A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID

hematopoietic stem cell gene therapy (GT) using a gamma-retroviral vector (gamma-RV) is an effective treatment for severe combined Immunodeficiency due to adenosine deaminase deficiency. here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. the patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low adenosine deaminase (ADA) activity resulting from methylation of viral promoter. the insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. the limited incidence of vector-related adverse events in ADA-deficiency compared to other gamma-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors.Leukaemia development has been reported as an associated risk of haematopoietic stem cell gene therapy (HSPC-GT) using retroviral vectors in different diseases. here, the authors show a case of T-cell acute lymphoid leukaemia in a patient with adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) treated with retroviral gene therapy.