Image by Betty Pace
A sickled red blood cell beside a normal one
Researchers have reported a favorable outcome in the first patient with severe sickle cell disease (SCD) to receive gene therapy in the HGB-205 study.
The subject, known as Patient 1204, was treated with LentiGlobin BB305, a product consisting of his own manipulated hematopoietic stem cells (HSCs).
A functional human β-globin gene was inserted into the patient’s HSCs ex vivo, and the cells were returned to him via transplant.
Fifteen months after receiving this treatment, Patient 1204 had high levels of anti-sickling hemoglobin (HbAT87Q), and there were no adverse events thought to be related to LentiGlobin BB305.
These results were published in NEJM. The research was supported by bluebird bio, the company developing LentiGlobin BB305.
Patient 1204 is a male with βS/βS genotype. In May 2014, at 13 years of age, the patient was enrolled in the HGB-205 study at Hôpital Necker-Enfants Malades in Paris, France.
The patient had received hydroxyurea from age 2 to 9 and had both a cholecystectomy and a splenectomy. He received regular transfusions (plus iron chelation with deferasirox) for 4 years prior to this study.
The patient had an average of 1.6 SCD-related events annually in the 9 years prior to starting transfusions. His complications from SCD included vaso-occlusive crises, acute-chest syndrome, bilateral hip osteonecrosis, and cerebral vasculopathy.
The patient underwent 2 bone marrow harvests to collect HSCs for gene transfer and back-up (6.2×108 and 5.4×108 total nucleated cells/kg harvested).
CD34+ cells were enriched from the harvested marrow and then transduced with LentiGlobin BB305 lentiviral vector.
The patient underwent myeloablation with intravenous busulfan (2.3 to 4.8 mg/kg per day for 4 days) with daily pharmacokinetic studies and dose adjustment. Total busulfan area under the curve was 19,363 μmol/min.
After a 2-day washout, the patient received LentiGlobin BB305 in October 2014 at a post-thaw total dose of 5.6×106 CD34+ cells/kg. Neutrophil and platelet engraftment were achieved on day 38 and day 91 post-transplant, respectively.
Red blood cell transfusions were to be continued after transplant until a sufficient proportion of HbAT87Q (25% to 30% of total hemoglobin) was detected. Transfusions were discontinued after day 88 post-transplant.
HbAT87Q reached 5.5 g/dL (46% of total hemoglobin) at month 9 and continued to increase to 5.7 g/dL at month 15 (48%). Hemoglobin S levels were 5.5 g/dL (46%) at month 9 and 5.8 g/dL (49%) at month 15.
Total hemoglobin levels were stable, between 10.6 and 12.0 g/dL, from months 6 to 15. Fetal hemoglobin levels remained below 1.0 g/dL.
No adverse events related to LentiGlobin BB305 were reported. There were, however, adverse events related to busulfan conditioning (grade 3 anemia, thrombocytopenia, and infection; grade 4 neutropenia).
During 15 months of follow-up, there were no SCD-related clinical events or hospitalizations. The patient was able to stop all medications, including pain medication.
The patient resumed regular school attendance and reported full participation in normal physical activities.
“We have managed this patient at Necker for more than 10 years, and standard treatments were not able to control his SCD symptoms,” said Marina Cavazzana, MD, PhD, of Hôpital Necker-Enfants Malades.
“He had to receive blood transfusions every month to prevent severe pain crises. Since receiving the autologous stem cell transplant with LentiGlobin, he has been free from severe symptoms and has resumed normal activities, without the need for further transfusions.”
