Anemia is common in patients with lower-risk myelodysplastic syndromes (MDS). Novel therapies for anemia in lower-risk MDS, such as luspatercept, are now available, but many treatment challenges remain. There is an interest in developing disease-modifying agents that can improve long-term clinical outcomes.

For a long time, the treatment of lower-risk MDS consisted of the use of growth factors with little effort to develop therapies that focused on these patients. More recently, there have been exciting developments in the treatment of lower-risk MDS, and there has been a concerted effort to change how we treat these patients. We currently have a few lines of therapy available that can produce 1 to 2 years of benefit, which is an amazing advance, but there continues to be a need for the following: (1) to understand how to sequence patients with available therapies; (2) to develop additional lines of therapy for treatments down the road; and (3) to develop agents that are disease modifying.

The results of the MEDALIST and the COMMANDS trials evaluating luspatercept as second- and first-line therapy, respectively, have changed our treatment practices. One goal of therapy is to keep patients free of my clinic for as long as possible, but we recognize that, at some point, anemia becomes a limiting factor for most patients. MEDALIST showed that, although luspatercept is a really good second-line option, it works best before patients become heavily transfusion dependent. This means that you need to switch patients from erythropoiesis-stimulating agents (ESAs) before they have a high transfusion requirement.

I struggle with the care of patients who are just beginning to have symptomatic anemia and are starting to require transfusions. Should I give them a trial of ESA therapy or just skip right to luspatercept? The way that I coalesce the data from MEDALIST and COMMANDS is probably by starting ESA therapy (usually darbepoetin alfa) early, but then moving to luspatercept quickly while the patient still has a low transfusion burden if they do not respond. So, I think that integrating what was learned from the 2 trials is the direction I am going. Part of that hedge is because I do not know how ESAs work after luspatercept.

Most of the agents that we have will treat the anemia, but developing disease-modifying agents has been more daunting. Our existing disease-modifying therapies are chemotherapy and transplant, and they have toxicity profiles that are not palatable to patients who have a type of blood cancer that they will live with for many years. Increasingly, we are looking at metrics that might be biomarkers or surrogates for disease modification, such as changes in clonal composition or the eradication of particularly high-risk subclones. For example, in patients with del(5q) MDS, lenalidomide has been associated with reductions in clone size and cytogenetic remissions.

There are also data with the new investigational drug imetelstat, which is a telomerase inhibitor. An analysis of the IMerge study presented at the 2023 American Society of Clinical Oncology Annual Meeting found that imetelstat was associated with significantly greater variant allele frequency reduction in 3 of 4 genes that are frequently mutated in MDS compared with placebo. This suggests that the agent may have disease-modifying potential. Such activity can change the risk/benefit considerations for lower-risk patients regarding the use of a drug that can cause cytopenias such as neutropenia and thrombocytopenia in a small percentage of individuals.

The use of such therapies would be even more palatable if they can be shown not only to reduce the clone and allow healthy cells to reconstitute the marrow but also to have a long-term clinical benefit, such as breaks in therapy with healthy hematopoiesis in the bone marrow, delayed progression to leukemia, or longer survival. This would be a whole different way of looking at lower-risk disease: a less toxic approach than transplant and a potentially less toxic approach than chemotherapy as a way to influence or nudge the disease trajectory in patients who are not yet at high risk.