Impact of Genetic Diagnosis on the Outcome of Hematopoietic Stem Cell Transplant in Primary Immunodeficiency Disorders

Abstract

To evaluate the relationship between knowledge of genetic diagnosis before HSCT and outcome, we reviewed all HSCTs for primary immune deficiencies (PID) performed at UCSF from 2007 through 2018. SCID, a distinct entity identified since 2010 in California by newborn screening and treated early, was considered separately. The underlying genetic condition was known at the time of HSCT in 85% of cases. Graft failure was less frequent in patients with a genetic diagnosis (19% with a genetic diagnosis versus 47% without, p = 0.020). Furthermore, event-free survival and overall survival (OS) at 5 years were better for those with a genetic diagnosis (78% with versus 44% without, p = 0.006; and 93% versus 60% without, p = 0.0002, respectively). OS at 5 years was superior for known-genotype patients with both SCID (p = 0.010) and non-SCID PID (p = 0.010). There was no difference in OS between HSCT done in 2007–2010 compared to more recently (p = 0.19). These data suggest that outcomes of HSCT for PID with known genotype may reflect specific experience and literature, or that a substantial proportion of patients with PID of undetermined genotype may have had underlying conditions for which HSCT may carry greater risk. The higher rate of graft failure in PID with unknown genotype may be in part explained by insufficient conditioning, which in turn could be dictated by compromised organ function in patients undergoing HSCT late in the course. Widespread availability of PID gene sequencing as standard care can provide genetic diagnoses for most patients with PID prior to HSCT, permitting optimization of transplant approach.

Personalized hematopoietic stem cell transplantation for inborn errors of immunity

“…There was no difference in OS between HSCT performed between 2007 and 2010 compared to more recently ( p = 0.19). These data show the importance of gene sequencing as standard of care ( 41 ).…”

Ex vivo T-lymphopoiesis assays assisting corrective treatment choice for genetically undefined T- lymphocytopaenia

“…Genetic testing of infants with severe T-lymphocytopaenia is crucial to determine a molecular diagnosis prior to corrective treatment. This reduces clinical uncertainty, facilitates family counselling and improves outcomes (18,19). Whilst clinical next-generation-sequencing (NGS) platforms with short turnaround times and array comparative genomic hybridization (aCGH) are rapidly becoming more available (20)(21)(22), a signi cant proportion of infants remain genetically unde ned (10,11,22).…”

Combined immunodeficiency caused by pathogenic variants in the ZAP70 C-terminal SH2 domain

“…The broad spectrum of pathological features of IEIs, even in the context of a single affected gene, has made it difficult to define an optimal transplant protocol. Nevertheless, genetic diagnosis has been found to be associated with improved outcome of SCID patients undergoing HSCT ( 3 , 4 ) and newborn screening, based on low or absent T cell receptor excision circles (TRECs), a biomarker for thymic output of newly differentiated T cells has accelerated the diagnosis and treatment of affected infants ( 5 ). Importantly though, not all IEI are associated with decreases in TRECs that fall below the threshold, hampering the diagnosis of this subset of immunodeficiencies.…”