Over 10% of patients with a fatal neurodegenerative disease who received bluebird bio’s FDA-approved gene therapy Skysona (elivaldogene autotemcel) have developed hematological cancers, further highlighting the well-known risks of using lentiviral vectors. The patients were treated with Skysona to slow the progression of cerebral adrenoleukodystrophy (CALD), an X-linked rare inherited neurodegenerative disease that affects a peroxisomal fatty acid transporter central to fatty acid metabolism. The mutation leads a toxic build-up of fatty acids, particularly in the white matter in brain and spinal cord and the adrenal glands. Skysona comprises autologous CD34+ cells engineered ex vivo to express the ABCD1 gene, which encodes a protein implicated in adrenoleukodystrophy.

Six of 67 patients had developed myelodysplastic syndrome and a seventh developed acute myeloid leukemia, between 14 and 92 months after treatment. Skysona uses a replication-deficient, HIV-1-derived vector named Lenti-D that contains the synthetic promoter MNDU3, which drives strong gene expression in multiple cell types. Six of the cases were associated with the expansion of a cell clone containing at least one vector insertion in a known proto-oncogene — five in MECOM and one in its closely related homologue PRDM16, the study authors report. The problems may not have been solely due to the lentiviral vector, however. Because six of the seven cases occurred in the ALD-104 study, the myeloablative conditioning regimen may also have been a contributory factor — in ALD-104, participants received busulfan and fludarabine, whereas in ALD-102 busulfan and cyclophosphamide were used. The patients who developed cancer were treated successfully, except for one who died after developing graft-versus-host disease and a lung infection. Given the life-threatening nature of CALD, the study can be considered a clinical success, but the possibility of further cancer cases cannot be eliminated.