Welcome to The MDS Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features Amer Zeidan, Peter Greenberg, Mario Cazzola, John Bennett and Ghulam Mufti – experts who were at the forefront of research in the early days of MDS recognition, diagnosis, classification and therapy.
“It actually was not recognized as a separate or as a true cancer until the 21st century in the year 2001, when the WHO designated it as a cancer, and that allowed a lot of understanding of its epidemiology.”
– Amer Zeidan
“We got to talking about the fact that we had no common language between countries about various types of either acute leukemias like myeloid leukemias or the so called pre-leukemic syndromes, smoldering leukemias, et cetera, and thought it might be useful to collect cases and meet together and see if we couldn’t come up with a classification”
– John Bennett
Unifying International MDS Advancements
“There are not many conditions or other cancers in which the treatment can vary all the way from observing the patient every three months and doing nothing, all the way to recommending allogeneic bone marrow transplantation from the initial visit.”
– Amer Zeidan
“Once the WHO classification was published, Luca Malcovati and I studied the prognostic impact of the WHO classification. We found significant differences in survival between the WHO subtypes and showed that the WHO classification of MDS could be a useful basis for clinical decision making.”
– Mario Cazzola
The MDS Foundation, disease biology and molecular prognostication
“The Chicago 1994 meeting, that was, I think, a game changer in terms of getting our American friends and colleagues involved and interested in this disease and then subsequently led to the MDS Foundation as well as the IPSS score and all the other developments since.”
– Ghulam Mufti
More recently, Luca Malcovati and I did a very large collaborative study showing that SF3B1 mutant MDS is a distinct nosologic entity associated with a favorable clinical course although co-mutations in genes like RUNX1 or STAT2 may involve a worse outcome, specifically leukemic evolution.”
– Mario Cazzola
Moving towards a cure beyond ASCT
“I think that we use the word myelodysplastic syndrome, and yet, the heterogeneity of the disease now defined by the molecular features, immunologic features, indicates that it’s a spectrum of disorders. And for us to begin treating it we’re going to need to have more specific therapies aimed at the classified subgroups, those that are classified in part molecularly and immunologically.”
– Peter Greenberg
“So, I’m quite confident that with the kind of brainpower that is now in MDS, that we will be able to link in all these things that we have done in the last 30, 40 years over the next decade to come up with – I’ve never liked the word personalized medicine or personalized treatment – but to come together with a treatment that actually has not just an effect on controlling the disease for a period of time, but hoping to cure the disease in a non-transplant way.”
– Ghulam Muftti
Amer Zeidan: Hi everyone. Thank you for joining us in this episode of MDS Sessions by VJHemOnc. So today, my name is Amer Zeidan. I’m an Associate Professor of Medicine at Yale University and Director of Hematology and Early Therapeutics Research. And today our episode is going to be about MDS history and how MDS evolved throughout the last 50 years and became a recognized entity.
Amer Zeidan: And many of you might know that MDS actually has lagged behind many of the other hematologic malignancies in terms of understanding of its biology, in terms of understanding of its diagnostic process, classification and risk stratification. It actually was not recognized as a separate or as a true cancer until the 21st century in the year 2001 when the WHO designated it as a cancer, and that allowed a lot of understanding of its epidemiology.
Amer Zeidan: However, there was a lot of research going on in those years to try to move the field forward and some of the pioneers who helped move this understanding were highly influential and their contributions still stand out until today. And some of them are still very active in the field. So, today I’m very honored and privileged to have four of the pioneers of MDS who will be sharing their thoughts about the history of MDS, and how did we get to where we are today, and how the future is looking.
Amer Zeidan: So I’m pleased to have Dr Mario Cazzola who’s a Professor of Hematology at the Fondazione IRCCS at the Policlinico San Mateo in Pavia, Italy. I hope I did not butcher that. Dr Peter Greenberg, Professor Emeritus and the Director of the Stanford MDS Center in Stanford, California. Dr Ghulam Mufti who is the former Head of the Hematologic Medicine at Guy’s, King’s and St. Thomas Hospitals, King’s College London, as well as currently being the Director of the King’s Health Partner and BMS/Celgene Research Program and Clinical Consultant in Hematology and Oncology. And last but certainly not least, Dr John Bennett who is a Professor Emeritus of Medicine, Pathology and Laboratory Medicine at the University of Rochester Medical Center in Rochester, New York. Thank you so much for joining me.
Amer Zeidan: So I’m going to start by showing a couple of slides looking at some of the early recognitions of MDS. Some of the viewers might know that looking as a disease entity was recognized in the year 1849 by Virchow Rudolf as well as another famous John Bennett, when the initial descriptions of leukemia were made. However, MDS was not recognized as a separate disease entity for much later.
Amer Zeidan: So here, what you can see is some of the early description of MDS. So the term “refractory anemia”, which still stands up with us today, was actually coined in the 1930s by Dr Cornelius Rhoads and this term actually exists until today. The idea is that anemia that results from MDS does not respond to liver extracts which was what they used to treat anemia with and it was called refractory anemia.
Amer Zeidan: Subsequently, it was recognized that some of those cases pre-exist before acute leukemia and the term “pre-leukemia” also was coined, as you can see in this slide from the 1950s. So “pre-leukemia” is still a common term that is used to refer to MDS although currently we understand that it’s a cancer and it can be quite aggressive as acute leukemia.
Amer Zeidan: Another term that comes often with MDS is ringed sideroblasts, which are iron deposits around the mitochondria, and that’s a disease entity that also was described in the 1950s. The definition of the deletion 5q syndrome also subsequently came in the 1970s before we even understood what is the pathogenesis of deletion 5q and how does it contribute to development of this specific subtype of MDS.
Amer Zeidan: So, I’d like to start with Dr John Bennett and take us through those days basically in terms of how the understanding of MDS has evolved and how does refractory anemia with excess blast, that term was coined, and maybe take us through the initial definitions of the French-American-British classification which has been pivotal and still largely used actually until today in terms of classification of MDS. So, Dr Bennett?
John Bennett: So, we, going back now over half a century, in the early 70s I met Georges Flandrin who was a hematopathologist. In those days you called yourself what you would. There were no boards. But he primarily functioned as a pathologist although he did indeed treat patients as well. And I met him at I think the second or third tutorial in Chicago that was run by Henry Rappaport, a well-known, established pathologist at the University of Chicago. And he was interested in leukocyte enzymes as I was because we had published at the same period of time a new assay for doing leukocyte alkaline phosphatase in patients with chronic myeloid leukemia.
John Bennett: So I visited him in his laboratory and spent about a week in Paris at St. Louis Hospital and met his associate Marie-Therese Daniel at the same time. And we got to talking about the fact that we had no common language between countries about various types of either acute leukemias like myeloid leukemias or the so called pre-leukemic syndromes, smoldering leukemias, et cetera, and thought it might be useful to collect cases and meet together and see if we couldn’t come up with a classification that would be useful.
John Bennett: I met Claude Sultan at Créteil Hospital in Paris at another meeting sponsored by Dr Rappaport and he and Drafus, who was his clinician, had recently published a paper on what they call RAEM, refractory anemia with excess myeloblasts, and tried to separate that from patients with chronic myelomonocytic leukemia.
John Bennett: So, we eventually formed a group that included the three French physicians, David Galton, and Dan Catovsky from Great Britain, and myself, and Harvey Gralnick from the US, and had a series of meetings which led to a first publication on AML and ALL in the British Journal on Hematology in ’76, which became the number one quoted article that the British Journal on Hematology has ever had.
John Bennett: In that paper we identified a group of patients that we reviewed morphologically that did not fulfill the criteria for acute myeloid leukemia, which in those days, believe it or not, was 50% blast and promyelocytes, subsequently dropped to 30%, subsequently dropped to 20% by the new WHO criterion. And we included the patients that Claude Sultan had described and renamed them RAEB, refractory anemia with excess blasts, preserved the refractory anemia component because all these patients were by definition anemia and refractory to the ordinary hematinics that were available like B12, folic acid, and iron, and separated them from chronic myelomonocytic leukemia that arbitrarily shows a breakpoint of 1,000 monocytes per microliter, which was about two standard deviations above the upper limit of normal for most university laboratories.
John Bennett: So that paper was published in ’76 and then in ’82 we expanded the definition to include patients that had relatively few blasts and called those patients either refractory anemia or refractory anemia with ringed sideroblasts. The ringed sideroblasts were defined as 15% or greater because in Claude Sultan’s laboratory they had a very large number of patients who behaved quite well who had very few blasts in their marrow. And the separation between those and those who did not do very well turned out to be on their scale at about 15%. Most of these patients had more than 15%.
John Bennett: So that gave us sort of two categories of the several that we mentioned, and the others were RAEB and then RAEB and transformation because we were trapped between a very high-grade neoplasm, between 20 or 30%, and the cut-off of 30% blasts because some of these patients actually behaved more like they were smoldering than behaving like patients with acute leukemia.
John Bennett: So that paper was published in ’82 and revised again in ’85. And during this whole period of time gradually people began to adjust to having this classification and a meeting was held that maybe Ghulam can discuss at the first international MDS meeting that we held in Austria that he and Franz Schmalzl jointly sponsored. And it brought together for the first time a group of investigators to present some of their early publications.
John Bennett: Yeah, that one there is it.
Amer Zeidan: Yeah, that’s ’88.
John Bennett: That one that just went by showed some of us having dinner in –
Amer Zeidan: ’88.
John Bennett: – in ’88, right, in Innsbruck.
Amer Zeidan: Yeah. Yeah, that was the first meeting and actually we’ll talk about that meeting [inaudible].
John Bennett: That sort of triggered a burst of energy and activity by a variety of different investigators. And then we had a subsequent meeting in Bournemouth. And then three years that Terry Hamlin organized. And three years later really the meeting that set us all off to establish a foundation.
John Bennett: And a lot of that effort was a result of Peter Greenberg being interested in why a study that he was organizing and doing showed a discrepancy between patients who seemed to sure behave better and wondered whether there was some way to better develop a prognostic scoring system. And the Amgen Corporation was kind enough to allow us to sponsor a review of 600 patients or so that he’ll talk about it in a moment, to develop a prognostic scoring system that sort of went beyond the FAB, French-American-British group, although that system was prognostic and was able to clearly identify patients who would do very well. Low-risk patients with refractory anemia or refractory anemia with ringed sideroblasts, from patients who had excess blasts greater than the 5% and less than 20%.
John Bennett: You can see on this survival curve basically that basically just using a pure morphologic classification including the del(5q) group, which was in blue, was able to clearly separate patients into more favorable categories and those who behaved extremely badly. And some actually had a median survival of even less than six months or so.
Amer Zeidan: Which is amazing, yeah. So I think we will be covering all of those points, I think, in terms of the MDS Foundation formation and the annual meeting, sorry the bi-annual meeting, as well as risk stratification. But before we go there, and I think as you pointed out, not many conditions like MDS have very significant correlation between morphology and survival as can be seen in the survival curve.
John Bennett: Right. Amer Zeidan:
But I think this took us to the WHO classification, and I would love if Dr Mario Cazzola can take us into these days in terms of how the WHO classification was proposed in the early 2000s around the time in which MDS was formally recognized as a cancer and what brought that into the current scene.
John Bennett: That’s a great picture because it shows Mario right there in the front –
Amer Zeidan: Yeah.
John Bennett: – standing up nice and straight and a bunch of other world renowned individuals that you’ll probably recognize without calling out, calling out, calling out their names.
Amer Zeidan: Yeah. Dr Cazzola?
Mario Cazzola: Clara is close to me.
John Bennett: Yeah.
Mario Cazzola: Claire [inaudible].
Mario Cazzola: Okay the WHO classification was proposed in 2001. They revised the FAB classification with the aim of integrating a morphologic and genetic information into a working clinical tool. Once the WHO classification was published, Luca Malcovati and I studied the prognostic impact of the WHO classification. We found significant differences in survival between the WHO subtypes and showed that the WHO classification of MDS could be a useful basis for a clinical decision making.
Mario Cazzola: We published this paper in JCO and extended our studies, and found that the most important prognostic variables in MDS at that time were WHO subgroups, carrier type, and especially transfusion requirement. We combined these parameters and developed the WPSS, which is a dynamic prognostic scoring system that provides an accurate prediction of survival and the risk of leukemic evolution in MDS patients at any time during the course of their disease.
Mario Cazzola: Also, this paper was published in the JCO and a few years later the revised IPSS was available, but Peter Greenberg will talk about this.
Amer Zeidan: Yeah, so I think since we are speaking about risk stratification, and I will get to Dr Mufti subsequently about the meetings. I think Dr Mufti also sounds like he describes one of the very first prognostic scoring systems.
Amer Zeidan: This is another slide courtesy of David Steensma, which is showing actually many of the prognostic scoring systems. There are like more than 20 that have been developed over the years and I think people might understand why this is needed in MDS because there are not many conditions or other cancers in which the treatment can vary all the way from observing the patient every three months and doing nothing, all the way to recommending allogeneic bone marrow transplantation from the initial visit. So it’s a disease in which risk stratification is clearly very important.
Amer Zeidan: Maybe Dr Mufti and Dr Greenberg can take us through the evolution of these risk stratification scores from the first ones that were described and the WHO prognostic scoring system that Dr Cazzola talked about until the revised IPSS and the IPSS which are the most commonly used scoring system these days.
Ghulam Mufti: Okay, shall I go first, Peter?
Peter Greenberg: Sure.
Ghulam Mufti: Okay. Well, so my journey began at Hammersmith Hospital with David Galton telling me that there is this disease called myelodysplastic syndrome. I think you ought to do some research on it, but you ought to go to a place where there are a lot of elderly people because this is a disease of elderly. And that’s why I was given a grant by the Leukemia Research Fund to go to Bournemouth, which is where people go to retire.
Ghulam Mufti: I went to Bournemouth and indeed there was a lot of MDS there. And I had at the back of my mind a simple scoring system that took note of peripheral blood features like hemoglobin neutrophil count and platelet count, and blast cell percentages in the marrow. We also were doing cytogenetics at that time, but that was relatively less commonly done.
Ghulam Mufti: So, on the basis of these four common factors which was blasts and the peripheral blood count, I put together the Bournemouth score and I published it in the British Journal of Hematology. And soon after that there were a series of other scores that were published and, as you can see from this slide, interest in MDS increased and the Spanish score included cytogenetics as well, which is there.
Ghulam Mufti: So, by the time we came to 1988, to the first international symposium there was already a little bit of buzz around in terms of prognostication beyond the FAB classification in the form of various scoring systems, but most of these scoring systems were named after the cities where people were working. Then, I think, it was kind of recognized that these parameters are important in terms of prognostication in addition what has been mentioned by John about FAB classifications.
Ghulam Mufti: That’s where Peter comes in because it was Peter who got all these groups together which are listed on the slide and we all kind of were very keen to put together a scoring system whereby everybody would have one scoring system to use. Peter then took over all the data collection and he will talk about how then we came finally to IPSS scoring system.
Ghulam Mufti: I won’t talk about the meetings first, but I’ll talk about the meetings and the rest of the journey a bit later on, if time permits. But I’ll hand over to Peter now.
Peter Greenberg: Well, similar to Ghulam in a way my journey began when I was a Fellow, a Hematology Fellow at Stanford in which my boss Stan Schrier said, “We have this disease pre-leukemia. Why don’t you take a look at it?”
Peter Greenberg: And at that time I was interested in regulation, hemopoietic regulation, and I was working on the in vitro culture system that had just been described. It had been described by Bradley and Metcalf and [Pluznik and Sachs for the use in mouse to look at in vitro hematopoietic regulation, but there was no human system. Serendipitously though, the year of my fellowship after I had begun work with the system for mouse, Bill Robinson went to the Metcalf’s Lab and did develop a system for human hemopoietic cell growth.
Peter Greenberg: So I then adapted the system I was working on in vitro in my lab at Stanford as a Fellow, to human, for humans, using that background, and worked for some years in the 70s on a variety of myeloid diseases. The first paper in 1971 in the New England Journal came out that described differences and similarities between so called pre-leukemia and AML and that is the myeloid colony forming cells of pre-leukemic cells often acted similarly to those of AML and yet we had a different disease trajectory, and the question was why.
Peter Greenberg: Now, at that time I had a Fellow, Rob Negrin, who now is the Head of Transplantation at Stanford and together we looked at the use of some of the growth factors that were involved in hemopoiesis in vitro and did some of the first studies looking at GCSF. At that time, it was colony forming activity or colony stimulating activity, not even a factor, but ultimately it became a factor.
Peter Greenberg: And so, Negrin had this molecule, GCSF, and we thought that this could be a useful differentiation inducing factor. And if it was, it might decrease replication of the abnormal stem cell. And so, we began a study and it was an international study looking at the effect of GCSF in vivo in higher risk MDS patients, those with RAIB and RAIB-T. 100 patients were randomly assigned to observation versus GCSF. And low and behold, we found that, no, it did not decrease evolution to AML, but it did not increase evolution to AML. However, there was some change in overall survival, better in the observation group, which really didn’t make a lot of sense because what turned out was the small number of deaths in the observation group were due to either patients having fallen and hit their head or having died after bone marrow transplant.
Peter Greenberg: So at that time, this was around between ’89 and ’93, the various scoring systems that you see here had come about and it was a veritable Tower of Babel in which each group was making some degree of advance. But the question is, how can we put them together?
Peter Greenberg: And so I spoke with John Bennett and a number of other people and the study with GCSF that I had done incorporated a large number of observation, patients in the observation arm that we used, as well as the patients that were involved in the previously published studies from England, Dr Mufti’s group as well some others: France, Germany, Japan, and Spain. And each of those groups had previously generated a scoring system with some differences in the variables that they found valuable. We put all of those into a common grouping and this was then analyzed with the help of John and Chris Cox at the University of Rochester. And this ultimately generated the IPSS. We discussed this at the MDS symposium in Chicago,1994. That meeting we discussed this. And then ultimately, it was published in Blood in 1997.
Peter Greenberg: Ultimately, another 15 years went by and there were again a series of studies suggesting the IPSS could be improved by a variety of other factors. And so, we met again as a group and we have been meeting for years at the international MDS symposium. And ultimately, with Heinz Tüchler as the statistician, put together data from a number of other groups and ours. And moving from approximately 700 to now several thousand patients, 7,000 patients, we then analyzed variables.
Peter Greenberg: And the particular change from IPSS was depth of cytopenias. The specific cytogenetic abnormalities that had been previously orchestrated by Professor, well, Dr Schantz, as well as Detlef Haase, and those plus the depth and proportion of blasts were used and were found to generate a more valuable scoring system. And that was what generated the IPSS-R.
Amer Zeidan: I think this is an amazing story of how collaboration between investigators across the work can really help move things forward. And I think several of you have talked about the international symposium on MDS and having like a specific meeting on such a rare disease entity and the creation of the MDS Foundation, which seems both of those factors have really helped to move the understanding of the disease and prognostication very well. So, I would love to hear from you about the initial planning, and how did the foundation and the meetings came about, and how do you see them evolve over the last now 40 years almost or 35 years?
John Bennett: The foundation came out of basically that ’94 meeting in which we felt the need for helping patients as well as educating physicians. And we were fortunate enough at that time that the early trials of new agents in MDS did get significant support from industry and were able to move forward with a series of meetings as well as educational pamphlets, patient advocacy groups, supporting care groups with dedicated risk oncologists who helped a lot of the patient anxieties that develop with a disease that is hard to pronounce. And have carried this forward up to the present day.
John Bennett: We tended to choose meetings in cities that had dedicated programs around the world, most in Europe, one in the US, one in Japan in Nagasaki about every two years or so. And these were tremendously exciting meetings because not only were there overview talks, a lot of abstracts, but an opportunity to present ideas about where the future was heading in this field.
John Bennett: The abstracts were polished in Leukemia Research for many years, which Elsevier supported and was supported as well the foundation. We had really very good attendance, as high as 1,200 to as low as 700 or 800. And the meetings lasted anywhere from three to five days. Really not competitive with the ESH meetings and ASCO and ASH held at a different time of the year and very well attended.
Amer Zeidan: Yeah, indeed. And actually one of the meetings that hopefully will manage to escape the pandemic and continue to be in an in-person format because I think this is such a great venue for interaction. So, the next one is going to be in September in Toronto. Hopefully, it will continue to happen in person.
Amer Zeidan: Maybe I go to Dr Cazzola?
Ghulam Mufti: Amer, can I just add about the meetings?
Amer Zeidan: Yeah.
Ghulam Mufti: I mean, can I just add about the meetings?
Amer Zeidan: Of course, yeah.
Ghulam Mufti: Just one contribution.
Amer Zeidan: Absolutely.
Ghulam Mufti: I think in terms of the start of the meetings, which was 1988, but it was actually 1986 that I met with Franz Schmalzl, and he is an Austrian hematologist and his main interest was staining peripheral blood marrow with peroxidase stains. And one of his key findings had been a partial peroxidase deficiency as determined by staining of the peripheral blood and marrow in patients with MDS.
Ghulam Mufti: So he had sent me a little book which had pictures of this partial peroxidase deficiency in the way he had. And then I wrote to him and I said, “Well, look, I am interested in MDS and I’ve just become a Consultant for King’s College London. Wouldn’t it be a good idea to have a meeting on this disease? It could be held in London.” But I was still quite junior and I thought it would be a daunting task having a meeting in London having just become a consultant in ’85. So he said, “Well, let’s do it in Innsbruck.”
Ghulam Mufti: So, we then put together a program and I think all of us here as well as many more who are not here took part in that Innsbruck meeting, which made a huge loss. It took us three years to actually pay the debt that we had from that meeting. And that is why you’ll find that there is a three year gap between the Innsbruck meeting and the Bournemouth meeting.
Ghulam Mufti: [inaudible] meeting didn’t take place. It was originally, I had said, in fact, I remember summing up at the Innsbruck meeting and saying that we will have another meeting in 1990 only to find out later that it will take us a year more to pay the debt off. And then we had Terry Hamlin, who again, was a great enthusiast of MDS, partly because I had been there, and he helped organize the 1991 meeting.
Ghulam Mufti: And since, that was okay, it was still going low-key up to that point, as John says, that the big change in MDS took place where there was interest and beginning to be global interest really was the Chicago 1994 meeting. And that was, I think, a game changer in terms of getting our American friends and colleagues involved and interested in this disease and then subsequently led to the MDS Foundation as well as the IPSS score and all the other developments since.
Ghulam Mufti: I think that’s my recollection of that period. Although, we will probably come to genetics and drugs probably later on.
Amer Zeidan: Sure, yeah. Did you go to all 15 of them, Dr Mufti?
Ghulam Mufti: I think I’ve been to all of them, yes.
Amer Zeidan: That’s great.
Ghulam Mufti: Yes. Yes, I haven’t missed any of them. Yeah.
Amer Zeidan: That’s great. So I think as we start talking about some of the biology a little bit of the disease and understanding now that we’ve covered the morphology and some of the risk stratification. Dr Cazzola, I really loved your review that was just published in the New England Journal of Medicine of MDS. I thought it was one of the most comprehensive reviews and the supplement is a resource by itself, so I really thank you for all the time and effort you had to put in that. And I think it’s a great reference for anybody who wants to have like a precise summary of MDS.
Amer Zeidan: So, you mentioned in that review the origin of the word myelodysplastic syndromes and it has been always very confusing as someone who deals with patients every day and I can tell not only patients but also oncologists and hematologists who don’t specialize in this cancer are really puzzled and confused about what MDS is and whether it’s a cancer or not. And myelodysplastic means abnormal maturation, but the syndrome is always tricky and there has been suggestions that it should be myelodysplastic cancers or myelodysplastic neoplasms rather than syndromes.
Amer Zeidan: And given all of your involvement in the biology and how things evolved over the last 30 or 40 years with the disease, what’s your take on the so different biologic processes that underline this disease probably contributing to why it’s so heterogeneous in terms of presentation and outcomes? Mario Cazzola: Okay. I will discuss at this point making the case of myelodysplastic syndrome with ringed sideroblasts. My journey in MDS started out quite early. In 1971-72, when I was a medical student and I was preparing my medical thesis, my boss invited me to prepare a thesis on the mechanisms of anemia in patients with refractory anemia with ringed sideroblasts, at that time called siderocrestic anemia from the German objective siderocrestische.
Mario Cazzola: So, I studied a series of patients. All had a erythroid dysfunction, ringed sideroblasts, low reticulocyte index. And I concluded that, in effect, the erythropoiesis was the mechanism of anemia. Then I started to use ferrokinetics for evaluating the pathogenesis of anemia and again studied these patients and found that, in effect, the erythropoiesis was indeed the major mechanism of anemia and published this paper in the British Journal of Hematology in 1982.
Mario Cazzola: I studied the natural history of the disease and found that these patients had a relatively benign disorder. The measured problems being transfusion requirement and parenchymal iron overload, but in a subset of patients leukemic transformation occurred. So, when we decided to study the molecular basis of the disease in 2010 in collaboration with the Sanger Institute, I suggested to focus on these patients with ringed sideroblasts because they had a unique phenotype and this could make it easy to identify the mutant gene.
Mario Cazzola: And indeed, we found somatic mutations in SF3B1, a spliceosome gene. At that time it was unknown that genes of the spliceosome could have somatic mutations. And we established a closer relationship between somatic mutation of SF3B1 and the myelodysplasia with ringed sideroblast and the paper was published in the New England Journal of medicine. At the same time Seishi Ogawa published a paper in Nature showing that mutations of a spliceosome genes were associated with myeloid malignancies, mainly with myelodysplastic syndromes.
Mario Cazzola: More recently, again in collaboration with Luca Malcovati, we found that SF3B1-mutant MDS is a distinct nosologic entity, normally associated with a benign course. Although computations in some genes, namely RUNX1 or STAT2, may involve a worse clinical outcome, especially leukemic evolution.
Mario Cazzola: More recently, Luca Malcovati and I did a very large collaborative study showing that SF3B1-mutant MDS is a distinct nosologic entity associated with a favorable clinical course although co-mutations in genes like RUNX1 or STAT2 may involve a worse outcome, specifically leukemic evolution.
Mario Cazzola: Very recently, I participated in a clinical trial on the use of luspatercept in the treatment of patients with lower risk MDS, most of whom had MDS with ringed sideroblasts. And luspatercept proved to be able to reduce the severity of anemia by targeting ineffective erythropoiesis. So, we have defined really a new nosologic and distinct nosologic entity which has a specific molecular basis and currently also a specific treatment.
Amer Zeidan: Yeah, and I think the evolution has been on a therapeutic level, we talked about this in the last segment, has been very accelerated in the last few years. However before we go to that, I want to go, Dr Greenberg and talk about all these molecular alterations that Dr Cazzola has mentioned, and we had an explosion of these between the late 80s to now where we have more than 40, 50 recurrently abnormal genes.
Amer Zeidan: We actually struggle all the time about, how do we integrate these in the daily care of patients? Because they have not been formally integrated in any of the prognostic scoring system. And the IWG has has been leading an effort, a similar international effort to integrate those markers. So, maybe you can talk about this process and how has it been going?
Mario Cazzola: Yes. Over the years, through the MDS Foundation, the International Working Group for Prognosis in MDS was generated and persisted in discussing various therapeutic and clinical options. Then Ebert and his group, and this was Raf Bejar and Ben’s paper in the New England Journal, I believe the year, I’m not sure of the year, but it was perhaps 2011 or so, indicated that there were five genes that were involved in major implications for prognosis in MDS.
Mario Cazzola: When that paper was presented, and this was a presentation at the American Society of Hematology, I subsequently spoke with Ben and we decided that we needed to put together another group to analyze these mutations for the large group of IWGPM. And we obtained a grant from Celgene through the MDS Foundation to do this.
Mario Cazzola: And then, over the next subsequent years, which has come to fruition here through the work with Elli Papaemmanuil at Sloan Kettering. There has been the accession of over 3,000 patients and sequencing of those genes to modify the IPSS-R into a molecular prognostic system. There’s a working group including Mario and a number of others for helping Elli and her group – the leading person at her group is Elsa Bernard – to put together the molecular underpinning of MDS.
Mario Cazzola: So far, things have developed into a potential reclassification of subgroups of MDS defined by mutations and co-mutations that are relevant for MDS, number one. And secondly, potential prognostic implications to modify the IPSS-R. This is a work-in-progress, but within the next few months it’s likely that this will bear fruition. At the moment there appears to be approximately 40 genes that are important for this analysis and these will be weighted statistically for evaluating prognostic implications for MDS.
Mario Cazzola: So again, it’s an international group composed of people such as Mario, Eva Helstrøm, Seishi Ogawa, Raf Bejar, Ben Ebert, Luca Malcovati, and others as a working group, but the entire International Working Group for Prognosis in MDS is engaged in that they have provided patients and samples for this effort. So, we believe that this will likely come out as a paper this year or be submitted this year and likely be presented at the Toronto meeting, somewhat, but also at the American Society of Hematology by the end of the year.
Amer Zeidan: Yeah, that would great. Many people have been waiting for this and I think it would be a huge improvement into the risk prognostication.
Amer Zeidan: Dr Mufti, maybe I can follow on that theme. One of the frustrating things I think during my fellowship has been basically a lot of work on prognosis and certification, which is, of course, very important. But the end of the day we are always stuck with the same drugs basically, especially for higher risk patients, which are the two hypomethylating agents which were approved in 2004 and 2006 in the US. And we really did not have much approved until this year, or last year sorry, 2020, when we had two drugs approved. One of them is an oral version of decitabine and the other is luspatercept that Dr Cazzola eluded to. And I think a big part of that difficulty in getting new drugs has been the biology of the disease, which seems very heterogeneous. And trying to treat MDS as one entity, higher risk or lower risk, is probably not the best way to do it and we should probably define it molecularly or by the abnormal pathways, similar to how it’s done in other diseases with IDH inhibitors, with FLT3 inhibitors, but those biomarkers or driver mutations are not very common compared to AML.
Amer Zeidan: So how do you see all of the biology work that you and others have been doing contributing to new treatment paradigms for patients? And do you see that bone marrow transplant will go away as something that we always say that’s the only potential cure for MDS?
Ghulam Mufti: That’s been a journey too for me. And I will start from the beginning in a way as to how I got interested in the immunology part of it. So, when I was in Bournemouth and doing the Bournemouth scoring system, at the same time I noticed that a number of patients who had MDS had also features of autoimmunity. And also there were a number of patients who had co-existent MDS and other neoplasms, mainly hematological neoplasms in the form of either myeloma or other B-cell malignancies.
Ghulam Mufti: So, this was published again in the British Journal of Hematology. I think it was in 1986 in two part paper. Just thinking back at that I kind of still remember getting this autoimmune screens and immunoglobulin levels and chronic myelomonocytic leukemia being high and all that. Then convincing myself at that stage that immune mechanisms had something to do with why the disease occurs predominantly when we are older and why there are these associated autoimmune features with it.
Ghulam Mufti: I remember the first patient that I saw with MDS was a patient who David Galton told me to look after with pyoderma gangrenosum and MDS. So, that was kind of the beginning of the immunological interest. And then, as you said, we had really nothing in terms of medications until we kind of – John Bennett will remember this – that we thought well low-dose Ara-C because Lotem and Sachs, which has been mentioned, had shown that in cell lines low doses of cytosine arabinoside lead to differentiation of some of these cell lines. And he had indeed shown in a letter to British Journal of Hematology that that induced a remission in, I think it was three patients.
Ghulam Mufti: And that led to a clinical trial on both sides of the Atlantic of low dose Ara-C in MDS. We had some interesting in results in high-risk MDS cases, particularly those with lower blasts, lower cellularity in the marrow. But really there was not, it was not a game changer. It was quite clear, although it did have an effect, but not a differentiation induction effect that had been shown in cell lines.
Ghulam Mufti: And that’s when I got interested in transplantation. And I think we then, it was a huge struggle, I have to say, to convince people, certainly in the UK, that MDS is a disease where the only treatment that can cure it and should be given is bone marrow transplantation. And I think that kind of was synchronous with the advances in transplantation, particularly with the advent of reduced-intensity conditioned transplants and particularly in Europe with the advent of campath and campath in the conditioning regimes or ATG and conditioning regimes. And that led really to a huge amount of interest in the treatment of MDS with allogeneic stem cell transplantation. So much so that it has almost become number one indication for allogeneic hemopoietic stem cell transplant. So that kind of clearly indicated that immunological cure of MDS was possible.
Ghulam Mufti: So which kind of deflects you into the second area of related interest of mine, which has been that what is the role of immunology both in terms of inflamma-aging and the causation of either clonal hemopoiesis or MDS? And also, the generation of some of the mutations that you have on the slide, particularly in relation to inflammatory microenvironment that occurs with aging.
Ghulam Mufti: And that, together with what Mario was mentioning in terms of RARS and where the cell of origin is and what the consequences of these mutations may be in terms of the immune response, that is something that’s where I think understanding what these mutations do. And my own feeling, and it’s a personal bias, is that we have probably been corrupted by BCR ABL as a target where you have a target, you have a drug, and you cure the disease in a high proportion of cases. I personally think that that’s probably not going to be the case in MDS or even in AML that has arisen out of an MDS background. But I think it is essential that we continue to study this, obviously, the role of these mutations, I mean, even in sideroblastic anemia, which Mario has brilliantly worked on and identified many of the steps in it, we still don’t know for sure why does a sideroblast become a sideroblast and how can we undo that?
Ghulam Mufti: And luspatercept has been a big step in terms of symptomatic improvement. But again, in terms of our truly understanding and deciphering the whole of the disease both in sideroblastic anemia as well as in non-sideroblastic type, I personally believe that we have a huge amount to learn and immunological abnormalities and immune system and awakening the immune system and recognizing what happens to it, that has been lacking. And I think, for me, that will become more of a dominant feature. And also then understanding, as Peter said, core mutations. Why do they occur together? And at the single-cell level what is the consequence of those?
Ghulam Mufti: It’s also interesting, I mean others might comment on it, that even in drugs that we have been using now for a decade plus, like azacitidine or decitabine, we really know the precise mechanism of action.
Amer Zeidan: Yeah. And I think, definitely, this has been one of the most I think frustrating aspects of MDS is the mechanism of action, mechanism of resistance of these agents.
Ghulam Mufti: Exactly. Exactly. So I think that’s why I see the next phase coming in, understanding it, understanding the consequences of mutations on pathways within cells and what happens if they are disrupted and also understanding what the role of the immune system might be.
Ghulam Mufti: And the other thing I would say also is I think it may be, it may be, it has wishful thinking that these diseases we may be able to prevent more than treat. Because if it is true that we can detect CHIP and its consequences and if we can prevent the consequences of CHIP at a cellular level as well as at an immunological level, then I think there’s a prospect then, at least theoretically, of trying to prevent these diseases. Because by the time they have actually occurred lots of things have happened to the body as well as to the genesis of these cells to respond to either a single drug or even multiple drugs.
Ghulam Mufti: I mean, you can see so many multiple drugs are coming both in the immunological space as well as in the non-immunological space. So, I’m quite confident that with the kind of brainpower that is now in MDS that we will be able to link in all these things that we have done in the last 30, 40 years over the next decade to come up with – I’ve never liked the word “personalized medicine” or “personalized treatment” – but to come together with a treatment that actually has not just an effect on controlling the disease for a period of time, but hoping to cure the disease in a non-transplant way.
Amer Zeidan: Yeah, and I think that’s the goal and ultimately hopefully will be the goal that we all strive to achieve. This was very comprehensive. Thank you so much, Dr Mufti. This discussion –
Peter Greenberg: If I could make a comment –
Mario Cazzola: Sure.
Peter Greenberg: – that relates to what Ghulam was saying and it reflects on the nature of what I will call the myelodysplastic syndromes. I think that we use the word myelodysplastic syndrome, and yet, the heterogeneity of the disease, now defined by the molecular features, immunologic features, indicates that it’s a spectrum of disorders. And for us to begin treating it we’re going to need to have more specific therapies aimed at the classified subgroups, those that are classified in part molecularly and immunologically.
Amer Zeidan: Yeah, this is a fascinating discussion. We probably could go for hours talking about all of this. I hope we do at one point get together back again and talk about CHIP and evolution. I think there’s a lot of fascinating aspects and how does that connect cardiovascular system and all of that? But we unfortunately are running out of time. In the last few minutes I’d love for you-
Ghulam Mufti: Can I just comment about myelodysplastic syndrome versus syndromes and pre-leukemia?
Amer Zeidan: Sure. Yeah, sure.
Ghulam Mufti: It’s historical. I wrote a book with David Galton on MDS and in that the preface was written by David Galton. And those of us who know him know how meticulous he was about the choice of words. Now, I had written in the preface “myelodysplastic syndrome” and he spent a lot of time with me on what did I mean by syndrome versus syndromes? Because a syndrome normally is a symptom complex. Therefore, it would be singular. But to justify it as “syndromes”, which Peter is saying, was if you include therapy-related MDS in it as well. So you have primary MDS as well as therapy-related MDS. Then he told me that in that context using the word syndromes is correct.
John Bennett: Yeah. That is, yeah.
Ghulam Mufti: Now, given these various diseases that we have and the heterogeneity, therefore, the “syndromes” might be more appropriate, although we might sort of think about other alternative names as well.
Ghulam Mufti: The reason why everybody called it “pre-leukemia”, lots of, I think most of the American centers were writing papers on “pre-leukemia” when they discussed MDS, but David Galton did not like the deterministic nature of the word “pre-leukemia” because that is deterministic because it says this disease will change into leukemia. It’s a pre-leukemia, but it’ll change into leukemia. And he felt, looking at sideroblastic anemia in particular, that there might be some types which do not transform to leukemia.
John Bennett: Correct.
Ghulam Mufti: So that’s why that was – I mean John might remember it – that is is why we had the discussion of not using the word “pre-leukemia” and more and more in all the texts subsequently “pre-leukemia” was dropped.
John Bennett: Yeah.
Ghulam Mufti: Sorry, that was just historical.
John Bennett: The other aspect of the immune situation that we might want to talk about in the future is the increasing ability of hematopathologists to recognize very, very tiny clones of T-cell abnormalities. T-Cell gene rearrangements. What we used to call LGL, large granular cell leukemia. We find that anywhere from 10 to 15 percent –
Ghulam Mufti: Absolutely.
John Bennett: – of our patients whether or not and sometimes with a PNH presence as well. And that’s very, very poorly, still to say, very poorly understood.
Amer Zeidan: Yeah, all of that is great. I’m hopeful and you will all accept an invite for a future talk to discuss a lot of those additional aspects.
Amer Zeidan: In the last few minutes, I’d like to take the opportunity to ask you one question. You are major pioneers in the MDS field and many of the medical students, fellows, residents, junior faculty look at you, at your career, and all of your contributions to MDS, and with the hope that we continue to add to that milestones that you see in this slide in the history of MDS and both biology, diagnosis, prognosis, and therapy. Maybe in one or two minutes for each of you, what’s your advice for people who are starting their career and how they can go in a path similar to yours in shaping the phase of the disease?
Amer Zeidan: I’ll start with Dr Bennett?
John Bennett: Well, I like what Professor Mufti said. Find a topic that no one else has really dealt with and stay focused, and stay with it. And he, I think, has demonstrated that perfectly well as well as Peter from the laboratory to the clinical aspects.
Amer Zeidan: Dr Greenberg?
John Bennett: Well, I would agree with John. I think a student needs to find something that excites him, something that’s very important for him to know, questions that he wants answered, and to continue to follow your nose. Pay attention to the literature and make contact with individuals involved in the field.
Amer Zeidan: Dr Mufti?
Ghulam Mufti: I would say to the student that you are such a lucky bunch of people because you live in an age where technology allows you to do almost anything. Any question that you want to ask, technology is ahead of the questions that we can ask. Ask a question in relation to pathogenesis or treatment of MDS and use all the technology and technological connections, be it mathematicians, biomathematicians, geneticists, immunologists, et cetera, to try and look at the completeness of a focused area within this heterogeneous disease. And then the rewards will come.
Amer Zeidan: Dr Cazzola?
Mario Cazzola: I would encourage the medical student to become a hematologist because a hematology is the discipline that combines research and clinical activity by definition. John Bennett: Great point.
Ghulam Mufti: Yeah.
Amer Zeidan: Well, thank you so much. This is definitely the longest session, MDS session, we’ve recorded and I enjoyed it so much. Again, thank you so much for accepting our invitation for this. I hope to have you again in the future. Thank you so much.
Ghulam Mufti: Thank you. Thank you very much.
John Bennett: Thank you for having us.
Peter Greenberg: Bye-bye, everyone.
Ghulam Mufti: Bye everybody.
Mario Cazzola: Bye.
Ghulam Mufti: Lovely to see everyone. John, your garden behind you is beautiful.