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My Thoughts on the Recent Advances in the Management of β-Thalassemia

Janet L. Kwiatkowski, MD, MSCE

Professor of Pediatrics
Director of Thalassemia Program

Division of Hematology
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania


Janet L. Kwiatkowski, MD, MSCE, has disclosed that she has served on advisory boards/as a consultant for Agios, Bluebird Bio, and Celgene; has received consulting fees from Imara and Silence Therapeutics; and has received funds for research support from ApoPharma, Bluebird Bio, Novartis, Sangamo, and Terumo BCT.


View ClinicalThoughts from this Author

Released: November 12, 2020

In this commentary, I preview key topics and issues that my colleagues and I will be discussing in depth at an upcoming live Webinar on treatment of β-thalassemia held in conjunction with the ASH 2020 Virtual Annual Meeting. Topics will include the pathophysiology, clinical manifestations, and current standard of care of β-thalassemia; the evolving role of biologic therapies for the treatment of this disease, including the recent approval of luspatercept and its optimal use in the management of transfusion-dependent β-thalassemia; the promise of investigational gene therapies on the horizon; and real-world patient case discussions. 

Advances in Therapy
Biologic therapies for β-thalassemia aim to improve the ineffective erythropoiesis associated with this disease. In November 2019, the FDA approved the first of these biologic therapies, luspatercept, a recombinant fusion protein that promotes erythroid maturation and differentiation of red blood cell (RBC) precursors, for the treatment of adults with transfusion‑dependent β-thalassemia based on data from the phase III BELIEVE study. In BELIEVE, luspatercept was shown to significantly reduce transfusion burden compared with placebo, with 21.4% of patients in the luspatercept arm vs 4.5% of patients in the placebo arm having achieved a ≥ 33% reduction in red blood cell transfusion burden from baseline in Weeks 13-24 (P > .0001)—the primary endpoint. During the Webinar, we will address questions on the optimal real-world use of this new agent, including patient selection and monitoring, and next steps to take in patients who do not respond.

In addition, we will discuss emerging novel agents currently under investigation. Of these, mitapivat (AG-348), a first-in-class, small molecule, allosteric activator of pyruvate kinase-R (wild type or mutated), is the furthest along in development. Mitapivat, which was first studied for the treatment of pyruvate kinase deficiency, is thought to increase ATP levels in erythroid precursors thereby improving their metabolic function and ultimately promoting RBC survival and increasing hemoglobin levels. A phase II clinical study evaluating mitapivat in nontransfusion-dependent thalassemia is currently under way, with plans to recruit an estimated 20 adults with β-thalassemia, Hb E β-thalassemia, or α-thalassemia (Hb H disease) (NCT03692052).

Another novel agent under investigation is IMR-687, an oral inhibitor of phosphodiesterase 9. IMR-687 is being evaluated in a phase II clinical trial in both transfusion-dependent and nontransfusion-dependent β-thalassemia (NCT04411082). In contrast to luspatercept and mitapivat, which improve RBC survival and consequently anemia without increasing globin production, IMR-687 appears to function by directly increasing levels of fetal hemoglobin. The distinct mechanisms of action exhibited by these agents paves the way for future trials to evaluate combination therapies for the management of β-thalassemia.

Advances in Gene Therapy
At the Webinar, we will also discuss advances in gene therapy for β-thalassemia, including both gene addition and gene editing strategies. In May 2019, the European Medicines Agency conditionally approved the first gene therapy, LentiGlobin BB305 (ie, betibeglogene autotemcel), which uses a gene addition approach, for patients 12 years of age and older who have transfusion-dependent β-thalassemia with non-β00 genotypes. Since that approval, which was based on data from phase I/II trials, the ongoing phase III Northstar-2 (HGB-207) and Northstar-3 (HGB-212) trials using a modified transduction process have shown improved outcomes with LentiGlobin BB305 in patients with both non-β00 genotypes and β00 genotypes—interim trial results will be reviewed at the Webinar. We will also look at emerging data for another gene addition approach using the GLOBE lentiviral vector and an intrabone delivery method of modified hematopoietic stem cells. In addition, we will discuss encouraging interim data from a phase I/II study using CRISPR-Cas9 gene editing of the BLC11a erythroid specific enhancer that resulted in high levels of fetal hemoglobin production and transfusion independence in the first 2 patients with β-thalassemia treated.

Some limitations impeding the widespread applicability of gene therapy for patients with β-thalassemia remain. In particular, the requirement for myeloablative conditioning may be prohibitive in older patients, particularly in those who have high iron burden and organ dysfunction, and may lead to infertility in younger patients who have not started their own families yet. The need for myeloablative chemotherapy could potentially be circumvented by using nonchemotherapy conditioning regimens, like antibody-based treatments against CD-117, a receptor present on hematopoietic stem cells.

In vivo gene therapy, which is still under preclinical investigation, is another strategy being considered to limit the toxicities associated with conditioning chemotherapy. In contrast to the ex vivo gene therapy strategies discussed above, the approach with in vivo gene therapy would be to give medications that mobilize hematopoietic stem cells out of the marrow into the bloodstream, inject a gene therapy vector into the bloodstream that can be incorporated into these circulating stem cells, and then allow the transduced stem cells to find their way back into the marrow, where they will hopefully express the added gene and make high levels of hemoglobin. Considering that the manufacturing process of gene therapies must occur in specialized facilities and is very costly, this approach also has the potential to allow access to gene therapy in countries with fewer resources.

Your Thoughts?
How is your practice changing? I invite you to join the conversation by sharing your experience managing patients with β-thalassemia in the comments box or by answering the poll question.

Do you want to learn more about optimizing the care of patients with β-thalassemia? Sign up here to attend the live Webinar “New Agents and Therapeutic Strategies in β-Thalassemia” on Friday, December 4, 2020, at 3:00 PM Pacific time with me and my colleagues Jeanne Boudreaux, MD, and Sujit Sheth, MD, where we will discuss the available evidence, key ongoing clinical issues, and new data in β-thalassemia.

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