Reduced-Intensity/Reduced-Toxicity Conditioning Approaches Are Tolerated in XIAP Deficiency but Patients Fare Poorly with Acute GVHD

Abstract

X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n = 30, 75%) and HLA-mismatched (n = 10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II-IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55-86%) and 64% (CI 46-77%), respectively. Recipient and donor HLA mismatch and grade II-IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5-23.3, p = 0.01) and 8.2 (CI 2.1-32.7, p < 0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.

Keywords: Austen Worth and Rebecca A. Marsh contributed equally to this work; Graft-versus-host disease; Hematopoietic cell transplantation; Hemophagocytic lymphohistiocytosis; Reduced-intensity conditioning; XIAP deficiency.

Fig. 1

Overall survival of the A cohort as a whole and by B age at transplant, C history of hemophagocytic lymphohistiocytosis (HLH), D conditioning regimen, E HLA match (matched related (MRD) and matched unrelated (MUD) versus mismatched unrelated (MMUD) and haploidentical donors), and development of F any acute graft-versus-host disease (GVHD), G grade II–IV acute GVHD, and H grade III–IV acute GVHD