CHIP: Clinical relevance, challenges & preventing myeloid malignancies

George Vassiliou: Hi, I’m George Vassiliou. I’m at the IBC 2024 meeting in Lisbon, and I’m joined today by Dr Lachelle Weeks and Dr Mrinal Patnaik, and we’re going to discuss myeloid cancer prevention. So, one question that’s been in my head a lot recently is how do I identify individuals who are at risk of developing myeloid cancers? And once identified, what do I do about it after that? So I don’t really have any fixed ideas yet. I wanted to, Lachelle, how you would you go about thinking about it?

Lachelle Weeks: Sure. So at the CHIP clinic at Dana-Farber, what we’re doing is taking advantage of the fact that we already, incidentally, identify clonal hematopoiesis and myeloid precursors using a lot of our standard of care, next generation sequencing modalities. So patients who have solid cancers, who undergo cell-free DNA testing, or germline hereditary next generation sequencing testing, those patients were, we’re incidentally picking up the fact that they have clonal hematopoiesis, or patients who are being screened with next generation sequencing because they have low blood counts, we’re picking up clonal hematopoiesis there as well. So that makes up the majority of the patients that we’re seeing in our CHIP clinic. We’re not going through and systematically screening people outside of the context of research protocols.

George Vassiliou: And what do you do at Mayo?

Mrinal Patnaik: Yeah, I think, you know, likewise, we started the CHIP clinic at Mayo in 2017, and we’ve seen over 900 patients now, you know, with research consent. And the way I approached it philosophically is that, you know, there’s age related CH, but then what’s more relevant for big cancer centers and hospitals like ours is context relevant CH. So we are very, very, you know, cognizant that there are certain therapeutic modalities that our colleagues are using that have the potential to cause a lot of damage, collateral damage to the hematopoietic compartment.
The most relevant, for example, is radio theranostics. As of today in the US, FDA has approved two beta particle emitting drugs lutetium 177, you know, Lutathera for neuroendocrine tumors and Pluvicto for prostate cancer. And if you look at the neuroendocrine data, anywhere from 2 to 10% of these patients will develop a myeloid neoplasm within two years. So against the dictum of a lot of therapy related things we were taught in medical school. And what we’re finding in these patients is that, you know, tiny clones, when you use dual index sequencing genes like PPM1D one or p53, they tend to get, you know, that fitness advantage and they rapidly engraft and so rapidly progress in the setting and lead to that. Other examples are, you know, women with germline mutations in homologous repair deficiency like BRCA1, BRCA2, they get exposed to platinum agents and now put on PARP inhibitors, you know, and up to 10% of these may develop, you know, very aggressive outcomes.

George Vassiliou: In fact even women without those predisposing mutations can do that, significant number.

Mrinal Patnaik: So, you know, I think apart from those incidental findings that Dr Weeks pointed out, which, you know, we always are happy to see, the only thing I’ll point out there is, using models such as what Dr Weeks has produced as well as coming out from your collaborations. You know, we’re trying to de-escalate care in people with incidental, low risk mutations, single mutations. We’re very cognizant that this may be a ubiquitous finding in the elderly, and we don’t want to over medicalize the situation, which we don’t.

George Vassiliou: And what do you do then with individuals that you find them at risk of the type of myeloid neoplasia described after?

Mrinal Patnaik: So this is a very good question, and I want to spend a minute here. Every time, you know, I’ve spoken to colleagues, whether it’s in the radiotheranostics space or those who are prescribing chemotherapy for ovarian or breast cancer. The question they ask is that, okay, you found a clone that may give rise to a myeloid neoplasm, but this patient has a high grade ovarian cancer or a fallopian cancer. So what do you want me to do? And I tell them that right now we may not be able to intervene. You know, obviously there are drugs working on the p53 pathway, there’s other things that we’re looking at, but it is very important for every patient to have a informed consent about what he or she is getting into.
If it was my mother or my sister getting this treatment, I would very much want her to know that there is this risk. And it’s not just the number because once they get these myeloid neoplasms, more than 90% of these patients are going to die. So putting the patient at the center of this, I’m highly passionate that educating and empowering them to understand their disease scores is what I really want this to be about.

George Vassiliou: No, that’s very interesting.

Mrinal Patnaik: Sorry I got emotional.
Lachelle Weeks: No I understand. I think it’s a big ethical issue, you know, making sure that there is appropriate informed consent of our patients, both for undergoing the genetic testing at diagnosis, clonal hematopoiesis, but also in determining what you do after you find it. You know, you cannot just test someone for something and then do nothing and you can’t hide information from patients. It’s very important that you have these sort of nuanced discussions about what the risk is, with the understanding that many patients who are faced with high grade ovarian cancer are going to choose to treat the cancer that’s in front of them. But we can’t make that assumption and be paternalistic about it for patients.

Mrinal Patnaik: The other thing, George, that I would point out is that, you know, we use this clinic also to prevent inadvertent treatments being prescribed to patients. Let me explain this to you. So a lot of our solid tumor colleagues love liquid biopsies. So these are cell-free circulating tumor or total nucleotide extraction assays. You will be surprised that even in prostate cancer, one of the top common CHIP mutations is BRCA2, and guess what? That if they find that in their cell free assay, they think it belongs to the tumor and the FDA has approved PARP inhibitors and prostate cancer.

So they would get PARP inhibitor.

So you are treating maybe ten to, and this has been published in JAMA Oncology where you know about the mutations in the wrong cell. The mutation in the wrong cell are being attributed to the primary cancer. So you’re making the treatment of disease more grievous than the endurance – and that is an important message, you know, principle that we have to comply with. So I feel that it’s really nice to focus on the science, but there’s a very humanitarian focus here, which we at Mayo Clinic are really driving forward.

George Vassiliou: I understand – that’s very laudable, I think.

Lachelle Weeks: That also comes into play with these sort of when you have patients who are undergoing the cell free DNA testing, and the question comes up of whether or not they have a germline BRCA, and then that if you are diagnosed with germline BRCA, it opens you up to a wealth of different screening modalities and medicalizations. And so making sure that that diagnosis is actually true, it’s not just mosaicism or clonal hematopoiesis that we’re actually diagnosing.

George Vassiliou: And so but that that is probably going to become more important as treatments intensify and escalate. And it will be a I mean, you mentioned some types of cancer that are incurable, but there are prostate cancer has long survival as well.So in that context, tou might want to have a way to eliminate or to anticipate and eliminate that clone.

Lachelle Weeks: And even neuroendocrine cancer, which is, you know, we don’t think about curing it, but these patients have a long, protracted course of therapy. Yeah.

Mrinal Patnaik: And so and what’s important is that, for example, in prostate cancer right now it’s only approved for advanced metastatic prostate cancer where the median survival is less than two years. But if you look at what’s happened at the recent ESMO meeting, they’re moving this earlier and earlier. So these patients and this is lutetium is one example. Actinium-225 is coming along, thorium, radium.. we just published a paper on, you know yttrium attached with CD20. 1 in 4 people these were heavily traded in for people developed. I guess they must have had some .. [overlapping conversation].

I feel that we can do a lot of good by both focusing on the right population and telling the other for sure, age related people.

George Vassiliou: In fact, I mean, that is something that I often found a bit of disconnect with that the solid tumor colleagues, they are aware of clonal hematopoiesis, but they see the cancer in front of them, put it that way. So they’re not going to think so hard about. But actually, as treatments improve, we have to think about this as toxic treatments are given earlier for a better effect on the primary tumor, we need to think about these things more and more and also develop specific therapeutic modalities. Because most treatment modalities are developed against primary, unprovoked, let’s say, neoplasms and not against these more difficult ones.

Mrinal Patnaik: Yeah, I fully agree, and I think all of us are very much on board with therapy.
And this may be a good segue into, you know, I think what we are challenged with is, how do we attack these precancerous clones without causing more problems or without causing serious side effects? You know, resistance patterns, new mutations, clonal drifts, which, you know, down the line would be more costly to the patient. So, as Dr Weeks said, very eloquently in the beginning, there are so many ethical issues that surround this field that this is prime time for all of us to really sit down and work them out. Absolutely. And we don’t know what we’re targeting, what the response rates are.

George Vassiliou: So I want us to move a little bit to the de novo cancers, as well as, as you rightly said, most instances of clonal hematopoiesis are not of clinical relevance to the individual with the clonal hematopoiesis, but a minority are. And, I’m trying to imagine whether in the next few years or even in the next 1 or 2 decades, whether you see that we might be moving to target these premalignant clones and trying to prevent these myeloid malignancies. And I’m thinking also a little bit about the talk from Dr Castle from the NCI, who described the different stages you can intervene to prevent cancer in general, like in lifestyle advice or identifying a pre clone and doing something about it, or even at the time of diagnosis to act correctly according to the stage or aggressiveness of the tumor. But moving back to the myeloid world, do you see this happening and how do you see, for example, clinical studies, if you agree that this might happen taking place?

Lachelle Weeks: I think we’re still in very early days, but there are a lot of really cool clinical trials that are being proposed and are being newly activated and just finished accruing and so forth in clonal hematopoiesis. I think we are at a place now where we have two really good risk stratification systems, where we can target –

George Vassiliou: Even if we say so ourselves.

Lachelle Weeks: Right, exactly. We’re a little biased. But we have two good risk stratification systems, so we can target a population of people who are high risk for progression or transformation to overt malignancy and pick those patients as the ones that we use our, you know, more toxic, potentially toxic interventions. So we have a trial opening up at Dana-Farber using decitabine and cedazuridine in patients with high-risk CCUS. So this is really the idea of taking a treatment that we use for MDS and moving it.

George Vassiliou: And how do you adjust the dosage to be appropriate, let’s say?

Lachelle Weeks: So we’re using the lower end dosage of decitabine and we chose Inqovy because this is a patient population that’s not normally drugged and is not a population that necessarily wants to come into clinic and sit in infusion center, and so oral medication is more ideal for that population as well. But there are also you know, we talked about lifestyle interventions and thinking about, you know, even earlier prevention. One of the things that’s remarkable to me about clonal hematopoiesis is that the risk of mortality exceeds the risk of developing myeloid malignancy, and so you can have the potential to have a lot of impact on mortality doing a lot of these lifestyle intervention things, even if it doesn’t actually reduce the, you know, the rate of AML or MDS.

Mrinal Patnaik: And I agree, I think George, work that you’ve been leading and others, in understanding, we may not be able to make these mutations go away, but we could target factors that promote growth. So understanding the cell autonomous the cell intrinsic extrinsic factors, clonal dynamics, how do they compete. So I feel like this all round work because if we put all our eggs in one basket and say we want to edit the gene or find a drug that neutralizes it, you know, we may be in for a surprise. We’ve seen that with some of the p53 targeting therapies and MDS AML. So I think we need to learn from our experiences.
And so, you know, a lot of credit to the both of you for the amazing science that you’re contributing in this field.

George Vassiliou: Well, and to you for having such a fantastic clinical setup, really, and considering the patient angle so carefully. So, I wonder, one other last thing perhaps I wanted to float, is to go now to the low-risk people. Because there are two angles I’ve thought about is one is that, low-risk individuals with DNMT3A clonal hematopoiesis, they only have a small risk of progression. But actually about a quarter of all acute myeloid leukemia arises in those individuals. So if you have a different angle. So yeah you have to treat a lot of people to stop leukemia, the few that do get leukemia, but we can’t get away from the fact that that’s how leukemia often starts. So do you think that I mean, it could be lifestyle advice, it could be a nontoxic intervention. But do you think we should be thinking about these people now, or do you think we should tackle the people who are at high risk with more targeted treatment and perhaps postpone this consideration for later, perhaps when we’ve learned even more about the biology of those conditions?

Lachelle Weeks: I mean, I think, you know, we’re in a place where we’re so early that it’s good to do a lot of things in parallel. And so I think that thinking about that low-risk population and what kind of acceptable toxicity and the appropriate treatment in that population, I think, you know, you’ll have to find the balance there and find regulatory agency approval for whatever balance is proposed there. And so that is really more of the challenge in managing that low-risk population is that we don’t want to take somebody who has a less than 1% risk of developing a blood cancer and give them side effects, or even select for more deleterious clones. And so, I think we still have a little bit of learning to do, but we should definitely be trying to do that learning in parallel to what we’re doing with the high-risk population.
Mrinal Patnaik: I mean, I echo that. The only thing I’ll say is that fortunately, if you look at the spectrum of DNMT3A variants in clonal hematopoiesis, most of them are not arginine – most of them are not in the.. domain [overlapping conversation] in that hotspot.

So you’re completely right that those that occur in that region where we may have to really focus. We know that fortunately, with R882, its impact on the methyltransferase, its location in the MT domain. But, you know, mutations in the AD domain, the PWWP domain, they have different epigenetic alterations, growth rates. So the last point that I will make is that CHIP should not be binarized, it’s not that you have CHIP or not, it’s so many variables. So again, you know, the more we talk about this, the better we will lay the ground for work in this field. So thank you George.

George Vassiliou: And thank you, thank you for this lovely discussion. So, we’ve not reached conclusions I think, but we have made suggestions and I hope you find them helpful.
Thank you to Lachelle and to Mrinal, and thank you to IBC 2024 for bringing us together.

CHIP & CCUS: knowledge gaps, ongoing trials & recommendations for hematologists

Dr Uma Borate: Good morning everybody, we are here at IBC 2024. My name is Dr Uma Borate. I’m a clinical hematologist at the Ohio State University, and I’m joined today by my colleagues, Dr Kelly Bolton and Dr Eric Padron. Dr Bolton and Dr Padron, maybe you want to introduce yourselves?

Dr Kelly Bolton: I’m, Kelly Bolton. I’m an oncologist at Washington University, and I have a lab that does work in clonal hematopoiesis.

Dr Eric Padron: I’m Eric Padron. I’m an oncologist in Tampa, Florida, at Moffitt Cancer Center, and we’re interested in clonal hematopoiesis, but also how these diseases start once they pass clonal hematopoiesis and what makes them progress.

Dr Uma Borate: So in case you guys are wondering, IBC stands for Intercepting Blood Cancers, and from what you heard from Dr Bolton and Dr Padron, all of us are very interested in identifying certain types of blood cancers early and hopefully intervening early before they progress to more aggressive blood cancers.

So maybe I’ll start with you, Dr Padron, and ask you, you know, we are here at this meeting today, from a patient or a clinician perspective, what do we know about this entity called clonal hematopoiesis? And more importantly, what do we not know about this entity? And so how are we kind of using this information to guide our patients?

Dr Eric Padron: Yeah, I think from a patient perspective, the hope lies in the fact that the amount of high-quality research being done by investigators at this conference here is really astounding. It’s a joke that we have, like, you know, every couple of weeks there’s something new that we learn about that is associated with these early precursor states like clonal hematopoiesis. And so I think in the what we know category, I think we know a lot about the things that are associated with clonal hematopoiesis at one static time point. And these things range from a broad swath of diseases of aging, but also associations with how therapies both work and are toxic to patients with clonal hematopoiesis.

The part that I think we don’t know that we need a lot more information on is, after you identify it at that static point, what next and how do we monitor that and is there, and I think the goal of this conference, is there a way to intervene in a manner in which causes minimal toxicity to people who feel okay and prevents this from getting worse?

Dr Uma Borate: Thank you for that great summary, and I’ll use that as a great segue to talk about your work. You’ve done a lot of work in what Dr Padron described of, you know, understanding why people with clonal hematopoiesis may progress and you’re doing even more exciting work on maybe intervening earlier in some aspects of the disease. So if you can tell us a little bit more.

Dr Kelly Bolton: Yeah so, you know, when you think about designing intervention studies, like this has been maybe a theme of the conference, it’s really important to understand the natural history of the disease, and that’s why we’re both doing a lot of work in trying to understand who with clonal hematopoiesis is going to progress to heme malignancy and who will not, because that kind of risk stratification that you get from better characterizing the natural history is really important in deciding who you’re going to treat. Because it’s really, you know, you need to have a population that’s at a high absolute risk of progression over a certain period of time to identify that as your target group.

And so I think maybe one target group that’s been clearly defined by a lot of people in our field is people that have clonal cytopenias of undetermined significance, CCUS, and that patient population seems to be at very high risk of progressing to malignancy in a 5 to 10 year period. So, you know, we have clinical trials and there’s a few clinical trials now in CCUS specifically. We have one using a targeted therapy, for IDH1 and IDH2 mutations, so we’re using ivosidenib and enasidenib in this space. But there’s a lot of other exciting trials, including yours, Uma, trying to target patients with CCUS.

Dr Uma Borate: And so, just to elaborate on that, maybe for the both of you, if you are a general oncologist practicing in the community, and maybe they have a patient that has low blood counts, what do you recommend that they do to identify the right patient with clonal hematopoiesis, or really CCUS because now they have low counts, and what advice do you recommend they give these patients? I’ll start with you.

Dr Eric Padron: I think it may be helpful to define what CCUS is. And really the distinction between CCUS and myelodysplastic syndrome is the presence of dysplasia, which is, you know, not quantitative, perhaps a bit subjective, and so I think the one thing that a community oncologist could do, especially when there’s not clear dysplasia, by that I mean way more than 10% dysplasia in any one lineage, is refer them to a center where it’s not necessarily about the oncologist, but really the hematopathologists that do this for a living and can say with confidence that this really is CCUS and not myelodysplastic syndrome. So I think if there’s one thing that they could do is make sure that they refer to a tertiary center.

Dr Uma Borate: So it sounds like what you’re recommending is you have these cytopenias, they’ve done all the workup, you don’t really have a cause, do a bone marrow biopsy and if the report doesn’t seem very clear, make sure you get them to a larger center where they can look at the report and kind of define this entity better.
Dr Eric Padron
Correct.

Dr Uma Borate: Do you have anything to add or any other sort of tips in that scenario?

Dr Kelly Bolton: Yeah, I think probably Eric you’ve seen this and I’m sure you have too, when patients come to us with CCUS, they often have had multiple different diagnoses before they’ve reached that. Like a center might diagnose them with MDS, and part of that’s just because, especially recently, there’s a lot of confusion with differences in the types of molecular features that define MDS between different guidelines. And so because of that local pathologists might not be as up to date or be as well versed in discriminating CCUS from MDS. And so, like just to echo that, it’s important to have the pathology report reviewed by a probably larger medical center that would have familiarity with CCUS specifically.

Dr Uma Borate: And what are your thoughts on in this scenario, ordering next generation sequencing like a myeloid panel earlier rather than later. What do you recommend? Because I think, as you know, we’re talking about clonal hematopoiesis, CCUS obviously, and we’re choosing these high-risk patients for potential trials, we need to know what mutations they have within their bone marrow when we do this.

Dr Kelly Bolton: Yeah, I mean it’s part of guidelines now when you’re worried about MDS to send a myeloid panel. So it makes a lot of sense on that initial bone marrow biopsy to send a myeloid panel.
I’d say maybe one thing that I’ve been noticing clinicians doing, which isn’t wrong it’s just a trend that, you know, when people are on the fence about whether to get a bone marrow biopsy or not, they’ll send myeloid panels on the blood and then only get a bone marrow biopsy if the person is positive, which can actually give you wrong results. I mean, in the sense that there are differences, we’ve noticed this, especially people with IDH1 and IDH2 in the VAF of the mutation between the blood and the bone marrow, so, you know, you might not detect something in the blood that you would in the bone marrow. So probably I would encourage people to, if it’s clinically indicated to get a bone marrow biopsy, to just get the bone marrow biopsy, because that’s going to be definitive. Doing the myeloid testing first, it’s not part of a well-established algorithm for testing for MDS.

Dr Eric Padron: Yes, I agree with that. I mean, I think there are two essential elements to CCUS. One is you have clonality, so you have to have a mutation, so you’ve got to order that. And then two, you have to have the absence of dysplasia. So if you don’t do a bone marrow you don’t know if you have that.

The one thing I will say though, in terms of the what we don’t know category, is to what degree absence or presence of dysplasia is truly a biologically and clinically meaningful distinction, you know. Because for all other intents and purposes, I mean, we have cases of CCUS that are transfusion-dependent, for example, or we can have cases of CCUS that have mutations at the same level and the same type that lower-risk MDS has. So even though I think it’s important to define what CCUS is, I think it’s also important to say that we’re not sure exactly what the distinction is between CCUS and MDS from a clinically and biologically meaningful perspective.

Dr Uma Borate: That’s a good point. I mean, we’re all hematologists here, right? We’re all worried about this entity, progression to blood cancers, but is there other things that you tell your patients with this diagnosis that these entities can be associated with that they need to worry about?
You know, we’ve talked about heart disease, other autoimmune diseases, and patients have questions about those things too, because sometimes they come through those doctors to us as referrals.

Dr Eric Padron: Yeah, I mean, in our center, I think what it highlights is that, if you’re a clinician focused on clonal hematopoiesis or CCUS, you have to be comfortable working in an interdisciplinary group. So for example, at Moffitt, we have a good relationship with our cardio oncologists because of the tight link between clonal hematopoiesis, especially for some mutations like JAK2, and cardiovascular disease. And, while we don’t know, as I said earlier, the what’s next category, we do know in cardiovascular disease how to risk modify, and so at least we can control the things that we can control.

I think it’s vital, I mean there’s a very long list of things that clonal hematopoiesis can affect.
There’s a few of them that are really outliers in that they can cause and are probably a major cause of mortality and contribute to that difference that we see in clonal hematopoiesis patients versus not, like cardiovascular disease. But there’s a long list of things.

Dr Kelly Bolton: But the best established is, like you said, cardiovascular disease, but there’s no guidelines about caring for people in terms of mitigating risk of cardiovascular disease, specifically with CHIP, but it’s very reasonable to just make sure people are up to date, like you said, Eric, with standard practice for primary and secondary prevention, like they should be even if they were without having clonal hematopoiesis or CCUS.

Dr Uma Borate: Well, thank you very much. This was very informative.