A new medical therapy for anemia in thalassemia

In this issue of Blood, Piga et al report results of a phase 2, open label, nonrandomized, uncontrolled dose-finding study evaluating the effects of luspatercept on erythroid maturation and differentiation in adult patients with β-thalassemia.¹  A high percentage of patients had an increase in hemoglobin or a reduction in transfusion burden, which helped lay the basis for future randomized trials.

Anemia is a frequent finding arising from many different causes. Endogenous erythropoietin and its receptor are fundamental for the survival, proliferation, and differentiation of erythroid progenitors during early-stage erythropoiesis.²  Erythroid precursor (erythroblast) maturation and differentiation during late-stage erythropoiesis are independent of erythropoietin.³  Late-stage erythropoiesis defects lead to ineffective erythropoiesis in which red blood cell levels are deficient despite a hypercellular bone marrow. Ineffective erythropoiesis occurs in different diseases such as β-thalassemia, myelodysplastic syndrome, and primary myelofibrosis. These diseases often require chronic blood transfusion and iron chelation to alleviate potentially fatal iron overload.

In β-thalassemia, unequal production of α- and β-globin chains causes apoptosis,⁴  oxidative stress, and inhibition of late-stage erythroid differentiation, leading to anemia that is unresponsive to erythropoietin, ineffective erythropoiesis, and subsequent dysregulation of iron homeostasis. Members of the transforming growth factor-β (TGF-β) superfamily of ligands act as inhibitors of late-stage erythropoiesis.⁵  They regulate Smad2/3 signaling which, as preclinical studies indicate,⁶  contributes to ineffective erythropoiesis.

Luspatercept (formerly ACE-536) is a soluble fusion protein with an adjusted extracellular domain of the activin receptor type IIB (ActRIIB) linked to the Fc domain of human immunoglobulin G1.^6,7  In preclinical studies, luspatercept has been shown to function as a ligand trap for selected TGF-β ligands, resulting in a reduction in aberrant Smad2/3 intracellular signaling.⁷  The removal of erythropoiesis inhibition is hypothesized to be the basis of the effects of luspatercept on promoting late-stage red blood cell precursor differentiation and maturation.

A phase 1 trial demonstrated luspatercept activity in normal healthy volunteers,⁸  and now Piga et al present the results of a phase 2 dose-finding trial of luspatercept in adult patients with either transfusion-dependent or non–transfusion-dependent β-thalassemia. The authors demonstrated erythroid responses of either increase in hemoglobin or reduction in transfusion burden in a relevant portion of the 64 adult patients enrolled in their study. Figure 2B from the article by Piga et al shows improvement in hemoglobin levels in non–transfusion-dependent patients who received 0.6 to 1.25 mg/kg luspatercept (see figure).

The goal of improving normal hemoglobin production in β-thalassemia major has been a target of (so far unsuccessful) studies for years. The potential clinical benefits of even a partial increase in hemoglobin for patients with β-thalassemia is easily understood: they have less anemia, fewer red cell transfusions, less anemia-related symptomatology, less iron overload, and fewer other clinically relevant complications that have an impact on the quality and duration of life.

As is often the case with phase 2 studies, several relevant issues remain: determination of the degree of improvement in a controlled trial powered to separate drug efficacy from hemoglobin variability and variable transfusion thresholds, creation of a detailed and more complete safety profile, consideration of the possibility of improving iron metabolism dysregulation, determination of the impact on iron chelation therapy, characterization of the patients who receive the greatest clinical benefit and the impact of age on treatment, assessing the use of luspatercept in pediatric patients, and addressing the cost of this therapeutic modality, given the distribution of thalassemia particularly in low-income countries.

It will be necessary to resolve these issues before the fundamental questions of the clinical benefit and the cost:benefit ratio of this new drug can be determined. Piga et al have provided the basis for randomized trials in patients with transfusion-dependent thalassemia in a study whose results were recently presented (NCT02604433: An Efficacy and Safety Study of Luspatercept [ACE-536] Versus Placebo in Adults Who Require Regular Red Blood Cell Transfusions Due to Beta [β] Thalassemia [BELIEVE]) and in non–transfusion-dependent patients in an ongoing study (NCT03342404: A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent Beta [β]-Thalassemia [BEYOND]).

What is important, if these results are confirmed, is that patients with β-thalassemia will soon have a new weapon in their therapeutic arsenal which may now include optimized medical transfusion and chelation therapy, a new drug that can alleviate disease severity, better treatment of complications, hemopoietic cell transplantation,⁹  and even gene therapy.¹⁰ 

The potential approval of luspatercept for clinical practice will offer us another opportunity. Today medical research frequently proceeds via clearly separated paths in different diseases, with little interaction among the researchers in their respective disease areas. The availability of a drug that demonstrates efficacy with the same mechanism of action in a wide spectrum of malignant (myelodysplastic syndrome, primary myelofibrosis) and nonmalignant (thalassemia) diseases will make it easier for basic science and clinical researchers to collaborate with each other. It will be important for collaborators to find the best use for luspatercept and the right combination or sequence of therapeutic options, especially given the limited availability and distribution of resources to care for patients with thalassemia.

The excellent work of the authors produced a significant set of data. It deserves to be confirmed, and further research should begin as soon as possible.