Luspatercept Generates Across-the-Board Benefit for Lower-Risk MDS in COMMANDS

Amer Zeidan, MBBS

Luspatercept-aamt (Reblozyl) elicited superior erythroid response rates and duration of red blood cell (RBC) transfusion independence across all end points compared with epoetin alfa in patients with lower-risk myelodysplastic syndromes (MDS), according to findings from an analysis of the clinical benefit of the agent from the phase 3 COMMANDS trial (NCT03682536) presented at the 2024 ASCO Annual Meeting.¹

At a data cutoff of September 22, 2023, compared with patients in the epoetin alfa arm, patients in the luspatercept arm achieved a longer median duration of RBC transfusion independence and higher rates of RBC transfusion burden reduction of at least 50%. Additionally, more patients in the luspatercept arm achieved at least 2 separate RBC transfusion independence response episodes lasting at least 12 weeks.

“Overall, luspatercept led to durable and clinically meaningful responses beyond the achievement of the primary end point, supporting its use as the treatment of choice over ESAs in patients with transfusion-dependent lower-risk MDS–associated anemia who are ESA naive,” lead study author Amer Zeidan, MBBS, of Yale School of Medicine and Yale Cancer Center in New Haven, Connecticut, and coauthors, wrote in a poster of the data.

In the COMMANDS trial, 58.5% of patients who received luspatercept (n = 182) achieved the trial’s primary end point of RBC transfusion independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks of treatment.2 This rate was 31.2% among patients who received epoetin alfa (n = 181; P < .0001). Based on these findings, in August 2023, the FDA approved luspatercept for patients with erythropoiesis-stimulating agent (ESA)–naive, transfusion-dependent, lower-risk MDS, regardless of ring sideroblast status.

The open-label, randomized, controlled COMMANDS trial enrolled patients at least 18 years of age with very low–, low-, or intermediate-risk MDS as defined by the Revised International Prognostic Scoring System.² Eligible patients were ESA naive, had less than 5% bone marrow blasts, and had endogenous serum erythropoietin levels of less than 500 U/L. These patients were eligible if they were RBC transfusion dependent, defined as needing 2 to 6 packed RBC units every 8 weeks for at least 8 weeks prior to randomization.¹

Patients were randomly assigned 1:1 to receive either subcutaneous luspatercept at 1.0 mg/kg (titration up to 1.75 mg/kg was allowed) once every 3 weeks or subcutaneous epoetin alfa at 450 IU/kg (titration up to 1050 IU/kg was allowed; the maximum total dose was 80,000 IU) once per week.

The clinical benefit analysis presented at the 2024 ASCO Annual Meeting evaluated the achievement and duration of the primary and key secondary end points over the entire treatment period (week 1 to end of treatment [EOT]) in responders. Beyond the criteria for the primary end point, RBC transfusion independence for at least 12 weeks and at least 24 weeks following treatment initiation were evaluated. Hematologic improvement-erythroid for at least 8 weeks was assessed per International Working Group 2006 criteria. Other secondary end points and assessments included transfusion burden on treatment between weeks 1 and 24; time to RBC transfusion after treatment initiation between week 1 and EOT; the achievement and duration of at least a 50% reduction in RBC units transfused over at least 12 weeks between week 1 and EOT; the achievement and cumulative duration of multiple RBC transfusion independence episodes lasting at least 12 weeks between week 1 and EOT; the achievement of a mean hemoglobin increase of at least 1.5 g/dL between weeks 1 and 24; the mean hemoglobin change over 24 weeks between weeks 1 and 24; and the mean hemoglobin change from baseline over time.

Patients in the luspatercept and epoetin alfa arms had respective median ages of 74.0 years (range, 46.0-93.0) and 74.0 years (range, 31.0-91.0), and respective mean hemoglobin levels of 7.8 g/dL (range, 4.7-9.2) and 7.8 g/dL (range, 4.5-10.2). Both arms had respective median transfusion burdens of 3.0 RBC units per 8 weeks (interquartile range [IQR], 2.0-4.0). The median endogenous serum erythropoietin level in each arm was 77.2 U/L (range, 7.8-495.8) and 85.4 U/L (range, 4.6-462.5), respectively.

When evaluated between week 1 and EOT, 70.9% of patients who received luspatercept achieved the trial’s primary end point vs 43.1% of those who received epoetin alfa (P < .0001). The median longest duration of response (DOR) until EOT was 128.1 weeks (95% CI, 108.3–not evaluable [NE]) in the luspatercept arm vs 95.1 weeks (95% CI, 75.6-186.1) with epoetin alfa (HR, 0.709; 95% CI, 0.444-1.132; P = .1482).

In total, 76.4% of patients who received luspatercept achieved RBC transfusion independence for at least 12 weeks between week 1 and EOT vs 55.8% of those who received epoetin alfa (P < .0001). Among these patients, those in the luspatercept arm had a median DOR until EOT of 126.6 weeks (95% CI, 93.0-NE) vs 75.6 weeks (95% CI, 47.0-111.1) for those in the epoetin alfa arm (HR, 0.569; 95% CI, 0.308-0.851; P = .0055).

A total of 65.9% of patients who received luspatercept achieved RBC transfusion independence for at least 24 weeks between week 1 and EOT vs 45.3% of those who received epoetin alfa (P < .0001). In this population, the median longest DOR until EOT was 135.9 weeks (95% CI, 112.7-NE) with luspatercept vs 91.1 weeks (95% CI, 74.9-157.3) with epoetin alfa (HR, 0.541; 95% CI, 0.339-0.862; P = .0088).

Hematologic improvement-erythroid for at least 8 weeks between week 1 and EOT was achieved by 80.2% and 57.5% of patients in the luspatercept and epoetin alfa arms, respectively (P < .0001).

In the luspatercept and epoetin alfa arms, the median number of RBC units transfused between weeks 1 and 24 was 1.0 (IQR, 0-5.0) and 3.0 (IQR, 0-8.0), respectively.

Eighty-three percent and 66.9% of patients in the luspatercept and epoetin alfa arms, respectively, achieved a 50% or greater reduction in RBC units transfused over at least 12 weeks between week 1 and EOT (P = .0002). In these patient populations, the median DORs were 130.0 weeks (95% CI, 99.0-NE) and 77.0 weeks (95% CI, 54.9-123.9), respectively (HR, 0.528; 95% CI, 0.360-0.774; P = .0009). This benefit with luspatercept was observed regardless of baseline transfusion burden. This reduction was observed in 89.0% and 73.9% of patients in the luspatercept (n = 118) and epoetin alfa (n = 111) arms, respectively, with a baseline transfusion burden of less than 4 units per 8 weeks. In that population, the median DORs were 129.9 weeks (95% CI, 85.9-NE) and 95.7 weeks (95% CI, 62.4-186.1), respectively (HR, 0.826; 95% CI, 0.532-1.282). This reduction was observed in 71.9% and 55.7% of patients in the luspatercept (n = 64) and epoetin alfa (n = 70) arms, respectively, with a baseline transfusion burden of at least 4 units per 8 weeks. In that population, the median DORs were 164.0 weeks (95% CI, 127.0-NE) and 36.4 weeks (95% CI, 21.9-73.7), respectively (HR, 0.374; 95% CI, 0.200-0.698).

In the luspatercept and epoetin alfa arms, the median time to RBC transfusion after treatment initiation was 155.0 days (95% CI, 80.0-266.0) and 42.0 days (95% CI, 23.0-55.0), respectively (HR, 0.579; 95% CI, 0.446-0.750; P < .0001).

Among the patients in the luspatercept (n = 139) and epoetin alfa (n = 101) arms who achieved RBC transfusion independence for at least 12 weeks between week 1 and EOT, 20.1% and 16.8%, respectively, achieved at least 2 separate response episodes. The median cumulative durations of all response episodes were 154.7 weeks (95% CI, 118.4-NE) and 91.1 weeks (95% CI, 73.1-123.9) in these respective arms (P = .0016).

Mean hemoglobin increases of at least 1.5 g/dL between weeks 1 and 24 were achieved by 74.2% and 52.5% of patients in the luspatercept and epoetin alfa arms, respectively (P < .0001). In these respective arms, the mean hemoglobin changes between weeks 1 and 24 were 2.0 g/dL (standard deviation [SD], 1.14) and 1.5 g/dL (SD, 1.12). The study authors noted that luspatercept treatment consistently increased hemoglobin from baseline levels vs epoetin alfa.

References

1. Zeidan AM, Platzbecker U, Della Porta MG, et al. Clinical benefit of luspatercept treatment (tx) in transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)–naive patients (pts) with very low-, low- or intermediate-risk myelodysplastic syndromes (MDS) in the COMMANDS trial. J Clin Oncol. 2024;42(suppl_16):6565. doi:10.1200/JCO.2024.42.16_suppl.6565
2. US FDA approves Bristol Myers Squibb's Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed June 11, 2024. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx