Delayed B-cell reconstitution in the bone marrow precedes the development of chronic graft-versus-host disease following pediatric hematopoietic stem cell transplantation

Abstract

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) in children remains challenged by chronic graft-versus-host-disease (cGvHD), significantly affecting morbidity and survival. While aberrant peripheral B-cell reconstitution has been implicated in cGvHD, B-cell development in the bone marrow (BM) remains less explored. Method We investigated the B-cell reconstitution in BM samples and its potential to predict cGvHD in 76 children undergoing HSCT for acute leukemia (2010-2021) by blinded immunophenotypic analysis. Results Children developing cGvHD exhibited delayed B-cell reconstitution in the BM with significantly lower proportions of total B cells and early B-cell precursors (BCP) I and II from +2 months to +9 months post-HSCT (all p<0.008) and reduced BCPIII and mature B cells at later time points compared to those without cGvHD (all p<0.05). In multivariable Cox proportional hazards models, low proportions of total B cells, BCPI, and BCPII at month +2 and month +3 were independent risk factors for cGvHD (HR=6.9-14.1, all p<0.017). At +2 months after HSCT, ROC analysis for predicting cGvHD with cut-off values of 0.16% (BCPI) and 0.99% (BCPII), yielded a sensitivity of 1.0 and a specificity of 0.69, while a cut-off value of 2.25% for total B cells resulted in a sensitivity of 0.90 and a specificity of 0.69. Discussion These findings support previous evidence of disturbed B-cell reconstitution in cGvHD and suggest that phenotypic monitoring of BM B cells following pediatric HSCT may facilitate early cGvHD risk stratification. As BM assessments are routinely performed after HSCT, such monitoring could be readily integrated into existing clinical workflows.