Erythropoiesis-stimulating agents (ESAs) have historically been the primary treatment option for patients with lower-risk myelodysplastic syndromes (MDS). However, as we understand more about the complexity of MDS, we are moving toward personalized treatment based on disease characteristics.

To determine risk in MDS, we use calculators such as the Molecular International Prognostic Scoring System (IPSS-M), which uses genomic profiling, cytogenetic abnormalities, and hematologic parameters. Two other classifications (ie, the World Health Organization Classification of Haematolymphoid Tumours and the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias) now recognize molecularly distinct groups of patients with del(5q) and mutations in SF3B1 and TP53. We hope to personalize treatment based on these molecular features because ineffective erythropoiesis is different among the various subgroups of patients.

Anemia remains the hallmark of lower-risk MDS, occurring in 90% of patients, and it is associated with eventual transfusion dependence in up to 50%. A subset of patients have thrombocytopenia or neutropenia, either in isolation or in conjunction with anemia. So, the main goal for patients with lower-risk MDS is to alleviate these cytopenias and their complications.

For those with del(5q), lenalidomide is my first choice for treatment. Historically, lenalidomide was approved by the US Food and Drug Administration (FDA) for del(5q) transfusion-dependent patients, but it is moving to earlier in the treatment algorithm based on the Sintra-REV study. This study randomized transfusion-independent patients with anemia and del(5q) to lenalidomide 5 mg per day or placebo for 2 years. Researchers showed that the time to transfusion dependency was 66.3 months for the lenalidomide-treated patients compared with 11.6 months for the placebo-treated patients. So, if I have a patient with del(5q), I am thinking of lenalidomide, and I am thinking of it earlier.

Patients with ring sideroblast or SF3B1 MDS have disease that is characterized by ineffective erythropoiesis and anemia. Nowadays, I think that luspatercept could be the first line of therapy for such patients based on the results of the COMMANDS trial. This study randomized transfusion-dependent patients to luspatercept or ESAs. Those who were ring sideroblast positive experienced a doubling of the response rate. We are now conducting a study of lower-risk patients to determine whether there are benefits to treatment prior to patients becoming transfusion dependent.

For the remaining patients, if someone has non-del(5q), lower-risk MDS with low blasts and without ring sideroblasts, I look at their endogenous erythropoietin (EPO) level. If their EPO level is high, then they are unlikely to respond to ESAs. Based on the COMMANDS study, luspatercept is a first-line option, and we will hopefully have imetelstat for patients with isolated anemia in the near future. In younger patients with low platelet or low neutrophil counts, we sometimes use immunosuppressive therapy, while, in older patients, we could use hypomethylating agents, which are available in oral formulations.

It is an exciting time for those of us who work in the MDS field. After a drought of more than a decade of not having new drugs for our patients with MDS, we finally have a few promising options that we hope will help more people.