Gene therapy exceeds expectations in β-thalassemia
The gene therapy LentiGlobin can reduce or eliminate transfusion dependence in patients with β-thalassemia, according to a pair of phase 1/2 studies.
Fifteen of the 22 patients in these trials were able to discontinue red blood cell (RBC) transfusions after receiving LentiGlobin.
In the 9 patients with severe transfusion-dependent β-thalassemia (TDT), LentiGlobin reduced the transfusion volume by 73%.
There were 5 adverse events (AEs) considered possibly or probably related to LentiGlobin, all them grade 1.
“These study results exceeded our expectations, with clinical benefit for nearly all patients . . . ,” said Alexis Thompson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.
“Since we saw such positive results, we are now enrolling patients as young as 5 years old on a phase 3 trial of gene therapy for transfusion-dependent thalassemia.”
Dr Thompson and her colleagues reported results from the phase 1/2 trials—known as HGB-204 and HGB-205—in NEJM. The studies were sponsored by Bluebird Bio, the company developing LentiGlobin.
Patients in HGB-204
HGB-204 (also known as Northstar) is a multicenter study that was recently completed. It included 18 patients with TDT. They had a median age of 20 (range, 12 to 35) at baseline, and 72% were female. Seventy-eight percent were Asian, and 22% were white.
Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.
The patients’ median monthly transfusion volume for 2 years before study enrollment was 13.6 ml/kg (range, 10.4 to 21.8). The median age at which patients started regular transfusions was 3.5 years (range, 0 to 26.0). Six patients had undergone splenectomy.
Patients in HGB-205
HGB-205 is an ongoing study being conducted at a single site in France. It was designed to evaluate LentiGlobin in patients with TDT or severe sickle cell disease.
The NEJM paper includes 4 patients with TDT from this study. They had a median age of 18 (range, 16 to 19) at baseline, and half were female. Half were Asian, and the other half were white.
Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.
The patients’ median monthly transfusion volume for 2 years before study enrollment was 15.2 ml/kg (range, 11.6 to 15.7). The median age at which patients started regular transfusions was 1.8 years (range, 0 to 14.0). Three patients had undergone splenectomy.
Treatment
For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients.
CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q).
The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.
In HGB-205 only, patients received enhanced RBC transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.
Safety
In HGB-204, there were 5 grade 1 AEs considered possibly or probably related to LentiGlobin. These included abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).
There were 9 serious AEs, including 2 episodes of grade 3 veno-occlusive liver disease that were attributed to busulfan.
The remaining serious AEs were Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis (all grade 3), as well as device-related thrombosis and infectious diarrhea (both grade 2).
