Luspatercept Misses Primary End Point, Shows Clinically Meaningful Secondary Benefits

The phase 3 INDEPENDENCE trial (NCT04717414) evaluating luspatercept-aamt (Reblozyl) in adult patients with myelofibrosis-associated anemia receiving red blood cell (RBC) transfusions did not achieve its primary endpoint of RBC transfusion independence (TI) during any consecutive 12-week period within the first 24 weeks of treatment.¹

Despite not reaching statistical significance for the primary endpoint (P =.0674), there was a numerical and clinically meaningful improvement in RBC TI consistent with prior phase 2 trial (NCT03194542)findings. Furthermore, several important secondary measures showed significant clinical benefits favoring luspatercept, including a higher proportion of patients achieving at least a 50% reduction in RBC transfusion burden (by at least 4 RBC units) and an increase in hemoglobin levels by at least 1 g/dL while maintaining TI for at least 12 consecutive weeks.

“Anemia remains a significant challenge in the treatment of myelofibrosis, with many patients still dependent on red blood cell transfusions or suboptimal treatment approaches that can sometimes worsen anemia associated with the disease,” said John Mascarenhas, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai and director of the Center of Excellence for Blood Cancers and Myeloid Disorders at The Tisch Cancer Institute, in a press release. “Patients with myelofibrosis and anemia are difficult to treat, and these results show that [luspatercept] can have an important impact on anemia associated with the disease.”

Myelofibrosis is a rare chronic myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, leading to impaired hematopoiesis and often severe anemia requiring regular RBC transfusions. This anemia significantly impacts patient quality of life and is associated with reduced overall survival. Current management strategies for myelofibrosis-associated anemia include RBC transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory drugs. While JAK inhibitors are standard for managing splenomegaly and constitutional symptoms in myelofibrosis, some can exacerbate anemia, highlighting a persistent unmet need for effective anemia-targeting therapies in this patient population, especially those on concomitant JAK inhibitor therapy.

Luspatercept is a first-in-class erythroid maturation agent that works by binding to several endogenous TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling. This mechanism promotes late-stage RBC maturation, addressing ineffective erythropoiesis that contributes to anemia in conditions like myelofibrosis. The drug is already indicated in the US for anemia associated with beta thalassemia requiring regular RBC transfusions and for certain adult patients with myelodysplastic syndromes who require RBC transfusions, including ESA-naive patients and those with ring sideroblasts failing ESAs.

The INDEPENDENCE trial is a phase 3, double-blind, randomized study comparing the efficacy and safety of luspatercept vs placebo in patients with myelofibrosis who were on concomitant JAK2 inhibitor therapy and required RBC transfusions. The primary outcome was the proportion of patients achieving RBC-TI over any consecutive 12-week period within the first 24 weeks. Key secondary end points included RBC-TI over any consecutive 16-week period within the first 24 weeks, an increase in hemoglobin levels, and at least a 50% reduction in RBC transfusion burden.

Despite not meeting the primary endpoint of 12-week RBC-TI within 24 weeks, the observed numerical and clinically meaningful improvements in RBC TI, transfusion burden reduction, and hemoglobin increases underscore the potential of luspatercept to address a significant clinical challenge. The safety profile observed in the trial was consistent with the known safety profile of luspatercept across its currently approved indications. Commonly observed treatment-emergent adverse events were in line with previous reports.

In August 2023, the FDA approved luspatercept for the treatment of anemia without previous ESA use in adult patients with very low- to intermediate-risk myelodysplastic syndromes who may require regular RBC transfusions, expanding the approval of luspatercept to earlier lines.²

REFERENCES:

1. Bristol Myers Squibb announces topline results from phase 3 INDEPENDENCE trial for Reblozyl® (luspatercept-aamt) in adult patients with myelofibrosis-associated anemia. News release. Bristol Myers Squibb. July 18, 2025. Accessed July 21, 2025. https://tinyurl.com/98eanj7a

2. U.S. FDA approves Bristol Myers Squibb’s Reblozyl® (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed July 21, 2025. https://tinyurl.com/mux7w47t