New research published in Lancet Oncology reported that the safety and efficacy of Luspatercept (a non-ESA agent) in the phase 2 trials might be a treatment of refractory anaemia, which often requires red blood cell transfusions in lower-risk MDS patients.

Myelodysplastic syndromes (MDS, clonal stem-cell disorders) are characterized by anaemia and a risk for transformation to leukaemia. A mainstay of treatment in low-risk or intermediate-risk patients is anaemia management by the use of erythropoiesis-stimulating agents (ESAs).

Luspatercept is a chimeric protein composed of the extracellular domain of the activin receptor IIB stabilized by the Fc region of IgG. It acts as a ligand trap for members of the transforming growth factor-β superfamily involved in the late stages of erythropoiesis. Luspatercept promotes late-stage erythrocyte precursor cell differentiation and maturation.

The researchers have enrolled 71 patients with low- or intermediate 1–risk MDS or non-proliferative chronic myelomonocytic leukaemia in the study (base and extension phases). Luspatercept was given subcutaneously once every 21 days at dose concentrations ranging from 0.125 mg/kg to 1.75 mg/kg.

The primary efficacy endpoint was modified hematologic improvement–erythroid (mHI-E) response. For patients with low transfusion burden, this was defined as Hb increase of at least 1.5 g/dL from baseline for at least 14 days in the absence of any transfusion. For those with high transfusion burden, mHI-E was defined as a reduction in transfusion of four red blood cell units or a 50% or greater reduction in red blood cell units over 8 weeks.

Of 71 patients, 51 received the higher dose concentrations during the base and extension phases of the study. Increases in mean Hb concentrations were sustained for at least 15 months in 13 patients with low transfusion burden receiving high doses of luspatercept. Of 51 patients who received therapeutic concentrations of luspatercept, 32 achieved mHI-E responses.

Based on transfusion burden, 65% patients with low transfusion burden and 62% patients with high transfusion burden showed mHI-E responses. The mHI-E response rate was highest in patients with low serum erythropoietin concentration at baseline and lowest in patients with high serum erythropoietin concentration at baseline.

Luspatercept is effective even in patients with higher erythropoietin concentrations. Of patients with ring sideroblasts who show refractory anaemia, 69% showed mHI-E responses and 42% were reported to show an RBC-TI. SF3B1 mutational status was strongly associated with responses. Higher mHI-E response rates were seen in 24 of 31 patients with SF3B1 (the most common mutation seen in MDS).

Luspatercept treatment was found to be particularly effective in patients who had 15% or higher ring sideroblasts, or an SF3B1 mutation, or both. However, the activity and tolerability of the agent have prompted an extremely rapid enrolment in the randomised study designed for patients with refractory anaemia with ring sideroblasts, the researcher said.