Gene therapy potentially curative for patients with transfusion-dependent beta-thalassemia
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Patients with transfusion-dependent beta-thalassemia who received betibeglogene autotemcel achieved durable transfusion independence with near-normal hemoglobin levels, according to study results with up to 7 years of follow-up.
“At this point, we believe that [betibeglogene autotemcel] is potentially curative for patients with [transfusion-dependent beta-thalassemia],” Alexis A. Thompson, MD, MPH, interim division head of hematology, oncology, neuro-oncology and stem cell transplantation at Ann & Robert H. Lurie Children’s Hospital of Chicago, said during a press conference at ASH Annual Meeting and Exposition.
Thompson described beta-thalassemia as a severe chronic inherited blood disorder due to one of many mutations in the beta-globin gene that result in ineffective erythropoiesis.
“In its most severe form, there is a complete absence of the ability to make beta-globin, which translates into not making hemoglobin A,” she said.
Transfusion-dependent beta-thalassemia requires lifelong, regular packed red blood cell transfusions and iron chelation therapy. Still, patients often experience iron overload, which can lead to serious complications such as progressive multiorgan damage and organ failure.
Betibeglogene autotemcel (bluebird bio), or beti-cel, is a one-time ex-vivo gene therapy that addresses the underlying cause of transfusion-dependent beta-thalassemia to potentially enable lifelong, stable production of modified adult hemoglobin (Hb) sufficient to achieve transfusion independence. The therapy adds functional copies of a modified form of the beta-globin gene into a patient’s hematopoietic stem cells.
At ASH, Thompson reported results of 57 patients with a broad range of genotypes who received beti-cel across four studies and enrolled in LTF-303, a 13-year follow-up study to examine the safety and efficacy of the one-time gene therapy.
“This is the largest-to-date gene therapy program in any blood disorder,” Thompson said.
Patients in the two phase 1/phase 2 studies and the two phase 3 studies ranged in age from 5 to 35 years, required 10 to nearly 40 red blood cell transfusions per year and had significant iron overload. All patients are offered fertility preservation, Thompson noted.
Median follow-up was 41.4 months (range, 23-87.5).
Among patients who completed phase 3 studies, 89% (n = 31 of 35) achieved durable transfusion independence (median duration, 32 months; range, 18.2-49.1; weighted average Hb, 11.6 g/dL). In addition, 68% (n = 15 of 22) of patients in the phase 1/phase 2 studies achieved transfusion independence.
Researchers also observed restoration of iron homeostasis and a lower iron management burden among patients who received beti-cel after discontinuing iron chelation.
After 2 years of follow-up, all patients remained alive and there have been no cases of vector-derived replication competent lentivirus, clonal expansion, insertional oncogenesis or malignancies, Thompson said. Two male patients, including one who received fertility preservation, reported births of healthy children.
“It would appear that this one-time beti-cel gene therapy is capable of achieving durable transfusion independence, that iron overload is improved and stable in these individuals, and that the adverse event profile seems quite favorable,” Thompson said.
Perspective
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Iberia Romina Sosa, MD, PhD
Thompson and colleagues provided an update on LTF-303, with long-term follow-up of patients with transfusion-dependent beta-thalassemia who received beti-cel, a novel ex-vivo gene therapy designed to add functional copies of a modified beta-globin gene into the patient’s hematopoietic stem cells. Once patients have the modified beta-globin gene, they have hematopoietic stem cells with the potential to produce gene therapy-derived adult Hb at levels that can eliminate or significantly reduce the need for transfusions.
During the parent study, 68% of patients in the phase 1/phase 2 trial and 89% of patients in the phase 3 trial displayed transfusion independence. The 7-year update shows a sustained response for all patients at 32 months. This is a remarkable achievement for a patient population in which transfusions have been the mainstay of therapy. Moreover, the study demonstrates a restoration of iron hemostasis, with most patients able to stop iron chelation and showing an improvement in cardiac and liver iron concentration. This is essential given the poor tolerability of some patients for iron chelation agents, consequently leading to poor compliance and long-term complications of iron overload in major organs.
Important with any therapy is the tolerability and side-effect profile. The study reports several rare serious adverse events, including endocrine (diabetic ketoacidosis, gonadotropic insufficiency), reproductive (ectopic pregnancy, fetal death) and gastrointestinal (cholelithiasis, gallbladder wall thickening/polyp) complications. It is not clear if these are complications of long-term disease or from the therapy. Although all of these were reported in single patients, the study sample is quite small.
Overall, the therapeutic intervention with beti-cel appears to show great promise.
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Thompson AA, et al. Abstract 573. Presented at: ASH Annual Meeting and Exposition. Dec. 11-14, 2021; Atlanta.
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