Presence of centromeric but absence of telomeric group B KIR haplotypes in stem cell donors improve leukaemia control after HSCT for childhood ALL

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Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.

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We thank all parents who gave their consent to use the biological material from their minors. This work was supported by the Deutsche Krebshilfe e.V. (M.U., R.M., and A.B.) (project 110351), the Forschungskommission of the Medical Faculty of the Heinrich-Heine University Düsseldorf (F.B.), and the TRANSAID - Stiftung fuer krebskranke Kinder (F.B.). The current affiliation of M.Si. is Department of Pediatrics and Mother and Child Center, Hospital Neuwerk, Mönchengladbach, Germany.

Author contributions

F.B., A.M., J.M., C.E. and N.S. performed the experiments; M.S., M.A., G.C., T.F., B.G., T.G., P.A.H., B.K., P.L., M.M., I.M., J.M., L.O., H.P., F.R.S., M.S., D.S., B.S., W.W., G.E., M.Z., M.S., A.B. and P.B. provided samples and conducted data the analysis and interpretation, and participated in patient care; E.G. and U.P. designed and performed the bioinformatic analyses; F.B., C.P., M.U. and R.M. wrote the manuscript, designed and directed the study; and all authors contributed to the research and approved the final manuscript.

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Correspondence to Florian Babor or Markus Uhrberg or Roland Meisel.

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