Luspatercept bests epoetin alfa in head-to-head LR–MDS-related anaemia trial

In the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (LR-MDS), luspatercept seems to perform better than epoetin alfa at restoring iron stores, according to the interim results of the open-label phase III COMMANDS trial.

The primary endpoint—which was defined as red blood cell (RBC) transfusion independence for at least 12 weeks in the first 24 weeks of treatment with a concurrent mean haemoglobin increase of at least 1.5 g/dL—was achieved with significantly greater frequency among patients treated with luspatercept than among those treated with placebo (58.5 percent vs 31.2 percent; p<0.0001), reported lead researcher Dr Matteo Giovanni Della Porta of Humanitas Cancer Center, Milan, Italy. [EHA 2023, abstract S102]

“The clinical benefit of luspatercept was observed in all patient subgroups defined by the baseline serum erythropoietin level (≤200 and >200 U/L), RBC transfusion burden (<4 and ≥4 U/8 weeks), SF2B1 mutation status, and ring sideroblast status,” Della Porta added.

Of note, higher mutational burden seemed to have a negative impact on treatment response in the epoetin alfa arm (p=0.016) but not in the luspatercept arm (p=0.56). Della Porta pointed out that patients with SF3B1, SF3B1a, ASXL1, and TET2 mutations all derived favourable clinical benefit with luspatercept than with epoetin alfa.

Results for secondary endpoints also favoured luspatercept. Specifically, the number of patients achieving haematological improvement-erythroid response for at least 8 weeks, RBC transfusion independence for 24 weeks, and RBC transfusion independence for at least 12 weeks in the first 24 weeks of treatment was found to be higher in the luspatercept arm than in the epoetin alfa arm.

The median duration of RBC transfusion independence ≥12 weeks (from week 1 to 24) was longer with luspatercept than with epoetin alfa overall (126.6 vs 77.0 weeks), which held true for clinically relevant subgroups including that defined by ring sideroblast status.

No new safety signal

“Luspatercept has a manageable and predictable safety profile, consistent with previous clinical experience and convenient administration (every 3 weeks),” according to Della Porta.

A total of 164 (92.1 percent) luspatercept-treated and 150 (85.2 percent) epoetin alfa-treated patients had treatment-emergent adverse events (TEAEs) of any grade, among whom eight (4.5 percent) and four (2.3 percent) discontinued therapy, respectively.

The most common TEAEs (any grade) were fatigue (14.6 percent), diarrhoea (14.6 percent), and hypertension (12.9 percent) in the luspatercept arm, and asthenia (14.2 percent), diarrhoea (11.4 percent), and anaemia (9.7 percent) in the epoetin alfa arm. The TEAEs in luspatercept-treated patients were mild to moderate in severity, not serious, and generally did not lead to discontinuation, Della Porta noted.

There were four patients (2.2 percent) in the luspatercept arm and five (2.8 percent) in the epoetin alfa arm who progressed to acute myeloid leukaemia. Mortality rates were similar at 18.0 percent in both treatment arms.

“Luspatercept is the first and only therapy to demonstrate superiority in a head-to-head study against ESAs and brings a paradigm shift in the treatment of LR-MDS–associated anaemia,” Della Porta said.

The interim efficacy and safety data from COMMANDS included 356 patients, of which 178 (median age 74 years, 39.9 percent women) received subcutaneous luspatercept (1.0–1.75 mg/kg once every 3 weeks) and 178 (median age 75 years, 48.9 percent women) received epoetin alfa (450–1,050 IU/kg weekly) for a median of 41.6 and 27.0 weeks, respectively. Baseline characteristics were balanced between arms.