Luspatercept a new SoC for TD LR-MDS?

The full analysis of the phase III COMMANDS trial continues to demonstrate the superiority of luspatercept over epoetin alfa for the treatment of erythropoiesis-stimulating agent (ESA)-naïve patients with transfusion-dependent lower-risk myelodysplastic syndromes (TD LR-MDS).

Sixty percent of luspatercept-treated patients achieved the primary endpoint of RBC transfusion independence (RBC-TI) for ≥12 weeks with concurrent mean haemoglobin increase ≥1.5 g/dL, said Dr Guillermo Garcia-Manero from The University of Texas MD Anderson Cancer Center, Houston, Texas, US, at ASH 2023.

With epoetin alfa, only a third (35 percent) were able to achieve the primary endpoint. A between-group comparison yielded a p value of <0.0001. [ASH 2023, abstract 193]

“Subgroup analysis of the primary endpoint showed greater response rates with luspatercept regardless of baseline transfusion burden, serum erythropoietin (sEPO) category, or SF3B1 mutation status,” Garcia-Manero said.

A total of 363 patients (median age 74 years, 55 percent male) were randomized 1:1 to SC luspatercept 1.0 mg/kg (titrated up to 1.75 mg/kg) Q3W or epoetin alfa 450 IU/kg (titrated up to 1,050 IU/kg) QW for ≥24 weeks. Median baseline haemoglobin level was 3.0 RBC U/8 weeks.

Luspatercept also outdid epoetin alfa in terms of the proportions of patients who achieved HI-E* (74 percent vs 53 percent; p<0.0001), RBC-TI ≥12 weeks (68 percent vs 49 percent; p<0.0001), and RBC-TI for 24 weeks (48 percent vs 31 percent; p=0.0003).

Response rates of the preplanned exploratory analysis of RBC-TI for ≥24 weeks were also greater with luspatercept compared with the comparator irrespective of baseline transfusion burden, sEPO category, or SF3B1 mutation status.

“RBC-TI during week 1–48 was consistent with week 1–24, demonstrating durability of response with luspatercept,” said Garcia-Manero.

Compared with epoetin alfa, luspatercept treatment led to a longer median duration of RBC-TI ≥12 weeks in the intention-to-treat cohort (126.6 vs 89.7 weeks; hazard ratio [HR], 0.586) and RS** (120.1 vs 61.9 weeks; HR, 0.650 [RS+] and not estimable vs 95.1 weeks; HR, 0.709 [RS-]) and sEPO subgroups (140.1 vs 89.7 weeks; HR, 0.635 [≤200 U/L] and 52.9 vs 23.9 weeks; HR, 0.657 [>200 to <500 U/L]).

The most common treatment-emergent adverse events tied to luspatercept were diarrhoea (18 percent), fatigue (18 percent), COVID-19 (15 percent), and hypertension (15 percent). The rates of progression to acute myeloid leukaemia were low in both luspatercept and epoetin alfa arms (2.7 percent and 3.3 percent).

About 60 percent of luspatercept recipients had events of interest, the most common being asthenia (including fatigue, malaise, and lethargy; 31 percent) and hypertension (16 percent).

“[Nonetheless,] the reported rates of fatigue and asthenia during weeks 1–24 decreased over time, and most events in the luspatercept arm were grade 1/2 and were not considered clinically significant,” noted Garcia-Manero. The grade 3 fatigue event reported did not lead to dose reduction or study drug discontinuation.

First and only therapy superior to ESA

ESAs are an established treatment for TD LR-MDS, but eligible patients often do not respond to treatment; if they do, the response duration is limited.

Luspatercept, an erythroid maturation agent that improves erythropoiesis, is the first and only therapy to demonstrate superiority over an ESA, leading to its FDA approval in the US for the treatment of MDS-related anaemia in ESA-naïve patients who may need regular transfusions. [N Engl J Med 2020;382:140-151; Lancet 2023;402:373-385; 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, accessed December 26, 2023]

“[The current results confirm the interim findings, suggesting] that luspatercept could represent a new standard of care for patients with TD LR-MDS,” Garcia-Manero concluded.