Optimizing Frontline LR-MDS Treatment: EHA 2026 Data Review

Lower-risk myelodysplastic syndromes (LR-MDS) are characterized by ineffective haematopoiesis, leading to cytopenias, most commonly anaemia. The primary goals of treatment in LR-MDS are to improve quality of life, reduce transfusion dependence, and delay progression to higher-risk MDS or acute myeloid leukaemia (AML).¹ Current guidelines recommend risk stratification using tools such as the Revised International Prognostic Scoring System (IPSS-R) to guide therapeutic decisions.² Patients classified as lower-risk (Very Low, Low, or Intermediate IPSS-R scores) often experience significant morbidity due to anaemia, necessitating regular red blood cell transfusions.³ Transfusion dependence is associated with iron overload, increased infection risk, and reduced overall survival.⁴ Therefore, effective frontline therapies that achieve sustained erythroid response and transfusion independence are critical.

Evaluating Frontline Therapeutic Strategies

A comprehensive review of data presented at EHA 2026 focused on the efficacy and safety of various frontline treatment options for LR-MDS patients. The analysis included studies evaluating erythropoiesis-stimulating agents (ESAs), lenalidomide, and luspatercept, among others. Patient cohorts typically included transfusion-dependent individuals with LR-MDS, often defined by a requirement of at least 2 units of red blood cells over 8 weeks.⁵ Key endpoints assessed were erythroid response (ER), defined as a haemoglobin increase of at least 1.5 g/dL or reduction in transfusion burden, and transfusion independence (TI), defined as no red blood cell transfusions for a specified period, typically 8 or 12 weeks.⁶

For patients with LR-MDS and serum erythropoietin (EPO) levels below 500 U/L, ESAs remain a standard initial approach. Studies consistently show that ESAs can achieve an erythroid response in approximately 40-50% of patients and transfusion independence in 20-30%.⁷ The duration of response, however, can be variable, with many patients eventually becoming refractory.⁸

Lenalidomide has demonstrated particular efficacy in LR-MDS patients with isolated del(5q) cytogenetic abnormality. In this specific subgroup, lenalidomide can achieve transfusion independence rates of 50-60%, with a median duration of response often exceeding 2 years.⁹ For LR-MDS patients without del(5q), lenalidomide's efficacy is lower, with TI rates around 20-30%.¹⁰

Luspatercept, a recombinant fusion protein that modulates TGF-β signalling, has emerged as an important option, particularly for patients with ring sideroblasts (RS) and SF3B1 mutations. Data presented at EHA 2026 reinforced its role, showing that in transfusion-dependent LR-MDS patients with RS, luspatercept achieved transfusion independence for at least 8 weeks in 38% of patients and for at least 12 weeks in 28%.¹¹ The median duration of TI was approximately 30 weeks.¹¹ These responses were observed regardless of prior ESA failure, positioning luspatercept as a viable option after ESA failure or as a frontline alternative in specific contexts.¹²

The safety profiles of these agents were also reviewed. ESAs are generally well-tolerated, with common adverse events including hypertension and thrombotic events, though these are infrequent.¹³ Lenalidomide is associated with myelosuppression (neutropenia and thrombocytopenia), fatigue, and rash.¹⁴ Luspatercept's most common adverse events include fatigue, nausea, and musculoskeletal pain, generally mild to moderate in severity.¹⁵

The data underscore the importance of patient stratification based on prognostic markers, including cytogenetics and molecular mutations such as SF3B1. For instance, the presence of an SF3B1 mutation strongly predicts response to luspatercept.¹⁶ Conversely, patients with very low serum EPO levels and no SF3B1 mutation may still benefit from ESAs.¹⁷ The choice of frontline therapy must therefore be individualized, considering the patient's specific disease characteristics, transfusion burden, and comorbidities. The goal is to achieve early and durable transfusion independence to mitigate the complications associated with chronic transfusions and improve patient quality of life.¹⁸