Article
作者: Meinhardt, Andrea ; Monti, Ilaria ; Giannelli, Stefania ; Bernardo, Maria Ester ; Meyts, Isabelle ; Karakas, Zeynep ; Galicchio, Miguel ; Silvani, Paolo ; Baumann, Ulrich ; Pituch-Noworolska, Anna ; Gallo, Vera ; Gabaldo, Michela ; Consiglieri, Giulia ; Migliavacca, Maddalena ; Calbi, Valeria ; Carlucci, Filippo ; Finocchi, Andrea ; Tommasini, Alberto ; Casiraghi, Miriam ; Di Serio, Clelia ; Ferri, Chiara ; Guner, Sukru Nail ; Duse, Marzia ; Levi, Margherita ; Darin, Silvia ; Montin, Davide ; Zancan, Stefano ; Tucci, Francesca ; Barzaghi, Federica ; Salerio, Federica Andrea ; Pasquet, Marlène ; Rabusin, Marco ; Leonardi, Lucia ; Cancrini, Caterina ; Ferrua, Francesca ; Cesana, Daniela ; Sambuco, Maria ; Aiuti, Alessandro ; Ciceri, Fabio ; Corti, Ambra ; Fossati, Claudia ; Pajno, Roberta ; Cicalese, Maria Pia ; Speckmann, Carsten ; Ladogana, Saverio ; AbdElaziz, Dalia ; Dionisio, Francesca ; Recupero, Salvatore ; Porta, Fulvio ; Notarangelo, Lucia Dora ; Garella, Vittoria ; Stepensky, Polina ; Rancoita, Paola M V ; Priolo, Alessio
Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .