Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients (pts) with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSP

6512 Background: In the phase 3 COMMANDS trial (NCT03682536), LUSPA was superior in improving red blood cell (RBC)-TI ≥12 wks with concurrent hemoglobin increase ≥1.5 g/dL in Wks 1 to 24 vs EA and had durable clinical benefit in pts with ESA-naive transfusion-dependent (TD) lower-risk MDS (LR-MDS; Della Porta MG, et al. Lancet Haematol . 2024; Garcia-Manero G, et al. ASH. 2024). Here, we report updated results including OS and duration of response. Methods: Eligible pts (≥18 yrs; ESA-naive; RBC TD; very low/low/intermediate-risk MDS) were randomized 1:1 (stratified by baseline [BL] RBC transfusion burden [TB], serum erythropoietin [EPO] level, and ring sideroblast [RS] status) to receive LUSPA (1.0-1.75 mg/kg) SC Q3W or EA (450-1050 IU/kg; max dose 80,000 IU) SC QW for ≥24 wks. Secondary endpoints included OS, duration of RBC-TI ≥12 wks, and safety. Results: As of Nov 4, 2024, median follow up (FU) was 29.0 and 27.1 mos for the LUSPA (n=182) and EA (n=181) groups, respectively. Median OS for LUSPA was not reached (NR) and was 46.7 mos for EA (HR, 0.86; 95% CI, 0.60-1.24); 3-yr OS rates were 63.8% and 62.2%, respectively, and 5-yr OS rates were 54.0% and 41.8%. In subgroups, similar OS trends were observed (Table). Overall, RBC-TI ≥12 wks (Wk 1 to end of treatment [EOT]) was reached by 76.4% (139/182) of pts in the LUSPA group and 55.8% (101/181) in the EA group. Median cumulative duration (95% CI) of RBC-TI ≥12 wks (sum of all durations of RBC-TI ≥12 wks episodes from Wk 1 to EOT) was 187.3 (119.6-NE) wks for LUSPA vs 94.9 (73.1-179.0) wks for EA (HR, 0.51; 95% CI, 0.34-0.77). Median duration (95% CI) of longest RBC-TI ≥12 wks period (from Wk 1 to EOT) was 126.6 (81.0-184.4) vs 86.7 (55.9-111.1) wks (HR, 0.64; 95% CI, 0.44-0.93). At cutoff, 24.7% of LUSPA pts and 11.2% of EA pts were on treatment; 84.6% and 82.7%, respectively, had ≥1 dose escalation. With longer FU, no new safety concerns emerged. Deaths occurred in both groups on- (10.4% vs 9.5%) and post-treatment (20.9% vs 26.3%). Progression to acute myeloid leukemia was comparable between groups (3.8% vs 4.4%). Conclusions: LUSPA led to improvements in response rate and duration, with a positive OS trend requiring further evaluation through more extended follow up. LUSPA signifies a new standard of care for anemia in first-line LR-MDS. Clinical trial information: NCT03682536 . Median OS, mos LUSPA EA HR (95% CI) Overall (ITT) (n=182)NR (n=181)46.7 0.86 (0.60-1.24) Stratification subgroup BL TB <4 U (n=118)NR (n=111)46.7 0.87(0.55-1.38) BL TB ≥4 U (n=64)NR (n=70)48.2 0.74(0.42-1.31) RS+ (n=133)NR (n=130)48.2 0.77(0.50-1.19) RS− (n=49)NR (n=50)46.2 0.93(0.50-1.75) BL EPO ≤200 U/L (n=145)NR (n=144)51.4 0.84(0.55-1.27) BL EPO >200 U/L (n=37)NR (n=37)35.4 0.81(0.40-1.64) ITT, intention-to-treat; U, units.