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.
Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency / Migliavacca, M.; Barzaghi, F.; Fossati, C.; Rancoita, P. M. V.; Gabaldo, M.; Dionisio, F.; Giannelli, S.; Salerio, F. A.; Ferrua, F.; Tucci, F.; Calbi, V.; Gallo, V.; Recupero, S.; Consiglieri, G.; Pajno, R.; Sambuco, M.; Priolo, A.; Ferri, C.; Garella, V.; Monti, I.; Silvani, P.; Darin, S.; Casiraghi, M.; Corti, A.; Zancan, S.; Levi, M.; Cesana, D.; Carlucci, F.; Pituch-Noworolska, A.; Abdelaziz, D.; Baumann, U.; Finocchi, A.; Cancrini, C.; Ladogana, S.; Meinhardt, A.; Meyts, I.; Montin, D.; Notarangelo, L. D.; Porta, F.; Pasquet, M.; Speckmann, C.; Stepensky, P.; Tommasini, A.; Rabusin, M.; Karakas, Z.; Galicchio, M.; Leonardi, L.; Duse, M.; Guner, S. N.; Di Serio, C.; Ciceri, F.; Bernardo, M. E.; Aiuti, A.; Cicalese, M. P.. - In: NATURE MEDICINE. - ISSN 1078-8956. - 30:2(2024), pp. 488-497. [10.1038/s41591-023-02789-4]
Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency
Rancoita P. M. V.;Ferrua F.;Recupero S.;Consiglieri G.;Sambuco M.;Priolo A.;Ferri C.;Corti A.;Levi M.;Di Serio C.;Ciceri F.;Bernardo M. E.;Aiuti A.;Cicalese M. P.
2024-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
