This week’s highlighted Anemia in MDS article can be viewed below. As noted by Rami S. Komrokji, MD, lower-risk MDS can be associated with considerable morbidity and mortality, even in the absence of progression to AML.

We presented a study on the natural history of lower-risk MDS last year at the 63rd American Society of Hematology Annual Meeting and Exposition, in which we included those with very low– and low-risk MDS according to the IPSS-R criteria. In our study, with a median follow-up of approximately 16.5 years, we saw that most patients who started with lower-risk MDS stayed at lower-risk status. Approximately 30% of patients progressed, and they progressed with differing patterns. Some went from lower-risk MDS to acute myeloid leukemia (AML), seemingly without a high-risk MDS phase; some transitioned to higher-risk MDS followed by AML; and others moved to higher-risk MDS but never crossed over to AML. It is also important to note from our study that lower-risk MDS was associated with considerable morbidity and mortality, even in the absence of progression. For those patients who remained in the low-risk category, one-third had an estimated median overall survival of less than 2 years, and one-third of deaths within 2 years were MDS related. Another common cause of mortality in lower-risk groups is cardiac related, which always raises the question about whether anemia from MDS could be contributing to cardiac events.

When attempting to glean prognostic information from the mutational landscape, it is important to note that the majority of patients with the SF3B1 mutation will stay at lower risk. Mutations that are observed in MDS only rarely, such as IDH1, IDH2, and NPM1, are associated with direct AML transformation. There are still other mutations that are associated with MDS progression. I think that it will be important to continue to improve on our current ability to risk stratify patients with MDS, and we need to identify the approximately 30% of patients with low-risk disease who are destined to progress to high-risk MDL and/or AML. The better the tools, the more we may be able to consider interventions such as early transplantation.

Most patients with lower-risk MDS, unfortunately, still have a median survival that is under 10 years, but there is certainly a population that starts at low risk and stays at low risk for a long time. We do not yet have any truly effective options for early preventive therapy, although there are clinical trials that are investigating early intervention in low-risk MDS.

A different subset of patients with low-risk MDS have disease that progresses more quickly (ie, within just a few years) to either high-risk MDS or AML. I agree that it is important to know which patients with MDS are at a higher risk for progression because we want to make the necessary preparations for transplantation, and we want to follow these individuals closely so that we can catch them before they do progress.

I think that this is where mutational data really play a key adjunctive role, along with the IPSS-R. When you consider a patient who has low-risk MDS according to the IPSS-R but has mutations that are associated with a higher likelihood of progression, you might approach that individual differently. For example, consider a patient with 10% bone marrow blasts with diploid cytogenetics and reasonably sustained counts. This patient is going have low-risk MDS by the IPSS-R, even though they have 10% bone marrow blasts. Now, suppose that they also have a mutation that is associated with a higher likelihood of progression (eg, IDH1, IDH2, SRSF2, or NPM1). This is a patient whom I will approach very differently from a patient with low-risk MDS by the IPSS-R who has low bone marrow blasts and does not have any of these mutations. Thus, an awareness of these mutations is important.

Clinical molecular genetic testing and the use of sequencing to identify inherited predispositions to hematologic malignancies are some of the fastest-growing areas of cancer genetics. As we sequence more and more patients with myeloid malignancies, we are learning that germline mutations likely play a role more often than we realize, and this may also be true in MDS. For instance, germline mutations in the RNA helicase DDX41 predispose patients to increased lifetime risks of myeloid neoplasms. Other germline mutations that are associated with telomere disease (eg, TERT and TERC) have been implicated in MDS pathogenesis and are relevant to donor and conditioning regimen selection in transplantation, for instance. Patients with germline predispositions to leukemia may not always present with the prototypical phenotypic features that may come to mind when considering familial leukemias, where patients typically present during their youth, so it is important to consider this diagnosis.

Not all genetic panels capture these mutations, and we are still learning about their penetrance, but thinking about genetic predisposition to malignancy is relevant in that there may be a patient who has low-risk disease, or even clonal hematopoiesis, but also has a DDX41 mutation. And you might want to follow that patient differently and also to consider genetic counseling. Similarly, DNMT3A clonal hematopoiesis may have a different risk of progression compared with U2AF1 clonal hematopoiesis, emphasizing how nuanced genomic data increasingly inform our understanding of disease pathogenesis and management.