The Balancing Act of Allogeneic Haematopoietic Stem Cell Transplantation: Graft Engineering and Post-Transplant Immune Reconstitution

Abstract

Allogeneic haematopoietic stem cell transplantation is a potentially curative treatment for haematological malignancies and severe bone marrow disorders. The donor immune system can eliminate residual malignant cells (the graft-versus-leukaemia effect), but transplantation may also cause serious complications, notably graft-versus-host disease (GVHD) and infections such as cytomegalovirus (CMV) reactivation. A central challenge is reducing complications without increasing the risk of relapse, which requires a better understanding of immune reconstitution. At University Medical Center Utrecht, αβ T cells are depleted from the graft before infusion. This thesis evaluated how this platform affects clinical outcomes and immune recovery. αβ T-cell–depleted transplantation was associated with low rates of acute and chronic GVHD and improved GVHD-free, relapse-free survival, although CMV-seropositive patients experienced CMV reactivation more frequently. Graft cryopreservation did not adversely affect survival or GVHD despite a reduced stem cell yield after thawing, supporting its use when logistics are constrained. In myelofibrosis, continuation of the JAK inhibitor ruxolitinib throughout the peri-transplant period reduced GVHD and non-relapse mortality and significantly improved survival. The thesis further examined immune reconstitution. Proteomic profiling during the first weeks after transplantation revealed distinct, disease-specific temporal changes. Using TCR sequencing and single-cell analyses, CMV reactivation was found to drive expansion of CD8+ αβT cells and Vδ2− γδT cells, while the transplant platform shaped which T cells persisted and the diversity of the repertoire at one year. Together, these findings support more personalised transplant strategies that balance GVHD prevention, infection risk, and immune reconstitution.