The Impact of Mutational Status on Treatment Considerations for MDS


James Foran, MD; Azra Raza, MD; and Gail Roboz, MD, discuss how mutation status in myelodysplastic syndrome may impact treatment considerations.

Gail Roboz, MD: James, talk to me about mutations and MDS [myelodysplastic syndrome]. Not only what do you send, where do you send them, and what do you do with them? But if you are trying to risk stratify a patient, have you moved over to using any of the mutational abnormalities to risk stratify?

James Foran, MD: Thanks very much. We do it routinely in everybody, but we’re lucky. I’m lucky where we work, we have that infrastructure. We have our own 42-gene panel. This doesn’t translate into community practice very well, but we have our own 200-gene discovery panel that we use in our bone marrow failure clinic that we have access to, for discovery work as well, for unexplained cytopenias if we cannot find a clear cause. We’re a bit lucky in that regard. But we do it on everybody. There is a significant minority of patients who have normal karyotype, and I think you get a lot of extra information in that group of patients from the next-generation sequencing. I say a lot of extra information; it will sometimes help you be more confident that it is MDS, when you start seeing TET2 mutations and others come back, if they are the right VAF [variant allele frequency]. And sometimes they are actionable. There are not any FDA-approved drugs in this setting, although we have sometimes accessed them for specific mutation subgroups. We have even had studies for some specific mutation subgroups like SF3B1 and others, but we use them.

Now, your question about how do we use them, it is more in confirming diagnosis, honestly. I have generally followed the, I am going to call it the…rule, that bad mutations upgrade you by 1 grade, give or take, on the IPSS [International Prognostic Scoring System]. I think that is generally true outside of TP53, which is its own group. They are useful for helping guide the patient into treatment decisions. I always cringe a little when I see ASXL1; we can get into that later, I suppose. Just because I have this internal conflict saying, well, they need therapy, and they have ASXL1, but they are not going to respond to therapy because they have ASXL1. I get into a little negative feedback loop when I see that, although I still treat with that, even though I think it predicts for lower benefit for some of the therapies we have. But we use it routinely in all patients; I cannot remember the last time we did not. I will finish by saying that the practitioners who refer us patients here in the south, I’m at the Mayo Clinic in Florida, they’re almost all getting next-generation sequencing. They are coming in with a 20- to 40-gene panel. I think it is rare that they’ve just done cytogenetics. There are different regions of the country where that changes. But they are being launched, I think, by their pathologist or in coordination with them, and then they’re asking what to do with it. That’s where we try to wade through it case by case.

Gail Roboz, MD: Whenever I have had the pleasure of seeing a patient, either before, or after or during, with Azra, she is one of the absolutely most careful doctors ever about going through with a patient, exactly what was found in all of the testing, and what that builds out in terms of an IPSS. It is extraordinary to hear about from patients how you do this. Can you share with us? And they always walk out happy too, even when the IPSS is like 12, so I do not know how you do that. You have now all the data, you have your marrow back. Do you pull up IPSS on the screen for them? Or how do you walk them through how you have put together all these pieces of the prognostic puzzle?

Azra Raza, MD: Thank you, Gail. Do you see all the books behind me? I think of MDS risk stratification a lot like author Leo Tolstoy’s happy versus unhappy marriages. When you have high-risk MDS, there’s very little doubt that you have lots of blasts, you have a couple of paragraphs long list of cytogenetic abnormalities, you have a TP53 mutation staring at you. Nobody is going to argue about any of that. So, you do not need an IPSS scoring table or an app on your phone; even a Luddite like me can go ahead and say, “OK, this is high risk.” But the lower risk, are all lower risk in their own special way. And that is where the problem comes in, Gail. Thank you for mentioning talking to my patients. I use a PowerPoint slide presentation with every patient to describe what it means to have a clonal hematopoiesis. How is it that 1 stem cell for whatever reason, transforms into, almost, in some cases, a new species, and in other cases blends in with the normal? The risk factor follows such a broad spectrum of diverse prognoses, especially for what we call the lower-risk disease, that all these special things that we have been talking about in terms of starting with the history, if it is a secondary MDS, then you are looking for very different things in terms of risk factors. Even if they have normal cytogenetics but they have a history of being exposed to a lot of chemotherapy or some kind of poisonous, toxic exposure, I would have no confidence in that normal cytogenetics here. I would be worried about finding something that’s going to go along with this therapy-related or toxic exposure-related kind of disease. So, I think even when we are talking about risk factors, just remember everybody, that we can have all the classifications we want until we are blue in the face, but we will be stumped a lot of times; 25% of what looks good, is not really good. That is one of the issues we need to discuss further.

Transcript edited for clarity.

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