Background: Anemia is a prevalent and prognostically adverse complication in myelofibrosis (MF). Although preliminary studies suggest that luspatercept may ameliorate MF-related anemia, robust clinical data remain scarce, and predictive biomarkers are undefined. This study aimed to evaluate the early efficacy and safety of luspatercept in MF-associated anemia while exploring potential biomarkers of treatment response.

Methods: This open-label prospective clinical trial enrolled adult patients (≥18 years) diagnosed with primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF), or post-polycythemia vera myelofibrosis (post-PV MF). Eligible participants met the following criteria: transfusion dependence defined as requiring <12 units of red blood cells within 12 weeks prior to enrollment, persistent pre-transfusion hemoglobin levels ≤8 g/dL following at least one prior anemia-directed therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Key exclusion criteria comprised severe hepatic or renal impairment, platelet counts below 50×10⁹/L, and cases where anemia was clearly attributable to alternative etiologies unrelated to myelofibrosis pathology or its treatment. All enrolled subjects received subcutaneous administration of luspatercept at a dose of 1.33 mg/kg every three weeks. The primary evaluation period encompassed two complete treatment cycles (equivalent to two administered doses), during which comprehensive efficacy and safety assessments were performed according to the predefined study protocol.

Results: Between November 2023 and July 2025, 19 patients were enrolled in the study, with one patient lost to follow-up after the first dose and excluded from efficacy analysis. Using a response threshold of ≥1.0 g/dL hemoglobin (Hb) increase at six weeks, 12 patients (63%) achieved this endpoint, including 9 patients (47%) who demonstrated a more robust response (>2.0 g/dL increase). The mean Hb elevation was 2.05 g/dL (31% increase from baseline 6.73 g/dL). Notably, among 7 patients with baseline erythropoietin (EPO) levels >500 IU/mL, 6 responded to treatment, while the single non-responder eventually showed significant Hb improvement after nine weeks of continued therapy. In the 11 patients who extended treatment beyond six weeks (median duration: 26 weeks), 7 patients (64%) achieved >2.0 g/dL Hb increases.

Comprehensive biomarker analysis was performed in 12 patients, evaluating serum ferritin, fetal hemoglobin (HbF), reticulocytes, multiple interleukins (IL-2, -4, -6, -10, -17), interferon-γ, tumor necrosis factor-α, and key regulators of erythropoiesis (GDF8, GDF11, TWSG1, BMP2, ERFE, hepcidin). While most biomarkers showed no significant treatment-related changes or predictive value, GDF8 demonstrated a consistent upward trend post-treatment. Interestingly, GDF11 dynamics showed potential clinical relevance: both patients with post-treatment GDF11 decreases were non-responders, whereas 4 of 5 patients with GDF11 increases responded, along with all 3 patients showing stable levels.

The safety profile remained favorable throughout the study. Most adverse events occurred within the initial six weeks and were transient, primarily consisting of anemia-related symptoms (fatigue, asthenia) and decreased appetite. Three notable exceptions included: (1) mild creatinine elevation after 30 weeks in one patient; (2) asymptomatic thrombocytopenia (80×10⁹/L) after 52 weeks in another patient; and (3) manageable hypertension exacerbation in a predisposed patient that resolved with medication adjustment.

Conclusion: Luspatercept (1.33 mg/kg Q3W) effectively improves hemoglobin levels in myelofibrosis-associated anemia with a favorable safety profile, showing particular efficacy in patients with elevated baseline EPO (>500 IU/mL). These findings support its potential as a treatment option for MF-related anemia.

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2025
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