In a scientific webinar on β-thalassemia management organized by the Hong Kong Society of Haematology, Professor Vip Viprakasit shared his insights into the novel management approaches for transfusion-dependent β-thalassemia. While highlighting the limitations of the current standard of care and the need for more treatment options, he presented the findings of the phase 3 BELIEVE trial, which demonstrated the high efficacy of luspatercept in reducing patients’ transfusion burden. Based on the positive results, the 2021 updated Thalassemia International Federation (TIF) guidelines include the use of luspatercept in its recommendations.

Existing burden among TDT patients

β-thalassemia is an inherited hemoglobin disorder characterized by low levels of hemoglobin production.¹ Patients with this condition have genetic mutations affecting the production of β-globin, thus leading to an imbalance of the α- and β-globin ratio, also triggering ineffective erythropoiesis and causing chronic anemia which is common among patients with β-thalassemia.¹ It also causes peripheral hemolysis facilitated by reactive oxygen species (ROS) formation, causing oxidative stress.² In addition, intramedullary hematopoietic expansion is common due to the increased proliferation of erythroid precursors in bone marrow, leading to extramedullary hematopoiesis (EMH), osteoporosis or osteopenia, hepatosplenomegaly, and maturation arrest.^2,3 Transfusion requirements vary with the severity of the disease condition, with some patients requiring blood transfusions for survival.³ This group of patients is said to have transfusion-dependent thalassemia (TDT).³ Currently, the standard of care for TDT patients is regular transfusion, followed by monitoring of iron overload.³ Currently, there are around 300,000 patients suffering from β-thalassemia worldwide, with 15,000 patients requiring regular transfusions.¹ Due to frequent transfusions, TDT patients are at risk of comorbidities associated with transfusions, such as blood-borne infections.³ Another major safety concern relating to transfusions is iron overload.³ For this reason, if serum ferritin (SF) is ≥1,000ng/mL or if patients have received >10 units of transfusions, iron chelation therapy (ICT) is recommended by the TIF guidelines.³ The iron contained in transfused blood may be accumulated in organs, thus leading to organ dysfunction.³ Iron overload from longterm regular transfusions is currently the leading cause of mortality in TDT patients.¹ Besides, the guidelines also consider allogeneic hematopoietic stem cell transplantation (HSCT) for eligible patients.³ However, patients who have received HSCT are at increased risk of death.¹

Luspatercept significantly reduces the transfusion burden

Luspatercept is a recombinant fusion protein which binds specific ligands of the transforming growth factor β (TGF-β) superfamily to limit the signaling via the suppressor of mothers against decapentaplegic (SMAD) 2/3 pathway, hyperstimulation of which leads to ineffective erythropoiesis.^4,5 In a phase 2 study, luspatercept has been shown to reduce transfusion burden by ≥20% in 81% of TDT patients.⁴

BELIEVE was a randomized, placebo-controlled, double-blind, phase 3 trial conducted to evaluate the efficacy and safety of luspatercept in adults with TDT.⁴ The study enrolled 336 adult patients with β-thalassemia who required regular red blood cell (RBC) transfusions, i.e., 6-20 RBC units in the 24 weeks prior to randomization with no ≥35 days transfusionfree period during that time.⁴ Patients were randomized 2:1 to receive either luspatercept 1mg/kg subcutaneously every 21 days with the best supportive care (BSC) and a possible up-titration to 1.25mg/kg or a placebo for a 48-week double-blind period.⁴ After the initial 48-week period, patients in the placebo arm were then crossover to receive luspatercept in an open-label follow-up study for up to 5 years, followed by a post-treatment follow-up for another 3 years.⁴

The study’s primary endpoint was the percentage of patients who had an erythroid response, i.e., a reduction in transfusion burden of ≥33% from baseline during weeks 13-24, and a reduction of ≥2 RBC units over this interval.⁴ The key secondary endpoints included a reduction in transfusion burden of ≥33% in weeks 37-48 and a reduction of ≥2 RBC units over this interval, a reduction of ≥50% in transfusion burden from baseline during weeks 13-24 and 37-48 plus a reduction of ≥2 RBC units in these 2 intervals, and the mean change in transfusion burden in weeks 13-24 from baseline.⁴

The study showed that the percentage of patients achieving the primary endpoint was significantly higher in the luspatercept group compared with the placebo group, with 21.4% vs. 4.5% (OR=5.79; 95% CI: 2.24-14.97; p<0.001).⁴ A significantly higher percentage of patients in the luspatercept group had reductions in transfusion burden of ≥33% from baseline during weeks 37-48 plus a reduction of ≥2 RBC units over this interval (19.6% vs. 3.6%; p<0.001).⁴ The luspatercept group also had significantly more patients achieving a reduction in transfusion burden of ≥50% in weeks 13-24 plus a reduction of ≥2 RBC units over this interval (7.6% vs. 1.8%; p=0.03), and a reduction in transfusion burden of ≥50% in weeks 37-48 plus a reduction in ≥2 RBC units over this period (10.3% vs. 0.9%; p=0.002).⁴ All in all, comparing with the placebo group, the luspatercept group had a significantly higher percentage of patients achieving the transfusion burden reduction of ≥33% (70.5% vs. 29.5%; OR=5.69; 95% CI: 3.46-9.35; p<0.0001) and ≥50% (40.2% vs. 6.3%; OR=9.95; 95% CI: 4.44-22.33; p<0.0001) in any 12-week interval (figure 1).⁴

Though patients receiving luspatercept experienced more adverse events (AEs) of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia, the safety profile of luspatercept was consistent with previous experience.⁴ Therefore, luspatercept can significantly reduce the transfusion burden of patients.

Luspatercept reduces the risk of iron overload complications

Moreover, SF, liver iron concentration (LIC), and the myocardial iron T2-star (T2*) levels of patients were evaluated in the BELIEVE trial.6 Among those with baseline SF ≥1,000μg/L, 17.0% of patients in the luspatercept group achieved a post-baseline mean SF <1,000μg/L compared with 5.0% in the placebo group during weeks 1-24 (p=0.023) (figure 2).⁶ The percentage of patients achieving post-baseline mean SF <1,000μg/L in weeks 73-96 increased to 46.4% in the luspatercept group.⁶ Among those with baseline SF ≥1,000μg/L, 12.3% of patients in the luspatercept group vs. 7.7% in the placebo group achieved a post-baseline mean SF <2,500μg/L in weeks 1-24 (p=0.527).⁶ The former increased to 33.3% in weeks 73-96.6 When comparing LIC, 4.2% and 9.7% of luspatercept patients at weeks 24 and 48 respectively shifted from LIC >3mg/g dry weight (dw) at baseline to ≤3mg/g dw, compared with 6.6% and 5.9% among placebo patients (figure 3).⁶ At week 96, 14.3% of luspatercept patients shifted from LIC >3mg/g dw at baseline to ≤3mg/g dw.⁶ About 20.0% of patients receiving luspatercept shifted from myocardial iron T2* ≤20ms at baseline to >20ms at week 48 compared with 9.1% of placebo patients.⁶ At week 96, 25.0% of patients of the luspatercept group shifted from ≤20ms to >20ms.⁶ The data showed a higher percentage of luspatercept-receiving patients shifted to lower SF, LIC, and the myocardial iron levels during the first 48 weeks, which was indicative of a lower risk of iron overload complications.⁶ In terms of long-term observation, luspatercept led to an increasing proportion of patients with SF <1,000μg/L and a decreasing trend of overall ICT use and deferasirox dosage.⁶ Prof. Viprakasit affirmed that “This novel therapy has been shown to be effective with very good tolerability.”

The TIF guidelines recommend using luspatercept in TDT

Following the promising results of a study in 2014, the TIF guidelines recommend the use of luspatercept in the treatment of TDT.³ The TIF cites luspatercept’s ability of improving the hemoglobin levels, reducing the transfusion burden, and lowering the SF levels as the reasons for its recommendations.³ The recommended starting dose of 1mg/kg once every 3 weeks by subcutaneous (SQ) injection.³ If a patient does not achieve a reduction in red cell transfusion burden after at least 6 weeks at the 1mg/kg starting dose, the dose can be increased to 1.25mg.³ The guidelines also recommend patients be monitored for signs and symptoms of thromboembolic events (TEEs), and that their blood pressure (BP) should be monitored prior to each administration.³ Since the effects of luspatercept on children have not been established, the guidelines recommend luspatercept be given to adult patients only.³

Conclusion

In summary, the unmet needs among TDT patients remain despite the standard of care with transfusion followed by SF monitoring.³ Luspatercept is the first of its class and a promising erythroid maturation agent with proven efficacy in decreasing transfusion burden and lowering iron intake, thus reducing the risk of iron overload complications.^4,6 Luspatercept has been recommended in the latest TIF guidelines as a novel approach to improve the treatment outcomes of TDT patients.³ Prof. Viprakasit concluded that “The clinical study results suggested a role of luspatercept as a recommended specific treatment for patients with β-thalassemia who are transfusion-dependent”.