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Report of the Inborn Errors Working Party Annual Conference - 22-24 September 2023 - Graz, Austria

Inborn Errors Working Party (IEWP)

The authors and EBMT exclude any liability for the content or its correct reproduction in terms of errors or mistakes as well as typos that may have occurred when taking notes.

Session I: The first session on Friday afternoon was dedicated to stem cell therapy in metabolic disorders and was chaired by María Ester Bernardo and Rob Wynn.

Valeria Calbi presented clinical outcomes after myeloablative busulfan-based conditioning regimens in young children below the age of 18 months affected by lysosomal storage diseases (LSDs): a retrospective study combining data and experience of two transplant centres and including 109 children receiving myeloablative Busulfan-based conditioning regimen prior to allo-HSCT or HSC-GT was performed.

Maria Escolar gave an update on the phase 1/2 Clinical Trial of Intravenous FBX-101 (AAVrh10.hGALC) - a novel AAV gene therapy - administered after UCBT in three patients with infantile Krabbe Disease. The combination of these procedures aims to prevent the recognition of GALC as neoantigen after GT alone. FBX-101 is an adeno-associated viral serotype rh10 (AAVrh10) gene therapy that is delivered intravenously after HSCT infusion delivering a functional copy of the galactocerebrosidase (GALC) gene to cells in both the central and peripheral nervous system followed by decreasing psychosine to the normal range, slowing or stopping demyelination, and improving myelination.

Valeria Calbi presented actual data in patients with early-onset Metachromatic leukodystrophy (MLD) treated with Libmeldy gene therapy. Atidarsagene autotemcel (Arsa-cel) is indicated for the treatment of late infantile LI-MLD without clinical manifestations of the disease and in children with the early juvenile EJ-MLD form, asymtomatic or with early clinical manifestations of the disease (still having the ability to walk independently and before the onset of cognitive decline). As early diagnosis is the key for treatment in time: she reported about the Newborn Screening (NBS) Pilot Project in Germany resulting in an European Consensus Project for disease prediction and clinical management in NBS positive MLD cases and she reported about MLDinitiative (MLDi), an European disease registry for MLD.

Rob Wynn presented the Licensing indications for Arsa-cel in the MLD subtypes and described the UK activity in patients referred for consideration of HSC-GT following Arsa-cel NHS approval. He concluded with three main messages, he highlighted the importance of NBS, the necessity of collaboration and continuously demonstrating results of treatment.

Rob Wynn further presented an update on Hematopoietic stem/progenitor cell gene therapy (HCT-GT; IMP) for Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo syndrome), reporting biochemical engraftment and clinical outcomes of MPSIIIA trial patients. MPSIIIA is known to be completely refractory to allo-transplant, with no possibility of modification disease phenotype despite early HSCT, wild type and fully donor engraftment. It is hypothesized that HCT-GT allows supraphysiologic enzyme delivery and corrects otherwise refractory disease. 5 patients were included in the trial, which opened in December 2019.

Francesca Tucci presented an update on hematopoietic stem/progenitor cell gene therapy (HSPC-GT) for Mucopolysaccharidosis type I- Hurler syndrome (MPSIH) with details on non-skeletal, non- neurological outcomes. HSCT as an early treatment in MPSIH patients is known to provide good effects regarding brain and hepatosplenomegaly, some effects to skeleton/spine/joint mobility, hearing/vision, respiratory tract, heart. ERT offers good effects against hepatosplenomegaly, some effects regarding respiratory tract and heart. Future perspectives: a phase III trial is close to opening (by Orchard Therapeutics).

Rob Wynn presented an update on hematopoietic cell transplantation/gene therapy (HCTGT) in Gaucher disease type III (GD3) and Mucopolysaccharidosis type II (MPSII; Hunter Syndrome). In a Phase I-II Study of cryopreserved autologous CD34+ haematopoietic stem cells transduced ex vivo with CD11b Lentiviral vector encoding for human IDS.ApoEII 5 patients with neuropathic MPSII (Hunter syndrome) were enrolled since 2022, a 24-month follow up is planned.

Jaap Jan Boelens reported on outcomes of transplantations for MPSI after newborn screening (NBS). BMT for inherited metabolic diseases has become safer (EFS >95%) due to international collaboration and harmonization. For optimized late outcomes a newborn screening and an early successfully performed transplantation are essential.

Session II: The second session on Friday afternoon was dedicated to pathophysiology of inborn errors of immunity and its role in cellular therapy and was chaired by Romain Levy and Fabian Hauck.

Fabian Hauck presented clinical and molecular functional details on a novel inborn error of pattern-triggered immunity. He presented an unusual phenotype of a paediatric Systemic Lupus Erythematosus (SLE) patient and gave details on autoinflammation and autoimmunity, e.g., that intactness of endomembrane system depending on BORC may prevent autoimmunity and autoinflammation and that late endosomal BORC complex and GTPase Arl8b are controlling TLR7 turnover.

Romain Levy gave details on therapy of primary atopic disorders (PADs) with Dupilumab (monoclonal antibody blocking interleukin 4 and interleukin 13). He gave insights in CEREDIH registry/France counting 8.656 patients with PADs. Allergy is a common manifestation of IEIs (in 26% of IEIs patients due to CEREDIH registry). He presented details on human germline heterozygous gain-of-function STAT6 variants causing severe allergic disease. He reported on a Dupilumab study for PADs called “DUPIDIP”. He concluded that Dupilumab is well tolerated and effective in various IEIs.

Session III: The first session on Saturday morning was dedicated to Hematopoietic defects (Telomeropathies) and was chaired by Carsten Speckmann and Carmem Bonfim.

Suneet Agarwal reported on Radiation- and Alkylator-Free Bone marrow transplantation (BMT) for Dyskeratosis Congenita (DC)/ Telomere Diseases. DC is the prototypic telomere disease with classic manifestations of irregular skin pigmentation, oral leucoplakia and nail dystrophy showing signs of a systemic degenerative disorder with bone marrow failure, pulmonary disease/fibrosis, liver disease and increased risk of cancer (MDS, AML, squamous cell cancers). Dyskeratosis congenita related telomere biology disorders (DC/TBDs) are characterized by very short telomeres caused by germline mutations. Flow-FISH for lymphocyte telomere length shows a high sensitivity and positive predictive value for detecting TBDs in children with myeloid failure. Although alloBMT is curative for hematopoietic defects in DC, historically, poor outcomes after BMT in DC patients were seen due to conditioning toxicity, graft failures, and co-morbidities. New approaches with reduced toxicity are being explored.

Carmem Bonfim presented the approach of HSCT for telomeropathies in Latin America. Diagnosis of DC/TBD by typical clinical findings is confirmed with flow-FISH (telomere length <1st centile for age in lymphocytes) and/or confirming mutations in the known genes. Diagnosis for major IBMFS (FA/TBD) including whole exome sequencing (WES) isn`t available in most countries around the world. She reported on a retrospective single-centre cohort study about 19 patients transplanted for telomere biology diseases 1993 – 2019. International collaborations to increase/improve diagnosis worldwide are needed. Open questions regarding HCT for TBD are graft sources and conditioning regimens.

Session IV: The second session on Saturday morning was dedicated to Conditioning/PK and was chaired by Arjan Lankester and Despina Moshous.

Jaap Jan Boelens reported on Busulfan exposure in 674 children and young adults with primary immunodeficiency (PID), a multicentre report of 16 centres. He discussed details about the optimal range (sweet spot) of Busulfan (Bu) exposures.

Christopher Dvorak reported on pharmacokinetics (PK) and pharmacodynamics (PD) and a model-based dosing to optimize fludarabine therapy in paediatric hematopoietic cell transplant recipients. Fludarabine is a prodrug, that needs active transport into cells, it’s effective to eliminate B- and T cells but doesn’t deplete NK cells. Due to data in adults published in 2011 Fludarabine (Flu) 40 mg/m² x 4 doses on days -5 to -2 resulted in an average cAUC of 20 mg*h/L. Flu cAUC >25 mg*h/L resulted in lower OS and higher TRM rates compared to <25 mg*h/L. Pediatric data were published in 2017 regarding Flu plasma concentrations in 133 patients. Flu doses ranged from 25 to 40 mg/m² over 3-5 days. Reported data suggest that intracellular peaks consistently decline with dose, by dose 5 peaks are equivalent to troughs, the authors mentioned there is no reason to give 5 days of Flu and they suggest that an infusion duration of 1 hour is better than 30 min. Christopher Dvorak summarized that standard mg/m² dosing works for many children, but for those with unusual exposure (obesity, renal insufficiency) it can result in TRM and/or rejection. He concluded that model-based dosing can dial in a specific exposure and that the optimal target is known (cAUC of 20 mg*h/L), therefore a real-time PK is not necessary.

Arjan Lankester presented actual data on ARTIC study final results or combined Treosulfan pharmacokinetics (Trep PK) data. Monoclonal CD52+ antibody Alemtuzumab targets T/B lymphocytes, NK cells, neutrophils and monocytes/APC inducing complement- and antibody-mediated cellular cytotoxicity leading to prevention of graft rejection and acute GvHD. These data constitute a first step for optimizing individualized dose recommendations to improve outcome in pediatic HSCT patients.

Arjan Lankester reported on Treosulfan/Busulfan (Treo/Bu) conditioning including endocrine side effects and fertility in 197 (post)pubertal pediatric HSCT patients with non-malignant diseases alive ≥ 2 years post SCT. Patients at Tanner stage ≥ G/B2 were screened for gonadal dysfunction (elevated gonadotropins) and hypogonadotropic hypogonadismus (low estradiol/testosterone with gonadotropins below/within reference range). Bu and Treo exposure and outcome were presented. Arjan Lankester summarized that Treo regimens showed less gonadal dysfunction vs Bu regimens with no clear correlation to exposure levels.

Despina Moshous showed data of three patients with osteopetrosis/craniometaphyseal dysplasia who successfully underwent “first-in-human" HSCT for this indication.

Keynote lecture given by Elie Haddad:

Elie Haddad gave a fascinating lecture on the Journey of HSCT in SCID patients beginning in 1968 with the first HLA identical HSCT for SCID. He resumed evolution of HSCT results in SCID over time, mentioned the impact of HLA matching on outcome. SCID newborn screening (NBS) started in 2008 in USA, transplant survival improves since 2010, multivariate analyses confirmed the hypothesis that NBS is the main driver for improved survival after HCT (enabling earlier diagnosis and treatment and fewer infections at the time HCT) even if corrected for other variables in the comparison of historical cohorts. NBS was also shown to erase the effect of racial disparities on survival after HSCT in SCID. He gave details on immune reconstitution (T and B cell reconstitution and its impact on survival) and mentioned some remaining questions regarding very long-term outcome, which conditioning strategy and which GvHD prophylaxis should be chosen in HLA matched siblings. Is the future a non-toxic conditioning regimen (Anti-CD117, anti CD45, CAR-T or CAR-NK cells targeting myeloid cells: anti-CD33, anti-CD123)? Is less toxic conditioning inducing less GvHD? Does TCR a/b deletion and/or Cyclophosphamide post-HCT reduce the gap between matched and non-matched HCTs? Are we prepared performing HCT in patients severely infected before HCT? How should immune reconstitution be monitored and when should retransplantations (HCT +/- thymus?) in poor immune reconstitution be performed? What is the position of gene therapy regarding those excellent results of HCT in SCID nowadays? Some of these questions are being tackled in ongoing PIDTC/CIBMTR trials.

Session V, Saturday afternoon: Challenging indication and novel approaches, chaired by Mary Slatter and Tom Fox.

Juliana Silva presented data on allogeneic HSCT for juvenile idiopathic arthritis (JIA). The timing and indications for transplantation are under debate.

Claudia Wehr and Emma Morris presented their data and experiences and entered a panel debate on pro’s and con’s for allogeneic HSCT in CVID. It was agreed upon the high clinical need for adults with poor outcomes on conservative therapy and a minority of patients with druggable defects. Nevertheless, of a large number presented for evaluation for HSCT, only few met the criteria. First, the definition of CVID and the grey zone between complex CVID and CID was discussed, and any signs of T cell dysfunction (CID or CVID-like monogenic IEI) need to be distinguished. Second, the onset and existence of autoimmunity, GLILD, enteropathy, liver disease need to be taken into account and scored; biomarkers of progression of organ disease (especially liver) are urgently needed. Younger patients with known genetic diagnosis and without organ dysfunction are more likely to benefit from HSCT in so-called “CVID”.

Paul Szabolcs reported on a trial with bilateral lung and sequential vertebral bone marrow transplantation from the same (cadaveric) donor in most severe cases of end-stage lung disease in patients with an underlying IEI with indication for HSCT. Engraftment and tolerance development are being studied carefully.

Session VI, Saturday afternoon: HLH and related diseases, chaired by Claire Booth.

Benjamin Fournier presented the hypothesis, based on the observations in inborn CTPS1 deficiency, and strategy of an ongoing murine study to apply CTPS1 inhibition therapeutically as treatment for autoreactive or alloreactive T- and/or B-cell diseases.

Svea Böhm presented data on the strategy to rescue chimerism in patients with HLH and sinking donor chimerism with repetitive DLI administrations before imminent relapse after HSCT.

Oliver Wegehaupt reported on a study investigating whether the combination of the relatively frequent, known polymorphism A91V in the PRF1 gene with a pathogenic mutation in trans led to FHL2. He took a population genetics approach and compared allele frequencies with ICD10 databases indicating HLH phenotype-associated diagnoses.

Claire Booth presented Annelotte Mudde’s and her data on gene therapy approaches for XIAP deficiency, both using lentiviral mediated gene addition as well as gene editing.

Session VII, Saturday afternoon, was a panel discussion of the conceptual approach to gene therapy for HLH. Panelists were Stephan Ehl, Claire Booth, and Despina Moshous.

Questions discussed were non-cytotoxic versus established cytotoxic regimens to induce and maintain remission in patients with HLH; the need and future role of newborn screening to detect patients before they become symptomatic; whether the target cell type should be HSC or T cells; and that a patient-tailored curative strategy should be pursued, including gene therapy options.

Session VIII, Saturday afternoon: IEWP studies and proposals, chaired by Bénédicte Neven and Michale Albert.

Christos Tsilifis reported outcomes of an ongoing study of HSCT in patients with CTLA4 haplo­insufficiency.

Catharina Schuetz presented data on HSCT for STAT1GOF.

Zohreh Nademi showed preliminary analyses of outcomes of second allogeneic HSCT in non-SCID IEI.

Stephan Ehl presented the up-coming FHL2/3 study.

Helena Buso proposed a study on HSCT in C1Q deficiency.

Bénédicte Neven reported results of a retrospective study on Haplo HSCT in CGD.

Claire Booth presented updates on the AGORA initiative (Access to Gene Therapy for Rare Diseases). The aim of this pan-European initiative is to reduce repetition and costs across countries, coordinate, support, and align activities, in part through harmonization of infrastructure and reduction of redundancy of regulatory processes, education and lobbying. A universal data repository is being created to be presented to regulatory agencies.

Session IX, Sunday morning: How can registries be used in a more effective manner? Chaired by Christopher Dvorak and Markus Seidel.

Markus Seidel and Christopher Dovrak presented the existing landscape of registries of patients in North America and Europe with inborn errors and stem cell transplantation and the potential course of a patient through them. New registries are supposed to work (in part) with automated data extraction from health records and interweave with human phenotype ontology, orpha and OMIM codes and genetics databases and facilitate the use of basic datasets for add-on disease-specific research studies. National and European networks of health care providers for rare diseases aim to generate networks for patient-centred problem-solving (boards), parallel but potentially synergistic platforms.

Stephan Ehl presented his views and suggestions to avoid patients getting “lost in registration” with an instructive example of a patient with HLH, being officially expected to be registered in at least five different registries. He pointed out that it is a clinical and scientific need that these registries are not run as research studies by individual PIs with time-limited funding but by medical societies with sufficient sustainability, integrating a pre- and post-HSCT clinical portal, a genetics portal, patient-reported outcome measures and serving as portal for GMP-concordant trials.

Larissa Broglie reported about the procedures of routine registration of patients in the CIBMTR as compared to EBMT and about the processes and modalities of evaluation, implementation, and carrying out of add-on studies. She pointed out various steps where collaborative trials between CIBMTR and EBMT could be discussed, approved, and initiated.

Session X, Sunday morning: Long-term follow-up and late complications, chaired by Reem Elfeky and Emma Morris.

Christopher Dvorak reported a PIDTC study on chronic late effects (CLE), which were most frequently detected as being neurological/neurodevelopmental issues. Furthermore, the study aims to define causes for late mortality after HSCT in patients with SCID.

Reem Elfeky presented data on osteopenic and non-osteopenic bone disease post-HSCT.

Emma Morris reported on long-term follow-up data of patients who underwent GT for IEI, the earliest treated patients now transitioning from paediatric into adult care.

Session XI, Sunday morning: Classic indications, chaired by Manfred Hönig and Andrew Gennery.

Sung-Yun Pai presented the randomized CSIDE trial in patients with SCID diagnosed early, comparing low and medium busulfan doses. IL2RG and JAK3 were in one arm, RAG1/2 formed the other arm, both arms were randomized for Bu at a target of 30 vs. 60 mg*h/L. The study is still ongoing and aims to define a new standard of care that achieves high T and B cell immune reconstitution with low rates of GvHD.

Manfred Hönig showed preliminary data of the German SCID registry. The effect of NBS on OS, age at HSCT and infections pre-HSCT are being analysed.

Arjan Lankester reported on the results of the ongoing RAG1/2 gene therapy trial and showed detailed immune reconstitution analyses, comparing results to the benchmark results of allogeneic HSCT for RAG1 (2015-2022) from SCETIDE.

Sung-Yun Pai presented data on the lentiviral codon-optimized GT for X-SCID after low-dose Bu chemotherapy conditioning.

Final remarks and Farewell concluded the meeting.