Navigating the dynamic landscape of lower-risk MDS: Advances and emerging insights

Myelodysplastic syndromes/neoplasms (MDS) are a group of clonal myeloid malignancies characterized by ineffective hematopoiesis, cytopenias, and an increased risk of transformation to acute myeloid leukemia (AML). In lower-risk (LR) MDS, as defined by the revised and molecular international prognostic scoring systems (IPSS-R and IPSS-M), anemia is often the predominant clinical manifestation. Treatment strategies have traditionally focused on supportive care, including transfusion support and erythropoiesis stimulating agents (ESAs). While allogeneic hematopoietic stem cell transplantation remains the only potentially curative option for select patients, LR-MDS remain otherwise incurable with current therapies. With the exception of lenalidomide which was approved in 2005 in USA, therapeutic advancements in LR-MDS have stalled for almost 15 years. Progress has been limited by the disease's inherent complexity, indolent nature, and significant heterogeneity, as well as challenges in clinical trial design and execution. Recent advances in gene sequencing and molecular analyses have significantly increased our understanding of disease biology. These insights, coupled with collaborative efforts across the academic community, have led to meaningful shifts in classification, prognostication, and response assessment paradigms in LR-MDS. This evolution has led to a number of approvals, including luspatercept approved in 2020, and imetelstat, which was approved in 2024 in USA. As the therapeutic landscape of LR-MDS continues to evolve, there is growing optimism that these recent milestones will pave the way for further advancements and improved patient outcomes. Next set of studies should focus on the optimal sequencing and combinations of existing agents, as well as moving forward novel effective agents.