Luspatercept for transfusion-dependent β-thalassemia: time to get real

The treatment landscape for patients with transfusion-dependent β-thalassemia (TDT) has evolved considerably over the past few decades with safer transfusion practices, advances in iron overload detection and management, and optimized bone marrow transplant protocols for pediatric patients. ¹ This has translated to improvements in patient survival as evident from comparisons between older and younger birth cohorts. ² However, several unmet needs remain for a disease with complex pathophysiology and chronic treatment burden. Regular transfusion and iron chelation therapy may not be accessible or adequately available to meet treatment targets, especially in resource-limited countries where the disease is highly prevalent. Even in well-resourced countries, limitations of blood supply, adverse events related to transfusions and iron chelation, and the burden of long-term therapy continue to impact a significant proportion of patients leading to diminished quality of life, poor adherence, increased healthcare resource utilization, with resulting morbidity and mortality.^3–5 Several potentially curative therapies and disease modifying agents have been approved or are currently in development, which aim to abolish or reduce the need for transfusion therapy by ameliorating/replacing ineffective erythropoiesis and improving anemia. ⁶

Luspatercept is the latest of such novel agents to come to the market following Food and Drug Administration and European Medicines Agency approvals for the management of anemia in adults with TDT. It is a recombinant fusion protein comprising a modified extracellular domain of the human activin receptor type IIB fused to the Fc domain of human immunoglobulin G1. The domains bind to select transforming growth factor β superfamily ligands, block SMAD2/3 signaling, and enhance erythroid maturation during late-stage erythropoiesis.^7,8 Approval in TDT was based on data from the phase III BELIEVE trial (NCT02604433), which met its primary endpoint and showed that a significantly greater proportion of luspatercept-treated patients achieved a ⩾33% reduction from baseline in transfusion burden during weeks 13–24 compared with placebo (21.4% versus 4.5%). ⁹ Similar results favoring luspatercept were also noted at weeks 37–48, and significantly greater numbers of patients also achieved ⩾50% reduction at both fixed timepoints compared with placebo. Luspatercept is now recommended for adult TDT patients in international management guidelines and expert reviews.^10,11

Thus, aside from specific warnings and precautions, luspatercept has a broad label indication for use in any adult TDT patient. Nonetheless, practitioners and policymakers may still be seeking some criteria for treatment prioritization in view of limited local resources or personal experience with associated outcomes. Subgroup analyses of the primary endpoint in the BELIEVE trial did not provide any additional actionable insights to help predict which patients would be “responders,” since response favored luspatercept over placebo across all subgroups.^9,12

Notably, the magnitude of effect was relatively higher in patients with non-β⁰/β⁰ patients, lower transfusion burden and higher hemoglobin level at baseline, likely indicating that activity may be more pronounced in patients with “less” ineffective erythropoiesis and some intrinsic ability to produce red blood cells. ⁹ Longer-term analysis, however, showed that β⁰/β⁰ patients eventually reached similar levels of response although later in the treatment course. ¹³ Real-world data from Greece also indicated that patients with high baseline transfusion burden, who would not have been included to the BELIEVE trial, had similar responses but may require increased doses to respond compared to the rest of the treated population. ¹⁴ This implies that disease severity may predict early versus delayed response or response on lower versus higher doses; rather than response per se. The proportion of responders was also somewhat higher in splenectomized versus non-splenectomized patients, ⁹ which may be attributed to increased trapping of mature red cells in the thalassemic spleen. Considering the limited data to provide objective clues on the best treatment candidates for luspatercept, we provide our own list, driven primarily by our long-standing experience in treating the disease and understanding patients and healthcare system needs in different geographies (Figure 1).

Figure 1.

(a) Treatment prioritization for TDT patients who are eligible for luspatercept therapy (and following consideration of applicable contraindications, warnings, and precautions per local prescribing information), and (b) suggested practical criteria for defining response to luspatercept therapy. Hb, hemoglobin; ICT, iron chelation therapy; pRBC, packed red blood cell; TDT, transfusion-dependent β-thalassemia.

In the real-world setting, if patients are offered luspatercept, defining a clinically meaningful response is complex. In the summary of product characteristics in Europe, response is evaluated after two or more doses to determine the need for dose escalation (from 1 to 1.25 mg) and is defined as ⩾33% reduction in transfusion burden. ¹⁵ The US prescribing information does require transfusion reduction but without indicating a specific magnitude. ¹⁶ Both labels recommend treatment discontinuation if no reduction in transfusion burden is noted (of any magnitude) following three doses at the maximum dose (15 weeks from initiation of therapy). In a practical setting, it may not be as straightforward. First, we know that a substantial number of patients who did not achieve the primary endpoint at weeks 13–24 in the BELIEVE trial, did eventually have a reduction in transfusion burden if they continued treatment longer. ¹⁷ Moreover, when looking at post-hoc rolling analyses of response (⩾33 and ⩾50% reduction) during any 12-week interval, it was clear that some patients had delayed response and others had multiple periods of response over time. ⁹ More importantly, in many countries with challenging access to transfusions, patients are often maintained on pre-transfusion hemoglobin levels lower than the recommended target of 9.5–10.5 g/dL. In such patients, achieving higher pretransfusion hemoglobin levels while receiving the same transfusion regimen, could be considered a beneficial “response.” In Figure 1, we also provide suggestions on how we believe response to luspatercept can be more practically evaluated in a clinical setting.

Experience with using luspatercept is only meant to grow over the next few years, and insights from real-world evidence studies will be essential to answer questions stemming from translating clinical trial findings to day-to-day practice. In parallel to real-world data generation, efforts to make luspatercept more affordable through pragmatic negotiations and patient support programs are needed. Most patients with thalassemia live in resource-limited settings, and although novel therapies may reduce the burden of conventional therapy and healthcare resource utilization, they still come at high cost. Economic evaluations will be helpful to strategize healthcare spending.