Dr Harrison on Implications of the INDEPENDENCE Data for Luspatercept in Myelofibrosis-Associated Anemia

The data suggest that luspatercept can give a benefit to these patients [with myelofibrosis-associated anemia], but there is still a way to go.

Claire Harrison, MD, a professor of myeloproliferative neoplasms and clinical director at Guy’s and St Thomas’ NHS Foundation Trust, reviewed findings from the phase 3 INDEPENDENCE trial (NCT04717414) evaluating luspatercept-aamt (Reblozyl) for the treatment of transfusion-dependent anemia in patients with myelofibrosis receiving stable JAK inhibitor therapy.

When recapping the data presented at the 2026 EHA Congress, Harrison emphasized both the complexities of anemia trial design and the clinically meaningful benefits observed with luspatercept, despite the study narrowly missing its primary statistical end point. Findings showed that 23.1% of patients treated with luspatercept (n = 208) achieved red blood cell transfusion independence (RBC-TI) for at least 12 consecutive weeks during the first 24 weeks of treatment compared with vs 13.3% of those given placebo (n = 105; risk difference, 9.74%; 95% CI, −0.27% to 18.17%; P = .0674). Notably, in a post hoc assessment, a patient in the placebo arm previously classified as an RBC-TI responder was reclassified as a non-responder after investigators determined the observed transfusion independence reflected a regional blood shortage rather than an effect of treatment. The updated rates of RBC-TI for at least 12 in the first 24 weeks were 23.1% in the luspatercept arm vs 12.4% for the placebo arm (nominal P = .0398).

Harrison noted that the trial enrolled a heavily transfusion-dependent population requiring 4 to 12 units of RBCs during the 12 weeks before enrollment. Patients had also been receiving JAK inhibitor therapy for at least 32 weeks and maintained a stable dose for at least 16 weeks, representing a population with significant unmet need.

Harrison also explained that the primary end point result was heavily influenced by unexpectedly high placebo response rates in the Asia-Pacific region, particularly for patients from mainland China, where restrictive transfusion practices and regional blood shortages may have contributed to prolonged periods without transfusions, despite the absence of active therapy.

Beyond the primary end point, Harrison emphasized that additional anemia outcomes provide important clinical context for the use of luspatercept, with 40.9% of patients in the luspatercept arm experiencing at least a 50% reduction in transfusion burden with at least 4 RBC units from baseline over any consecutive 12-week period vs 22.9% of patients in the placebo arm (risk difference, 17.3%; 95% CI, 6.9%-27.7%).

Overall, Harrison concluded that the findings support luspatercept as a beneficial treatment option for myelofibrosis-associated anemia, underscoring the challenges of evaluating transfusion-based end points in global clinical trials and the need for additional work to better define the role of luspatercept for this patient population.