Allogeneic HSCT with reduced-intensity conditioning for UBE2T-related Fanconi anemia: current standard and considerations for c.205C>T (p.Arg69Ter)

For UBE2T (FANCT) c.205C>T (p.Arg69Ter), a pathogenic nonsense variant that abolishes UBE2T ubiquitin-conjugating enzyme activity in the Fanconi anemia DNA repair pathway, allogeneic hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) remains the only curative option for the bone marrow failure and leukemia predisposition. FA patients are hypersensitive to alkylating agents and radiation, making RIC regimens (typically fludarabine/cyclophosphamide-based without total body irradiation) essential to avoid excessive toxicity.

Fanconi anemia is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The FA pathway repairs DNA interstrand crosslinks (ICLs) through coordinated monoubiquitination of FANCD2/FANCI by the FA core complex, which includes UBE2T as the E2 ubiquitin-conjugating enzyme. The p.Arg69Ter variant truncates UBE2T within the UBC domain, completely abolishing its catalytic function. HSCT outcomes for FA have improved dramatically: Mehta et al. (Blood 2017) reported >90% overall survival for matched sibling donor transplants and 70-80% for matched unrelated donors when RIC protocols are used. The Memorial Sloan Kettering and Cincinnati groups have pioneered fludarabine + low-dose cyclophosphamide + anti-thymocyte globulin (ATG) regimens that avoid the genotoxic agents (busulfan, high-dose radiation) that cause excessive complications in FA cells. HLA-matched sibling donors are preferred; when unavailable, matched unrelated or haploidentical donors with post-transplant cyclophosphamide are increasingly successful alternatives.

HSCT corrects the hematological manifestations of FA but does NOT prevent the solid tumor predisposition (head and neck squamous cell carcinoma, gynecological cancers) that arises from the underlying DNA repair defect in all somatic tissues. Post-transplant conditioning may paradoxically increase solid tumor risk due to additional DNA damage. Graft-versus-host disease (GVHD) remains a significant complication, especially with unrelated donors. FA patients who develop MDS/AML before transplant have significantly worse outcomes. FANCT (UBE2T) is one of the rarer complementation groups, and specific transplant outcome data stratified by complementation group are limited — most published series are dominated by FANCA and FANCC patients. Gene therapy using lentiviral ex vivo HSC correction is being developed for FANCA (RP-L301/Rocket Pharmaceuticals), but no gene therapy program exists specifically for FANCT/UBE2T.