Journal Article

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

Barzaghi, Federica, Strocchio, Luisa, Locatelli, Franco, Naldini, Luigi, Tucci, Francesca, Pizzi, Simone, Riccardo, Sara, Ciceri, Fabio, Fossati, Claudia, Pais, Giulia, Tartaglia, Marco, Giannelli, Stefania, Cavazzana, Marina, Ciolfi, Andrea, Rudilosso, Laura, Scala, Serena, Calabria, Andrea, Gentner, Bernhard, Volpin, Monica, Merelli, Ivan, Colantuono, Chiara, Migliavacca, Maddalena, Bruselles, Alessandro, Pacillo, Lucia, Schmidt, Manfred, Vinti, Luciana, Cacchiarelli, Davide, Benedicenti, Fabrizio, Barcella, Matteo, Cesana, Marcella, Merli, Pietro, Spinozzi, Giulio, Casiraghi, Miriam, Cesana, Daniela, Gallina, Pierangela, Vago, Luca, Dionisio, Francesca, Caruso, Roberta, Gazzo, Francesco, Cancrini, Caterina, Aiuti, Alessandro, Draghi, Eleonora, Six, Emmanuelle, Carlucci, Filippo, Montini, Eugenio, Cicalese, Maria Pia

2024

Overview

Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-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 γ-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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/15 / 38/22 / 38/23 / 38/43 / 38/70 / 38/77 / 38/91 / 631/208/69 / 631/67/2332 / Acute lymphoblastic leukemia / Adenosine / Adenosine deaminase / Adenosine Deaminase - deficiency / Adenosine Deaminase - genetics / Agammaglobulinemia - genetics / Agammaglobulinemia - therapy / Blast cells / Chemotherapy / Clinical trials / DNA methylation / Expression vectors / Gene therapy / Genetic Therapy - methods / Genetic transformation / Genetic Vectors - genetics / Health services / Hematopoietic Stem Cell Transplantation / Hematopoietic stem cells / Humanities and Social Sciences / Humans / Immune system / Insertion / Leukemia / LIM protein / Lymphocytes T / Male / multidisciplinary / Mutation / Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - therapy / Progenitor cells / Proto-Oncogene Mas / Remission / Retroviridae - genetics / Science / Science (multidisciplinary) / Severe combined immunodeficiency / Severe Combined Immunodeficiency - genetics / Severe Combined Immunodeficiency - therapy / Stem cells / Thymus / Transgenes