Author: Mike Bassett, Special Writer, MedPage Today December 13, 2021

Atlanta-Based on the results of the long-term follow-up study provided here, the total hemoglobin and transfusion independence of patients receiving gene therapy for transfusion-dependent β-thalassemia (TDT) reached normal or near-normal levels, and the iron markers were stable.

Of the 57 patients participating in the four trials evaluating betibeloggene autotemcel (beti-cel), 46 patients achieved transfusion independence, defined as no longer needing blood transfusion for at least 12 months, while maintaining weight Chicago Ann & Robert H. Lurie Alexis Thompson, MD and Master of Public Health of the Children's Hospital reported that the average hemoglobin is at least 9 g/dL.

These results were announced at the annual meeting of the American Society of Hematology (ASH), and the results of one of the phase III trials were also published in the New England Journal of Medicine.

Thompson said at a press conference at the ASH conference: "This is by far the largest gene therapy program of any blood disease, which really includes various genotypes of thalassaemia in a wide age range." "It looks like this one-off. beti-cel gene therapy can be independent of blood transfusion for a long time, the iron overload of these individuals is improved and stabilized, and the adverse event characteristics seem to be very favorable, so at this point we believe that beti-cel may cure TDT patients."

Beta-thalassemia is a chronic inherited blood disease. In the most severe cases, it can lead to the inability or almost inability to produce adult hemoglobin, leading to severe anemia and lifelong dependence on red blood cell transfusion.

Beti-cel is a one-time gene therapy that adds a functional copy of the βA-T87Q globin gene to the patient's own hematopoietic stem cells. Once patients have the βA-T87Q globin gene, they may produce adult hemoglobin levels that do not require blood transfusion.

57 patients in this long-term follow-up study participated in two original phase I/II trials (22 patients) and two phase III trials (35 patients).

The patients in these studies ranged in age from 5 to 35 years old, had massive blood transfusions (10 to nearly 40 red blood cell transfusions per year), and had significant iron overloads.

In the phase III beti-cel study, 31 of 35 evaluable patients were considered to have achieved blood transfusion independence, with a median duration of 32 months and a weighted average hemoglobin of 11.6 g/dL.

Of the 22 patients treated in the Phase I/II study, 15 achieved blood transfusion independence, with a median duration of continuous blood transfusion independence of 65.9 months, and a weighted average hemoglobin of 10.3 g/dL.

"Long-term follow-up also gives us the opportunity to learn more about the iron management of these patients," Thompson pointed out.

"For long-term blood transfusions, patients will inevitably experience iron overload, not only from the blood transfusion, but also from the increased absorption of iron from the intestine," she explained. "This can cause iron overload in the heart and liver, which can be fatal, but it can also cause iron overload in the endocrine organs, which can lead to severe disability and dysfunction."

For patients with β-thalassemia, iron can be removed by chelation. Of the 46 patients who achieved blood transfusion independence, 34 restarted chelation after beti-cel infusion. Of these 34 cases, 20 cases stopped after a median duration of 25.7 months. 11 of the 46 patients who achieved independent blood transfusions were able to undergo phlebotomy, which is another method of reducing iron and is only suitable for patients with sufficient hemoglobin levels that do not require blood transfusions.

"We are convinced that once we achieve disease control through gene therapy first and then iron control through chelation, both seem to be durable," Thompson said. "This is what I think is particularly exciting-the idea of ​​these people being able to disconnect themselves from the healthcare system and their current management methods is really exciting for patients."

As for safety, vector-derived lentivirus development, clonal amplification, insertion tumor development, or malignant tumors have not yet occurred. Thompson also pointed out that two male patients — one of whom received maternity protection — reported that they had given birth to healthy children with their partner.

Although beti-cel has been approved in Europe, bluebird bio, the developer of the therapy, has made a commercial decision to withdraw the drug's marketing authorization in the United Kingdom and the European Union in 2022.

"Of course, as a clinician, this is disappointing," Thompson said, noting that the FDA granted beti-cel a priority review for beta-thalassemia. "I look forward to seeing successful approval in the United States, seeing patients through a process that can obtain it commercially, and hope to then re-examine the opportunities in Europe."

Mike Bassett is a full-time writer, focusing on oncology and hematology. He lives in Massachusetts.

This research was sponsored by Bluebird Bio.

Thompson reported on consulting with Agios, Beam, bluebird bio, Celgene, Bristol Myers Squibb, CRISPR, Editas, Graphite Bio, Novartis, and Vertex; holding equity in Global Blood Therapeutics; and sources from Baxalta, bluebird bio, BioMarin, Celgene, Bristol Myers Research funding for Squibb, CRISPR, Editas, Graphite Bio, Novartis, Vertex.

Source reference: Thompson A et al. "Recovering iron homeostasis in transfusion-independent patients after receiving betibeglogene autotemcel gene therapy: 7-year follow-up results" ASH 2021; Abstract 573.

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