In patients with transfusion-dependent beta-thalassemia, a single gene therapy infusion is capable of yielding durable transfusion independence and substantial improvements in iron overload, an investigator reported at the annual meeting of the American Society of Hematology.
Among patients who received betibeglogene autotemcel (beti-cel) in a phase 3 trial and enrolled in a long-term follow-up study, nearly 90% achieved durable transfusion independence, according to Alexis A. Thompson, MD, MPH, of the hematology section at the Ann & Robert H. Lurie Children's Hospital of Chicago.
The median duration of ongoing transfusion independence was nearly 3 years as of this report, which Thompson described in a press conference at the meeting.
In a subanalysis of this international study, Thompson and co-investigators reported that in patients who achieve transfusion independence, chelation reduced iron, and iron markers stabilized even after chelation was stopped.
Beyond 2 years post-infusion, no adverse events related to the drug product were seen. This suggested that the therapy has a favorable long-term safety profile, according to Thompson.
"At this point, we believe that beti-cel is potentially curative for patients with TDT [transfusion-dependent beta-thalassemia]," Thompson said in the press conference.
This study answers one of the major outstanding questions about beti-cel and iron metabolism, according to Arielle L. Langer, MD, MPH, an instructor in medicine at Harvard Medical School and attending physician for adult thalassemia patients at Brigham and Women's and Dana Farber Cancer Institute, both in Boston.
"Seeing the restoration of iron metabolism, it really takes us a step closer to really thinking the term 'cure' might truly apply," Langer said in an interview.
Langer said she looks forward to "very long-term outcomes" of beti-cel-treated patients to see whether endocrinopathies and other long-term sequelae of TDT are also abated.
"This [study] is a great intermediate point, but really, when we think about how thalassemia harms and kills our patients, we really sometimes measure that in decades," she said.
Beta-thalassemia is caused by mutations in the beta-globin gene, resulting in reduced levels of hemoglobin. Patients with TDT, the most serious form of the disease, have severe anemia and are often dependent on red blood cell transfusions from infancy onward, Thompson said.
With chronic transfusions needed to maintain hemoglobin levels, TDT patients inevitably experience iron overload, which can lead to organ damage and can be fatal. Consequently, patients will require lifelong iron chelation therapy, she added.
Beti-cel, an investigational ex vivo gene addition therapy currently under review by the U.S. Food and Drug Administration, involves adding functional copies of a modified form of the beta-globin gene into a patient's own hematopoietic stem cells. Once those cells are reinfused, patients may produce adult hemoglobin at levels that eliminate the need for transfusions, according to Thompson.
At the meeting, Thompson reported on patients from two phase 1/2 and two phase 3 beti-cel clinical trials who subsequently enrolled in LTF-303, a 13-year follow-up study of the gene therapy's safety and efficacy.
A total of 57 patients were included in this report, making it the largest gene therapy program to date in any blood disorder, according to Thompson. Before receiving beti-cel, the patients, who had a broad range of thalassemia genotypes, were receiving between 10 and almost 40 red blood cell transfusions per year, she reported.
Patients ranged in age from 5 to 35 years. The median age in the phase 1/2 studies was 20 years, while in the phase 3 studies it was 15 years.
"The early experience in the phase 1/2 trials allowed us to be more comfortable with enrolling more children, and that has actually helped us to understand safety and efficacy and children in the phase 3 setting," Thompson said.
Fertility preservation measures had been undertaken by about 59% of patients from the phase 1/2 studies and 71% of patients from the phase 3 studies, the data show.
Among patients from the phase 3 beti-cel studies who could be evaluated, 31 out of 35 (or 89%) achieved durable transfusion independence, according to the investigator.
The median duration of ongoing transfusion independence was 32 months, with a range of about 18 to 49 months, she added.
Thompson also reported a subanalysis intended to assess iron status in 16 patients who restarted and then stopped chelation. That subanalysis demonstrated iron reduction in response to chelation, and then stabilization of iron markers after chelation was stopped. Post-gene therapy chelation led to reductions in liver iron concentration and serum ferritin that remained relatively stable after chelation was stopped, she said.
Serious adverse events occurred in eight patients in the long-term follow-up study. However, adverse events related to beti-cel have been absent beyond 2 years post-infusion, according to Thompson, who added that there have been no reported cases of replication-competent lentivirus, no clonal expansion, no insertional oncogenesis, and no malignancies observed.
"Very reassuringly, there have been 2 male patients, one of whom underwent fertility preservation, who report having healthy children with their partners," she added.
Thompson provided disclosures related to Baxalta, Biomarin, bluebird bio, Inc., Celgene/BMS, CRISPR Therapeutics, Vertex, Editas, Graphite Bio, Novartis, Agios, Beam, and Global Blood Therapeutics.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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Cite this: Beta-Thalassemia Gene Therapy Achieves Transfusion Independence - Medscape - Dec 12, 2021.