Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study

Francesca Ferrua, Maria Pia Cicalese, Stefania Galimberti, Stefania Giannelli, Francesca Dionisio, Federica Barzaghi, Maddalena Migliavacca, Maria Ester Bernardo, Valeria Calbi, Andrea Angelo Assanelli, Marcella Facchini, Claudia Fossati, Elena Albertazzi, Samantha Scaramuzza, Immacolata Brigida, Serena Scala, Luca Basso-Ricci, Roberta Pajno, Miriam Casiraghi, Daniele CanaruttoFederica Andrea Salerio, Michael H. Albert, Antonella Bartoli, Hermann M. Wolf, Rossana Fiori, Paolo Silvani, Salvatore Gattillo, Anna Villa, Luca Biasco, Christopher Dott, Emily J. Culme-Seymour, Koenraad van Rossem, Gillian Atkinson, Maria Grazia Valsecchi, Maria Grazia Roncarolo, Fabio Ciceri, Luigi Naldini, Alessandro Aiuti

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC)gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. Methods: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP)expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462)and EudraCT (number 2009-017346-32). Findings: Between April 20, 2010, and Feb 26, 2015, nine patients (all male)were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1–12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5–5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8–35·6)before gene therapy to 66·7% (55·7–98·6)at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1–31·0)to 76·6% (53·1–98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44–3·72)per patient-year of observation (PYO)in the year before gene therapy to 0·31 (0·04–1·11)per PYO in the second year after gene therapy and 0·17 (0·00–0·93)per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 10 9 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20–50 × 10 9 per L in one patient, 50–100 × 10 9 per L in five patients, and more than 100 × 10 9 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%)of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. Interpretation: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. Funding: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.

Original languageEnglish
Pages (from-to)e239-e253
JournalThe Lancet Haematology
Volume6
Issue number5
DOIs
Publication statusPublished - May 1 2019

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Wiskott-Aldrich Syndrome
Cell- and Tissue-Based Therapy
Genetic Therapy
Stem Cells
Wiskott-Aldrich Syndrome Protein
Therapeutics
Platelet Count
Clinical Studies
Safety
Observation
Vaccination
Infection
Tissue Donors

ASJC Scopus subject areas

  • Hematology

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Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome : interim results of a non-randomised, open-label, phase 1/2 clinical study. / Ferrua, Francesca; Cicalese, Maria Pia; Galimberti, Stefania; Giannelli, Stefania; Dionisio, Francesca; Barzaghi, Federica; Migliavacca, Maddalena; Bernardo, Maria Ester; Calbi, Valeria; Assanelli, Andrea Angelo; Facchini, Marcella; Fossati, Claudia; Albertazzi, Elena; Scaramuzza, Samantha; Brigida, Immacolata; Scala, Serena; Basso-Ricci, Luca; Pajno, Roberta; Casiraghi, Miriam; Canarutto, Daniele; Salerio, Federica Andrea; Albert, Michael H.; Bartoli, Antonella; Wolf, Hermann M.; Fiori, Rossana; Silvani, Paolo; Gattillo, Salvatore; Villa, Anna; Biasco, Luca; Dott, Christopher; Culme-Seymour, Emily J.; van Rossem, Koenraad; Atkinson, Gillian; Valsecchi, Maria Grazia; Roncarolo, Maria Grazia; Ciceri, Fabio; Naldini, Luigi; Aiuti, Alessandro.

In: The Lancet Haematology, Vol. 6, No. 5, 01.05.2019, p. e239-e253.

Research output: Contribution to journalArticle

Ferrua, F, Cicalese, MP, Galimberti, S, Giannelli, S, Dionisio, F, Barzaghi, F, Migliavacca, M, Bernardo, ME, Calbi, V, Assanelli, AA, Facchini, M, Fossati, C, Albertazzi, E, Scaramuzza, S, Brigida, I, Scala, S, Basso-Ricci, L, Pajno, R, Casiraghi, M, Canarutto, D, Salerio, FA, Albert, MH, Bartoli, A, Wolf, HM, Fiori, R, Silvani, P, Gattillo, S, Villa, A, Biasco, L, Dott, C, Culme-Seymour, EJ, van Rossem, K, Atkinson, G, Valsecchi, MG, Roncarolo, MG, Ciceri, F, Naldini, L & Aiuti, A 2019, 'Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study', The Lancet Haematology, vol. 6, no. 5, pp. e239-e253. https://doi.org/10.1016/S2352-3026(19)30021-3
Ferrua, Francesca ; Cicalese, Maria Pia ; Galimberti, Stefania ; Giannelli, Stefania ; Dionisio, Francesca ; Barzaghi, Federica ; Migliavacca, Maddalena ; Bernardo, Maria Ester ; Calbi, Valeria ; Assanelli, Andrea Angelo ; Facchini, Marcella ; Fossati, Claudia ; Albertazzi, Elena ; Scaramuzza, Samantha ; Brigida, Immacolata ; Scala, Serena ; Basso-Ricci, Luca ; Pajno, Roberta ; Casiraghi, Miriam ; Canarutto, Daniele ; Salerio, Federica Andrea ; Albert, Michael H. ; Bartoli, Antonella ; Wolf, Hermann M. ; Fiori, Rossana ; Silvani, Paolo ; Gattillo, Salvatore ; Villa, Anna ; Biasco, Luca ; Dott, Christopher ; Culme-Seymour, Emily J. ; van Rossem, Koenraad ; Atkinson, Gillian ; Valsecchi, Maria Grazia ; Roncarolo, Maria Grazia ; Ciceri, Fabio ; Naldini, Luigi ; Aiuti, Alessandro. / Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome : interim results of a non-randomised, open-label, phase 1/2 clinical study. In: The Lancet Haematology. 2019 ; Vol. 6, No. 5. pp. e239-e253.
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abstract = "Background: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC)gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. Methods: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP)expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462)and EudraCT (number 2009-017346-32). Findings: Between April 20, 2010, and Feb 26, 2015, nine patients (all male)were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1–12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5–5·6). Overall survival was 100{\%}. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9{\%} (range 1·8–35·6)before gene therapy to 66·7{\%} (55·7–98·6)at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1{\%} (range 4·1–31·0)to 76·6{\%} (53·1–98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95{\%} CI 1·44–3·72)per patient-year of observation (PYO)in the year before gene therapy to 0·31 (0·04–1·11)per PYO in the second year after gene therapy and 0·17 (0·00–0·93)per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 10 9 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20–50 × 10 9 per L in one patient, 50–100 × 10 9 per L in five patients, and more than 100 × 10 9 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85{\%})of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. Interpretation: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. Funding: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.",
author = "Francesca Ferrua and Cicalese, {Maria Pia} and Stefania Galimberti and Stefania Giannelli and Francesca Dionisio and Federica Barzaghi and Maddalena Migliavacca and Bernardo, {Maria Ester} and Valeria Calbi and Assanelli, {Andrea Angelo} and Marcella Facchini and Claudia Fossati and Elena Albertazzi and Samantha Scaramuzza and Immacolata Brigida and Serena Scala and Luca Basso-Ricci and Roberta Pajno and Miriam Casiraghi and Daniele Canarutto and Salerio, {Federica Andrea} and Albert, {Michael H.} and Antonella Bartoli and Wolf, {Hermann M.} and Rossana Fiori and Paolo Silvani and Salvatore Gattillo and Anna Villa and Luca Biasco and Christopher Dott and Culme-Seymour, {Emily J.} and {van Rossem}, Koenraad and Gillian Atkinson and Valsecchi, {Maria Grazia} and Roncarolo, {Maria Grazia} and Fabio Ciceri and Luigi Naldini and Alessandro Aiuti",
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TY - JOUR

T1 - Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome

T2 - interim results of a non-randomised, open-label, phase 1/2 clinical study

AU - Ferrua, Francesca

AU - Cicalese, Maria Pia

AU - Galimberti, Stefania

AU - Giannelli, Stefania

AU - Dionisio, Francesca

AU - Barzaghi, Federica

AU - Migliavacca, Maddalena

AU - Bernardo, Maria Ester

AU - Calbi, Valeria

AU - Assanelli, Andrea Angelo

AU - Facchini, Marcella

AU - Fossati, Claudia

AU - Albertazzi, Elena

AU - Scaramuzza, Samantha

AU - Brigida, Immacolata

AU - Scala, Serena

AU - Basso-Ricci, Luca

AU - Pajno, Roberta

AU - Casiraghi, Miriam

AU - Canarutto, Daniele

AU - Salerio, Federica Andrea

AU - Albert, Michael H.

AU - Bartoli, Antonella

AU - Wolf, Hermann M.

AU - Fiori, Rossana

AU - Silvani, Paolo

AU - Gattillo, Salvatore

AU - Villa, Anna

AU - Biasco, Luca

AU - Dott, Christopher

AU - Culme-Seymour, Emily J.

AU - van Rossem, Koenraad

AU - Atkinson, Gillian

AU - Valsecchi, Maria Grazia

AU - Roncarolo, Maria Grazia

AU - Ciceri, Fabio

AU - Naldini, Luigi

AU - Aiuti, Alessandro

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC)gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. Methods: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP)expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462)and EudraCT (number 2009-017346-32). Findings: Between April 20, 2010, and Feb 26, 2015, nine patients (all male)were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1–12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5–5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8–35·6)before gene therapy to 66·7% (55·7–98·6)at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1–31·0)to 76·6% (53·1–98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44–3·72)per patient-year of observation (PYO)in the year before gene therapy to 0·31 (0·04–1·11)per PYO in the second year after gene therapy and 0·17 (0·00–0·93)per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 10 9 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20–50 × 10 9 per L in one patient, 50–100 × 10 9 per L in five patients, and more than 100 × 10 9 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%)of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. Interpretation: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. Funding: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.

AB - Background: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC)gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. Methods: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP)expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462)and EudraCT (number 2009-017346-32). Findings: Between April 20, 2010, and Feb 26, 2015, nine patients (all male)were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1–12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5–5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8–35·6)before gene therapy to 66·7% (55·7–98·6)at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1–31·0)to 76·6% (53·1–98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44–3·72)per patient-year of observation (PYO)in the year before gene therapy to 0·31 (0·04–1·11)per PYO in the second year after gene therapy and 0·17 (0·00–0·93)per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 10 9 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20–50 × 10 9 per L in one patient, 50–100 × 10 9 per L in five patients, and more than 100 × 10 9 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%)of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. Interpretation: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. Funding: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.

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