Sanam Loghavi:

Hi, my name is Sanam Loghavi I’m a hematopathologist and a molecular pathologist at MD Anderson Cancer Center in Houston, Texas. And I’m joined here by my colleague, Dr. Shahram Kordasti, who’s a hematologist oncologist with expertise in myelodysplastic syndromes at King’s College London.

Shahram Kordasti:

I am Shahram Kordasti, as you introduced me, and so today, we are going to talk about i4MDS and the guide that we have published about immune monitoring in myeloid malignancies. And basically, i4MDS is a consortium of around 27 different centers from 10 countries, and the focus of this i4MDS is really to standardize the way we immune monitor in myeloid malignancies, and to find a way that results from different centers can be compared, can be combined, have a better understanding of what’s happening in myeloid malignancies. And how we can have a standard panel that can be used, different centers’ results can be analyzed in the same way, combined together and analyzed.

So this paper, just published recently in the i4MDS guideline, which is a consensus guideline for immune monitoring of MDS in Hema Sphere and it’s available now, and it’s including seven different panels that can be used for different cell types, immune cell types, to be used for immune monitoring. So this is what i4MDS is and what we are doing, but what do you think about it? What do you think about the clinical use? Why do you think it’s good to have such a panel?

Sanam Loghavi:

So of course my view is biased because I’m part of i4MDS, but I think this is really a timely and very critical aspect of MDS diagnosis and MDS monitoring, which is actually something that clinically, we’re not doing at all yet. If you look at standardized guidelines for the diagnosis, prognostication, or management of patients with MDS, there’s really no immune monitoring aspect built into any of these guidelines at this point in time. Yet we know, and as a field we have the knowledge and we know, that MDS is closely related to immune dysfunction. So even though MDS is a clonal disease, we know that there is a direct link between immune failure or immune dysfunction and progression of what we think is clonal hematopoiesis to clonal cytopenia of uncertain significance and finally to MDS.

So why we’re not really incorporating the immune aspect of MDS into current diagnostic guidelines or prognostication is really because of lack of standardization. It’s not because of lack of knowledge, it’s because of lack of guidelines and lack of standardization. It’s because it’s so complex that we really don’t know what to look for, yet some of the aspects are very simple. And I think the effort with i4MDS was really to introduce at least a preliminary guideline to say, here’s a roadmap of what you should be looking at for a patient at the time of diagnosis and hopefully throughout their treatment journey and for prognosis and surveillance, and I think it’s a great start.

Shahram Kordasti:

Yes. And do you think, down the line, in a few years, when we have more data, more centers involved, and when we have a panel that is validated for clinical use, will it change our clinical practice? [Is there] a particular group of patients that you think they’d benefit from this kind of approach?

Sanam Loghavi:

Absolutely. So I think, again, I think there definitely is a knowledge gap here. Even though we know that in MDS, there’s immune dysfunction, we don’t necessarily know who are the patients that have the immune dysfunction. There’s sometimes immune senescence, there’s sometimes cytotoxic T-cells that are active, but I think we know, at least anecdotally and obviously some from trials and established knowledge, that a subset of patients, for instance, we think of aplastic anemia as being closely related to MDS in some aspects, and we know that these patients respond to immunosuppressive therapies. We know that a subset of patients with established bona fide MDS, like hypoplastic MDS, they respond to immunosuppressive therapies.

So for sure, we know that there are groups, but I think having a standardized approach where we can, at the baseline before the patients are treated, monitor or characterize their immune system, and then throughout therapy, monitor their immune system. I think that’ll definitely provide us with the knowledge to-

Shahram Kordasti:

Exactly, and the other thing is, for instance, in hypoplastic MDS that are more AA-like MDS, if you like, we know that they have an element of autoimmunity and we know that they are more likely to respond to ATG, which we are not using enough. And one of the reasons is we don’t know which patient is more likely to respond, and therefore, it is clinically important, and a group of patients that we don’t have a standard therapy for them may have a standard therapy. And the other thing is these kind of patients that are more AA-like, in the longer term, we may have a signature that we can identify in other patients that are not so obvious autoimmune elements, and therefore, those can be treated.

And the other aspects which we shouldn’t forget, is we know a lot more about the inflammatory side of MDS, and we know that the inflammatory pathways are very much activated in MDS. But what we don’t know much about is when this chronic continuous inflammation or what we call smoldering inflammation leads to immune switch and to remodeling of the immune system, and that’s the time that perhaps no intervention with inflammation could reverse this.

And that is the time of no return, and we need to think about other management strategies. Whereas now, we have anti-inflammatory treatments and we give it to everyone, but we need to… And it has side effects. They may increase the risk of infections, etc. etc. Can we identify those patients that they are still at earlier stage, they have not remodeled their immune system and we can treat them at the right time.

Sanam Loghavi:

Early intervention.

Shahram Kordasti:

And early intervention, and that is another thing that hopefully will help us.

Sanam Loghavi:

Absolutely. And I think I want to highlight that for those that are interested and are going to look into the details of the paper, you’ll see that in the paper, there are actually two panels that are recommended or put forth. One is a basic panel that can be done essentially in any CLIA type or clinical grade laboratory, and we hope that more and more laboratories will adopt this approach and generate data. And of course, there’s the expanded panel that is being done by experts that have expertise in flow cytometry and different immune monitoring techniques, and I think that panel will hopefully, with the help from EHA who is generously supporting this effort, will generate research data that we can use to inform, again, further establishing formal guidelines and hopefully help push the field forward.

Shahram Kordasti:

Yes, and to finish this, I think everybody will ask now, okay, if you have these standard panels and you’re going to recommend to be used by clinical labs, which patients should be included? Of course, we have patients with AA on one side that are aplastic anemia autoimmune side, and the other side, you have patients with very clinically auto-inflammatory response like VEXAS or Sweet syndrome. But in between, perhaps a range of patients needs to be-

Sanam Loghavi:

Absolutely.

Shahram Kordasti:

… to be used on which patients you’ve seen.

Sanam Loghavi:

So the recommendation in the paper, and I think this is more, again, because we’re at the stage where we’re trying to learn, is to cast a broad net, and so we’re trying to look at every patient with unexplained cytopenias. So if you generally want to think about it, any patient where you’re considering a diagnosis of MDS, may it be at the end clonal cytopenia, aplastic anemia, actual MDS, VEXAS. So all of those patients should really be considered for this panel and for the monitoring, because again, that’s where we’re going to learn and where we’re going to see the differences, and hopefully inform the field.

Shahram Kordasti:

Yes, exactly. So I’m sure you can find the paper online and hopefully there will be a link that you can find it, but if you search for the recommendation, you can find it. As I mentioned, there are seven different panels for different cell types. There is the basic panel that is necessary, markers that you need to use, additional markers that are optional, and it’s designed in a way that almost every lab with a decent flow cytometry machine can do that, and a panel of cytokines that is required.

Sanam Loghavi:

Yes.

Shahram Kordasti:

So yeah, I hope it’s helpful for the society and everybody could join this effort, and we have more information, which helps better patient stratification.