Hello, everyone. My name is Sanam Loghavi, I’m a hematopathologist at MD Anderson Cancer Center, and I am thrilled to be joined here today by my colleague and friend, Dr Rami Komrokji from Moffitt Cancer Center. And we’re going to speak to you about lower-risk MDS today.

Thank you. It’s a pleasure to be here. So maybe I’ll start kicking off asking you some questions. As you know, I think we have evolving classifications, risk stratification, and you still remain the main, most important thing for us as a hematopathologist to make the diagnosis. Can you walk us through the diagnosis for MDS, how it’s evolving, what’s needed for a community doctor to be sure to get when they ask for the hematopathology report?

Sure. I think, you know, obviously, like any other diagnosis, our job starts with knowing good clinical history. So I would say, you know, the most important thing for us, other than looking at the slides and obviously knowing the genetics, is knowing the history of the patient. So we always appreciate getting good history. Other than that, I think, you know, the standard of care, the basic workup for any patient with suspected myelodysplastic neoplasm or myelodysplastic syndrome should be obviously a peripheral blood smear and a peripheral blood count. So a CBC with a differential count, a bone marrow biopsy and an aspirate because we need both samples to evaluate thoroughly for morphologic dysplasia. Ideally, you would also do flow cytometry to look at the immunophenotype of the stem cell compartment and the maturing myelomonocytic cells. And then of course, the most important probably now for classification is the genetics of the disease. And by genetics of the disease, I mean the cytogenetic or karyotypic abnormalities as well as the somatic mutations. So a thorough workup would include getting a routine karyotype. Now, more sophisticated technologies include optical genome mapping, which gives you a higher resolution karyotype and then looking for somatic mutations. So I would say in clinical practice, right now, the majority of labs are doing targeted panels to look for recurrent somatic mutations. But I think as sequencing becomes cheaper and more accessible, the field is probably going to move towards doing more thorough sequencing and whole exome and whole genome sequencing. But right now, we’re happy with a limited panel.

Absolutely. And is it okay sometimes to order the NGS on peripheral blood if it was not ordered at the time of the bone marrow testing? Yes, it is, actually. So, you know, right now, the way we do testing at MD Anderson is we’re still using bone marrow. And I don’t know how you guys are doing it. Are you doing bone marrow or peripheral blood? Yeah. So if you have a bone marrow, ideally, you know, we do it on the bone marrow. But there are studies that have shown actually one presented at EHA last year where you can essentially get the same information from peripheral blood that you can get from bone marrow. So if you don’t have a bone marrow, if you don’t have access or for some reason NGS wasn’t ordered on it, you can always order it on peripheral blood.

Absolutely. Yeah. So I cannot emphasize more what you said, like from a clinician point of view, having a good hematopathologist review the slides is a key. You know, we always give those examples of patients that were misdiagnosed as MDS where they have nutritional deficiency going back to the history and the needed information. And we’ve had patients with really clear MDs that they were not called. So really, as you know, simple as it sounds, the most important step is the diagnosis. And then we obviously move to the risk stratification. Any comments on the IPSS-M? Are you going to use that?

Well, let me let me ask you one thing first, Rami. So from a clinical perspective, you know, we talk a lot about low-risk versus high-risk MDs. What do we mean when we say that? What is low-risk and what is high-risk? Is it the risk of transformation essentially?

So I think the risk is basically two things. Historically mostly was the risk of transformation to acute myeloid leukemia and probably the overall survival as well. So when we say somebody has lower-risk disease, it means that they probably have better overall survival and less likelihood of progression to leukemia. Now, even lower-risk, unfortunately, when we look when we take all MDS, patients in general, around 30% of them will transform to AML. The rest actually will not particularly what we label as a lower-risk. But when we look at the mortality, unfortunately most of it is still directly related to the MDS and the cytopenias. So a lower-risk disease doesn’t mean that this is a disease that’s not going to impact the patient survival and quality of life. So it’s very important and we kind of simplify things, saying lower-risk and higher-risk because then we decide on mostly who we are going to transplant or not, and we use those risk models. But that’s historically how we look at things. And obviously this has evolved. Now we have the IPSS-M. So I’m curious to know your take on the IPSS-M from heme-path, especially that we don’t all have the variables needed for that in current time. Well, not all the places have it so…

Of course. Yes. So, you know, for the audience, the IPSS-M is the molecular iteration of the IPSS, which is the system that we that we were using for the longest time to risk stratify patients with MDs. So the IPSS-M system and paper was essentially designed and published by Elsa Bernard and Elli Papaemmanuil at Memorial Sloan Kettering. I think it’s an incredibly powerful tool. It takes into account somatic mutations in addition to the other parameters that we were using before for IPSS. And I think, you know, what happens is the majority of the patients, if you reclassify patients based on IPSS-M, because you’re adding molecular information, you’re actually upstaging the majority of the patients. So they tend to be higher risk by IPSS-M than what we presume them to be by IPSS. And you know, there are good mutations. Well, there’s never good mutations, but maybe better mutations. And then there are very adverse and unfavorable mutations that can upstage the risk of the patient. Now what happens is, you know, I think where it gets a little bit tricky is, first of all, IPSS-M is really applicable at diagnosis, right? So this has been validated for an untreated patient at diagnosis. I think where it comes a little bit more tricky is, you know, what do you do when the patient’s been exposed to hypomethylating agents? What do you do at progression? Does that risk still hold or not? And I think this is yet to be probably seen, but it’s most powerful in the setting of a new diagnosis when you’re establishing the risk at baseline. And just to say that, you know, the risk calculator is online, it’s freely available to everybody and it does work, you can actually get the risk. Even if you’re missing some parameters, the calculator will still do an adjusted or maybe modified risk for you based on the information that you have and you can input.

Absolutely. I totally agree. I think it’s, you know, a refinement for the prognosis. I think it’s a very powerful tool that refines the prognostic value. Better prediction, as you mentioned. Exactly. In most of the cases, it updates patients in almost like 47% of the patients that staging change. How we act upon it clinically, I think, is important. So for me, if I upstage a patient currently with IPSS-M and let’s say they are a little bit on the younger side, I’m starting to think of transplant earlier for those patients because this is a powerful tool to detect the survival for patients or leukemia risk. So if somebody I know that have a survival estimated in 2 to 3 years, I’m going to be thinking of transplant, it doesn’t always necessarily mean that I have to treat those patients with like, for example, hypomethylating agents because I upstaged them. If somebody doesn’t have profound cytopenia just by upstaging them is not an automatic trigger to pull the trigger on treating with hypomethylating agents, but to think about transplant, to discuss with the patient. Obviously hopefully down the road for clinical trials, it’s very, very important.

So I have a treatment question for you, Rami. You know, with the FDA approval for luspatercept, for front line therapy for MDS, we know that the drug was approved. You know, the main indication, I guess, or, you know, where we think of luspatercept is in the setting of ring sideroblasts and SF3B1 mutation. But of course the drug has approval regardless of the presence of ring sideroblasts or having an SF3B1 mutation. So can I ask you what would make you favor one, luspatercept maybe over EPO in a patient with lower-risk MDS?

So first, I think definitely the landscape for management of MDS, lower-risk is changing. Actually, we call this here the breakthrough in lower-risk MDS because we had the luspatercept data, we had another positive Phase III trial with imetelstat, so it’s changing. Now in general as a principal, first, when we are treating in lower-risk MDS, in most of the cases we are treating anemia. Sometimes the concomitant thrombocytopenia or neutropenia may dictate our choice, but in majority of the cases we are treating for anemia. There are simple facts we know that transfusion dependency is bad in MDS, so patients that are needing blood transfusion, that’s not a good outcome for those patients, partly because this reflects more of bone marrow failure, disease biology, partly because of the complications of blood transfusions. So our goal is typically to treat or alleviate cytopenias, anemia is the most common thing. Most patients are actually symptomatic when they are below hemoglobin of nine. So although most of the studies look at transfusion independency or treatment at the time of transfusion dependency, in real life, many patients start on treatment even before they get transfusion dependent once they get to symptomatic anemia. And obviously the quality of life is another important fact in treating lower-risk MDs. So we want to obviously alleviate transfusions. We want to make those patients feel better. Historically, erythropoietin had been our first-line therapy for those patients with limited success, maybe 30, 40% responses that lasts for a year, year and a half. And there are some predictors of the response. So if somebody is getting a lot of blood transfusions or their endogenous serum EPO level is high, they are unlikely to respond. But then after that, they had limited options. Luspatercept came first based on the MEDALIST study to be approved for patients with ring sideroblasts after ESA failure. Now, with the COMMANDS study you are alluding to, they compare that head to head to erythropoetin in the upfront setting in patients that are needing some transfusion with their endogenous serum EPO level less than 500, and the study met the primary end point, doubling the response rates and the duration. Now when you look in the details of the study, the study was mostly ring sideroblast positive patients or SF3B1 mutant. There were a handful, maybe 40 patients on each arm that were RS negative. The intent to treat shows the responses. I think my take on it that obviously in ring sideroblast, it’s no brainer that luspatercept was really double the response than ESA, longer duration, so it should be used there. In the RS negative, it was similar. The responses were similar, maybe a little bit longer duration. So one could say I’m just going to use this for everybody. Some people will say I’m kind of more cautious about the cost effectiveness of this approach and I want to look at subsets. For me, if patients are RS negative, if they have higher mutational burden, if their EPO level is more than 200, those patients did not perform well with ESA. So I may think of luspatercept as a first step for them and our next step. Actually, we are already starting a study called The ELEMENT, is to move luspatercept versus ESA in patients that are not even transfusion dependent. Speaking of that, like one patient just become anemic to start the treatment for those patients.

And sorry, one clarification. When you say higher mutation burden, are we talking about the number of mutations or are we talking about the variant allele frequency, the size of the clone?

That’s a good question. So I think it’s the number of mutations. So the French group also published earlier on, there is not much data on mutations with ESA, but once patientS had two mutations or more, responses to ESA were less, and the durability was also less. So when patients have more than two mutations, the ESAs don’t perform well. But nobody had my knowledge looked at the the variant allele frequency in terms of the response.

Correct. And I think one other thing to clarify and please correct me if I’m wrong, but the COMMANDS study was based on IPSS-R and not based on IPSS-M, correct?

So yeah, absolutely. It’s based on IPSS-R. So intermediate or lower-risk patients can get the treatment. And again, we are starting to see like, you know, in the field is like, what’s the impact of those treatments? Dr Santini presented data from the MEDALIST study that was after ESA failure, looking at survival among responders versus no responders. It’s always a little bit biased analysis, but actually responders do derive survival advantage. And this is something our group had been interested in looking at. When we render patients transfusion independent with those treatments, do they drive survival advantage? And the short answer, probably yes. So there is a benefit beyond just the alleviation of transfusion needs, obviously, definitely making the patient feel better in quality of life, but also probably improving the survival for those patients.

Thank you. That’s very helpful. Thank you. And I have maybe just one last question and then maybe you can have one last question for me. So as a pathologist, I obviously want to deliver the best possible patient care that I can. So how would my report be constructed to be most helpful to you as a clinician that wants to give your patient the best possible therapy?

Absolutely. I think, you know, it differs in the setting. So obviously you are at MD Anderson, their interest sometimes could be different to Dr Garcia Manero could have a trial that he wants to know one thing only on the report versus in the community. I think in the community the reports have to be clear sometimes, you know, I think the hematopathologists do have the responsibility to weigh on the diagnosis, not just be descriptive. Say in the best this is MDS-RS type, rather than just being descriptive. At your place, you could be descriptive sometimes for a clinical trial or something like that. So diagnosis obviously, you know, estimate of like let’s say myeloblast percentage, because even at our place, sometimes we get confused. There will be like three blast estimate on the report, one on the aspirate, one on the biopsy and one the flow cytometry. And I think for a busy community oncologist, like I want to know definitively that I think integration of the molecular data in the report is important nowadays. Obviously, you and I talk all the time about the classification, the evolving ICC, WHO, I think a clinician, it’s so busy. You need that also in the report that’s on your shoulder, unfortunately. Then the last thing, some people take it to the next level where they actually provide the IPSS-M and the calculation there. So ideally for a community oncologist, I think the report should include that. Again, in academic center, it may be tweaked for the purpose of trials or research interest and so forth.

So yeah, I really like that and I think that that essentially is our practice is, you know, when I’m looking at a case, when I get the case, I obviously don’t have access to every piece of information, particularly the molecular cytogenetics, because they’re going to come out later. But I think that, you know, the standard of care, an ideal way to practice, should be that every piece of information should be incorporated into one report that’s available to the clinician when the information becomes available. And if we can do the IPSS-M, that’s even better.

Absolutely. Absolutely. So my last question for you is basically like for somebody that doesn’t have access to like, let’s say NGS panels all the time? Are there things from the pathology still that are good tricks that we can use in this era? You know, I’m alluding to obviously for RS, SF3B1, p53 all that stuff. Can you comment?

Absolutely. You know, I think it’s actually incredible what we can do with just simple tools. So ring sideroblasts, we can, you know, pick up with an iron stain. It’s a very easy and effective and inexpensive method to pick up ring sideroblasts. And we know that 85% of patients that have ring sideroblasts defined as having more than 15% ring sideroblasts actually do have an SF3B1 mutation. So you’re casting a very wide net there and then doing a p53 IHC immunohistochemical stain for p53 can be very informative because if you see a marked overexpression meaning three plus staining in the nuclei or complete absence of staining, that really correlates well with the presence of a TP53 mutation. Of course, this is independent of the allelic state, which is also very important in MDS, but at least you can tell that you have a mutation there or not with pretty high confidence. And then I think, you know, fibrosis is, you know, if you do a reticulin stain and if you have increased fibrosis, particularly when the, you know, the aspirate smear is poor and hemodilute, that can give you information. Typically cases with fibrosis have bad molecular markers and are enriched for TP53 mutations. And then the other thing, you know, if you have a poor sample that doesn’t have a good aspirate, it’s just doing a CD34 stain, right? Looking at the number of blasts. Fortunately, the majority of MDS, unlike AML, actually have CD34 positive blasts. So it’s unusual to see MDS where where the blasts are CD34 negative. And in fact if you do see that you may want to look for AML defining markers like NPM1. So I would say that yeah with just a TP53 stain, CD34, iron and a reticulin stain, you can get a lot of information on if you don’t have NGS available to you. And a good hematopathologist could tell you this looks like deletion 4q, the characteristic, megakaryocytes are very  – yes we can. We can tell you a lot of things by just looking at the slides. I always wish I have the vision of a hematopathologist.

We complement each other.

Absolutely. Absolutely. So All right. Thank you. Thank you.