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.Fifteen years' follow-up of clinical development and real-world data from 43 patients show that gammaretroviral gene therapy for adenosine deaminase deficiency has a positive long-term efficacy profile, warranting continued safety monitoring of patients receiving gene therapy.

Migliavacca, M., Barzaghi, F., Fossati, C., Rancoita, P., Gabaldo, M., Dionisio, F., et al. (2024). Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency. NATURE MEDICINE, 30(2), 488-497 [10.1038/s41591-023-02789-4].

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency

Migliavacca, Maddalena;Barzaghi, Federica;Recupero, Salvatore;Consiglieri, Giulia;Finocchi, Andrea;Cancrini, Caterina;Aiuti, Alessandro;
2024-02-01

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.Fifteen years' follow-up of clinical development and real-world data from 43 patients show that gammaretroviral gene therapy for adenosine deaminase deficiency has a positive long-term efficacy profile, warranting continued safety monitoring of patients receiving gene therapy.
feb-2024
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/38
Settore MEDS-20/A - Pediatria generale e specialistica
English
Con Impact Factor ISI
Migliavacca, M., Barzaghi, F., Fossati, C., Rancoita, P., Gabaldo, M., Dionisio, F., et al. (2024). Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency. NATURE MEDICINE, 30(2), 488-497 [10.1038/s41591-023-02789-4].
Migliavacca, M; Barzaghi, F; Fossati, C; Rancoita, Pmv; Gabaldo, M; Dionisio, F; Giannelli, S; Salerio, Fa; Ferrua, F; Tucci, F; Calbi, V; Gallo, V; R...espandi
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/389419
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 6
  • ???jsp.display-item.citation.isi??? 5
social impact