“Intra-Bone” Gene Therapy Reduced Transfusion Need in Patients With Beta-Thalassemia

Gene therapy could represent an alternative to hematopoietic stem cell transplantation (HCT) – the only curative therapy for beta-thalassemia – and may offer several advantages over HCT, including tailored conditioning with no need for immunosuppression after gene therapy and no risk of graft-versus-host disease or rejection. According to results from a phase I/II trial presented at the 2017 ASH Annual Meeting, patients with transfusion-dependent beta-thalassemia had a significantly reduced need for blood transfusions after receiving a single infusion of cells carrying corrected genes.

Sarah Marktel, MD, of the Hematology and Bone Marrow Transplantation Unit IRCCS San Raffaele Scientific Institute in Milan, Italy, explained during her presentation that the investigational gene therapy protocol used in this trial was based on the high-titer vector GLOBE, a third-generation, self-inactivating lentiviral vector encoding for the human beta globin gene.

“In the TIGET-BTHAL trial, patients with beta-thalassemia of any genotype undergo stem cell harvesting, and stem cells are then transferred to the pharmaceutical [sponsor] for insertion of the human beta globin gene,” she said. “Once genetically corrected, stem cells are infused into the patient after a conditioning regimen … directly in the bone marrow (BM).” The hematopoietic stem cells (HSCs) are administered into the hip, with the goal of enhancing engraftment and minimizing first-pass intravenous filter.

Three days after gene therapy, previously collected unstimulated autologous peripheral blood (PB) leukocytes (1-10×107 CD3+/kg) are reinfused intravenously to promote immune-reconstitution.

The trial began in 2015, with a goal of treating 10 patients in three age cohorts: three adults (group 1), three patients eight to 17 years (group 2), and four patients three to seven years (group 3). Enrollment was staggered based on evaluation of safety and preliminary efficacy in adult patients before inclusion of pediatric patients.

As of August 2017 (data cutoff), seven patients (3 adults 31-35 years and 4 pediatric patients 6-13 years) with different genotypes (β0/β0, β+/β+, and β0/β+) have been treated with GLOBE-transduced CD34+ cells at doses ranging from 16×106 to 19.5×106 cells/kg.

Patients were followed for a median of 13 months (range = 8-22 months). The procedure was well tolerated by all patients, Dr. Marktel noted, with no treatment-related adverse events (AEs), no evidence of replication competent lentivirus, and no abnormal clonal proliferation on regular PB and BM analyses. Grade 3/4 AEs or serious AEs were mostly infectious in origin, which the researchers called “expected after a myeloablative autograft.”

The median time to neutrophil engraftment was 19 days (range = 17-25 days) and 15 days (range = 10-21 days) to platelet engraftment. Multilineage engraftment of gene-modified cells was observed in PB and BM, with a median of 0.58 VCN/cell (range = 0.37-1.55 VCN/cell) in BM erythroid cells at six months post-gene therapy.

After a median of 16 months follow-up (range = 8-22 months), five of the seven patients had a reduced need for transfusions, including three pediatric patients who were transfusion-independent beginning one month after receiving the gene therapy until last follow-up (at 13, 10, and 8 months, respectively). Three adult patients had a reduction of transfusion requirement, but were still transfusion-dependent at last follow-up (at 22, 18, and 16 months, respectively), and one pediatric patient continues to receive regular blood transfusions.

Compared with previous trials in which the genetically modified HSCs were infused intravenously, the “intra-bone” administration demonstrated earlier evidence of successful engraftment, suggesting that this is a promising route of administration for gene therapy, Dr. Marktel said.

“Although the number of patients is small, our preliminary results also suggest the benefit could be greater in children than in adults,” Dr. Marktel concluded. “Our hypothesis is that younger stem cells in pediatric patients may be more favorably corrected by gene therapy and in general may lead to better engraftment and performance.”

The authors report financial relationships with GlaxoSmithKline, which licensed the beta-thalassemia gene therapy and funded this clinical trial.


Marktel S, Cicalese MP, Giglio F, et al. Gene therapy for beta thalassemia: preliminary results from the PHASE I/II Tiget-Bthal trial of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector. Abstract #355. Presented at the 2017 American Society of Hematology Annual Meeting, December 10, 2017; Atlanta, GA.