Despite Encouraging Safety Thus Far, Long-Term Follow-Up for TDT Gene Therapy Beti-cel Remains Important


Alexis Thompson, MD, MPH, the chief of hematology at Children’s Hospital of Philadelphia, discussed an analysis of follow-up data for bluebird bio’s beti-cel she presented at ASH’s 2023 conference.

Alexis A. Thompson, MD, MPH, chief of the Division of Hematology and Elias Schwartz Endowed Chair in Hematology at Children's Hospital of Philadelphia

Alexis A. Thompson, MD, MPH

Long-term follow-up research on bluebird bio’s cell-based gene therapy betibeglogene autotemcel (beti-cel, Zynteglo) has continued since its 2017 FDA-approval for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell transfusions (transfusion dependent thalassemia; TDT). The latest analysis of data from patients treated with beti-cel was recently presented by Alexis Thompson, MD, MPH, the chief of hematology at Children’s Hospital of Philadelphia, at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California

To learn more about the findings, CGTLive™ sat down with Thompson for an interview at the conference. She emphasized that although long-term safety findings thus far are encouraging, continuing long-term follow-up with these patients is essential to monitor for potential risks such as replication-competent lentiviruses or insertional oncogenesis.

CGTLive: Can you tell us about the long-term follow-up data you presented at ASH 2023?

Alexis Thompson, MD, MPH: I was really, really privileged and proud to present the updated data from the entire suite of clinical trials looking at beti-cel and TDT. The poster that we presented this year covered up to 9 years of follow-up for the gene therapy in these patients. While there were 63 patients that have now been in follow-up up to 9 years, the focus of the poster really were the phase 3 patients. Those [patients’ data] are particularly important today because they form the basis for the commercial approval for beti-cel in 2022. But it is also important to consider the safety of the long-term data that included the phase 1 and phase 2 patients [HGB-204, NCT01745120; HGB-205, NCT02151526].

I think the important findings were that beti-cel seemed to be effective at all ages, with the youngest patient being 4 years old and the oldest being in their late 30s, and all genotypes or subtypes of TDT; that most of the side effects seem to be those that are consistent with an autologous transplant using busulfan for conditioning; and then, finally, that when patients become transfusion-independent, they remain so. I think another important part of our presentation was looking at patient-reported outcomes—looking at quality of life. Whether patients actually had relatively good quality of life prior to gene therapy or had some areas where they really had impaired quality of life compared to the general population, everyone seems to have benefit by-and-large from completing gene therapy.

Is there further research you would like to see done with beti-cel?

I think we will benefit from continuing to have long-term follow up for these individuals. We've not had any major complications like replication-competent lentiviruses or insertional oncogenesis. I think that we need to continue to monitor patients for these. It's been very encouraging that we're not seeing that. Also, by and large, once they recover, their hemoglobin and other parameters remain stable, but they do need long-term follow up.

Is there any other research from your center that you would like to discuss?

We had a second poster presentation, which occurred last night, looking at iron control after gene therapy. We know that because patients have had lifelong transfusions with TDT, it is expected that they have some degree of iron overload, even when receiving iron chelation. As such, it was very exciting to see the number of patients who have either resumed iron control (with either oral chelators or phlebotomy)—seeing them actually be able to be safely treated after gene therapy—but most importantly when they discontinued chelation or phlebotomy that their iron accumulation remains flat, meaning that they do not reaccumulate iron. What that speaks to is that their degree of iron dysregulation or ineffective erythropoiesis have improved to the point where they are not likely to have reaccumulation of iron.

This transcript has been edited for clarity.

1. FDA approves first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular blood transfusions. News release. FDA. August 17, 2022.
2. Thompson AA, Olson TS, Walters MC, et al. Sustained efficacy, safety, and improved quality of life in adult and pediatric patients with transfusion-dependent β-thalassemia up to 9 years post treatment with betibeglogeneautotemcel (beti-cel). Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #1102
3. Kwiatkowski JL, Olson TS, Walters MC, et al. Improvement in iron burden in patients with transfusion-dependent β-thalassemia (TDT) treated with betibeglogene autotemcel (beti-cel) gene therapy: up to 9 years of follow-up. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract #2480
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