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Gene therapy appears effective in patients with transfusion-dependent beta-thalassemia
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SAN DIEGO — The infusion of a lentiviral vector containing an engineered betaA-T87Q-globin gene effectively reduced or eliminated the transfusion needs of patients with beta-thalassemia major without leading to severe adverse events, according to updated results of a full cohort from the Northstar Study presented at the ASH Annual Meeting and Exposition.
Researchers developed the gene therapy drug product, LentiGlobin BB305 (Bluebird Bio Inc.), which uses a non-communicable virus to deliver a fully functioning HBB gene to the patient’s blood-producing stem cells.
Alexis A. Thompson, MD, MPH, head of hematology at Ann and Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics at Northwestern University Feinberg School of Medicine, and colleagues conducted a full cohort follow-up analysis of the phase 1/phase 2 HGB-204 multi-center study to assess the safety and efficacy of LentiGlobin.
The analysis included 18 patients (women, n = 13; median age, 22 years; range, 12-35) with transfusion-dependent beta-thalassemia, including eight patients with the beta0/beta0 genotype, six with the beta0/betaE genotype and one with the beta0/beta+ genotype.
Fourteen patients had at least 6 months or more of follow-up and one patient completed the 24-month primary analysis.
The patients received a median of 8.1 x 106 CD34-positive cells/kg (range, 5.2 to 18.1 x 106/kg) with a median vector copy number of 0.7 (range, 0.3-1.5 copies/diploid genome).
Patients engrafted with a median time of 18.5 days (range, 14 to 30 days) to neutrophil recovery.
Patients underwent myeloablation with intravenous busulfan, followed by infusion of CD34-positive cells transduced with LentiGlobin.
The researchers then monitored hematologic engraftment, vector copy number, hemoglobin AT87Q expression and transfusion requirements.
“The toxicity profile appears to be consistent with a single agent myeloablation busulfan and there has been no evidence of clonal dominance,” Thompson said during the presentation.
After a median follow-up of 14.4 months (range, 3.7 to 27 months), no grade 3 or higher treatment-related adverse events had occurred and there was no evidence of replication competent lentivirus.
Fourteen patients have been monitored for at least 6 months post-infusion. These patients produced a median hemoglobin AT87Q of 5.2 g/dL (range, 1.9-8.2), with a median VCN in peripheral blood of 0.4 (range, 0.2−1).
Patients with non-beta0/beta0 genotypes and 12 months or more of follow-up (n = 5) have remained free of transfusions (median, 19.4 months; range, 15.3 to 24 months) with total hemoglobin ranging from 9/dL to 11.9 g/dL at their most recent visit.
Five patients with beta0/beta0 genotype with a follow-up of 12 months or more continued to require transfusions. However, the annual median transfusions volumes decreased 60% from baseline (median, 171.9 mL/kg/year; range, 168.1 to 223.2 mL/kg/year) to 67.8 mL/kg/year (range, 14.8-123.7 mL/kg/year) post-treatment.
“LentiGlobin BB305 continues to show promise in treatment for patients who have transfusion-dependent beta-thalassemia,” Thompson said. “Patients who have non-beta0/ beta0 genotypes and more than 12 months of follow-up remain red cell-transfusion independent. While we are very pleased about the success in both patients who are non-beta0/beta0 and beta0/beta0, we think there is room for improvement.” – by Ryan McDonald
Reference:
Thompson AA, et al. Abstract 1175. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: Thompson reports receiving research funding from Amgen, ApoPharma, Baxalta, Bluebird Bio Inc., Celgene, Eli Lily, Mast and Novartis. Please see the full study for a list of all other relevant financial disclosures.