Luspatercept Plus Concomitant JAK Inhibitor Therapy Misses Primary End Point in Myelofibrosis-Associated Anemia

The phase 3 INDEPENDENCE trial (NCT04717414) examining luspatercept-aamt (Reblozyl) with concomitant JAK inhibitor therapy for the treatment of adult patients with myelofibrosis-associated anemia receiving red blood cell (RBC) transfusions did not meet its primary end point of RBC transfusion independence during any consecutive 12-week period, according to topline data from the study.¹

Patients who received luspatercept did not achieve RBC transfusion independence during any consecutive 12-week period at a significantly higher rate compared with those who received placebo (P = .0674). However, patients in the luspatercept arm experienced a numerical and clinically meaningful improvement in RBC transfusion independence vs the placebo arm which was in line from prior data from a phase 2 study (NCT03194542). Bristol Myers Squibb plans to engage with the FDA and the European Medicines Agency to discuss the submission of marketing applications, according to a news release.

“It is promising to see that luspatercept led to clinically relevant improvement of anemia for patients with myelofibrosis, where patients often become increasingly transfusion dependent over time,” Anne Kerber, MD, senior vice president and head of development, Hematology, Oncology, and Cell Therapy at Bristol Myers Squibb, stated in the news release. “We remain confident in the ability of luspatercept to improve outcomes for patients with myelofibrosis-associated anemia and believe the totality of these results, including meaningful improvements in transfusion burden and hemoglobin levels, support the potential to address an unmet need in patients who have few treatment options.”

INDEPENDENCE was a double-blind, randomized study that enrolled patients with myeloproliferative neoplasm–associated myelofibrosis and anemia who were receiving a concomitant JAK2 inhibitor and required RBC transfusions with an ECOG performance status of 2 or less.² Patients needed to be at least 18 years of age and be receiving 4 to 12 RBC units every 12 weeks immediately up to random assignment without an interval above 6 weeks without at least 1 RBC transfusion. Eligible patients also needed to receive continuous JAK2 inhibitor therapy without dose interruptions lasting at least 2 consecutive weeks as part of standard-of-care therapy for at least 32 weeks, have received a stable dose for at least 16 weeks immediately up to random assignment, and be anticipated to receive a stable daily dose of the agent for at least 24 weeks following random assignment.

Patients were randomly assigned 2:1 to receive subcutaneous luspatercept at a starting dose of 1.33 mg/kg with titration up to 1.75 mg/kg or placebo every 3 weeks.³ Best supportive care was permitted. The treatment phase included a 24-week core period with a disease response assessment at day 169. Patients with a clinical benefit were permitted to continue with luspatercept treatment until a loss of benefit, disease progression, unacceptable toxicity, or withdrawal. Those in the placebo arm without a clinical benefit at day 169 were permitted to cross over to receive open-label luspatercept.

The primary end point was RBC transfusion independence over any consecutive 12-week period starting within the first 24 weeks.² Secondary end points included RBC transfusion independence over any consecutive 16-week period, duration of RBC transfusion independence, reduction of transfusion burden of at least 50% and by at least 4 units per 12 weeks from baseline over any consecutive 12-week period, duration of reduction in transfusion burden, RBC transfusion independence of at least 12 weeks and 16 weeks during the treatment period, change in RBC transfusion burden, cumulative duration of RBC transfusion independence, mean hemoglobin increase of at least 1 g/dL from baseline over any consecutive 12-week period without RBC transfusions, and safety.

Although the study did not meet its primary end point, patients in the luspatercept arm achieved a clinically meaningful benefit in several secondary end points vs those in the placebo arm.¹ A higher number of patients experienced a minimum of a 50% reduction in RBC transfusion burden. A higher number of patients in the investigational arm also achieved an increase in hemoglobin levels by at least 1 g/dL and remained transfusion independent for at least 12 consecutive weeks compared with those in the control arm.

In terms of safety, frequently observed treatment-emergent adverse effects were consistent with the known safety profile of luspatercept.

“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,” 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, both in New York, New York, added in the news 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.”

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 18, 2025. https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Announces-Topline-Results-from-Phase-3-INDEPENDENCE-Trial-for-Reblozyl-luspatercept-aamt-in-Adult-Patients-with-Myelofibrosis-Associated-Anemia/default.aspx
2. An efficacy and safety study of luspatercept (ACE-536) versus placebo in subjects with myeloproliferative neoplasm-associated myelofibrosis on concomitant JAK2 inhibitor therapy and who require red blood cell transfusions (INDEPENDENCE). ClinicalTrials.gov. Updated July 10, 2025. Accessed July 18, 2025. https://clinicaltrials.gov/study/NCT04717414
3. Kiladjian JJ, Harrison C, Mesa RA, et al. MPN-346 INDEPENDENCE: enrolling phase III trial to study the efficacy and safety of luspatercept versus placebo in patients with myelofibrosis on JAK2 inhibitor (JAK2i) therapy requiring red blood cell transfusions (RBCTs). Clin Lymphoma Myeloma Leuk. 2023;23(suppl 1):S390. doi:10.1016/S2152-2650(23)01234-X