Evolving Approaches: Low-Risk MDS / MDS 08/01/2026

Ep. 2: Imetelstat, Luspatercept, and ESAs: Treatment Sequencing in Lower-Risk MDS

Professional woman with blonde hair wearing a black pinstripe blazer, smiling confidently with arms crossed in a modern office setting. Hetty Carraway, MD Smiling man with beard wearing a white shirt, professional headshot, suitable for oncology or cancer research content, emphasizing healthcare and medical expertise. Rahul Gosain, MD, MBA Close-up portrait of a woman wearing a purple and pink patterned hijab, looking confidently at the camera with a neutral background. Yasmin Abaza, MD Professional portrait of a smiling man in a suit and blue shirt against a gray background, suitable for medical or healthcare-related content. Thomas LeBlanc, MD, MA Portrait of a male doctor in a white lab coat at Yale Cancer Center, smiling confidently, with a neutral background. Amer Zeidan, MBBS, MD

Key Points

  • Treatment selection in lower-risk myelodysplastic syndromes (MDS) requires consideration of serum erythropoietin (EPO) levels, transfusion burden, ring sideroblast status, SF3B1 mutation status, and prior response to therapy.
  • The phase 3 IMerge trial demonstrated improved transfusion independence with imetelstat compared with placebo in patients with lower-risk MDS who were erythropoiesis-stimulating agent (ESA)–refractory, ESA-intolerant, or unlikely to respond.
  • Experts emphasize individualized sequencing of luspatercept and imetelstat, with close monitoring required for imetelstat-associated cytopenias and other toxicities.

In a Clinical Insights discussion, Rahul Gosain, MD, MBA, Wilmot Cancer Institute, and Hetty Carraway, MD, of Cleveland Clinic, were joined by Yasmin Abaza, MD, of Northwestern Medicine; Thomas LeBlanc, MD, MA, of Duke Cancer Center; and Amer Zeidan, MBBS, MD, of Yale School of Medicine, to discuss evolving treatment strategies for patients with lower-risk MDS. The panel reviewed how clinical factors, including EPO levels, transfusion burden, and molecular characteristics, influence treatment selection and sequencing with ESAs, luspatercept, and imetelstat.

Dr. LeBlanc highlighted the importance of identifying patients who are unlikely to benefit from continued ESA therapy. Although ESAs remain an established treatment option for anemia associated with lower-risk MDS, patients who do not respond after approximately 6 to 8 weeks at an appropriate dose should generally transition to alternative therapies. 

When considering frontline therapy, EPO levels, ring sideroblast status, and SF3B1 mutation status can help predict response, Dr. LeBlanc noted. Although some clinicians may favor ESA therapy for patients with lower EPO levels, he prefers frontline luspatercept in select patients, particularly given the potential for durable responses and improved transfusion independence.

The panel also reviewed IMerge trial data that supported the FDA approval of imetelstat in June 2024 for adults with lower-risk MDS with transfusion-dependent anemia. Dr. Carraway explained that the randomized, double-blind, phase 3 trial enrolled patients with International Prognostic Scoring System (IPSS) low- or intermediate-1 risk disease who required significant transfusion support and had either ESA failure or intolerance or elevated EPO levels. In the study, 40% of patients receiving imetelstat achieved at least 8 weeks of transfusion independence within the first 6 months, compared with 15% of those receiving placebo. These results demonstrated imetelstat’s ability to provide meaningful clinical benefit in a patient population with historically limited treatment options.

Drs. Zeidan and Abaza then described how they incorporate imetelstat into treatment sequencing in clinical practice. Both emphasized that patient selection remains critical, with factors such as baseline EPO level, transfusion burden, and prior luspatercept exposure guiding decisions. Dr. Zeidan generally favors luspatercept as an initial therapy, reserving imetelstat for patients with higher EPO levels, ESA resistance, or prior treatment failure. Dr. Abaza noted that patients with serum EPO levels above 500 mU/mL and significant transfusion requirements may be appropriate candidates for frontline imetelstat, while those with lower EPO levels may benefit from luspatercept. 

The panel also emphasized that due to thrombocytopenia and neutropenia risks, imetelstat requires careful monitoring, including dose modifications, treatment delays, transfusion support, and infection management.