BACKGROUND: Autologous hematopoietic stem cell (HSC) gene therapy could be an effective treatment for transfusion-dependent β-thalassemia (TDT) without some of the limitations and risks associated with allogeneic HSC transplantation. LentiGlobin Drug Product (DP) contains autologous HSC (CD34+ cells) transduced ex vivo with the betibeglogene darolentivec (BB305) lentiviral vector encoding a human β-globin gene with the anti-sickling T87Q mutation (HbAT87Q). The Northstar Study(HGB-204; NCT01745120) is an international, multi-center phase 1/2 clinical trial examining the safety and efficacy of LentiGlobin investigational gene therapy in patients with TDT. As of the most recent data cut (June 2, 2017), all patients have 1 to 3 years of follow-up post DP infusion.

METHODS: Patients (12-35 years of age) with TDT were enrolled at participating sites in the U.S., Australia, and Thailand. Autologous CD34+ cells were collected by mobilization and apheresis and transduced with the BB305 vector in a centralized facility. Patients underwent myeloablative conditioning with intravenous busulfan prior to infusion of transduced cells. Patients were monitored for hematologic engraftment, vector copy number (VCN), levels of HbAT87Q, and red blood cell (RBC) transfusion requirements post-infusion. Safety data, including adverse events (AEs), vector integration site analysis, and surveillance for replication competent lentivirus (RCL), were evaluated post-infusion. The primary analysis period for the study is 24 months following infusion; patients then transition into a long-term study for an additional 13 years of follow-up.

RESULTS: Eighteen patients with TDT (8 with β00 and 10 with non-β00 genotypes; aged 12-35 years) received LentiGlobin DP. The median DP VCN was 0.7 (range: 0.3-1.5) copies/diploid genome, the median cell dose was 8.1 x 106 (range: 5.2-18.1 x 106) CD34+ cells/kg, and the proportion of transduced CD34+ cells was 17-58%. The toxicity profile observed to date has been typical of myeloablative conditioning. During a follow-up period of up to 38.3 months post-infusion (median 25.5 months; range: 14.9-38.3 months), there have been no ≥ grade 3 DP-related AEs and no evidence of clonal dominance or RCL. Serious AEs occurring after DP infusion have been reported in 6/18 (33%) patients: venoocclusive liver disease (n=2) and 1 case each of cellulitis, diarrhea, gastroenteritis, Klebisella infection, cardiac ventricular thrombosis, device-related thrombosis, and hyperglycemia. No serious AEs were considered related to DP.

Of the 10 patients with non-β00 genotypes, 8 have been free of transfusions for a median of 27.1 (range 12.5-35.2) months. At their latest study visit (n=8: Months 15-36), their total Hb level ranged from 9.3-13.7 g/dL, and their HbAT87Q level was 3.6-9.6 g/dL. The peripheral VCN ranged from 0.1−1.0. Notably, of these 8 patients, 6 have achieved "transfusion independence" (TI), defined as ≥12 months without transfusions with a weighted average Hb ≥9 g/dL. The 2 patients with non-β00 genotypes who still require intermittent transfusions had annual transfusion volumes reduced by 30% and 94%; both received DP with a VCN in the lower range (DP VCNs: 0.3 and 0.4).

Two patients with β00 genotypes have not received a transfusion in more than a year. At the patients' last study visit (Month 24/Month 12), total Hb levels were 9.0 and 10.2 g/dL, HbAT87Q levels were 8.4 and 6.8 g/dL, and peripheral VCNs were 0.9 and 0.6, respectively. Six patients with β00 genotypes have continued transfusions. However, their annual transfusion volumes have decreased by a median of 63% (range: 19% to 81%), from an annualized volume of 124.4-261.3 ml/kg/year at baseline to an annualized volume of 31.4-212.6 ml/kg/year (from 6 months post-infusion to data cut).

CONCLUSIONS: With up to 3 years of follow-up, the Northstar Study is the largest international gene therapy trial in TDT to date. All patients, 9 of whom have at least 2 years of follow-up, have demonstrated ongoing clinical benefit with a manageable safety profile. A total of 10 patients (8/10 with non-β00, 2/10 with β00 genotypes) have been able to discontinue RBC transfusions and remain clinically well. The 8/18 patients still receiving transfusions have significantly reduced annualized transfusion volumes (up to 81% and 94% in patients with β00 and non-β00 genotypes, respectively).


Kwiatkowski: Bluebird Bio: Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Agios: Consultancy, Honoraria; Ionis: Consultancy, Honoraria. Thompson: Novartis: Consultancy, Research Funding; Baxalta: Research Funding; Celgene: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding. Rasko: Genea: Equity Ownership; IMAGO Biosciences: Consultancy, Equity Ownership; Rarecyte: Consultancy, Equity Ownership; Novartis: Other: Clinical trials, Speakers Bureau; Spark: Equity Ownership, Other: clinical trials, Speakers Bureau; President-Elect International Society for Cellular Therapy: Membership on an entity's Board of Directors or advisory committees. Schiller: bluebird bio: Research Funding; mateon therapeutics: Research Funding. von Kalle: bluebird bio: Consultancy; GeneWerk: Equity Ownership. Leboulch: bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Deary: bluebird bio: Employment, Equity Ownership. Asmal: bluebird bio: Employment, Equity Ownership. Walters: bluebird bio: Research Funding; AllCells, Inc: Other: Medical Director; Sangamo Therapeutics: Consultancy; ViaCord Processing Lab: Other: Medical Director.

Author notes


Asterisk with author names denotes non-ASH members.

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