Luspatercept (REBLOZYL) is a first-in-class erythroid maturation agent that promotes late-stage red blood cell maturation and is jointly developed and commercialized by Bristol Myers Squibb and Merck through a global collaboration established following Merck’s acquisition of Acceleron Pharma in 2021. The therapy is currently approved in the United States for the treatment of anemia associated with beta-thalassemia and lower-risk MDS, where it has demonstrated clinically meaningful improvements in transfusion burden and hemoglobin levels. Building on its success in hematologic disorders characterized by ineffective erythropoiesis, the drug is being evaluated in myelofibrosis-associated anemia, an area of significant unmet need where anemia remains a common and debilitating complication despite treatment with JAKi.

In January 2025, Bristol Myers Squibb reported that the Phase III INDEPENDENCE trial of luspatercept in transfusion-dependent myelofibrosis-associated anemia missed its primary endpoint of RBC transfusion independence versus placebo (p=0.0674). However, the study demonstrated clinically meaningful improvements in transfusion independence, transfusion burden, and hemoglobin levels, consistent with prior Phase II findings.

At EHA 2026, primary results from the Phase III INDEPENDENCE trial are as follows:

Key Efficacy Highlights:

• RBC transfusion independence (RBC-TI) ≥12 weeks: Achieved in 23.1% of patients receiving luspatercept vs 13.3% with placebo (p=0.0674)

• Following reassessment, RBC-TI ≥12 weeks within the first 24 weeks was achieved in 23.1% of luspatercept-treated patients vs. 12.4% with placebo (nominal p=0.0398)

• RBC-TI ≥16 consecutive weeks: 19.2% vs. 11.4% (risk difference: 6.5%)

• ≥50% reduction in transfusion burden with ≥4 fewer RBC units: 40.9% vs 22.9% (risk difference: 17.3%)

• Combined RBC-TI ≥12 weeks plus mean hemoglobin (Hb) increase ≥1 g/dL: 15.9% vs 5.7% (risk difference: 9.3%)

• Consistent benefit across key secondary endpoints, including greater reduction in transfusion burden (TB) and higher hemoglobin (Hb) improvement

• Benefits were observed despite a heavily pretreated population, with all patients receiving prior JAKi therapy and 70.6% having a high baseline transfusion burden (≥6 units/12 weeks)

Key Safety Highlights: 

• Any-grade TEAEs: Reported in 96.1% of luspatercept-treated patients vs. 92.4% with placebo

• Serious TEAEs: Occurred in 44.0% vs. 38.1% of patients, respectively.

• After adjusting for treatment exposure, serious TEAE rates were comparable between luspatercept and placebo (64.3 vs. 62.4 events/100 patient-years)

• Overall, luspatercept demonstrated a manageable safety profile with no meaningful increase in exposure-adjusted SAEs compared with placebo

KOL insights

“Anemia remains a significant challenge in the treatment of patients with myelofibrosis, with many patients still dependent on RBC transfusions or suboptimal treatment approaches that can sometimes worsen anemia associated with the disease.” – Expert Opinion

“The Phase III INDEPENDENCE study results support luspatercept as a clinically meaningful option for myelofibrosis-associated anemia, demonstrating improvements in transfusion independence and anemia-related outcomes despite missing the primary endpoint. In a setting with limited effective therapies, these findings reinforce its potential role in addressing a significant unmet need.”– Expert Opinion

Conclusion-

Myelofibrosis-associated anemia remains a major therapeutic challenge, significantly impacting quality of life and clinical outcomes, while effective treatment options remain limited, particularly for patients receiving JAK inhibitor therapy. Luspatercept (REBLOZYL), a first-in-class erythroid maturation agent, represents a novel approach that directly addresses ineffective erythropoiesis and transfusion dependence. In the Phase III INDEPENDENCE trial, luspatercept demonstrated clinically meaningful improvements in transfusion independence, transfusion burden, and hemoglobin levels despite not achieving statistical significance for the primary endpoint. These findings reinforce the therapeutic potential of luspatercept in a setting with substantial unmet need and support its emerging role in the management of myelofibrosis-related anemia. 

Overall, the results strengthen the rationale for incorporating luspatercept into the evolving treatment paradigm for anemia in patients with myelofibrosis.