Disease-Course Differentiation: Low Risk and High Risk

EP: 1.Heterogeneity and Presentation of MDS

EP: 2.Ensuring an Accurate Diagnosis

EP: 3.Challenges of MDS Management

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EP: 4.Disease-Course Differentiation: Low Risk and High Risk

EP: 5.IPSS/IPSS-R Reliability in Various Disease Settings 

EP: 6.The Role of Supportive Care 

EP: 7.Initiating First-Line Treatment

EP: 8.The Role of Hypomethylating Agents and Transplantation

EP: 9.Overview of Luspatercept-aamt as MDS Treatment

EP: 10.The Future of MDS Management

Amy DeZern, MD, MHS: I was wondering if you think about this similarly in terms of risk stratification, from low-risk and high-risk patients. Because the disease course is so different, it gets into this expectation management that I was alluding to.

Rami Komrokji, MD: Absolutely. I totally agree. Obviously, we’ll talk more about what we use to risk-stratify patients, but in the end, we are putting patients in almost 2 categories: a lower-risk disease and a higher-risk disease. I think it’s important to remember that if we take all MDS [myelodysplastic syndromes] patients, all comers, roughly around 30% will transform to AML [acute myeloid leukemia], much higher in the higher risk obviously and probably lower in patients with MDS ring sideroblasts. It’s probably less than 10%. However, when we look at the data, 50% to 60% of the patients will still unfortunately die from complications of MDS. The fact that some patients are lower risk doesn’t mean that this disease cannot be life-threatening or serious. In lower-risk disease, there’s a lot of interaction and…the cytopenias may exacerbate the comorbidities or the other way.

Together in this consortium, we published some data years ago about looking at what we labeled as lower risk. Even when we labeled patients as lower risk, around 25% of those patients unfortunately died from the disease and died within a couple of years. It could be comorbidities, but like a patient with coronary artery disease, if they become anemic with hemoglobin less than 8.0 g/dL, the cytopenia could exacerbate comorbidities. In general, obviously, the higher-risk disease seems to dominate the course, so those patients are at higher risk of developing AML. Their cytopenias are more profound, we tend to see more thrombocytopenia, and the rapidity of the course of the disease is higher. In the lower-risk disease, the severity and the depth of the cytopenia dictates a lot of the outcome of those patients. There’s no doubt in my mind that the disease does affect the patients both in terms of quality of life and survival, both in the lower- and higher-risk disease, maybe in a different pattern.

The point you bring to the comorbidity is important, and we didn’t pay much attention to it for many years. Now we know fascinating data that some of the somatic mutations that we see in MDS can contribute to inflammation and lots of certain comorbidities. Also, the comorbidities feed into the MDS as well, where again, a patient with coronary artery disease may have a heart attack, but it could be prompted by the severity of the cytopenia and so forth.

We should talk about how we label those patients as lower risk or higher risk. What do you use? How reliable are the risk stratifications? What’s state of the art that you’re practicing now?

Amy DeZern, MD, MHS: I try to be state of the art, but it’s challenging because I always come back to the same refrain to every patient. I want to give them the best quality of life for the longest quantity. I do personally use the International Prognostic Scoring System–Revised [IPSS-R] most often to couch that particular discussion. When I was training and in my early years on faculty, we did use its earlier predecessor, which was the IPSS [International Prognostic Scoring System]. I have found in my practice that the IPSS has fallen a little behind, and I try to stick concretely to the IPSS-R. I do this for a couple of reasons. The publication was a little more recent, though it’s still further back in our minds. Also, the IPSS-R incorporates morphology and cytogenetics, similar to the IPSS but with increased granularity of detail.

There are more categories of cytogenetics. The blasts are separated out a little more, and there are actually 5 categories. I find it is a helpful starting point as I put people in lower- or higher-risk boxes. Then I think about how to explain to them why we need to be more aggressive in the context of how many blasts they have, if their cytogenetic markers are particularly unfavorable and really suggest they’re much more likely to get leukemia sooner than a patient who doesn’t have that particular cytogenetic marker. One of the best examples is a chromosome 7 abnormality, whereas something like the –Y in a man is a much less bad cytogenetic abnormality.

The IPSS-R is a good tool, but there are limitations. For 1 thing, there’s this intermediate category. In the past, you and I have debated whether we should treat these intermediate patients like low risk or high risk. It is a challenge. That’s where I really lean quite heavily on molecular information, even if someone doesn’t have a lot of blasts. Or perhaps their karyotype is normal but they have mutations that I know are associated with an accelerated path to truly high-risk disease, whether elevated blasts or acute leukemia. I bring that into the discussion with the patient even though it’s not part, at this time, of the formal IPSS-R. We’re going to have another R there soon, or maybe the IPSS-R Molecular. That really will incorporate these data based on large series.

Transcript edited for clarity.