Welcome to The MDS Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features Amer Zeidan, Valeria Santini and Eva Hellström-Lindberg – experts at the forefront of research.
“I was very blessed because of wonderful teachers and professor I had. I was very interested in the pathobiology of diseases and then hematology seemed to be a natural choice because it couples clinical aspects and, of course, what we call now translational aspects. So, I worked in the lab and I worked in the clinics.”
– Valeria Santini
“I think that, for me, a good leader, whether it’s a man or a woman, he doesn’t ask questions how you should do things, just that you do things.”
– Eva Hellström-Lindberg
Current State of the Field & Advice
“Even if you have an environment that writes papers in Nature, and you know that people are mean to each other, that you have bullying, don’t choose that. Choose an environment that, even if you have to work extremely hard, that is known to produce good science and where people are good to each other.”
– Eva Hellström-Lindberg
“If you are assertive, not aggressive, I mean assertive, and you are self-confident, you can do whatever you wish. But you have to really be confident and work and be present and know that you are really valuable. And if you have ideas, bring forward your ideas.”
– Valeria Santini
Where is MDS moving?
“But I think we have to know all the mutations, we have to know all the cells, we have to work with precision diagnostics. And we have to use all the fantastic techniques.”
– Eva Hellström-Lindberg
“Historically we had the HMAs and HMAs have been combined with many other agents, but so far any combination has not been shown to be better than HMAs alone. And then, lo and behold, in the last three years, we have, I think, an unprecedented number of Phase III trials.”
– Amer Zeidan
Watch the full session
Amer Zeidan: Hi, everyone. Thank you for joining us in this new episode of MDS Sessions of VJHemOnc. This episode is actually quite special because it’s going to celebrate the Women in Science Month. And we have two highly esteemed clinical investigators and scientists in the field of MDS who will share with us their personal story and their contributions in the MDS field and how do they see the field going forward.
Amer Zeidan: So, my name is Amer Zeidan. I’m an Associate Professor of Medicine at Yale University and the Director of Early Hematology Therapeutics Research. It’s really a pleasure to have Dr Valeria Santini who’s an Associate Professor at the University of Florence, highly esteemed researcher in MDS and the Director of the MDS work basically in the University of Florence and very respected Italian contributor. And we’re also very happy to have another highly esteemed researcher, Dr Eva Hellström- Lindberg, who is a Professor of Hematology in the Karolinska Institute in Stockholm and who has been the past President of EHA as well as a number of other highly esteemed positions and highly amazing contributions to the field of MDS. So, thank you both for joining us and it’s really a pleasure to have both of you with us today.
Amer Zeidan: So, maybe I can start with Valeria. So, Valeria, maybe you can share with us your story in terms of how did you decide to go into medicine science and specifically in MDS?
Valeria Santini: That’s a long story, so I will try to be very short. But it’s a, it’s a strange story. When I started to study medicine, it was because I have chosen to be useful to people. My real interest was art and art history but then I thought that’s for myself and not for the others, and I thought I had to be a little bit more useful. So, it was a social choice that I made. And then later on, I was very blessed because of wonderful teachers and professors I had. I was very interested in the pathobiology of diseases and then hematology seemed to be a natural choice because it couples clinical aspects and of course, what we call now translational aspects. So, I worked in the lab and I worked in the clinics.
Amer Zeidan: And for MDS, was there like a particular mentor or what how did you choose to work in MDS?
Valeria Santini: No, that was I spent three years in the Netherlands, and I worked with Bob Löwenberg. When I came back, I was too young to take the Chair of something and to be the expert of something, and I had an experience in AML, so acute myeloid leukemia, that seemed to my Director a little bit too much for a younger doctor. So, they assigned to me the MDS. I mean, at that stage many years ago, there was nothing to do so I was quite unhappy in the beginning. And in the end, and in some years, it became a very, very interesting and challenging subject. But the beginning was just because…
Amer Zeidan: Yeah, and it’s actually a very common theme when we talk to people, you know. For me, I always knew I liked malignant hematology, but you know I worked with a great mentor when I was at Hopkins with Steve Gore and because of him I actually got more interested in MDS. And it’s always interesting to see how people can take this opportunity when it comes and run with it.
Amer Zeidan: Dr Lindberg, how about you?
Eva Hellström-Lindberg: Well, it’s a story that begins some years before yours, Valeria. So, I trained, I had my medical MD degree in 1983 and I thought I was going to be a gastroenterologist but then a range of serendipities led me to hematology. And so, I started at hematology and I started to, I liked internal medicine, I liked hematology. And I got a mentor, he was not at all in MDS, but he worked with something called cell differentiation. And that was in the mid-80s when people had learned how to differentiate immature cells in vitro.
Eva Hellström-Lindberg: You remember the stories of all-trans retinoic acid and so forth? So, I started to work on that in the lab. And then my mentor said, “Well, you can test these cells because they seem to mature very poorly.” So, my first papers were on vitamin D and vitamin A and things like that. And then in parallel, at that time MDS wasn’t even a disease, so in parallel to that, MDS sort of was coined and then we realized that we had patients that had these immature features and lack of restored maturation and so forth. And that actually led to the fact that I started the MDS research in Sweden and then within a few years also led it in the Nordic countries.
Eva Hellström-Lindberg: And I actually became, I sort of, I coined the Nordic MDS group. I was not even a PhD, [inaudible] PhD then, I was a junior doctor. I think the reason was that no-one believed that this was going to be interesting. All the professors dealt with acute myeloid leukemia and, you know, high-grade lymphoma, and allotransplantation. And I was actually allowed, though I was extremely young, to paddle on and form my own interest. And then that is on the way.
Eva Hellström-Lindberg: So, we published studies on, clinical studies on low-dose AraC which was then what we gave and this vitamin A, vitamin D, interferon, and that led to the use of epo, G-CSF and so forth. So, that was my start, with a mentor that had nothing to do with myeloid disorders, but he was interested in differentiating cells in vitro and in vivo.
Amer Zeidan: Yeah, that’s fascinating. So maybe, I guess, I will take advantage of this to kind of go into the second subject. And since we have, I think, maybe different generations in terms of entry into the field. And so, Dr Lindberg, basically did you feel like during – European countries have been always, I think, leaders in giving women full equality and ability to participate – but probably across the whole world, there have been always, I think, more challenges for women to gain recognition. And I wonder, like Nordic countries, I assume are among the most advanced in that regard. Did you feel like there were any differences in the opportunities or your ability to kind of do these types of things compared to some of your kind of male colleagues?
Eva Hellström-Lindberg: That’s a very good question. I think I was lucky because my mentor, he worked with CLL, he had a very open view. And my old mentor, [inaudible] who I think is quite famous but he’s now almost 90, he was truly, he didn’t really care if someone was a man and a woman. I can tell you a funny story of Dr [inaudible].
Eva Hellström-Lindberg: So, I think that they were very good and then I started to work with something that wasn’t a threat to anyone because no one believed that MDS really existed. I think that some other men in the environment would have liked to stop me if they had known how an important disease this would develop to, but at that time when they realized that it was too late. And I think that, for me, a good leader, whether it’s a man or a woman, he doesn’t ask questions how you should do things, just that you do things.
Eva Hellström-Lindberg: There’s a funny story, you can cut that out if you like. But when I got my second, so, I defended my PhD thesis when my youngest child was about one and a half year old. And he was involved in my last paper in the thesis. So, I entered his room, and I had the baby then in this baby bag, carrying her in. And we had about one hour’s discussion about how to work with the cytogenetics in this study. And then I said, rose and I said, “Well, bye then.” And then I said, “By the way, this is Freida,” and I pointed to my baby, and he said, “Oh my goodness, you have a child there!” Which is kind of funny.
Eva Hellström-Lindberg: So, that was my upbringing. I had good people around me. I had a very good husband. We shared a lot. And so, I think that I could have been stopped had I been in another subject and perhaps with some other people around me, but it didn’t happen. I had a very good journey. No-one really tried to hinder me to do things.
Amer Zeidan: That’s great.
Eva Hellström-Lindberg: If that was thanks to MDS, I don’t know. I suppose you’re kind of ten years later, Valeria.
Valeria Santini: No, not so young. I would like to, but I’m not so younger. But really, I must agree with you. You have to be lucky a little bit. You have to meet the right person, and probably MDS saved us in a way that we had a space that men didn’t want in that moment, because was not so, let’s say, prestigious as AML, for instance. I don’t know. Maybe this is part of it.
Valeria Santini: But what I must say is that, by my mentor who just passed away a few, I don’t know, days ago, he was also very traditional but at the same time he didn’t care. If the results and the studies were good, he didn’t really care whether I was a girl or a boy. So, he was very happy on seeing me working. And that is the first thing. So, he sort of believed in me and what is very important, and I think it still is, even if it’s less determinant now is to have a good family around. If you have social pressure coming first of all from your family then you can be in trouble.
Valeria Santini: And you’re right that in Europe, women have much more protection than in the States or in other parts of the world. We have free time when we get a baby, but at the same time, we are kept in our position. So, there is no real competition or fight when you are having a baby, or you are in your maternity leave. That is much longer in Europe than in the States.
Valeria Santini: Having said so, I think I also share with Eva the fact that my husband, even if he has a completely different career, he is a very supportive person in my choices. So, that’s also helpful. You don’t have to fight or discuss at home. You already fight enough the diseases and the situation in the hospital. So, I think this is helpful.
Valeria Santini: So, I had a very good support from my mother. You know that in Italy, families are very tight. My mother, my father, my uncle. So, they are present, and they help you. And this is releasing any possible social pressure you may have that I don’t think is present now in these days, but it used to be.
Amer Zeidan: Yeah, this actually takes me to my next question, Valeria, basically your last sentence. So, do you think there is still more to be done or do you think we are in a world of, or at least in some countries where the opportunity is completely equal at this point for women and men in science? Maybe you can speak more about things in Italy, I guess, and then from a broader perspective.
Valeria Santini: No, I think that there is a lot to be done. You know that a couple of years ago there was a big discussion because there was a paper that was rejected, and one of the reasons of the rejection was that the authors were all women. And the reviewers said you may find some men to add, but it would have never happened the other way around. And that was not ten years ago.
Amer Zeidan: They actually wrote that?
Valeria Santini: Yes, they did. There was a big, really a big, there was a big discussion about it. And as a matter of fact, if you check the grants that are assigned to women, the amount really of budget on money and the number of grants is lower and it’s, and there are less grants that are assigned to women. Now, this is fading away, and it’s going to be less and less over the years. But it’s still true. And it’s still true that there are still less women in top position than men at the university. There are very few Directors women.
Valeria Santini: So, I think we are still a long way to go. And it’s up to us, I don’t know whether Eva shares this vision, but I think it’s us. If you are assertive, not aggressive, I mean, assertive and you are self-confident, you can do whatever you wish. But you have to really be confident and work and be present and know that you are really valuable, and if you have ideas, bring forward your ideas. This is something that is not yet completely the same between women and men, I think.
Amer Zeidan: How about you, Dr Lindberg?
Eva Hellström-Lindberg: No, I do agree. I mean, there are a lot of differences that remain. I mean, we know that women become doctors, perhaps even slightly more than men. I mean, if I look at the Karolinska Institute, we have as many female as male PhD exams. The postdoc level is quite similar, they’ve become specialists in hematology. But then you see, still see a breakpoint, so that if you look at the higher levels, if you look at the higher grants, the more substantial grants, even in Sweden who is supposed to be sort of a fairly equalized country, we still have a lot of difference. You have more Professors; you have more people getting into the power positions.
Eva Hellström-Lindberg: And I think we are working a lot, but we have to do very much more about mentor programs for all young people. So, we have, I mean I lead a big research institution of about 100 people involved in hematology, and we have mentor programs for men and women, of course. But I think that you have to mentor women in a slightly different way because you have still more demands from the society to be at home with your children. Even if men and women divide the first years, but I mean, then it sort of ends up more on the female side. And I think also that there are differences that we have to meet with mentorship and to really spread confidence and also to hook down on things that you see that are really wrong.
Eva Hellström-Lindberg: I mean, men suggest men for if you wanted, it’s not only research, but it could also be leading a committee or doing things that actually may help you to learn the system. And you have to do that as a woman, you have to say yes to doing these things that men very easily say yes to.
Eva Hellström-Lindberg: So, I think we need mentor program for men and for women. And I wouldn’t say in particular for women, but women really need mentorship, role models and mentorship. And you have to tell them what is possible to do, which is more or less everything.
Eva Hellström-Lindberg: And then you can choose against some things. I mean, I have chosen for some things as when I was asked to be President of EHA. That was probably one of the most fascinating journeys in my life. But I’ve later on chosen against things like saying I don’t want to be Head of the, I mean Chair of the whole Department of Medicine because that would make me spend less time with my research. So, you have to choose all the time, and you have to have support and mentorship in your choice. I think that is important.
Amer Zeidan: And on that last point of choosing, and you know, I hear from people, I do think there is probably some systematic bias in some situations and some countries potentially against women, you know, especially as you were saying, like going into the highest positions within institutions and organizations, et cetera. Some people argue that some of these could be individual choices, you know, I guess, naturally, or sometimes women could be more focused on family. And so, how do you find balancing that? I imagine like having the right partner, as Valeria mentioned, and having the right support from their family is extremely important but-
Eva Hellström-Lindberg: That goes in the other way too. You have to have the right wife in order to be successful. No, but I mean I think that what you have to learn as a woman is to, because at least in Sweden it’s so that everything should be, all reviews, everything, when you’re competent, you should estimate something, review something, whatever it is, it should be 50/50. 50 men and 50 women.
Eva Hellström-Lindberg: Since there are still only 25 or 20%, 25% female professors, if you don’t protect yourself, you actually will do very much more of this common work. Review articles, review people’s CVs, all these things. Review grants, for example. And if you don’t protect yourself, you will end up doing much more of that than your male colleagues because you have more male colleagues. And then you will lose time to merit yourself, to really work on your qualitative research.
Eva Hellström-Lindberg: So, for many years now, I think that was EHA who taught me that when people asked me to do something I said, “Do you want me, or do you want my X chromosomes?” And if they then become silent, I know that they want my X chromosomes and then I say, “No, thank you. They are not for sale today.” I do a lot of these things, but you have to make sure, at least in Sweden, you will drown in that kind of work if you don’t just say no.
Amer Zeidan: Yeah. Valeria, do you have anything to add to this?
Valeria Santini: Yes. I think I agree completely. And I recognize myself in many things that Eva said. Another very important thing is that we have to be model for the younger ones. Because, if they see that you reach some levels and if you can do your research well, if your interest it’s kept on high during the years, they will say, “Well, if she has done, I can do it.” And having a female model is very, very important.
Valeria Santini: So, once I was addressed by a young hematologist and she said, “You are a myth.” Now, I’m not a myth, evidently, but I just had my child, and I was there, and I was discussing my data, my results, and at the same time, I was making just some jokes about my daughter at home. So, they, they thought that was very relevant and very important for them because they thought, “Well, we can do it.” And of course, as Eva said, you have to make choices and you have to say no sometimes, you have to believe in yourself and believe in your strength and not just do things because they asked you to do it.
Valeria Santini: And one thing that I still feel women have a little bit too much is they want to have the approval from the others, from the society, from the family, from the colleagues. You don’t necessarily always need to be approved. You need to do the right thing and to in research to get results and to promote your career.
Amer Zeidan: Those are very good words. I don’t know if Eva, do you have any additional advice for, for- I know that many young fellows and residents watch this segment basically. Do you have any specific advice for those who are interested in advancing their career in MDS and in science for women in particular?
Eva Hellström-Lindberg: Well, I would say that the best step in your career, I mean, you start, actually, your career, when you start to do your PhD, or equivalent. Normally there’re differences between countries. But in Sweden and in many countries in Europe, you have to do a PhD. And I think the important thing is to choose, not your mentor necessarily, I mean, that is important too, but to choose your research environment and to make sure that you have not only one mentor but many mentors that you come into a team that is supportive and where people help out and where you, you know that is the important and high-quality science is performed.
Eva Hellström-Lindberg: I think that is my main advice to people. Choose an environment that is known to be qualitative, but also qualitative by human things. I mean, choose against. Even if you have an environment that writes papers in Nature, and you know that people are mean to each other, that you have bullying, don’t choose that, choose an environment that, even if you have to work extremely hard, that is known to produce good on the science, and when people are good to each other. I think that is my main message.
Amer Zeidan: That’s very good advice. Valeria before we move on to the next subject. Do you have anything to add?
Valeria Santini: No. I couldn’t be more supportive of this last sentence. It’s so important. We spend so much time working and building our research. And if you are among aggressive and mean people, that’s not really, it’s not really the case and it’s not really what you should choose.
Amer Zeidan: I really enjoyed this discussion. It’s really fascinating, and I am sure many people will benefit from it. In the second segment, I want to talk more about your contributions to the MDS field and put it more in context of where are we going, like both of you mentioned that MDS did not get a lot of attention in the past, you know. It used to be that I don’t want to say a basket type of situation where the diseases that did not have any therapies and because mostly older people not a lot of attention. And now in the last few years, as both of you mentioned a lot of interest therapeutically, after a lot of progress on the biology over the last, you know, 10-15 years.
Amer Zeidan: So, Valeria, you had a lot of contributions in this field. And maybe you can just summarize, for us, like you, what do you see your work in the big context of where MDS is currently? And where are we going in the next five to 10 years?
Valeria Santini: That’s a very difficult question. First of all, my contribution was mainly clinical in promoting the optimal clinical care and then management of MDS. And I think that we made really good paces, we are not yet really happy, and as we are not for many hematological, neoplasias and disease. But I think the desire, let’s say, the project we have now is really to get a personalized medicine, we talk a lot about it. But for our MDS patient, this is really something very complicated. Patients are elderly, they have a very difficult and complex disease with many comorbidities with different biological and clinical features. Therefore, the word that are overused of personalized medicine are really difficult to apply to MDS.
Valeria Santini: But this is nevertheless the way I would like to go. Because the more I go deep into managing MDS patients, the more I understand that we have to adjust every time. So okay, big trials, big studies, new drugs, new combination of drugs, but still you have done to go to the granularity of the single individual patient and apply, it’s different. The management of MDS patient can also be different because of sex. So probably women, elderly women have a completely different response to some agents than men. So, this has to be implemented in our not only our future studies, and I think, interaction with other disease, I think we have so much to do still that I’m very eager to continue, to maintain my line of study.
Amer Zeidan: So on that same front, Valeria. Like we each time we talk about MDS, we always say like, you cannot cure it, except potentially with a bone marrow transplant. And, you know, we have some subsets in MDS and AML, where the patients are cured with just chemotherapy. Do you, how do you foresee the future of MDS? Do you think the goal is to cure some patients with MDS or do you think, sometimes I tell my patients, you know, our goal is to convert the disease into hypertension or diabetes, where the patient is living on one drug or another, but living as, you know as close to normal in terms of both the duration and the quality of life as you can be too normal? So, how do you view like the direction of the treatments Valeria, before I get to Eva’s thoughts on this?
Valeria Santini: This is a one-million-dollar question. How do I say it, or one million euros, that is more? Well, I would like to see or foresee a cure. But if not, I think that currently having a chronic disease that doesn’t worsen your quality of life. Look at chronic myeloid leukemia. The great majority of patient is managed very well, and without many side effects. Now, we are also trying to stop treatment but nevertheless, patients were, are kept in a very good condition for many, many years. It’s a chronic disease, they don’t even sometimes feel that they are sick, or they need treatment. So this would be my ideal for MDS patients, you know, especially for the very elderly ones, for the young ones, the very and the younger, I would like to cure, but as a matter of fact, at present, I cannot tell you more than I would like to.
Amer Zeidan: What about you Dr Lindberg? When I was going into like, during my fellowship, actually, when I was contemplating, you know, different areas to go into this was in 2010, I considered bone marrow transplant at one point and, you know, some people advised me that bone marrow transplant is going to disappear and we have so many good therapies and lo and behold, now we are actually transplanting way more people and people like, you know, with the alternative donors and also with all the cellular therapies and that field is, is booming. So, do you think that our goal is to make transplant much easier for as many patients with MDS as we can so we can cure, as many of them, or is our goal really to try to move away from transplant?
Eva Hellström-Lindberg: So, I will talk about something else, but I will start by responding to your question. I do think that the majority, vast majority of MDS patients will not be cured by any pill or drug. The reason for that is that, with extremely few exceptions, the disease starts in the hematopoietic stem cell. And you can’t really kill that, I mean it has too many good protection mechanisms. I do think that we will, we transplant more and more MDS because now we transplant up to, without too much problem, 74, 75, people who are otherwise fit. So, the increase of MDS patients undergoing transplant, is really quite marked.
Eva Hellström-Lindberg: And I think one of our big challenges is to improve transplant. Half of my projects last years have been really to work with individualized, personalized MRD tools to detect the relapses early to be able to address them. We have a huge Nordic study, including hundreds of patients, where we now have in real-time, we get the MRD so we can react to this. So, I think that we will be, I think that we will most likely need to transplant MDS in order to cure.
Eva Hellström-Lindberg: On the other hand, I think we perhaps in the lower risk states can find ways of addressing the clone, I don’t think we can remove it, but we can address it. And then that would lead me to what I thought first when you post a question. So, I am in I started very vulnerable with epo developed epo, and then and then epo plus G-CSF treatment. It’s not even considered a treatment anymore, but it is.
Eva Hellström-Lindberg: So we made our first epo stand in 1989, and then we continued with the large studies also giving predictive variables that would enable people to choose treatment. But that had, that in parallel led me to the biological standards we have done on MDS, in particular MDS with ring sideroblasts, where we have learned a lot about the apoptotic mechanisms when we, discovered the SF3B1, we started to look at what was mispliced, and what were the expression levels.
Eva Hellström-Lindberg: What we do now, so for me starting with the clinical treatment, now and in doing extremely detailed transcriptome sequencing, single-cell sequencing, trying to ask the question, why does an SF3B1-mutated stem cell compete over the wild type stem cells. Because if you take SF3B1-mutated cells and put them in vitro and only they grow, less colony stays that than survive in vitro, they just give up on they come out on the body. But inside the body, they managed to take over the stem cell pool. And that takes decades.
Eva Hellström-Lindberg: So, we now know by sequencing colonies that actually the primary mutations tells us that they arose decades. So that gives you something that people that deals with CHIP [inaudible] is working with. Could we by finding mutations early on in the course of a human being actually develop approaches that would, could we understand why they compete? That is question number one. And two, if you understand it, could you find pharmacological ways of actually keeping the clone back like, as you said, I mean treating their high blood pressure, so that doesn’t harm. So, these things have to go between clinical trials. And single cell sequencing is what really fascinates me and I will probably spend the rest of my working time on that.
Eva Hellström-Lindberg: The same goes for, how could we understand why p53-mutated stem cell relapses? Why does it relapse? A lot of the clones we can actually address by allografting. P53 is much worse. And could we by single sequencing, understand why it breaks the immune surveillance? And could we if we can do that, we can find ways perhaps of addressing it. So, for me the most fascinating part of MDS research is to be able to go from the stem cell to the bulk to clinical trials, bulk sequencing to the stem cells and trying to get the questions back and forth. This is what my home, many people in my lab work, and also other PIs.
Amer Zeidan: Yeah, and to be able to go from the clinic to the lab and back, forth, I think is one of them very satisfying aspects of a lot of the researchers there. And Valeria, you also have done a lot of work on ESA, and lenalidomide and in terms of also understanding the role of lower risk MDS. Do you foresee, especially for lower risk MDS, that it could become along the lines of what you mentioned for CML, and potentially CLL-like diseases and which largely we, life would not be significantly limited by the disease? We, you know, it mostly happens in older patients, but we still know that most patients with MDS even the lower risk will die from MDS or is complications. So, do you think the sequencing of all of those therapies and the new developments will take us in that direction? What excites you from all these evolving treatments about being able to do something along those lines?
Valeria Santini: Again, you were focusing on low-risk MDS. It’s a very articulated question you’re posing, because we have agents that can target single clones. But an MDS has a clean architecture that changes over time, and that can be modulated only partially by our single agents. That’s why there is the tendency now to quote to combine more agents, but we are doing it very clinically. So, we need to have more background and biological background to what we are doing. We are targeting one clone while we use another agent that has a more general mechanism of action. And we think that may, in fact, lead to a synergistic action, but we don’t know. Because we really don’t know enough. We don’t know about the progression of the clones during the natural history of MDS. And I want to touch upon one thing that there I’ve said, we are using ESAs as supportive therapy.
Valeria Santini: I don’t believe that ESAs are supportive therapy, but we do not know enough about how this is the erythropoietin modulates clones, are we pushing some of the clones present in a lower risk MDS by stimulating with direct erythropoietic growth agents? Or are we just giving something similar to a transfusion? I do believe that we have to study even that. Are we modulating gene expression in a different way in a different sub population of MDS is one very basic question, but it’s important and it’s not answered yet. So, if I’m targeting one’s clone, am I giving advantage to a second one or not, how much is important and how important are co-mutations, for instance? So, I think that given all these questions that are still open, answering your question is really demanding and it’s really difficult.
Valeria Santini: So, there are many, many doubts about- we know a lot we have a lot of knowledge we have been really making good progress, but we do not know yet enough. So, there are agents, new agents that are used and just improved. They are giving let’s say inducing maturation final maturation like luspatercept just by keeping on talking about the low-risk MDS, but we do not know whether this is really acting externally to the clones or doing something to the clone, the MDS clone itself, it could be that it’s just a passive tear an anti-inflammatory drug, I’m just using let’s say this word, but of course, it’s not really adequate, but just to make you understand what I think is that we have so many still pathway to understand, and also the biology of the MDS stem cell has to be understood.
Valeria Santini: So, it is difficult to speak about low risk by themselves, and then higher risk by themselves. We do so to manage them, and to give a prognostic idea to our patients. But I do not think that we should really dichotomize in this way in terms of in biology in terms of biology of MDS. It’s very, very difficult, I think that the techniques I just mentioned so, the single cell arrays and transcriptome will answer many questions, but we will have other arising from the knowledge we accumulate.
Amer Zeidan: Now that’s, I think that’s a very good pivot actually into the last segment, the last five minutes. And I completely agree with you that, you know, the division into higher risk and lower risk is, you know, flawed. It’s a biological spectrum. However, therapeutically, of course, we always approach these patients somewhat differently in terms of goals of care, as well as treatments, and I would like to get your thoughts in the last five minutes or so about, you know, patients with high-risk MDS and what I would call, you know, a therapeutic revolution in terms of the options. You know, historically we had that HMAs and HMAs have been combined with many other agents, but so far everything has not, any combination has not been shown to be better than me alone. And then lo and behold in the last three years, we have, I think, which is unprecedented number of phase three trials.
Amer Zeidan: Basically, we have five agents from very different mechanisms of action between the BCL-2 inhibitors, such as venetoclax, the TIM-3 MBG453 sabatolimab, which is an immune checkpoint inhibitor and potentially other mechanisms of action as well as pevonedistat, which is a proteasomal upstream agent, NED88 activating enzyme inhibitor, the CD47, the macrophage activating drug, and then the TP53 refolding agent along the lines of what Eva was talking earlier, about how bad TP53 and the drugs that [inaudible] this agent, and those are the ones that are in Phase three trials, there’s a large number of other agents that are even in different trials.
Amer Zeidan: So with all of these agents, do you think we are finally going to make a dent in higher risk MDS? You know, studies have shown us that hypomethylating agents, while they are helpful, but when you look at the population level, the outcomes continue to be dismal. Maybe I can start with Valeria and go to Eva to conclude the talk today.
Valeria Santini: I will be try to be very brief, but the discussion could last forever here. Because, the data are very challenging and interesting, and I want to come back to what I said in the beginning. I think that we have to select subpopulation of patients based on the biological and characteristics of the disease itself, and of the patient. So, the combinations are welcome if we have a good background, and if we do understand if we do not have a background a priori, to understand why the drug works in that specific situation. I don’t think that is one good for all, we have to choose the right combination for the individual patient.
Valeria Santini: And one question we still have to answer is why some patients stop responding to hypomethylating agents. You know that I have a long-standing interest in understanding resistance to hypomethylating agents, and in finding, if possible, some biomarkers predictive of response. We are really not there yet. We do not understand why some patients respond and some others do not or some- and that’s really an open and a big problem, why stop responding? So, I think individualizing the treatment and the combinations and try to move from the empirical results to the biological reason for response, clinical response.
Amer Zeidan: Thanks, Dr Lindberg?
Eva Hellström-Lindberg: So, as I said, in what we today call higher risk MDS, the vast majority, I don’t think you can cure the disease, not with all these fancy drugs that you, that you listed. But I do think that by, and I do think that allogeneic transplantation is to cure. And I think our aim should be to make that as effective and untoxic as possible. And I think that the new drugs for different mutational combinations will help us to reduce the clone size before an allogeneic transplantation so that the new immune system has a fair chance to out compete. The disease I think for the higher risk and then I think the border, we have to, will have to be discussed, but I think for higher risk MDS, to really put efforts in reducing the clones, making the allografting as untoxic as possible, and trying to balance GVHD, and relapse risk so that you actually can choose.
Eva Hellström-Lindberg: Today, I mean, I think that cure 60, younger patients would cure 60, 70%. So [inaudible] deal with a relapse risk, that is would be fantastic. And then all these new treatments that you mentioned, will be part of that. For the lower risk, whatever that is, but for the ones with few mutations and some specific mutations, the lack of other mutations, I think that we have to work on protecting the wild type. Remain residual normal hemiparetic stem and progenitor cells to allow them to produce erythropoiesis to that can prevent transfusion and all the other cells.
Eva Hellström-Lindberg: So, I think that we have two concepts. Both are precision medicine. But we have to realize when, and for some patients they are so old so you can’t aim towards some allografting then you can use the lower risk concept also for these patients. But I think we have to know all the mutations, we have to know all the cells, we have to work with precision diagnostics. And we have to use all the fantastic techniques. Actually, in the lab we have fantastic techniques, we have to sharpen our research questions. So, this is I think, is the challenge for the future.
Amer Zeidan: Yeah, very well said. I think it’s exciting times, definitely a lot of developments on the biology and the genetics and also on the therapeutic front. So, at the end, I really like to thank you both. This has been a great discussion. And it’s a pleasure to have you both today. Thank you so much for being with us in this episode of MDS sessions and look forward to the next time. Take care.