Allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

With recent advances in genetic sequencing and its widespread adoption for clinical diagnostics, the identification of a primary immunodeficiency (PID) as the underlying cause of diseases presenting to hematologists including refractory autoimmunity, cytopenias, immune dysregulation, and hematologic malignancy, is increasing, particularly in the adult population. Where the pathogenic genetic variants are restricted to the hematopoietic system, selected patients may benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although it is generally accepted that early allo-HSCT (ie, in infancy or childhood) for PID is preferable, this is not always possible. The clinical phenotype of non-severe combined immune deficiency forms of PID can be very heterogeneous, in part because of the high number of genetic and functional defects affecting T, B, and natural killer cells, neutrophils, and/or antigen presentation. As a result, some patients have less severe disease manifestations in childhood and/or a later de novo presentation. For others, a delayed diagnosis, lack of a genetic diagnosis, or a previous lack of a suitable donor has precluded prior allo-HSCT. Specific issues which make transplantation for adult PID patients particularly challenging are discussed, including understanding the natural history of rare diseases and predicting outcome with conservative management alone; indications for and optimal timing of transplant; donor selection; conditioning regimens; and PID-specific transplant management. The role of gene therapy approaches as an alternative to allo-HSCT in high-risk monogenic PID is also discussed.