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EBMT 2021 Annual Meeting - Inborn Errors Working Party Session

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Inborn Errors Working Party (IEWP)
Paediatric Diseases Working Party (PDWP)

Paediatrics Day - Paed2 Inborn Errors Working Party Session

Tuesday, March 16, 11:00 - 12:15, Auditorium 4

The second of today’s Paediatrics session is presented by the Inborn Errors Working Party. The session will be opened by Assistant Professor Agnieszka Czechowicz, Stanford University School of Medicine, Stanford, CA, USA, who will present on antibody-based conditioning in severe combined immune deficiency (SCID).

She will discuss how conditioning regimens for hematopoietic cell transplantation today consist of high doses of genotoxic radiation and/or chemotherapy that can cause considerable morbidity and mortality limiting the use of these otherwise curative procedures. While many efforts have been pursued to decrease the dosage of these agents, many patients still experience both short-term and long-term toxicities ranging from severe cytopenia, mucositis, organ damage, infertility to secondary malignancies.

She explains: “Over the last decade our work has led to the development of attractive alternative antibody-based conditioning regimens that target host hematopoietic stem cells prior to infusion of an incoming hematopoietic graft.  These agents are at various stages of clinical development with the most advanced already in patients showing both early safety and efficacy.”

She concludes: “These agents are likely to improve and expand use of both allogeneic hematopoietic stem cells and gene-modified stem cells to enable safe, curative treatment of a variety of non-malignant and malignant blood and immune diseases in addition to inborn errors of metabolism.”

Professor Arjan Lankester, Leiden University Medical Center, Netherlands, will then present “clinical and immunological outcome after HSCT in severe combined immune deficiency, a SCETIDE cohort study". He will discuss how hematopoietic stem cell transplantation (HSCT) represents an established curative treatment for patients with SCID, a group of monogenic immune disorders with an otherwise fatal outcome. During the last decades, survival has increased due to better insight in the biology of SCID, early diagnosis, management of infections, and advances in HSCT approaches.

He explains: “Currently, a comprehensive multicentre analysis of contemporary and genotype specific HSCT outcome is nevertheless lacking. Moreover, a detailed analysis of immune reconstitution parameters and their predictive value for long term clinical outcome has not been performed to date.”

In this IEWP/SCETIDE multicentre study, HSCT outcome characteristics were analysed in a cohort of genetically confirmed SCID patients (n=338), transplanted between 2006 and 2014. Professor Lankester says: “Data will be presented on the impact of SCID genotype, patient and donor characteristics on overall and event-free survival. In addition, the pattern of immune reconstitution and its correlation with long term clinical outcome was studied in a representative subgroup (n=152) resulting in the identification of predictors for a favourable clinical and immunological outcome.” 

Professor Stephan Ehl (University Hospital Freiburg, Germany) will then present on “HSCT decision in patients with Profound Combined Immunodeficiency (P-CID): a prospective cohort study.”

He explains: “Absent T-cell immunity in patients with severe combined immunodeficiency (SCID) provides a clear rationale for HSCT. In contrast, patients with profound combined immunodeficiencies (P-CID) including 'atypical' SCID show reduced, not absent T-cell immunity. For these patients, outcome data are lacking that help decide if and at what time point HSCT should be performed.”

Between 2011-2018 the P-CID study has recruited 129 untransplanted pediatric P-CID patients and is following their natural history irrespective of the initial HSCT decision into early adulthood. 51 patients had a genetic diagnosis of combined immunodeficiency, 37 patients had 'atypical' SCID and 41 had no genetic defect identified. At study inclusion, there was no difference in the incidence of infections, immune dysregulation, chronic lung disease or the severity of T cell deficiency between the 3 groups. 59 patients were classified as having a mild disease course, 10 were nevertheless transplanted within one year. 68 patients had a severe disease course, of which 39 were transplanted within one year. In this interim analysis of 10 years P-CID study, Prof Ehl’s team reports that 18 late transplants were performed during follow-up and 21 patients died, indicating limitations of the initially employed HSCT decision criteria.

Professor Ehl concludes: “During the final study evaluation in 2024 we will analyse overall outcome including quality of life and a matched-pair analysis of suitable transplanted versus non-transplanted patients to improve data-based HSCT decision criteria for P-CID patients.”

In the last talk, Dr Valeria Calbi (Pediatric Immunohematology, Ospedale San Raffaele, Italy) will present on advances in stem cell therapy in metachromic leukodystrophy.

She explains: “Metachromatic leukodystrophy (MLD) is a fatal genetic demyelinating disease with no effective treatment. Positive efficacy and safety data have been reported with fresh formulation of hematopoietic stem cell (HSC) based gene therapy in early onset MLD. A cryopreserved formulation was subsequently introduced.” (clinical trial NCT03392987).

A total of 29 patients (16 Late Infantile (LI) and 13 early juvenile (EJ) MLD) were treated with fresh formulation and compared for outcome with 31 untreated patients. Additional analyses were performed on the 8 EJ MLD patients symptomatic at time of treatment. Nine patients treated with the cryopreserved formulation were evaluable for safety and initial efficacy results.

All patients demonstrated sustained engraftment of genetically-modified HSC with sustained ARSA activity in blood cells and cerebrospinal fluid. Preliminary results for the cryopreserved formulation were comparable to those observed for the fresh formulation.

“Most treated patients displayed acquisition or maintenance of locomotive abilities and normal cognitive development,” explains Dr Calbi. “Differences with natural history were particularly significant among patients treated before symptom onset. However, clinically relevant treatment effects were also observed in EJ patients treated before the onset of the rapidly progressive phase of the disease (before the onset of cognitive decline with maintained ability to walk independently). There was no evidence of abnormal clonal proliferation and no serious adverse events or deaths related to treatment.”