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ATLANTA -- Patients with transfusion-dependent β-thalassemia (TDT) who received a gene therapy achieved normal or near-normal levels of total hemoglobin and transfusion independence, with stable iron markers, according to long-term follow-up study results presented here.

Of 57 patients who participated in four trials evaluating betibeglogene autotemcel (beti-cel) with a combined median follow-up of 41.5 months, 46 achieved transfusion independence, defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average hemoglobin of at least 9 g/dL, reported Alexis Thompson, MD, MPH, of the Ann & Robert H. Lurie Children's Hospital of Chicago.

These results were presented at the American Society of Hematology (ASH) annual meeting, and results from one of the phase III trials were published concurrently in the .

"This is the largest to date gene therapy program in any blood disorder that has really included a broad range of genotypes of thalassemia across a broad age range," Thompson said during a press briefing at the ASH meeting. "It would appear that this one-time beti-cel gene therapy is capable of durable transfusion independence, that iron overload is improved and stable in these individuals, and that the adverse event profile seems quite favorable, and so at this point we believe that beti-cel is potentially curative for patients with TDT."

β-thalassemia is a chronic inherited blood disorder. In its most severe form, it results in the inability or near inability to produce adult hemoglobin, which can lead to severe anemia and lifelong dependence on red blood cell transfusions.

Beti-cel is a one-time gene therapy that adds functional copies of the β^A-T87Q-globin gene into a patient's own hematopoietic stem cells. Once patients have the β^A-T87Q-globin gene, they have the potential to produce adult hemoglobin at levels that can eliminate the need for transfusions.

The 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).

Patients across these studies ranged in age from 5 to 35, were heavily transfused (from 10 to almost 40 red blood cell transfusions annually), and had significant iron overload.

In the phase III beti-cel studies, 31 of 35 evaluable patients were deemed to have achieved 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 studies, 15 achieved transfusion independence, with a median duration of ongoing transfusion independence of 65.9 months, and a weighted average hemoglobin of 10.3 g/dL.

"The long-term follow-up has also given us an opportunity to understand more about iron managment in these patients," noted Thompson.

"With chronic transfusions, inevitably patients will have iron overload, not only from the transfusions, but also from increased intestinal uptake of iron," she explained. "This results in iron overload in the heart and liver, which can be fatal, but also in endocrine organs, which causes tremendous disability and dysfunction."

For patients with β-thalassemia, iron can be removed through chelation. Of the 46 patients who achieved transfusion independence, 34 restarted chelation after beti-cel infusion. Of those 34, 20 have since stopped after a median duration of 25.7 months. Eleven of the 46 patients who achieved transfusion independence were able to receive phlebotomy, another method of iron reduction only possible for patients who have sufficient hemoglobin levels without red blood cell transfusions.

"We are reassured that once we first accomplish disease control with gene therapy, then accomplish iron control with chelation, both appear to be durable," said Thompson. "And that's what I think is particularly exciting -- the notion that these individuals are being able to uncouple themselves from the healthcare system, and the way they are currently managed, is really very exciting for the patient."

As for safety, there has been no vector-derived competent lentivirus occurrence, clonal expansion, insertional oncogenesis, or malignancies. Thompson also pointed out that two male patients -- one of whom underwent fertility preservation -- have reported births of healthy children with their partners.

While beti-cel has been approved in Europe, bluebird bio, the therapy's developer, has made a business decision to withdraw marketing authorization for the drug in the U.K. and European Union in 2022.

"Certainly, as a clinician, it is disappointing," Thompson said, noting that the FDA granted priority review to beti-cel for β-thalassemia. "I am looking forward to seeing a successful approval in the United States, seeing patients move through a process where they can get it commercially, and hoping then to revisit what the opportunities are in Europe."

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