Anemia is a common complication in patients with lower-risk myelodysplastic syndromes (MDS), and it has clear prognostic implications. Appropriate management is important to optimize clinical outcomes. The number of treatment options is increasing, and clinical trials for novel agents are ongoing.

Red blood cell transfusions are extremely common in patients with lower-risk MDS. However, for multiple reasons, we are trying to reduce the need for transfusions in these patients. Transfusion dependence is directly and indirectly associated with poorer outcomes. Moreover, patients who are transfusion dependent have reduced survival and a decreased quality of life, and they are required to spend a lot of time in transfusion units. Iron overload is also common in patients who are transfusion dependent due to both repeated transfusions and MDS-related alterations in iron metabolism. Additionally, transfusions place a lot of burden on medical institutions due to increased regulations and a decreased number of donors. There has also been a decreased threshold for transfusions, with a hemoglobin level requirement of 7 g/dL at some institutions when significant symptoms of anemia are present.

Fortunately, there is an increasing number of agents that are useful for the management of MDS-related anemia. Lenalidomide has been the standard of care for more than 15 years for the treatment of patients with del(5q) MDS, which occurs in approximately 15% of patients. Additionally, the results of the MEDALIST trial showed that luspatercept is effective for the treatment of patients with lower-risk MDS with ring sideroblasts who have previously received erythropoiesis-stimulating agents (ESAs).

More recently, the COMMANDS study demonstrated that luspatercept was superior to the ESA epoetin alfa as first-line therapy in the majority of the patient groups in the study, including those who were ring sideroblast positive, those with an EPO level of more than 200 U/L, those with a high transfusion burden, and those with an SF3B1 mutation. There is some controversy regarding the subgroup of patients in COMMANDS who were ring sideroblast negative in that it was not clear whether luspatercept was superior to ESA therapy. Thus, we need a better understanding of the true activity of luspatercept in ring sideroblast–negative disease.

In addition, the MAXILUS study is evaluating whether we can streamline the dose escalation that is required with luspatercept. Currently, the dosing guidelines require a dose escalation from 1 mg to 1.33 mg to 1.75 mg out of concerns about raising the hemoglobin levels too high, which could increase the risk of embolic events. However, the risk of these types of events was low in COMMANDS, so perhaps for patients with a high transfusion burden, we could go directly to a higher dose because the majority of these patients require 1.75 mg.

While the results of COMMANDS were very exciting, I think that we need to become more ambitious and see if we can further improve on the 59% response rate that we saw in that study for luspatercept. Therefore, we should start thinking about combination studies to see if we can render a majority of our patients transfusion independent. If we can do that, then I think that we should be able to significantly improve overall survival.

We also need to consider moving toward initiating treatment to earlier stages of the disease for potentially better survival. The ELEMENT-MDS trial is currently evaluating this concept by comparing luspatercept with an ESA in the treatment of anemia in adults with ESA-naive, non–transfusion-dependent, very low- to intermediate-risk MDS.