MDS updates from iwMDS-iwMPN 2024 | New trends in CHIP/CCUS: impact of CH on transplant outcomes & distinguishing between MDS & CCUS

Uma Borate:

Hello everybody. We are here at the iwMDS meeting in sunny Boston. We just finished our first session on clonal hematopoiesis where we talked about a lot of different interesting data. And I’m joined by my two wonderful colleagues from Dana-Farber, Dr. Coleman Lindsley and Dr. Lachelle Weeks. We will start this discussion by talking about some of their very intriguing presentations. The first one by Dr. Lindsley, talking about the role of clonal hematopoiesis in donors and its effect on allo stem cell transplant. So do you want to give us a little short overview of what you presented today?

Coleman Lindsley :

The problem we were trying to address initially was the observation that outcomes in transplant recipients are worse in those who receive transplants from older donors. And so because of the link between older age and the presence of clonal hematopoiesis, we asked the question whether clonal hematopoiesis was driving those adverse outcomes in recipients. And so we looked at a group of about 1700 donor-recipient pairs, measured clonal hematopoiesis in the donors and asked whether the presence of clonal hematopoiesis was linked to outcomes in recipients. We were extremely surprised to find that DNMT3A clonal hematopoiesis in donors was not linked to bad outcomes, but was instead linked to favorable outcomes.

Uma Borate:

Interesting.

Coleman Lindsley :

And then we looked at why that might be, and what we found was that patients who received transplant from donors with DNMT3A mutations had a lower risk of relapse that drove their better outcomes. And it was particularly noticeable among patients who went in with more high-risk disease that was active at the time of transplantation.

Uma Borate:

And what do you think this lower risk of relapse was related to based on your cohort?

Coleman Lindsley :

Yeah, so we were wondering whether in native hematopoiesis or hematopoiesis in the normal population, clonal hematopoiesis has been linked with altered or increased inflammatory signaling, and in the absence of a transplant that is usually associated with pathologic processes, so increased inflammation, increased inflammatory pathologies. But transplant actually relies on immune signaling and immune activity for its positive effects. And so what we found was that that inflammation that was higher in the recipients actually drove better immune function, which reduced the risk of relapse.

Uma Borate:

So I think from a transplanter perspective in the real world, people are going to look at your data and say, “Well, is this something we can do in the clinic? Is this clinically actionable?” What would your thoughts be on that?

Coleman Lindsley :

It’s a great question, how do you translate retrospective data to clinical decisions? So I’ve gotten that question-

Uma Borate:

A lot, I imagine.

Coleman Lindsley :

Yes. And so what it relies on is the ability to detect clonal hematopoiesis, the ability to prove in a prospective fashion that this result, that was done in a retrospective study, is applicable and to prove the safety of that sort of approach. So I would say we’re not there yet and instead, we’re moving towards a larger validation cohort, for one. Two, we’re trying to assess the safety of that sort of approach. And so we looked at donor cell leukemia and other outcomes, but I would say it also opens the door for therapeutic modulation of the pathway that DNMT-3A regulates maybe as a more promising approach than large-scale screening.

Uma Borate:

And I know you sort of started this project with the hypothesis that maybe the presence of CH would increase the risk of donor-derived leukemia and obviously, it went down a different path, but were there findings in your research that showed that there were some mutations that increased the risk of donor leukemia?

Coleman Lindsley :

Yeah, so donor cell leukemia is a very rare complication of allotransplant. It’s also a very rare complication of clonal hematopoiesis. And so we did identify every donor cell leukemia that arose in that cohort and then, specifically evaluated the link between donor clonal hematopoiesis and that leukemia. And it was in a very specific subset of CH in the donors and that was those who had atypical clonal hematopoiesis involving genes like p53 and splicing factors that are more associated with MDS. And so they were getting a high-risk clonal hematopoiesis, which I think Dr. Weeks can speak to a little bit more, but high-risk clonal hematopoiesis may drive the donor cell leukemia risk in transplant.

Uma Borate:

Well, thank you for that great summary and we will move to Dr. Weeks as the next topic of conversation. And I loved your presentation and I think it was obviously meant to be a provocative topic where you have these two different disease entities. One is CCUS, which is clonal cytopenias of uncertain significance, and the more sort of traditional entity, which is MDS and whether low-risk MDS and CCUS are essentially the same thing. And this is your area of expertise. You’ve done a lot of research on it, you’ve published on it. So maybe if you can give us a high-level summary of what you presented and some open questions.

Lachelle Weeks:

Yeah. So I think it’s an entire field of open questions, which makes it very exciting. So we really were talking about what is the distinction between clonal cytopenias and low-risk MDS. And where I think it really breaks down is that clonal cytopenias of uncertain significance or CCUS is actually a spectrum of different conditions and there are individuals who have high-risk CCUS and there are individuals with low-risk CCUS. And when we think about where we might do an intervention, for example, we want to target the people who are most likely to have some sort of adverse health outcome and that would be the individuals that we are defining using the CHRS and other risk scores as high risk. And I think that that in terms of management principle is very similar to the way that we think about low-risk MDS.

So a patient with symptomatic cytopenias or with a higher propensity to transform to an actual malignancy is a population that I might start to maybe equate the highest risk, skim off the very top of that clade and say that those individuals are more likely to behave like a low-risk malignancy.

Uma Borate:

And I thought you said something really interesting in your talk, and when you were developing your CHRS score, which I think we all use a lot to make those distinctions, that you were surprised that it really isn’t the cytopenias that are more weighted towards this definition of who is high risk and risk of progression, it’s other things. And I think that’s important because if you’re a general oncologist or even a primary care physician, obviously these patients are coming to attention because of cytopenias, but you have other parameters that you reference. Maybe if you can elaborate a little bit more on that for clinical relevance.

Lachelle Weeks:

So the clonal hematoparesis risk score incorporates molecular features, so the number of mutations, which gene is mutated, the variant allele fraction of that mutation, and it also incorporates red cell indices, so red cell distribution with an MCV. And those have been consistently associated with increased risk of progression to myeloid malignancy. And all of those features were weighted higher than cytopenia, which was actually weighted on the same order as age. So the distinction between age over 65 or under 65 was similar to the presence or absence of cytopenia and these are all as a binary. I’m sure that the extremes, at the extremes list, severe cytopenia, for example, probably has a higher rate of transformation, but there were too few severe cytopenias in the healthy population that we derived the CHRS in. And I think the really interesting thing there comes when you’re thinking about high-risk CHIP and CCUS together. There are individuals without cytopenia who have just as high of a risk of transformation as individuals with cytopenia and there are some individuals without cytopenia who have a higher risk of transformation as individuals with mild anemia, for example.

Uma Borate:

Interesting. So I think the catch buzzword now in everything medical and everything anything is AI. And when you talk about certain things that are easily measured, like red cell indices and things like that, do you foresee a situation where with thousands of patients being seen in our clinics that you could maybe identify some of these patients and then work them up or would that be just over-medicalizing people that don’t actually need to know that there are these things happening?

Lachelle Weeks:

So I think in the context of research, these are really interesting questions. I think we’re still ways from systematically identifying patients and diagnosing people with these sort of pre-malignant entities, particularly since we don’t really have any way to really mitigate the risk right now. We’re still sort of in a very research phase. But one of the things that my lab is doing now is taking peripheral blood smears, for example, and looking to see whether or not we can use machine learning technologies to actually identify differences that we can’t see with our naked eye, but that perhaps a computer image processor can pick up in the white blood cells, in the red blood cells and then compute that into a risk of having a genetic lesion or of progressing to myeloid malignancy.

So these are the types of things that I think we’ll start to see more of. And in the bone marrow space, one could envision using similar type of technologies to really drive down and hone in on what is the actual meaning of having dysplastic features and how do we link those dysplastic features at a macro level and at a micro level to the presence or absence of particular gene mutations.

Uma Borate:

Well, thank you so much. As you can see, we had a great start and a very provocative session on clonal hematopoiesis to begin the iwMDS meeting. The dynamic duo from Dana-Farber, as we were calling them, have presented some really provocative work, and so we’ll stay tuned for some very, very interesting sessions as the meeting progresses. Thank you.