Lentiviral Gene Therapy: A Major Win for Patients With Beta-Thalassemia Major?

Lentiviral vector gene therapy via autologous hematopoietic cell transplantation (AHCT) reduced transfusion needs and even led to transfusion independence in patients with β-thalassemia major, according to updated results from the Northstar Study, an open-label, multicenter, phase I/II study.

Lead investigator Mark C. Walters, MD, from the University of California, San Francisco Benioff Children’s Hospital in Oakland, California, presented updated results from the Northstar Study at this year’s ASH annual meeting, saying that, although this was a small study with short-term follow-up, the results are “promising.”

In the Northstar Study, researchers used a lentiviral vector to transport a functioning hemoglobin (Hb) gene (an engineered ßA-T87Q-globin gene, known as LentiGlobin BB305 Drug Product) into patients’ hematopoietic stem cells and then transfused them back into the patients. Earlier results indicated that patients with ß-thalassemia major who underwent AHCT with the lentiviral drug product experienced improved ßA-T87Q-globin production, potentially leading to transfusion independence.

While the study is ongoing, results from the first 10 treated patients (median age = 26 years; range = 18-35 years) with transfusion-dependent β-thalassemia major have been presented:

  • Five with β0/β0 genotype
  • Three with β0/βE genotype
  • One with β0/β+ genotype
  • One with heterozygous β0 genotype

All of the patients included in the study had undergone myeloablation with busulfan prior to infusion with the lentiviral drug product.

Patients were monitored for hematologic recovery, vector copy number, ßA-T87Q-globin expression, adverse events, and transfusion requirements after drug product infusion. Safety was monitored through integration site analysis and replication-competent lentivirus assays.

Patients received a median of 7.9 x 106 CD34+ cells/kg, and engraftment was seen in all of the patients after infusion; median time to engraftment was 17 days for neutrophils (range = 13-29) and 30 days for platelets (range = 17-35).

“All of the subjects treated in the study had a clinical benefit, which was most pronounced in the patients with non-β0/β0 genotypes,” Dr. Walters said. All subjects had detectable vector-derived HbAT87Q, with a median peak level of 5.4 g/dL (range = 2.4-8.9 g/dL) at three or more months post-infusion.

Among the seven subjects who were monitored for at least six months post-infusion, median HbAT87Q production was 5.2 g/dL (range = 1.9-8.2 g/dL). At the last follow-up visit, total Hb ranged from 8.5 to 11.1 g/dL.

Prior to infusion, patients had received a median of 170 mL/kg per year of red blood cell (RBC) transfusions. After treatment, of the seven subjects followed for six months or longer, β-globin and HbAT87Q expression was sufficient for transfusion independence in all four patients with a non-β0/β0 genotype. These patients remained transfusion-free for at least 90 days (median = 287 days; range = 171-396 days) and, at the time of last follow-up, their total Hb ranged from 9.1 to 12.2 g/dL.

Two patients with β0/β0 genotype have received a single RBC transfusion post-discharge, the authors noted, while one patient with β0/β0 genotype remains transfusion-dependent.

After a median follow-up of 198 days post-infusion, the researchers found that the safety profile was consistent with AHCT, with no grade 3 or higher treatment-related adverse events recorded. There was also no clonal dominance or replication-competent lentivirus observed.

“The updated data from the Northstar Study continue to show acceptable patient safety with regard to myeloablation, drug product infusion risks, and genotoxicity at this early follow-up,” said Dr. Walters, but he noted that “longer follow-up is needed to understand the clinical significance of this data.”


Walters MC, Rasko J, Hongeng S, et al. Update of results from the Northstar Study (HGB-204): a phase 1/2 study of gene therapy for beta-thalassemia major via transplantation of autologous hematopoietic stem cells transduced ex-vivo with a lentiviral beta AT87Q-globin vector (LentiGlobin BB305 Drug Product). Abstract #201. Presented at the ASH Annual Meeting, December 6, 2015; Orlando, Florida.