Treosulfan-fludarabine conditioning in infants with severe combined immunodeficiencies: Extended study of the UK paediatric treosulfan study

Su Han Lum; Sinéad Greener; Irum Latif Memon; Persis Amrolia; Zohreh Nademi; Robert Chiesa; Juliana Silva; Helen Young; Stephen Owens; Eleri Williams; Khuen Foong Ng; Terry Flood; Andrew R Gennery; Sophie Hambleton; Kanchan Rao; Mary Slatter

doi:10.1111/bjh.70453

Treosulfan-fludarabine conditioning in infants with severe combined immunodeficiencies: Extended study of the UK paediatric treosulfan study

Br J Haematol. 2026 Apr 10. doi: 10.1111/bjh.70453. Online ahead of print.

Authors

Su Han Lum^{1

2}, Sinéad Greener^{1

2}, Irum Latif Memon³, Persis Amrolia³, Zohreh Nademi^{1

2}, Robert Chiesa³, Juliana Silva³, Helen Young², Stephen Owens², Eleri Williams², Khuen Foong Ng^{1

2}, Terry Flood², Andrew R Gennery^{1

2}, Sophie Hambleton^{1

2}, Kanchan Rao², Mary Slatter^{1

2}

Affiliations

¹ Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
² Children's Haematopoietic Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle Upon Tyne, UK.
³ Bone Marrow Transplant Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

PMID: 41958357
DOI: 10.1111/bjh.70453

Abstract

Allogeneic haematopoietic stem cell transplantation (HSCT) is a curative therapy for severe combined immunodeficiency (SCID). Conditioning improves donor engraftment and freedom from immunoglobulin replacement (IgR) but increases the risks of acute and late toxicity. Treosulfan, a reduced toxicity alkylating agent, has emerged as an alternative to busulfan. In this UK multicentre study, we evaluated outcomes of 104 infants with SCID who underwent first HSCT following treosulfan-fludarabine conditioning between 2006 and 2022. After a median follow-up of 5.4 years, 5-year overall survival (OS) and event-free survivals (EFS) were 81% and 77% respectively. On multivariate analysis, molecularly undefined SCID (OS hazard ratio [HR] 5.61; EFS HR 5.55) and pre-HSCT cytomegalovirus (CMV) infection (OS HR 3.94; EFS 3.68) were independently associated with inferior OS and EFS; RAG-DCLRE1C genotypes also predicted worse EFS (HR 4.35). Cumulative incidence of endothelial cell dysfunction (ECD) was 11%. Treosulfan dose was not associated with OS, EFS, ECD or donor myeloid chimerism. Low mixed donor myeloid chimerism was observed across all treosulfan doses, but IgR freedom was achieved in 92% of survivors after first HSCT. Treosulfan-fludarabine provides excellent survival with low endothelial toxicity for SCID HSCT, with potential for optimisation via pharmacokinetic guided dosing.

Keywords: HSCT; SCID; fludarabine; treosulfan.