Luspatercept scores in nontransfusion-dependent β-thalassemia

The first-in-class erythroid maturation agent, luspatercept, improved anaemia in adults with nontransfusion-dependent β-thalassemia (NTDT) in the phase II BEYOND study reported at EHA 2021.

“Until this study, we do not have any approved therapy for the treatment of anaemia in NTDT,” said lead author Dr Ali Taher, director of the Naef K. Basile Cancer Institute at the American University of Beirut Medical Center, Beirut, Lebanon. “Now, we have a new agent that showed benefit ... This presents a landmark achievement for this population who have limited treatment options.”

Assistant Professor Kevin Kuo from the University of Toronto, Canada, couldn’t agree more. “This is a neglected subgroup of patients. Hence, luspatercept is an exciting addition to the armamentarium in the treatment of β-thalassemia.”

BEYOND included 145 adults (median age 40 years, 41.7 percent men) with NTDT,  who were randomly assigned to luspatercept 1 mg/kg titrated up to 1.25 mg/kg (n=96) or placebo (n=49) every 3 weeks for 48 weeks. All patients continued to receive red blood cell (RBC) transfusions and iron chelation therapy as best supportive care. [EHA 2021, abstract S101]

Seventy-seven percent of patients treated with luspatercept achieved the primary endpoint of an increase of at least 1.0 g/dL in haemoglobin (Hb) from baseline to weeks 13 through 24 without requiring RBC transfusions vs zero in the placebo group (p<0.0001).

Luspatercept benefit was observed regardless of baseline mean Hb level.

Of the 55 patients with mean baseline Hb levels of <8.5 g/dL in the luspatercept group, 40 (72.7 percent) achieved the primary endpoint vs none in the placebo group (p<0.0001).

Of 41 with a mean baseline Hb of ≥8.5 g/dL in the luspatercept group, 34 (82.9 percent) achieved the primary endpoint vs none in the placebo group (p<0.0001).

Overall, 52.1 percent of patients in the luspatercept group achieved the secondary endpoint of an increase of ≥1.5 g/dL Hb at weeks 13 through 24, vs none in the placebo group (p<0.0001).

The need for transfusions also declined with luspatercept, with most treated patients (89.6 percent) not requiring RBC transfusions at weeks 1 through 24 vs 67.3 percent with placebo (p=0.0013).

Patient-reported quality of life outcomes, including tiredness and weakness, also improved. “As a clinician, this is what matters,” said Taher.

Luspatercept was well-tolerated. Bone pain, headache, and arthralgia were the most common treatment-emergent adverse events (TEAEs) of any grade reported and were higher for luspatercept than placebo. Rates of grade ≥3 TEAEs occurred in 28.1 percent of patients in the luspatercept group vs 24.5 percent in the placebo group. No deaths, malignancies, or thromboembolic events were reported in either group.

“There is the perception that patients with NTDT tend to do better than their transfusion-dependent counterparts,” said Kuo. “But we realize that’s not the case because these patients have complications stemming from both haemolysis and ineffective erythropoiesis. So, I’m pleased that we may be seeing a better treatment option for these patients.”

As patients with NTDT are susceptible to iron overload, Taher said they will also monitor reductions in iron overload with luspatercept over time, as well as morbidity.  

Luspatercept works by binding to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. By interfering with the signals that suppress RBC production, the drug improves the patients’ ability to manufacture their own RBCs, thus reducing the need for transfusions.

Luspatercept is US-FDA and EMA-approved for the treatment of anaemia in adult patients with transfusion-dependent thalassemia.