Retrospective, Landmark Analysis of Long-term Adult Morbidity Following Allogeneic HSCT for Inborn Errors of Immunity in Infancy and Childhood

Abstract

Purpose: Allogeneic hematopoietic stem cell transplant (HSCT) remains the treatment of choice for patients with inborn errors of immunity (IEI). There is little published medical outcome data assessing late medical complications following transition to adult care. We sought to document event-free survival (EFS) in transplanted IEI patients reaching adulthood and describe common late-onset medical complications and factors influencing EFS.

Methods: In this landmark analysis, 83 adults surviving 5 years or more following prior HSCT in childhood for IEI were recruited. The primary endpoint was event-free survival, defined as time post-first HSCT to graft failure, graft rejection, chronic infection, life-threatening or recurrent infections, malignancy, significant autoimmune disease, moderate to severe GVHD or major organ dysfunction. All events occurring less than 5 years post-HSCT were excluded.

Results: EFS was 51% for the whole cohort at a median of 20 years post HSCT. Multivariable analysis identified age at transplant and whole blood chimerism as independent predictors of long-term EFS. Year of HSCT, donor, conditioning intensity and underlying diagnosis had no significant impact on EFS. 59 events occurring beyond 5 years post-HSCT were documented in 37 patients (45% cohort). A total of 25 patients (30% cohort) experienced ongoing significant complications requiring active medical intervention at last follow-up.

Conclusion: Although most patients achieved excellent, durable immune reconstitution with infrequent transplant-related complications, very late complications are common and associated with mixed chimerism post-HSCT. Early intervention to correct mixed chimerism may improve long-term outcomes and adult health following HSCT for IEI in childhood.

Keywords: Very long-term outcome; allogeneic HSCT for IEI.

Fig. 1

Overall and event-free survival. A. Overall survival (OS) was 97% and event-free survival (EFS) was 51% at 20 years post-transplant for our cohort (n = 83). B. Impact on EFS of age at transplant. EFS at 20 years post-transplant was 61% in patients less than 1 year, 51% in those aged 1 to 4 years, and 41% in those 5 years or older at transplant

Fig. 2

Post-transplant peripheral blood chimerism. A. Longitudinal distribution of whole blood chimerism at 1, 5, 10, 15 and 20 years post-transplant (n = 71). B. Lineage-specific peripheral blood chimerism at last follow-up (median 15 years post-transplant) for 62 patients (n = 23 SCID; n = 29 CID; and n = 12 PD). PBMC (upper left panel) shows 35% of SCID patients had more than 95% engraftment compared to 70% and 72% of CID and 67% of phagocyte disorder sub-groups respectively. T cell chimerism (upper right panel) shows that 100% of SCID patients had > 95% T cell engraftment compared to 79% and 67% of CID and phagocyte disorder sub-groups. Granulocyte engraftment (lower left panel) shows that 35% of SCID patients had > 95% engraftment, 72% CID and 75% phagocyte disorders. B cell engraftment (lower right panel) shows that 53% SCID patients had > 95% engraftment, 78% CID and 70% phagocyte disorders. Patients with FISH analysis only were excluded from this analysis