Good, good day, everybody. My name is Zina Peric and Nico Gagelmann and myself will discuss some of the highlights of the EBMT and we wanted to particularly focus on GVHD. So um I think one of the big, big surprises and I think a very interesting study that we saw at the presidential symposium and also was the winner of the Van Bekkum Award was the study presented, by Yngvar Floisand who presented phase three randomized double-blind placebo controlled study of vedolizumab, in addition to standard GVHD prophylaxis for GVHD. Um And this study was a bit disrupted, of course, with, with the all whole COVID era, but still um included a very respectable number of 340 patient’s and uh and evaluated the addition of6 doses of vedolizumab to the standard calcineurin plus MMF or methotrexate prophylaxis uh for acute GVHD and evaluated uh as primary endpoint, the intestinal acute GVHD-free survival uh and met its primary endpoint as this was 85 towards 70% or statistically significant in comparison to the, uh to the standard uh standard GVHD prophylaxis. Um And I think this study is, uh, well, what do you think, Nico? But this study, I think it’s really, it’s really amazing how the addition of this drug that we usually know from the IBD setting can maybe change the future of um, acute GVHD patient’s, which we know that has already decreased in terms of incidents. But we still have this, uh this uh well, let’s say minority of patient’s that do suffer from intestinal gvhd uh and should, should of course be improved uh in terms of outcomes.

Yeah, thank you, Zina. I completely agree with you and thank you for summarizing it so nicely. I think one major thing is that it targeted specifically GI-GVHD, which I think you also know is one of the most horrible forms of especially acute GVHD. So patients suffer a lot from diarrhea, from pain, etcetera, weight loss. So I think it’s a very, very clinically and practically relevant study that has been done. Um One major thing is despite the COVID pandemic, they managed to recruit more than 300 patients’ and with 160 or so in both arms. So this is very, very helpful to also uh that also allowed subgroup analysis. And um I particularly found the subgroup analysis quite um interesting and that um it was effective and significantly effective despite for instance, ATG use. So patients who received ATG or no ATG, they both benefited significantly from, from Vedolizumab. And um some other questions that are very useful. I think that’s what, what a good study is there for is that it also started some hypotheses that for instance, there was a significant benefit in uh reduced intensity arm but a trend but not a significant difference in the myeloablative arm. Um So that was for me, a very, very interesting study that we definitely hope to see more in the publication. Um And another thing is that I really, really enjoyed uh seeing is because it’s so helpful for patient’s to when we can say yes, there was not a significant difference in non relapse mortality, not, not significant, but the P value was 0.06. So there is this, we, we can say yes, we treat GVHD uh significantly better with vedolizumab and this also results and we’ll probably results in a benefit in a non relapse mortality. So I think that was a very, very astonishing and very helpful result in that study. And that’s why it’s so valuable and deserves the Van Bekkum. Absolutely.

I agree. And the other thing is of course, that we are hoping what we’ll see in the future is the reduced identity of the chronic gvhd as well. Because I think in the past, in the past year, we have seen lots of progress in the treatment of chronic GVHD, new drugs approved in the steroid refractory setting. And I think it seems to me that this EBMT was more, more focused on acute GVHD and of course, we are moving towards uh prevention of uh of both. So which we all of course, are waiting to have uh the least gvhd possible to focus for more from treatment to prophylaxis. So I agree absolutely with you. I’m looking forward to the update of the results for chronic GVHD. Um But we’re still focusing on acute GVHD. I think uh I also wanted to mention one of the, one of the very, very interesting abstracts from the presidential symposium, which was chosen as the best oral abstract as well. Um And was presented by James Ferrara and really relates to how we conduct clinical trials and how we evaluate the clinical response because uh this study tried to and succeeded in proving that actually evaluate evaluating overall response at week two. Um after the initiation of uh the treatment of acute GVHD works at least good. Uh Well, they showed actually that it has a better positive and negative predictive value um uh in comparison to the week for response, which of course cuts are waiting time in 22 weeks and helps us prevent all the side effects of the treatment that we might have. But also in this week to response is combined with biomarkers with, with the because this was the magic uh population of the patient’s uh analyzed in this, in this study. So when this week to response is combined with, with, with the magic or the map, the score, the algorithm of the biomarkers, actually, it’s very well differentiates, differentiates patient’s who have complete response, partial response and no response because actually partial response or the group of patients who have a clinical response but have a high high biomarker score or the patient’s who do not have a response but have a low biomarker, which is, which is really, really important that this this group of patient’s has a similar nonreligious mortality and very very well differentiation, differentiation of the responders from non responders. So it seems that this, this uh week two might work well uh in the clinical setting and in, in uh in clinical trials as well well, which is worth worthy as well.

Yes, again, I can only agree with you. Um I think it’s, it’s very, very helpful and especially in that horrible scenario when you have acute GVHD grade three or four and, and try out, you need to wait for four weeks until you can decide what the actual response was. So um from a um clinical perspective, what I really liked is that they basically uh provided clinicians with the usefulness of two models like the one model which was just clinic um clinically relevant, just tried to develop the dynamics from the onset of acute gvhd, too weak to grade and um defined these two or three better, three distinct risk groups. When you have, for instance, only one or two grade acute GVHD and you keep your grade two GVHD because we know okay may be grade two acute GVHD in GI It’s still something clinically relevant for patients because you still have 400-500 mL of diarrhea. But still what they showed is if you keep the grade two GVHD until two week two, you have a very, very low um non relapse mortality of just like 10%. But instead if you, if your acute GVHD increases from 2 to 3 or four, even already after two weeks, we have a very, very high likelihood of dying from, from the procedure with 50% patient’s. But also what I really liked is that they also looked at clinically relevant question of what happens with patients who develop initially very severe acute GvHD like grade three or four. And if they respond completely, respond within two weeks, um no gvhd or only one grade one gvhd, which we wouldn’t treat anymore, they basically have um non relapse mortality of 17%. So from that perspective, I really liked it because when they added the biomarkers, ST2 or REG3a, not everyone might have this, right. You, I don’t know as you know, if you have this in your clinical practice for every patient, we do that in, in in a trial setting also because we work with the MAGIC coalition. But on a very daily basis, I think this is very helpful for clinicians because this is much, much more useful to guide patients. And then obviously, if you have the biomarkers and this distinguishes even more what you already said this to three risk groups that they also could distinguish between these risk groups, clinical risk groups. Again, three risk groups who have no response, partial response or complete response. So I think it’s a very, very helpful tool for both heavy university hospital setting, but also for like a smaller setting where they don’t have immediate access to biomarker analysis.

Yeah, absolutely agree. This study really can help us uh lead our, our clinical judgment, let’s say. So, I agree with you. So, is there anything that you wanted to highlight uh from the, from the EBMT from the treatment? Maybe?

Yes, we agreed beforehand that we maybe focus on a very hot topic um which is a fecal microbiota transplantation for the treatment of um acute GVHD or high risk naive treatment, naive acute GVHD. And they were um two oral abstracts. Um one from the US and rum one from France. Um They both basically looked at the same um saw the study from from the US from Professor Defilipp, looked at third party, fecal microbiota transplantation for the treatment of high risk treatment, naive acute graft-versus-host disease and also focused on the lower gi tract or basically all fecal micro transplant studies do that because it targets the this very same organ and this is a still very small study. The other studies also a very small and open label single arm pilot study um of 10 subjects. Um they were enrolled, nine of them were treatment naive and one patient was a steroid refractory GVHD. Um The responses seemed to be quite promising in that study. So almost all patient um achieved um some kind of response. Um also in the in the other study from Professor Malard and Professor Mohty, which looked at the pool fecal allogeneic microbiotherapy for refractory GI acute GVHD. Um what I would like to highlight and maybe discuss a little with you Zina is um that despite the responses, we still see some safety signals regarding infections. Um So um patient’s in the, in the US group, they almost all had in infectious complications including sepsis, uh and so on and the other other study as well. So despite the uh efficacy of that treatment, which is all also already used by many GI physicians. And I imagine I remember when I did internship in my, I don’t know, second year it was in the clinic, a GI clinic because we have to rotate during med school. I stood in a room, very small room in (inaudible) where uh like the stool from a nurse that donated this um feces was mixed and then put via endoscopy in that patient with C diff infection. And um the responses were enormous but still, um this patient also developed uh severe pneumonia, overcame it. But still, so I wanted to ask you Zina, what, what do you think of that dilemma we have to face? Are we still there or do we need improvement for the products?

Well, that’s a great question, Nico. Oh, thank you. I mean, of course, this is the main, main problem with the fecal transplant. Well, of course, it is uh it’s not a drug, it’s cheap, it’s, it’s available. So it’s, it’s very, very attractive. But of course, what we fear all is uh is infections. But today this is really, really very well standardized and they’re so very strict criteria for choosing the product. So I think this, this does decrease. Of course, there’s the, the intestine which is uh disrupted which uh any microorganism can, can actually make, make a problem. Um And of course, some of the problems are overcome with these microbiota products which are not as you said, the feet, as uh let’s say, uh modified and then, and then uh done to a patient. Now we have pills, we have, we have those pulled microbiota product like in the, in the uh Professor Malard’s study and this and this um expanded access program. So I think this probably improves the product, but I absolutely agree with you. We need to see more patients and more, more data, more, more safety data that, that we are absolutely sure that, that we can do it without, without any risk. Although these studies do show that safe is pretty good. And uh they, they’re only a couple of uh cases related to, to the, to the product that actually uh cause infections. What I also wanted to. And I really think it’s interesting here. Um Maybe two to just mention it shortly with you is the in the easy expanded access program with the study by Professor Malard. Um is the very high rate of response in steroid dependent. Um So not the steroid refractory but the steroid dependent. I think that we all have this, this few, one or a few patients that uh you uh give him immunosuppression, take off immuno suppression, then they have diarrhea, then you’re, then you hospitalize them, then you get them out of the hospital, they get hospitalized 10 times that it’s two at one or two years after transplant, they still have diarrhea when they eat something wrong. Uh They are cachectic. This is this is I think a huge, huge problem. And I think this is really, this really relates to, to, to this steroid dependent patients where it might uh there are some data showing that actually this happens really because this disrupted their intestines and dysbiosis and these are the patients where we can maybe do more with, with, with something like fecal microbiota transplantation than with the drugs. So, uh the, the rate of response was something like 92% which was really, really overall response, which is really impressive. And I think that this may be steroid dependent setting. Uh is the, is the setting where, where we, we can make it where we can improve with, with, with the fecal microbiota transplant.

Yes, I I completely agree and, and probably um what has also been shown in that study from Professor Malard also by Professor DeFilipp. But also what has been shown in other microbiome studies is that responses were very, very high when the acute GVHD was not so severe because if you don’t have too much telangiectasia or bleeding issues with uh which is which is caused by the severe infection and inflammation, inflammatory processes in the GI. Um there could be a very, very useful tool to like initiate early treatment with with these microbiota products. And I think that there that is a beautiful combination of what we already discussed this, that we make this huge improvement and how to better and earlier define GVHD to see it earlier and then to act earlier for trials and, and and for design of new products. So completely agree. I think um the response rates and, and some subgroups are enormous and very promising. And therefore, I think it’s worth uh it’s worthy that these two studies has been, have been chosen for oral abstracts. Well, Zina, you wanted to discuss or present a last study um from Ivan I think.

Yes. So well, maybe we can just shortly mention it because this was, this was I thinkthe grand finale of EBMT the closing ceremony where we saw some the new incoming awards. So the Springer Nature Award was given to Ivan Moiseev with the transplant complications working party secretary and who led the study on addition on a comparison were very interesting study. It was a poster presentation of PTCy with standard prophylaxis in comparison to PTCy with ruxolitinib. So this was like an interim analysis of I think 1st 1st set of patients’, first. How many was it? 90 patient’s or or something like that? Uh uh This, this is very interesting because this is a strategy that was used in both unrelated and haploidentical setting. Uh And showed that the combination of PTCy and Ruxolitinib, which we know is today approved in the steroid refractory setting and now moved into the, the prophylaxis, one is non inferior to the combination of PTCy and the standard prophylaxis in this setting. So I think it’s really, we’re looking forward to, to the uh results uh future results of this study. But I think uh this is a really interesting concept of moving the uh moving the drugs from the steroid refractory setting to first line and to prophylaxis, then we all really um would like to come to the steroid free approach once. So I think this is, this is the goal. So if we have good drugs, we, we uh want to use them. Right? Nico.

Exactly. I agree as usual with you. And what I also really liked about the study as we do now with these studies with Vedolizumab, we try to specifically target the immune system, not just flush everything with steroids on it. And what this study also did nicely very nicely is to look at the immune immune reconstitution because we saw on at least in the poster and that there were no quite late acute gvhd grade 2 to 4 events and, and this also corresponds um I think a little bit with what they report is that they have more pronounced um expansion of naive T cells, uh sorry of memory cells and, and more naive T cell depletion. So this shows that there may be some kind of a deviation of the immune system towards more guarding our body than to really act on, on our own body and, and and induce some kind of auto immunity. Um So this was really, really nicely done that they looked also on the on the shift. I completely agree. I think where we live in a very, very lucky time that um we have this new, new approaches and even these new designs, these new hypotheses, how we can improve our, the outcomes of our patients with GVHD, but also prevent GVHD.

Thank you, Nico. I think this is what we wanted to highlight from this year’s EBMT.

Thank you.