Stem cell transplant (SCT) outcomes in high-risk (HR) and relapsed/refractory (R/R) paediatric acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) have been poor historically. Cord blood allows T-cell replete transplant (TRCB), enabling enhanced graft-versus-leukaemia. We collected data from 367 consecutive patients undergoing TRCB (112 patients) or other cell source (255 patients) SCT for paediatric AML/MDS in the UK and Ireland between January 2014 and December 2021. Data was collected about patient's demographics, disease and its treatment including previous transplant, measurable residual disease (MRD) status at transplant, HLA-match, relapse, death, graft versus host disease (GvHD) and transplant-related mortality (TRM). Univariable and multivariable analyses were undertaken. There was a higher incidence of poor prognosis features in the TRCB cohort: 51.4% patients were MRD positive at transplant, 46.4% had refractory disease and 21.4% had relapsed after a previous SCT, compared with 26.1%, 8.6% and 5.1% respectively in the comparator group (all p <0.001). Within the TRCB cohort, Event Free Survival (EFS) was 64.1%, 50% in MRD positive patients and 79% in MRD negative (p= 0.009). To allow for the imbalance in baseline characteristics, a multivariable analysis was performed: the TRCB cohort had significantly improved EFS (0.57[0.35-0.91], p=0.019), time to relapse (0.46[0.26-0.81), p=0.008), and reduced chronic GVHD (HR 0.28 [95% CI 0.11-0.70]; p=0.007), with some evidence of improved Overall Survival (OS) (0.65[0.39-1.07], p = 0.088). The effect appeared similar regardless of MRD status, (interaction p-value= 0.29). CB transplant without serotherapy may be the optimal transplant option for children with myeloid malignancy.

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare, x-linked recessive, progressive, multi-system, lysosomal storage disease caused by the deficiency of iduronate-2-sulfatase (IDS), which leads to the pathological storage of glycosaminoglycans in nearly all cell types, tissues and organs. The condition is clinically heterogeneous, and most patients present with a progressive, multi-system disease in their early years. This article outlines the pathology of the disorder and current treatment strategies, including a detailed review of haematopoietic stem cell transplant outcomes for MPSII. We then discuss haematopoietic stem cell gene therapy and how this can be employed for treatment of the disorder. We consider how preclinical innovations, including novel brain-targeted techniques, can be incorporated into stem cell gene therapy approaches to mitigate the neuropathological consequences of the condition.

No abstract

Metachromatic leukodystrophy (MLD) results from ARSA gene mutations. Affected individuals meet early milestones before neurological deterioration and early death. Atidarsagene autotemcel (arsa‐cel), an autologous haematopoietic stem cell gene therapy (HSC‐GT) product, has demonstrated sustained clinical benefits in MLD. Arsa‐cel was approved for NHS treatment in February 2022 for asymptomatic late infantile or early juvenile disease, or early symptomatic early juvenile MLD. We evaluate the impact of this approval in the largest real‐world dataset of MLD HSC‐GT. Hospital records were reviewed for all patients referred for NHS treatment following arsa‐cel approval. Information was gathered about disease phenotype, presentation, eligibility, and affected siblings. In the year following NHS approval, 17 UK MLD patients were referred for treatment. Four patients met eligibility criteria and have been treated, including 1 infant who weighed 5 kg at leukapheresis. Eleven patients failed screening: 10 symptomatic patients with late infantile disease and 1 with early juvenile disease and cognitive decline. Two further patients with later onset subtypes did not meet the approval criteria. Three out of four treated patients were diagnosed by screening after MLD was diagnosed in a symptomatic older sibling. The success of HSC‐GT for MLD has heralded a new era of hope for families affected by this devastating disease, yet currently, most patients are ineligible for treatment at diagnosis. The feasibility of apheresis in infants and the availability of a licenced, effective HSC‐GT product highlights the urgent need for newborn screening to ensure that patients can be diagnosed and treated before symptom onset.