFS. I think if there’s a role, I think only for that group of patients, patients older than 65 years old who receive maintenance with Lenalidomide. We haven’t incorporated that in our every day clinical practice, but I think all the other studies show no benefit of Lenalidomide in any other setting.

Dr Savage: Yeah, and the elephant in the room is that it is an expensive drug. So, I think

Dr Pavlovsky: That’s true, and also, I think it’s a toxic drug because it’s not easy to give Lenalidomide. I haven’t done it in my every day practice, but to give Lenalidomide as maintenance in elderly people who have already received six cycles of R-CHOP, I think it will have its toxicity.

Dr Savage: Okay.

Dr Pavlovsky: So, yes. I agree that the Polatuzumab R-CHOP, POLARIX trial, we will see what happens with that; and if we go on, and this is also a trial that has been presented in different [Audio Not Clear], didn’t have the results of everyone knew that this was going on and this is the difference between allogeneic or autologous transplant and first time therapy for young patients with PTCL. We know that patients with T-Cell lymphoma have a bad prognosis with an overall survival, which is about 30% in five years. So, many of us wonder whether doing allogeneic in first line for young patients would be of benefit, and this was a randomized trial. Patients 18 through 60 years old with an ECOG of zero two three and [Audio Not Clear] peripheral T-Cell lymphoma received injection chemotherapy, and if patients had some kind of response, they will receive DHAP, and if they had an available donor, they will go on to allogeneic stem cell transplantation or randomized to autologous stem cell transplantation. This was every day or every patient discussion, young patients who had this disease, we always discuss whether allogeneic would be a choice.
We know that there’s no other lymphoma who has to receive allogeneic stem cell transplantation in first CR, and these are the causes of death in both groups, in autologous stem cell  transplantation and allo transplantation, and I think we see what we could imagine that would happen. More patients in the auto group died related to progressive disease, but more patients in the other group died with a treatment related mortality. So, this gives us this event-free survival curves, which are absolutely superimposed in both groups, and also, there was no difference in overall survival. So, I think the conclusion of this trial is that, I didn’t show this, but also this is something to keep in mind that many of the patients would relapse before going onto auto or allo. So, one third of the patients of the randomized patients could not proceed to these procedures because of refractory disease or early relapse. There was no significant difference for event free survival, PFS, or overall survival between these two groups, or the transportation gives low toxicity, but more relapse, and allo transplantation has a better tumor control, but more transplant related morbidity and mortality. So, I think this is something we see in other hematological diseases, but I think there’s no road for other transplant in first complete remission for patients with peripheral T-Cell lymphoma.

Dr Savage: We saw the interim analysis at ASCO a couple of years ago, so this was more mature, but there are some rare subtypes that I think it’s still reasonable to do an allo. An example would be hepatosplenic TCell lymphomas and really, those gamma deltas, but yeah, this kinda puts the nail in the coffin for the other common subtypes.

Dr Pavlovsky: Absolutely. I agree for those very rare type of diseases in young patients because we know of the bad prognosis with chemotherapy. We are offering also allo transplant in first complete remission; and this is now going on to Hodgkin’s lymphoma. This is a trial with the Nivolumab plus Doxorubicin, Bleomycin, Dacarbazine, for newly diagnosed advanced stage classical Hodgkin’s lymphoma. This is the two year extended follow up of the cohort D of the Checkmate 2005. The Checkmate 2005 was the one that introduced Nivolumab for patients with relapsed refractory Hodgkin’s lymphoma and the Cohort D included Nivolumab for patients in first line. We had already seen some of the results, and this is a phase two. It is not a randomized trial, so patients with advanced stage two B, three, or four received four weekly doses of monotherapy with Nivolumab, and then continued with this combination of Nivolumab plus AVD for a total
of 12 doses of Nivolumab and then they would be followed. The primary endpoint was safety and tolerability of this new type of treatment. We will go into the end of therapy results. I think here we learned quite a few things. First, in the first interim analysis we were shown these two results and this difference of CR between the IRC on the investigator’s assessment, and we see that CR was 69 versus 80%, so we wondered why this big difference, and I think this is related to the interpretations of PET CT when we’re using Checkpoint inhibitors. So, this is something that we have to keep in mind about the difficulty of the interpreting response in this group of patients; and here, they added this new evaluation of response where they added the Deauville score, and there was a higher concordance between the two groups with a 75 metabolic complete response for this group of patients.

Dr Savage: I’ll just add the response for the study was by the 2007 criteria, but of course, investigators are getting information based on the Deauville. I think that’s also a reason, in addition to what you said, sometimes immunotherapy can cause false positives, but now that they’ve gone back and done central by Deauville, that is a more accurate assessment. Yeah, thank you.

Dr Pavlovsky: So, at the beginning we had only these two curves, and now we know, as you said, adding the Deauville criteria, there is a higher concordance and the CR rate was 75%, and this is the PFS by the investigator, which at 21 months, the PFS was 83%. So, it’s not a randomized trial. I am not sure whether this is better than doing a PET adapted therapy with chemotherapy. I don’t know. What do you think about this, Kerry?

Dr Savage: Well, I think this was, because it was a small phase two study, it was really a pilot. It was added on to the two oh nine two oh five. It tells us it’s feasible and it’s safe, and encouraging efficacy, but we can’t say anything more than that about whether it’s better than anything else out there. As you probably are aware, the inter group is going to be launching very soon a randomized study of ABD and Nivolumab to a standard ABD and Brentuximab Vedotin. So, we’ll see if it’s better over that line of therapy, but obviously, PD one inhibitors have excellent efficacy in Hodgkin’s, so the study needs to be done and this [Audio Not Clear] pilot provides the rationale to move it forward.

Dr Pavlovsky: Okay. So, we will move over. These are the conclusions, the summary of this trial and this two year extended follow up of this trial. Nivolumab plus MAVD. At the end of therapy, we said that the PFS for investigator was 83% at 21 month, and that using the Deauville criteria was 75%, so as we said, this needs further follow up and a randomized trial to see whether it is better to incorporate Nivolumab in first time treatment better than what we already know; and these are also, this is the final analysis of the FIL HD 0607 trial where patients with advanced stage Hodgkin’s lymphoma with IPS zero two seven were included. All patients received two cycles of ABVD and were evaluated with a PET CT. For those patients who were PET negative, they continued with AVBD for four cycles, and if they remained PET negative, they were randomized into no further therapy or consolidation radiotherapy. So, this is a question that different comparative groups have been trying to answer whether it is necessary to do consolidation radiotherapy for PET negative patients, both in localized stage and, in this case, for advanced stage patients; and the primary end point was a three year PFS, and we see that for the standard arm who received radiotherapy versus the experimental arm for patients who are PET two negative and end of treatment negative. There was no benefit in adding radiotherapy, and then they divided the patients according to the size of their lymph nodes. This is mainly because the bulky disease, traditionally bulky disease needed radiotherapy, and advanced stage, at the end of treatment, so we divide the different groups according to their size and we see that there’s no benefit in radiotherapy, even though in patients with a bulky disease more than 10 centimeters. So, the conclusion of this trial is that consolidation radiotherapy could be safely omitted in advanced stage Hodgkin’s lymphoma presenting with lymph nodes both for PET negative and end of treatment negative, irrespectively of their size, that there was no difference in the pattern of relapse between patients who were irradiated or nonirradiated, and like this, more than 80% of the patients, we know that more than 80% of the patients had mediastinal bulky mass, so this reduces a great number of patients that would need radiotherapy, and this will hopefully translate into a reduction of mortality due to secondary tumors and coronary artery disease in this young group of patients without curable hematological malignancy. So, I think most of us, different clinical trials have shown this. I think you also had retrospective experience on British Columbia showing more or less the same conclusions. So, I think it’s safe to omit radiotherapy in patients with advanced stage Hodgkin’s lymphoma who have interim PET negative and end of treatment PET negative.

Dr Savage: As you’ve indicated, we’ve been doing this since 2005, actually. We observed patients with bulky, but I think it was interesting that they chose five centimeters as their definition. Most of us would not consider that bulky, and we use 10 centimeters, but there’s the landslide you showed segregated by mass size is reassuring, even in the bulky; although, the numbers become much smaller in that group, but I think this is similar to what our experience is in the real world. Omitting radiation in patients who are PET negative enter into treatment.

Dr Pavlovsky: Well, I think with that, I conclude there were lots of very interesting presentations in the meeting. So, audience can look up from other results, and this, I just conclude, hoping to be there on the next ICML, which is in June 2021. So, I have no further comments. I just hope to be there and meet you, Dr. Savage, in such a beautiful place.

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