Longer luspatercept treatment continues to benefit TDT patients

Patients with transfusion-dependent β-thalassemia (TDT) continued to benefit from over 3 years of treatment with luspatercept, a first-in-class erythroid maturation agent that enhances late-stage erythropoiesis, according to the longer-term efficacy analysis of the phase III BELIEVE study.

Patients with TDT require lifetime red-blood-cell transfusion (RBC-T) for survival and iron chelation therapy to manage iron overload. However, multiple morbidities due to iron toxicity are not uncommon, and this includes increased mortality. [Haematologica 2004;89:1187-1193] “[As such,] there is an unmet need for effective treatments for TDT-associated anaemia that could lessen the burden of transfusions on patients,” said Dr Maria Domenica Cappellini from the University of Milan, Italy, at EHA 2022.

In the primary analysis, there were five times more luspatercept than placebo recipients who achieved a ≥33-percent reduction from baseline in RBC-T burden from weeks 13 through 24 (21 percent vs 4 percent; p<0.001). [N Engl J Med 2020;382:1219-1231]

The rate in the luspatercept arm continued to improve in the current analysis across three* data cut points, be it during any 12-week (70, 76, and 77 percent for the respective data cuts 1, 2, and 3) or 24-week interval (41, 45, and 52 percent, respectively). [EHA 2022, abstract S270]

The longest duration of reduction in RBC-T burden jumped from a median of 104 to 114 days from data cut 1 to 3 at any 12-week period.

“[These findings suggest that] continued luspatercept treatment allowed for more patients to experience reduction in RBC-T burden with longer durations of response compared with previous data cuts,” Cappellini said.

The fraction of luspatercept recipients achieving ≥50-percent reduction in RBC-T burden at data cut 1 at any 24-week period was 16 percent, which increased to 24 percent by data cut 3. Over the entire treatment period, these patients experienced an increase in time between transfusions compared with baseline (mean, +9.9 days).

Luspatercept recipients had a mean total (cumulative) duration of RBC-T burden reduction during any rolling 12-week interval of 627.3 days. They also required fewer RBC units transfused over time (mean change from baseline, –4.8 RBC units/48 weeks [weeks 1–48]; –6.4 RBC units/48 weeks [weeks 145–192]).

Twenty-four luspatercept recipients demonstrated RBC-T independence (RBC-TI) of ≥8 weeks at data cut 1. Three more patients were able to achieve RBC-TI by data cut 3. Median longest duration of RBC-TI was 72 days.

Liver iron concentration

The study included 336 patients (median age 30 years, 58 percent female) with β-thalassemia (30 percent β0/β0) or haemoglobin E/β-thalassemia** requiring regular RBC-T. They were randomized 2:1 to receive SC luspatercept at an initial dose of 1 mg/kg Q3W (uptitration to 1.25 mg/kg was allowed) or placebo, on top of best supportive care. Median treatment duration was 64 weeks at data cut 1 and 153.6 weeks by data cut 3.

As of data cut 3, 125 out of the 224 luspatercept recipients (56 percent) completed 144 weeks of treatment, while six participants completed 192 weeks.

There also appeared to be a decreasing trend in liver iron concentration (LIC) compared with the baseline median level of 5.6 mg/g dry weight (mean change at week 144, –3.7 mg/g dry weight). Cappellini however noted that this should be interpreted with caution. “We have to perform LIC analysis in longer follow-up … because the reduction will take some time.”

LIC analysis is underway.