Lentiviral hematopoietic stem and progenitor cell gene therapy for Wiskott-Aldrich Syndrome: Early access experience in Italian patients based on 648/1996 law

Abstract Background Wiskott-Aldrich Syndrome (WAS) is a rare, X-linked immunodeficiency, also characterized by microthrombocytopenia, eczema, autoimmunity and susceptibility to malignancies. Hematopoietic stem cell transplant (HSCT) is the standard of care for this condition, but it's still hampered by several limitations, including donor availability and patients' age (Albert, 2022). Over the past 15 years, we were involved as clinical center into the development of an autologous lentiviral hematopoietic stem and progenitor cell (HSPC) gene therapy (GT), named as Etuvetidigene autotemcel (Etu-cel) (Ferrua et al, 2019), with which 27 patients have been treated in the context of 2 clinical trials (NTC01515462 and NTC03837483) and expanded access program. Today, Etu-cel is administrated through an early access scheme in Italy (Law 648/1996), being included in the reimbursement list of the Italian National Health System of medicines that are not yet authorized but have shown solid safety and efficacy data in clinical trials. Etu-cel can be prescribed for WAS patients aged 6 months and older who have a mutation in the WAS gene and no availability of a suitable Human Leukocyte Antigen (HLA) matched related stem cell donor. Here we describe the initial experience in 6 Italian male patients treated with Etu-cel in our Centre under such early access between December 2023 and May 2025, focusing on 4 patients with a minimum follow-up (FU) of 6 months post-GT. Methods Inclusion criteria for early access scheme are in line with those adopted for the clinical development program. All 6 patients had severe thrombocytopenia: median platelet count pre-GT was 22 x109/L. Four patients presented with significant autoimmunity/autoinflammation signs prior to treatment (inflammatory bowel disease, post-Covid-19 Multisystem Inflammatory Syndrome in Children, vasculitis). Notably, one patient was treated with Etu-cel after 3 unsuccessful and complicated HSCT, followed by an autologous back-up reinfusion, having demonstrated the complete absence of previous donor-derived cells in his peripheral and bone marrow-blood. All patients received the cryopreserved formulation of Etu-cel product, obtained from mobilized peripheral blood HSPC, after a submyeloablative conditioning regimen based on rituximab, fludarabine and busulfan. Median age at treatment was 27 months (range: 11-64 months). Vector Copy Number (VCN) on drug product and cell dose were in line with those of the clinical development program. Results All patients are alive and in good clinical conditions with a follow up currently ranging between 2 and 18 months (median 9 months). No product-related adverse events or reactions were recorded. Neutrophil engraftment was achieved at a median of 26 days (range: 24-36 days) after infusion of drug product. In all patients, engraftment of gene corrected cells was demonstrated, leading to WAS protein (WASP) expression increase in both platelets and lymphocytes, and progressive improvement of WAS manifestations. Four patients reached a minimum FU of 6 months, experiencing significant clinical benefit. They all showed platelet count increase above 100 x109/L starting from FU +90 days; afterwards, median platelet count was 132 x109/L at FU +6 months (n=4), 123 x109/L at +1 year (n=3) and 217 x109/L at +1.5 years (n=1). All patients stopped platelet transfusions regimen between 8 and 15 days post-GT and are currently transfusion independent. Moreover, no bleeding events were recorded after treatment. Infection rate decreased and no moderate or severe infective events were registered after 6 months post-GT. Antimicrobial prophylaxis were discontinued in 2 patients at FU +1 year, approximately. Three patients stopped immunoglobulin replacement therapy between 10 and 14 months post-GT; 2 of them already started vaccinations. Eczema improved in all patients and resulted absent from the FU +1 year. No signs of autoimmunity were detected post-GT over time and previous autoimmunity resolved. ConclusionsAll patients are alive and experienced clinical benefit up to now, and WAS-related clinical manifestations are recovering or resolved. In this early access scenario, Etu-cel has proved to be as effective and safe as in patients treated with the experimental autologous GT in the context of the clinical development program.