Welcome to The Post-EBMT VJ Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features Christian Chabannon, Nico Gagelmann, Zinaida Perić, and Eolia Brissot.
“PTC-y was a true game-changer in the context of haploidentical transplant more than 10 years ago now, but it’s not that novel. It doesn’t seem to replicate the same results exactly in the context of match donors.”
– Christian Chabannon
Novel approaches to managing GvHD
“There is a rising new star in the field of steroid-refractory chronic GvHD, which is pretty impressive. The drug is called belumosudil, a ROCK inhibitor, which changes the balance of Th17 and T-Reg’s towards T-Reg’s of course. This drug might be the third drug which will actually get an approval sometime soon. It has already granted an FDA evaluation which is due in May this year. So we’ll see what happens, but I think this drug could really change the field, which was until recently really a field in which we had no actual treatments available.”
– Zinaida Perić
Transplantation for myelofibrosis and CMML
“CMML as you all know is a very rare disease in transplantation and currently has only limited risk stratification in the transplant setting. We gathered molecular information, molecular genetic and clinical characteristics and then tried to find patients who would benefit the most from a transplant or maybe not benefit and could therefore be targets for other therapies than transplant. We then found that an ASXL1 mutation in combination with an NRAS mutation, as well as the co-morbidity index of the patient at transplant and the bone marrow blasts prior to transplant were independent prognostic factors.”
– Nico Gagelmann
PROs, CAR-T & immune effector cell therapies, and final thoughts
“EBMT remains a very active professional association, an inclusive professional association, trying to reflect the diversity of it’s community and it makes a great effort to draw young and talented investigators.”
– Christian Chabannon
Christian Chabannon: Good evening to everyone. Maybe good morning or good afternoon for some of you if you are listening from other places in Western Europe. We are very happy to welcome you to the VJHemOnc session during which we will discuss some of the highlights of the latest EBMT annual meeting that took place at the beginning of this week. Unfortunately, fully virtual format again, because of the coronavirus, COVID-19 situation. Nevertheless, provided a lot of exciting new information.
Christian Chabannon: So this is my pleasure today to welcome Dr. Zinaida Peric who is the newly elected Transplant Complication Working Party Chair at EBMT. Dr. Nico Gagelmann, who is one of the chairs of the EBMT Trainee Group and Dr. Eolia Brissot who is the recipient of the Van Bekkum Award at this year’s EBMT annual meeting.
Christian Chabannon: So altogether we will try to cover some of the again, most interesting aspects of the meeting, a lot of new information, so we cannot be exhaustive, but hopefully you will get some useful information from our discussion today. Maybe I’ll start with Dr. Brissot. Eolia, please, can you describe the results of your study and possibly further elaborate on new information and conditioning regimens in the context of allogeneic transplantation?
Eolia Brissot: Thank you very much. Good morning or good evening everyone. So we presented during the EBMT, a randomized Phase II study, where we compared GvHD prophylaxis with PTC-y versus ATG. Only adult patient were included who received a match related donor, or a 10 out of 10 match unrelated donor. The conditioning was fludarabine for all patients and only PBSC were included. Finally, when we compare, we include 90 patients. At the end 37 patients underwent allogeneic stem cell transplantation with ATG and for those in the arm of PTC-y, the primary objective was GRFS, so grade three and four GVHD free/relapse-free survival and extensive chronic GvHD-free survival.
Eolia Brissot: At the end of the day, we find that the two curves were exactly comparable with GRFS around 50%. When we look at specifically PFS, progression-free survival, it was similar in the two arms around more than 70%. There was no statistical difference and looking at the GvHD, they were a little bit higher of grade two to four GvHD in patients who received PTC-y versus ATG, but it was not significant. We have also to know the limit of the study, because this is a Phase II study and the cohort is quite small but the conclusion was quite interesting to see that there were no real difference between the two arms.
Eolia Brissot: We are just getting the final result to do a final analysis, but it was an interesting study we think. I think another study which also was presented in the presidential session was related by Dr. Lusnik. They compared, they were asking the question of GvHD prophylaxis without calcineurin inhibition and it was a Phase III study. They randomized patients in three arms. One arm, they received PBSC cell dose for CD4+. They received also… The second arm, it was PTC-y with bone marrow and the third arm was tacrolimus and methotrexate with bone marrow.
Eolia Brissot: The endpoint was CRFS. So it was a new endpoint. It was a disease-free survival and extensive chronic GVHD-free survival. Finally, there was no difference in CRFS across the treatment arms. What they saw is that patients who received CD34 selected grafts had lower overall survival because they has higher TRM. When they look at the arm between tacrolimus, methotrexate and the calcineurin inhibitor-free with PTC-y with bone marrow, they were equivalent strategies. So this was really interesting to see this is a prospective big trial in GvHD prophylaxis.
Christian Chabannon: Thank you, Eolia. So PTC-y was a true game changer in the context of haploidentical transplant more than 10 years ago now it’s not that novel. It doesn’t seem to replicate the same results exactly in the context of match donors. Any insights in why PTC-y does not have the same beneficial effects?
Eolia Brissot: Yes. On the Acute Leukemia Working Party published one retrospective study on sibling donor and also in a 10 out of 10 match unrelated donor, they compared PTC-y with ATG and they did not find also difference between the two court, but seemed very interesting and it was published in blood by Betty Baya and colleagues with the retrospective study with patient who received the 9 out of 10 mismatched unrelated donor and PTC-y did really better in term of acute and chronic GvHD compared to ATG.
Christian Chabannon: Thank you, Eolia. Nico, any special comments on this issue?
Nico Gagelmann: Did you look at, or did you have the opportunity to look at the immune reconstitution between the two arms or was that able in your cohort, would be quite interesting to know?
Eolia Brissot: Yes, we have a biological collection but it’s still under study. Another thing we looked at CMV and EBV reactivation, and it was a little bit surprising because we didn’t find a difference between the two courts. We were guessing more viral reactivation with ATG, we didn’t find that. Maybe because patient received FB2 and have maybe a quicker immune reconstitution, but we have to look at that.
Christian Chabannon: Thank you. Zinaida, in terms of a medium to long-term complications? Is there any difference between the different conditioning regimen? And then maybe you can tell us a little bit of what you heard about GvHD control, GvHD treatment during the meeting.
Zinaida Peric: Thank you. I muted myself because of the noise. Thank you. It’s my pleasure to participate in this post EBMT event, which we said already was a bit unusual but exciting. We hope next EBMT will be in it’s normal setting so say, but what I remember the most, especially when it comes to transplant complications from this EBMT are the changes that we are seeing in the setting of steroid refractory GvHD, both in chronic and acute, because as we know all of us are dealing with transplant patients. This was a pretty devastating setting in the early and late transplant period, where we for ages didn’t have any drug available for steroid refractory, both acute and chronic GVHD.
Zinaida Peric: Then ruxolitinib came which is also, as you say, a game changer in the field and at the EBMT, we have seen the updated results of both REACH-2 and REACH-3 trial where ruxolitinib did show a sustained response, both in acute and chronic GvHD patients. But then what, when patients are refractory to ruxolitinib and this is actually what I wanted to comment on. The two studies, which analyzed patients who are refractory to ruxolitinib as well, there is a rising new star in the field of steroid refractory chronic GvHD, which is pretty impressive. The drug is called belumosudil, ROCKstar study because the drug is really a rising star. It is actually a ROCK inhibitor, which changes the balance of Th17 and T-Reg’s towards T-Reg’s of course.
Zinaida Peric: This drug was evaluated in a phase two study into those levels twice and once daily in 132 patients who already received two to five previous lines of therapy and were diagnosed with chronic GvHD at a median of two years before the inclusion in the study. Also a third of these patients had already received ruxolitinib or ibrutinib. So these patients were included as well and the responses were really impressive because they saw responses in over 70% of patients, 75% actually. The median time to response was about four weeks. Also, the response was sustained for about 50 weeks and the most impressive responses were in gastrointestinal GvHD, in joint and fascia GvHD as well. About 20% of patients were able even to discontinue steroid treatment.
Zinaida Peric: So I think this drug might be the third drug which will actually get an approval sometime soon. It has already granted an FDA evaluation, I think, which is due in May this year. So we’ll see what happens, but I think this drug could really change the field, which was until recently really a field which we had no actual treatments available. There’s also one thing in acute GvHD I could mention, if you want? In the steroid refractory acute GvHD, also in patients who already received ruxolitinib actually, it’s a French study so Eolia can maybe comment on it as well.
Zinaida Peric: It’s a very impressive data that was shown by Professor Malard from Saint Antoine and this is a use of FMT products, actually product which is pooled from different donors and then was used again in refractory GI-GvHD patients, 29 of them. They saw also really impressive responses by day 28, about 60%, and also more than 50% responses in patients who are refractory to ruxolitinib as well. So I think in the field of steroid refractory acute GvHD, fecal microbiota transplantation could be something which is also a game changer.
Christian Chabannon: Thank you Zinaida, Eolia do you want to comment on the Florent study and presentation?
Eolia Brissot: Its really interesting to see that FMT for patients who are GvHD type three. So I think it was 29 patients who were included and the response was almost 60%. There were no really adverse events for these patients so I think this is a really, we have to get more patients and everything to have more data but this is really promising treatment for refractory GvHD and even for GvHD after steroids.
Christian Chabannon: Thank you Eolia. We don’t hear you very well actually when you speak, but I think we caught your response. Nico, any comment on these GvHD issues?
Nico Gagelmann: Maybe one comment and maybe a small question, it’s really interesting that we see these differences between actual characterization and targeting of GvHD like intestinal or skin, fascia. Zinaida, do you think there will be in the future, we will specifically target, for instance there will be different drugs for intestinal GvHD or skin GvHD which we saw a first report with pomalidomide, or do you think this new drug will cover it all? Or what do you think, will we be capable to personalize treatment for GvHD patients?
Zinaida Peric: Thank you, Nico. Of course this is the aim. This is probably easier in acute GvHD because we know that chronic GvHD is seldom a one organ disease. So in chronic GvHD, it is usually a place where we have to target many organs but maybe the field maybe, which is the weakest point in chronic GvHD is probably lung GvHD. So unfortunately even with the new drugs such as ruxolitinib, we haven’t really moved much and I don’t know, we probably have to know more on pathophysiology as well in lung GvHD and have more patients and better organized studies to see what is best for these patients because this is a highly morbid form, and this is a real problem which hasn’t been unfortunately still addressed with the new drugs as well.
Christian Chabannon: And since this is very good news that we actually now have additional and efficient drugs, what is the role of ECP in the management of steroid refractory GvHD?
Zinaida Peric: ECP they’re of course different, not all centers have experience with ECP because there’s always this problem of technical difficulties when doing it but I personally have a really good experience with ECP, especially with chronic GvHD, chronic skin GvHD. So I think the future of ECP is still probably in some combination therapies, for example, with ruxolitinib and ECP, I think could be a very good tool when tapering off immunosuppression. So to include ECP in order to bridge the phase of decreasing and stopping other more potent drugs. So I think there is definitely a role of ECP in the future.
Christian Chabannon: So you see a sort of sequence and combination of different approaches to optimize the control of GvHD and possibly as you alluded to, personalize the choice of combinations and sequence based on the major target organ?
Zinaida Peric: Exactly. Yes.
Christian Chabannon: Well, thank you. Maybe we move to Nico. Nico, you heard some interesting information about myelodysplastic syndrome, myeloproliferative disorders. So the floor is you, tell us please.
Nico Gagelmann: Thank you. I would concentrate myself on one study from the EBMT on ruxolitinib pre-treatment before allotransplantation for myelofibrosis. And after that, maybe a small report on the CMML front. So there was this huge EBMT Chronic Malignancies Working Party effort to study a ruxolitinib pre-treatment and allotransplantation for myelofibrosis primary and secondary. The first really interesting thing about this study is that they tried to gather not only the information that ruxolitinib was given or not, but also whether they responded due to the spleen size.
Nico Gagelmann: What this study then found is that the ruxolitinib response was really, really important for outcome after transplantation. So patients who lost response during treatment, or had no response had the same outcome as patients who did not receive ruxolitinib, which was worse than patients who received ruxolitinib and responded, then received the transplantation and went into long-term overall survival. So this was quite interesting and intricate finding to maybe personalize the approach and to find a way to communicate diseases and patients from diagnosis to transplant a bit better. Because now in myelofibrosis, we started with transplant-specific risk stratification and by this study now tries the approach to further dissect patients who received pre-treatment and may benefit the most from a transplant or may not benefit from it. So this was quite important.
Nico Gagelmann: The other study on CMML was the first transplant specific risk stratification in CMML with clinical and molecular information, because CMML as you all know, is a very rare disease in transplantation and currently has only limited risk stratification in the transplant setting. The risk stratification for newly diagnosed patients is quite well developed, but transplantation was very, very difficult due to missing data, et cetera. So EBMT studies and CIBMTR studies found controversial factors affecting post-transplant outcome and that’s why this one study evaluated 240 patients, which was done from our center, Seattle Center, and several German centers, one center in Paris and one center in Nijmegen, the Netherlands.
Nico Gagelmann: We gathered molecular information, molecular genetic and clinical characteristics and then tried to find patients who would benefit the most from a transplant or maybe not benefit and could therefore be targets for other therapies than transplant. We then found that an ASXL1 mutation in combination with an NRAS mutation, as well as the co-morbidity index of the patient at transplant and the bone marrow blasts prior to transplant were independent prognostic factors.
Nico Gagelmann: Then we calculated the system, continuous system which can be found on the website which was made available and will be available with the article, which will be published soon. These two studies, I think are pointing towards all what we are discussing now is that transplantation and the whole Congress went to finding the right patients who benefit the most and I think this personalization or even separate level is now really, really important for patient counseling.
Eolia Brissot: Can I ask a question to Nico?
Christian Chabannon: Absolutely.
Eolia Brissot: About the first study you presented on ruxolitinib in patients who underwent allogenic stem cell transplantation for myelofibrosis. Do we have any pathophysiological hypothesis to explain this result? Why patients who received ruxo and respond to ruxolitinib would have better outcomes?
Nico Gagelmann: Not really, I think it would be interesting to have this information from these patients and it could be very interesting. So the response in ruxolitinib is also a very difficult measurement because this EBMT study just used the decrease in spleen volume with 50%. So in myelofibrosis, you find that leukocytosis and thrombocytopenia are really, really important factors for post-transplant outcome.
Nico Gagelmann: So whether this is a pathophysiological or just a cell dynamic characteristic that leads these patients into better outcome? That’s not identified yet, but that’s a good question. I think this study is the maybe the first stone for new personalized approaches to really define what’s the response, how do they perform and how can we characterize them a bit better before transplant that they benefit from that?
Christian Chabannon: Thank you Zinaida. Any comment or any question?
Zinaida Peric: We know about pre-transplant ruxolitinib and we all know that it’s very difficult sometimes to manage myelofibrosis patients because after you stop ruxolitinib then the spleen increases in size and then you decrease immunosuppression and then you get GvHD and then you give immunosuppression and steroids and then spleen increases again. It’s a very complicated disease to manage. So I’m always wondering what about ruxolitinib in the post-op setting, meaning as soon as GvHD occurs or even sooner, do you have any experience or knowledge about ruxo in the post-transplant setting?
Nico Gagelmann: There weren’t any reports at EBMT I saw but there were, I remember three small center, one from France I cannot remember where. These studies had difficult findings. We have now actually two patients with primary myelofibrosis who just receive ruxolitinib for steroid refractory GvHD after transplant very early on.
Nico Gagelmann: The one is in his day 60 and the other one is day 120 and they actually performed quite well but as you mentioned, it’s very difficult. What do you reduce first? Do you reduce immunosuppression or do you reduce ruxolitinib? But these two young men actually performed quite well but post-transplant ruxolitinib in myelofibrosis is completely rarely documented so far.
Christian Chabannon: It’s important to stress that the CMML studies that you described Nico, was selected as one of the presentations during the presidential symposium, recognizing the value of the work done on this rare disease, as you mentioned. So a key word from your presentations is personalized, we personalize treatments, pre, post-transplant depending on patient conditions. This is the status and patients are increasingly part of the annual meeting. Maybe Zinaida, a short word about patient-reported outcomes and how patients can contribute to actually optimize and improve the results of their transplant and post-transplant treatments.
Zinaida Peric: There’s been now a really big effort in the EBMT on the engagement of patients with Helen Schoemans from Transplant Complications Working Party being a very important let’s say, wheel in the whole process. So we are very happy to be involved in this and this is also I think, something that is going to be very important in the future. We’ve seen now that all studies have started including patient-reported outcomes and report those as outcomes as one of the most important outcomes of the studies as well, which of course makes sense and is logical.
Zinaida Peric: I think EBMT has really in the last year moved towards really gathering the group of patients and physicians and EBMT subcommittees and Working Parties together. We still need to find the best way to improve this communication and to find a way how to collect this data in the best possible way and how to use them in the best possible way but I think the first step has been done and I think this last year has been really, really good. This EBMT, there was really an important change when compared to previous EBMT’s in this field. So I think we are on a good track here.
Christian Chabannon: Yeah. Thank you Zinaida and as you were speaking, I realize we are already coming close to the end of this session and we spent most of the time discussing various aspects of allogeneic hematopoietic cell transplantation and it is important here to stress that this is still a very important part of EBMT activity and I would say core business but since I’ve been a CAR-T person for the last few years, I cannot resist just to give you a flavor of what has been said around CAR T-cells during this EBMT annual meeting.
Christian Chabannon: So very briefly we’ve seen new medicinal products coming to the market, in particular for multiple myeloma. We’ve seen improved experience with already approved CAR T-cells in a real-world condition and from this viewpoint, there was sort of a little red signal coming from one of the presentations, a Jian-Jian Luan abstract reporting on the German experience in real-world conditions with CAR T-cells and showing that the response rate and the overall efficacy of axi-cel and tisa-cel were somewhat lower in real-world conditions than they were in the registration study. So a bit different from what has been reported by our American colleagues.
Christian Chabannon: We were very positive and optimistic as to the efficacy profiles of these drugs in real-world conditions. So definitely this needs to be further explored. We had very nice presentations on the future of immune effector cells, therapies, and how to address issues such as resistance, tumor escape to CAR T-cells and how can we also improve genetic engineering of the T-cells by substituting gene editing techniques to the conventional, if I can say so, retro or lentiviral approaches to transduce T-cells.
Christian Chabannon: So as we come to the conclusion of this session, we can say that EBMT remains a very active professional association, an inclusive professional association, trying to reflect the diversity of it’s community and it makes a great effort to draw young and talented investigators and Nico is one of the key actors at the moment, trying to bring young and dedicated people to the field.
Christian Chabannon: We need new people to keep improving results and also as it’s been stressed by Zinaida, we try to involve patients because all the efforts that we carry through EBMT ultimately are for the benefit of patients and their families as represented by patient’s advocate. So, as a conclusion, Dr. Brissot, Eolia, Dr. Peric, Zinaida and Dr. Gegelman, Nico, I would like to thank you warmly for being there today with me and for accepting to answer questions and describing your work and what you heard from others during the EBMT annual meeting. Thanks to all of you for listening to the VJHemOnc Journal. Take care.