Anemia is common in patients with myelodysplastic syndromes (MDS). Historically, patients have been treated with erythropoiesis-stimulating agents (ESAs), but novel therapies have recently been developed. A patient’s disease characteristics and risk status should be used to guide treatment selection.

One of the big advancements that we have had in MDS is that we are now much better at identifying who is truly at low risk, meaning those whose disease is going to progress slowly and whose chances of dying directly from disease complications are low. For example, the incorporation of mutation scoring in the Molecular International Prognostic Scoring System (IPSS-M) gives us a better understanding of who will have a slower disease trajectory. For those patients who are going to live with their MDS for a long time, a lot of my efforts have been focused on trying to prolong their lives with as little impact from their disease as possible.

We have good therapies now, particularly for low-risk disease, and this allows for a number of treatment options for patients, which is great. The challenge that I often have is that any therapy I choose adds a clinical burden. Often, the most complex discussions that we have with patients are those that focus on when it is worth it to start treatment, in part because patients have to come in every week or every few weeks for labs and treatment, and this usually takes half a day for them. I work in Boston, and the impact that making patients come back and forth for many of our therapies has on their lives is not trivial. I tend to wait until patients begin needing monthly red blood cell transfusions. Needing only 1 unit of red blood cells every 2 to 3 months, having only rare infections, or having low counts during an intercurrent illness that subsequently resolve are usually not triggers.

Historically, ESAs have been used for treatment, but we now also have luspatercept. We are still trying to figure out who benefits the most from starting treatment right away with something like luspatercept. I think that this is analogous to the discussions that we have with patients with del(5q) about choosing between starting them on lenalidomide or giving them a trial of ESA therapy.

We look at MDS as a spectrum, and the first steps in the management of MDS are to establish the diagnosis and classify the disease. This is a hot area of discussion because we have different classifications. What we have learned from those classifications is that there are unique disease entities, such as MDS with del(5q) and SF3B1-mutant MDS, which are subsets of lower-risk MDS. For patients with del(5q), lenalidomide is useful. SF3B1 splicing factor mutations cause splicing alterations that are commonly associated with the ring sideroblast phenotype in the bone marrow. Luspatercept is particularly active in these patients. There is also a small subset of patients with an entity called hypoplastic or hypocellular MDS who can benefit from immunosuppressive therapy.

We have recently made progress in risk stratification. The IPSS-M integrates molecular data to refine the risk stratification. Notably, approximately 35% of patients are upstaged when using this system compared with the IPSS-Revised. We used to say that two-thirds of patients had lower-risk MDS and one-third had higher-risk MDS; however, as we apply more modern stratification, the percentage of patients with lower-risk disease becomes closer to 40%. Most of these patients with low-risk disease never progress, but, unfortunately, they still suffer from complications of cytopenias directly or from the interplay with comorbidities.

Approximately 90% of patients with MDS are anemic at diagnosis, and half of them will become transfusion dependent. For asymptomatic patients with a hemoglobin of at least 10 g/dL, we absolutely do not treat, because I do not think that we have clear evidence that it can change the natural history of the disease.

However, there is an argument for not waiting for patients to become transfusion dependent before treating them, as there are studies showing that anemia is associated with cardiac hypertrophy. In my practice, we typically start treatment in patients who are symptomatic if their hemoglobin is approaching 9 g/dL. We do not wait for transfusion dependency. With ESAs, the yield is much lower in patients who are transfusion dependent. Even with luspatercept, the most important predictor of response is the transfusion burden, so response rates are lower if you wait until patients are transfusion dependent. This has also been seen with lenalidomide in patients with MDS with del(5q).

One of the problems we are facing is that we are in a transition period. For a long time, the standard of care has been to treat patients when they are transfusion dependent. But it is complicated because, since the start of the COVID-19 pandemic, local institutions have not always been allowing patients with hemoglobin levels of 7 to 8 g/dL to receive transfusions if there is not enough blood. This makes the current definition of transfusion dependency unclear.

In my mind, we are starting to see a shift toward early therapy rather than waiting until patients are technically transfusion dependent. For example, luspatercept includes an indication for patients with very low- to intermediate-risk MDS who have anemia without prior ESA treatment if they might require regular transfusions. So, my understanding is that the patient does not need to be transfusion dependent, they should just be a candidate. There are data with luspatercept suggesting that treatment lowers the transfusion burden, which results in cost benefits. There are also data from patients with MDS with del(5q) showing that treatment with low-dose lenalidomide is extremely effective at delaying the time to transfusion dependence. Similarly, the early data with growth factors suggest that the only patients who derive benefits from EPO or G-CSF are those who are transfusion independent.