Professor of Internal Medicine
Chief, Internal Medicine Unit
Internal Medicine Department
University of Milan-Fondazione IRCCS Ca' Granda Policlinico Hospital
Maria Domenica Cappellini, MD, has disclosed that she has served on advisory boards for Bluebird Bio, Celgene, CRISPR, Ionis, Novartis, and Sanofi/Genzyme.
In November 2019, the FDA approved luspatercept, a first-in-class erythroid maturation agent that targets select TGF-β superfamily ligands to block aberrant Smad2/3 signaling and thereby augment late-stage erythropoiesis, for the treatment of anemia in adult patients with transfusion-dependent β-thalassemia. This is the first approval of a biologic agent that alters the natural history of β-thalassemia, thereby ushering in a new era in the treatment of this disease. Both physicians and patients alike are excited by this step forward toward improving the quality of life for patients with β-thalassemia who require regular red blood cell (RBC) transfusions. Furthermore, having an alternative to RBC transfusions, which may be subject to shortages as well as carry a continued risk of blood-transmitted viral infection, is an amazing achievement.
Phase III BELIEVE Trial: Luspatercept vs Placebo for Transfusion-Dependent β-Thalassemia
The approval of luspatercept was based on results from the ongoing phase III BELIEVE trial, a name that is meaningful to me as it unlocked a new perspective on the treatment of β-thalassemia.
In this multicenter, randomized, double-blind, placebo-controlled trial, a large cohort of 336 patients with transfusion-dependent β-thalassemia from 65 sites in 15 countries was randomized 2:1 to subcutaneous luspatercept 1 mg/kg every 21 days (with the option to titrate up to 1.25 mg/kg as needed) vs placebo, with both arms receiving standard best supportive care. The primary endpoint was met, with 21.4% of patients receiving luspatercept achieving a reduction in RBC transfusion burden of ≥ 33% from baseline, with a reduction of ≥ 2 units from Week 13 to Week 24, vs 4.5% of those who received placebo (odds ratio [OR]: 5.79; P < .0001). Key secondary endpoints also showed significant improvement with luspatercept, most notably that 70.5% of patients receiving luspatercept achieved a reduction in RBC transfusion burden of ≥ 33% during any 12-week interval vs 29.5% of those who received placebo (OR: 5.69; P < .0001). Furthermore, a recent report from BELIEVE at ASH 2019 showed that for the majority of patients who responded to luspatercept treatment, the clinical benefit was durable over the follow-up period, with a median clinical benefit duration of 76.3 weeks (range: 24.0-128.1).
Considerations for Use of Luspatercept in the Clinic
Luspatercept is administered subcutaneously at a dose of 1 mg/kg every 3 weeks, which was the dosing schedule in the BELIEVE trial. Hemoglobin must be assessed prior to each administration.
Response to this agent is demonstrated by a delay or reduction in the amount of RBC transfusions that patients require, which is reflected in their hemoglobin levels. For patients who receive transfusions regularly, I typically try to maintain their hemoglobin level at 10-11 g/dL and plan their transfusions at a standard interval. With luspatercept treatment, if patients return to clinic for their next scheduled visit with a high hemoglobin level that does not require the support of blood transfusion, I consider them a good responder.
However, luspatercept is not a curative therapy, and it is expected that patients will require long-term treatment, as the ineffective erythropoiesis caused by the underlying genetic defect in HBB that reduces hemoglobin production will resume when treatment is stopped. That said, we may be able to decrease the frequency of injections to less often than every 3 weeks once patients have responded, which will be revealed as we gain more experience using luspatercept in our clinics.
Which Adult Patients With Transfusion-Dependent β-Thalassemia Should Receive Luspatercept?
Because luspatercept targets the primary pathophysiologic mechanism causing β-thalassemia, ineffective erythropoiesis, I would consider giving it to any adult patient with transfusion-dependent disease, even those with a long-standing history of RBC transfusions.
That said, it is likely that patients will respond to luspatercept at different rates because, as we know, there is a gradient in the severity of ineffective erythropoiesis in this disease. I anticipate that those with less severe ineffective erythropoiesis will be more likely to rapidly respond, whereas those with more severe ineffective erythropoiesis will require more time to respond. In fact, in BELIEVE we saw that patients may respond in different ways and at different times: In addition to significant reductions in RBC transfusion burden at 2 different time periods of observation (Weeks 13-24 and 37-48), significantly more patients treated with luspatercept vs placebo achieved reductions in RBC transfusion burden of ≥ 33% and ≥ 50% during any 12-week or 24-week interval, with up to 70% of patients eventually responding.
Furthermore, the greatest benefit with luspatercept in BELIEVE was seen in patients with the non- β0/β0 genotype, which means, genetically speaking, those with less severe ineffective erythropoiesis. But responses are likely even in those patients who are homozygous for the β0 allele (β0/β0) and are expected to have more severe ineffective erythropoiesis, with the caveat that they may require more frequent injections and more time to respond than those with a non-β0/β0 genotype.
What Adverse Events (AEs) Can Be Expected with Luspatercept?
My enthusiasm for this drug for the treatment of transfusion-dependent β-thalassemia is in part due to the relative lack of concerning AEs. Most AEs were quite similar in treated patients compared with the placebo group: Any grade treatment-emergent AEs with luspatercept were reported in 96.0% of patients vs 92.7% with placebo, and grade ≥ 3 AEs in 29.1% and 15.6% of patients, respectively. The AEs with a slightly higher incidence in the luspatercept arm, for example, bone pain (19.7% vs 8.3% with placebo), were often those common even in untreated patients with β-thalassemia or were observed at a very early stage and were transient. For particularly intense bone pain with luspatercept, I would suggest reducing the dose or holding the drug temporarily but would not stop treatment.
Of note, the package insert for luspatercept contains a warning regarding thrombosis/thromboembolism in patients with β-thalassemia and suggests monitoring patients for signs and symptoms of thromboembolic events and treating promptly if detected. In BELIEVE, all grade thromboembolic events occurred in 3.6% (8/223) of patients with luspatercept and grade 3/4 in 0.9% (2/223) of patients as compared with none with placebo. However, I want to emphasize that an increased risk of thrombosis is well known in β-thalassemia, especially those patients who are splenctomized, so it is not surprising that a few patients receiving luspatercept experienced thrombotic events, which are reversible. My suggestion is to evaluate patients starting luspatercept for risk factors for increased thrombosis and, if present, pay increased attention to monitoring for signs and symptoms of thrombotic events. For patients who do experience a thrombotic event, we know how to manage these and could consider stopping the drug temporarily. However, I do not consider this a limitation or major concern to using luspatercept, and only in rare cases of patients with repeated thrombotic events, pulmonary hypertension, or considerable coagulopathy would I avoid luspatercept.
To learn more about this new drug, we will continue monitoring patients receiving luspatercept for any potential AEs in the coming years, and I expect that management of the AEs associated with this drug will improve over time as more patients are treated in the real-world setting. Already an update of BELIEVE at ASH 2019 with longer follow-up was promising, showing a safety profile consistent with the original report as well as that dose did not affect frequency of AEs and that the incidence of AEs decreased over time regardless of luspatercept modification/continuation.
Future Directions for Luspatercept
We hope that approval of luspatercept by the European Medicines Agency will quickly follow the FDA approval and that we will see additional approvals for myelodysplastic syndromes and myelofibrosis as well. There are also ongoing studies evaluating luspatercept for additional β-thalassemia indications, including the phase II BEYOND study in adult patients with nontransfusion dependent β-thalassemia where we hope to demonstrate an increase in hemoglobin levels and positive effect on quality of life for these patients, and a phase IIa dose-finding study in pediatric patients with transfusion-dependent β-thalassemia.
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