Introduction: Anemia and RBCT dependency are strong predictors of adverse clinical outcomes in pts with MF. Despite JAKi therapy, pts with MF develop anemia requiring RBCT. LUSPA is a first-in-class erythroid maturation agent that demonstrated improvements in hemoglobin (Hb) levels, RBCT burden, and transfusion dependency, in pts with MF-associated anemia, in a phase (ph) 2 trial (NCT03194542). We report the primary analysis of the ph 3 INDEPENDENCE trial (NCT04717414), evaluating the efficacy and safety of LUSPA versus PBO in pts with MF-associated anemia receiving concomitant JAKi therapy and dependent on RBCT.

Methods: In this ph 3, double-blind, randomized trial, pts (≥18 years) with intermediate- to high-risk MF requiring 4–12 RBC units/12 weeks (wks), who had received ≥32 wks of concomitant JAK2i therapy at a stable dose for ≥16 wks were randomized (2:1) to subcutaneous LUSPA (starting at 1.33 mg/kg; titration up to 1.75 mg/kg) or PBO, every 3 wks. Primary endpoint was the proportion of pts who achieved RBC-transfusion independence (TI) over any consecutive ≥12-wk period starting within the first 24 wks (RBC-TI 12). Key secondary endpoint was the proportion of pts who became RBC-TI over any consecutive ≥16-wk period starting within the first 24 wks (RBC-TI 16). Other secondary endpoints included the proportion of pts achieving RBC-TI 12 combined with a mean Hb increase ≥1 g/dL from baseline, ≥50% reduction in RBCT burden from baseline and by ≥4 RBC units/12 wks, and safety.

Results: As of 26 May 2025, 313 pts (North America n=17 [5.4%], Europe/Middle East/Latin America, n=191 [61.0%], and Asia-Pacific n=105 [33.5%]) were randomly assigned to LUSPA (n=208) or PBO (n=105). Baseline characteristics were generally well balanced between tx arms. Median (range) age was 73.0 years (43.0, 92.0) and 60.1% were male. Median (range) at baseline for Hb levels was 7.6 (3.3, 10.0), RBCT burden was 7.0 (3.0, 16.0) units/12 wks, and time since first RBCT for MF was 76.6 wks (3.6, 1347.5). Most pts had an intermediate-2 Dynamic International Prognostic Scoring System score (79.2%). Median (range) time since MF diagnosis was 4.0 yrs (−0.01, 36.5) and median (range) time from start of first JAKi to start of tx was 96.7 wks (19.0, 527.0). Mean (SD) duration of tx was 47.3 wks (45.9) with LUSPA and 37.1 wks (34.7) with PBO.

A higher proportion of patients who received LUSPA versus PBO became RBC-TI 12 (23.1% vs 13.3%; common risk difference [CRD] 8.27%, 95% CI −0.04, 16.57, P=0.0674). Numerically more pts in the LUSPA group (19.2%) achieved RBC-TI 16 versus PBO (11.4%; CRD 6.51% [95% CI −1.26, 14.28]). RBC-TI 12 combined with a mean Hb increase ≥1 g/dL from baseline was achieved by 15.9% of pts in the LUSPA group versus 5.7% of pts in the PBO group (CRD: 9.3%, 95% CI 2.7, 15.8). A higher proportion of pts treated with LUSPA achieved ≥50% reduction in RBCT burden from baseline and by ≥4 units/12 wks versus PBO (40.9% vs 24.8%; CRD 15.4%, 95% CI 4.8, 25.9). LUSPA demonstrated a consistent benefit of achieving RBC-TI 12 response versus PBO across most subgroups. However, regional differences in baseline characteristics and responses were observed.

In the safety population, tx-emergent adverse events (TEAEs) occurred in 96.1% of pts (exposure-adjusted incidence rate per 100 pt-years [EAIR/100 PY] 747.6) with LUSPA and 92.4% (EAIR/100 PY 574.8) with PBO. Serious TEAEs occurred in 44.0% with LUSPA and 38.1% with PBO. After adjustment for exposure, serious TEAE incidence rates were not significantly different in LUSPA versus PBO arms; EAIR/100 PY were 64.3 and 62.4, respectively.

Conclusions: Among pts with advanced MF-associated anemia, LUSPA demonstrated numerical and clinically meaningful benefits in RBC-TI, transfusion burden, and Hb levels compared to PBO, consistent with the ph 2 results (ACE-536-MF-001; NCT03194542). Frequently observed TEAEs were generally consistent with the known safety profile of LUSPA and prior reports in pts with advanced MF. The primary and key secondary endpoints (RBC-TI 12 and 16) did not achieve statistical significance due to regional differences. Overall, pts treated with LUSPA experienced clinically meaningful benefits with a manageable safety profile, supporting the potential of LUSPA to address an unmet need in pts with advanced MF-associated anemia who require RBCT and are receiving JAKi therapy, who have limited tx options.

This content is only available as a PDF.
2025
Sign in via your Institution