European expert recommendations for comprehensive pre-treatment, treatment-phase and post-treatment care of patients with metachromatic leukodystrophy treated with autologous haematopoietic stem and progenitor cell gene therapy

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BACKGROUND: Metachromatic leukodystrophy (MLD) is a rare, progressive neurodegenerative disorder caused by arylsulfatase A deficiency, leading to accumulation of sulfatides and widespread demyelination. Autologous haematopoietic stem and progenitor cell gene therapy (HSPC-GT; atidarsagene autotemcel, arsa-cel) has emerged as an effective treatment for early-onset MLD when administered before or at very early stages of neurological involvement. However, standardized recommendations for pre-treatment evaluation, treatment phase care, and long-term follow-up are lacking. METHODS: Under the auspices of the INTEGRATE-ATMP project, a European multidisciplinary expert panel conducted a multi-round consensus process. Following a literature review, key clinical questions were addressed during five structured virtual and hybrid meetings. Recommendations were developed for pre-treatment assessment, treatment-phase management, and post-treatment follow-up. Investigations were classified as "mandatory" or "optional" based on expert agreement. RESULTS: The panel defined comprehensive, phase-specific recommendations for children undergoing HSPC-GT for MLD. Pre-treatment guidance emphasizes rapid diagnostic confirmation, standardized neurological and developmental assessments, and multidisciplinary eligibility evaluation. Treatment phase recommendations address stem cell collection, busulfan conditioning, supportive care, and monitoring for acute complications. Post-treatment guidance outlines a structured long-term follow-up programme, including neurological, developmental, imaging, and laboratory surveillance. Long-term data collection and systematic biobanking are strongly encouraged for a minimum of 15 years to support safety monitoring and outcome evaluation. CONCLUSION: These European expert recommendations provide a practical framework for standardized care of children treated with HSPC-GT for MLD. Implementation across qualified treatment centres may improve clinical consistency, facilitate real-world data collection, and support sustainable delivery of gene therapy programmes. By detailing the comprehensive monitoring and follow-up required, including assessments beyond current standards of care, this work highlights the resource-intensive nature of gene therapy. It also provides a framework for the multidisciplinary care efforts needed to support planning and appropriate reimbursement by health authorities.

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