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iwMDS 2022 | Clonal hematopoiesis and pre-MDS states

In this exclusive roundtable discussion, leading experts Mrinal Patnaik, MBBS, Mayo Clinic, Rochester, MN, Zhuoer Xie, MD, MSCR, Moffitt Cancer Center, Tampa, FL, and Eric Padron, MD, Moffitt Cancer Center, Tampa, FL, hold a fascinating discussion on clonal hematopoiesis and the impact of mutations in myelodysplastic syndromes (MDS), highlighting the importance of improving response criteria and gaining a deeper understanding of somatic mutations and pre-MDS states. This discussion took place at the 1st International Workshop on Myelodysplastic Syndromes (iwMDS) 2022 held in Miami, FL.

Transcript (edited for clarity)

Mrinal Patnaik:

Well, good morning, everyone, I’m really privileged today. We are at the iwMDS meeting and we’ve had a great session on clonal hematopoiesis and clonal cytopenias, and I’m joined today by my panel. We have Dr Zhuoer Xie, who is going to be a new faculty member at the Moffitt Cancer Center, and then Dr Eric Padron, a very established investigator in this field...

Mrinal Patnaik:

Well, good morning, everyone, I’m really privileged today. We are at the iwMDS meeting and we’ve had a great session on clonal hematopoiesis and clonal cytopenias, and I’m joined today by my panel. We have Dr Zhuoer Xie, who is going to be a new faculty member at the Moffitt Cancer Center, and then Dr Eric Padron, a very established investigator in this field. So, thank you both for joining me, and a great session.

Zhuoer Xie:

Thank you so much, Dr Patnaik.

Eric Padron:

Thank you.

Mrinal Patnaik:

Let me just start off by asking, Dr Xie, I’ll ask you a question. You very elaborately brought out the need for intervention in certain high-risk patients with CH CCUS, and then you beautifully showed where the field is currently, and how we don’t have response criteria to adjudicate. So we’re a little bit ahead of ourselves. We have a trial, but we don’t have response criteria.

Zhuoer Xie:

That’s correct.

Mrinal Patnaik:

So, could you comment a little bit on that?

Zhuoer Xie:

Yes. Currently, we are using a high dose of ascorbic acid in patients with the type 2 mutated CCUS, where we are running the clinical trials, so we have gained the knowledge and experience, but we also identified a significant knowledge gap. We don’t have any response criteria to evaluate this patient, whether they respond to the treatment or not. Currently, we adopted the IWGMDS response criteria, the hematology improvement response criteria, to our patients with the CCUS, but whether this is correct response criteria to use or not, this is still a question.

Zhuoer Xie:

And how do evaluate the response rate, and when should we evaluate the response rate, and what are the appropriate endpoints? It is still something that we need to discuss, and I think we should all get together and discuss the response criteria as more of the proposing clinical trials for CCUS are coming. And we should set up the response criteria up front.

Mrinal Patnaik:

Thank you, Dr Xie. Dr Padron, again, great talk. And just one question that comes up all the time for us, is when we detect somatic  mutations with variant allele fractions, so much depends upon the method of sequencing, how deep you go, the panel depth, the coverage, etc. And then, the second question is, how do you understand whether a change in a variant allele fraction is inherent variability of the assay sampling or the true clonal progression? And I thought you brought up very nicely in the case that you presented. So any comments on this?

Eric Padron:

Sure. I think intuitively as clinicians, we know that trends are more important than single numbers. We know that, as hematologists, when we look at hemoglobin platelets, it’s not really a single number that drives decisions. Obviously, those are more standardized and less expensive assays to do, so we can get them at many time points. And the same thing then is true with next-generation sequencing. And the way I would categorize this sort of VAF issue is technical VAF issues versus biologically-driven VAF issues, that may or may not be clinically significant. And so the technical issues are those that you outlined, assay issues, coverage issues, there’s some genes, for example, like CEBP alpha, that’s highly GC rich. And oftentimes when the probes get old, or when other technical issues occur, their coverage is lower. And so there’s a lot of variation there. There’s variation in blood counts. Of course, these mutations are harbored in the myeloid cells, and if there’s any cytopenias that could influence the VAF.

Eric Padron:

So those are some technical issues, but I also think that there’s biologic variation that’s present and it’s real, but we are not at the stage yet in which we know what the clinical significance is. So in the case I presented, the variant allele frequency went from 17 to 24%. Intuitively, that means something to me, but does it really mean that this is going to turn into a therapy-related leukemia, is to be determined.

Mrinal Patnaik:

Thank you. Those are great comments. And I guess a general question for both of you, I think the community, and it’s very natural, we consider CHIP as a binary variable. So if you look at all the data points, it’s bad if you have CHIP, CHIP is associated with cardiovascular disease, therapy-related, and now when people are splitting hairs, you’re seeing a differential effect, not all mutations are the same, not all VAFs. And what we really have to take into account is the clonal selection pressures. If both of you could briefly comment a little bit on how, as a community, do we need to start integrating this, especially when we counsel patients?

Zhuoer Xie:

Yeah. First of all, as we discussed during the meeting, the clone definitely is not a binary. And we should definitely look at the trend, and how the clone evolved over time. And keep in mind, if a patient only has a CHIP mutation, and more than 90% of the clones, actually they grow pretty slowly, except the splicing factors. But, under the clone selection, definitely there is more clonal evolution, particularly under the autologous stem cell transplant, especially the DTA mutations, not really necessarily about the DDR mutations. So I think it is really context dependent.

Eric Padron:

Yeah, I agree. The way that I view clonal hematopoiesis mutations is really as a dance, if you will, between the somatic mutation and its environmental stress. And so I think what really will move the field further is a deep understanding. I think we have that for p53, right? Platinum therapy radiation, but a deep understanding as to what are the unique selection pressures. Hopefully, some of them can be mitigated. Hopefully, some of them are modifiable, that then lead to expansion of pre-existing clonal hematopoiesis.

Eric Padron:

So you can envision a clinic discussion in which someone has a DNMT3A mutation, and you recognize that these chronic inflammatory stimuli are associated with its expansion, and you can potentially intervene and mitigate those if present. So I think to me, that’s a clinically useful way to view the clonal hematopoiesis ecosystem.

Mrinal Patnaik:

Excellent. I’ll just make one last comment before we end. The data that I presented from the UK group in Cambridge and Oxford, where they were able to sequence progenitor colony assays with whole genome sequencing, there are three take-home points that I think will drive the field forward.

Mrinal Patnaik:

The first point is that a lot of these somatic mutations that we think are of the elderly actually occur extremely early in life. And especially with JAK2 and myeloproliferative neoplasms, the discovery that these could be embryonic in origin, preconception, and then have a very long latency, has really shed light on the field.

Mrinal Patnaik:

The second point is when you look at hematopoiesis, which is inherently polyclonal, as you age, somewhere along that 70-year mark this hematopoiesis becomes oligoclonal. And that is very, very sharp, and very, very reckoning for us. Suddenly you go from multiple cLADs to ten or 12 cLADs which have driver mutations, but in 50%, couldn’t identify driver mutations.

Mrinal Patnaik:

So our obsession, the final point is with protein coding genes now needs to extend, are there other mechanisms, other genes that we consider passengers, epigenetic mechanisms? And then, most importantly, somatic copy number alterations. They all have to be included if we basically understand this, and this will not only shed light, CHIP and CCUS but clonal progression and oncogenesis in general.

Eric Padron:

Absolutely.

Mrinal Patnaik:

So thank you for joining me. Great session, and really enjoyed it.

 

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