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. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01103-6.

Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency

“…XIAP deficiency is an inborn error of immunity with a range of severe manifestations, and even when diagnosed early, provision of prophylactic therapies and close monitoring may not prevent fatal complications such as HLH. Outcomes following HSCT are significantly worse in patients with XIAP deficiency than those with other familial forms of HLH and even low grade GvHD is associated with disproportionate mortality [ 8 , 9 , 68 ]. Studies by Marsh et al [ 8 ] and Varghese et al [ 68 ] show high levels of toxicity following conventional myeloablative conditioning, likely due to loss of XIAP.…”

“…Studies by Marsh et al [ 8 ] and Varghese et al [ 68 ] show high levels of toxicity following conventional myeloablative conditioning, likely due to loss of XIAP. A high incidence of GvHD, mixed donor chimerism (< 95%) and relapsed HLH post-HSCT have been observed when using RIC-HSCT [ 9 ]. As such, development of autologous gene therapy strategies can offer patients lacking suitable donors an alternative clinical option which removes any risk of alloreactivity and allows the use of reduced toxicity conditioning.…”

“…More recent reports of reduced-intensity conditioning (RIC) regimens suggest these approaches are better tolerated with improved survival [ 8 – 10 ]. However, HSCT is associated with graft-versus-host disease (GvHD), which significantly increases the risk of mortality in patients with XIAP deficiency [ 9 ]. Autologous hematopoietic stem cell (HSC) gene therapy abrogates any risk of alloreactivity due to GvHD making it an extremely attractive potential therapy.…”

Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation

“…Forty children and young adults with a median age at HSCT of 6.5 years (0.45-27) reached an overall survival rate of 74% and a rate of event-free survival of 64% at two years post transplant, but the incidence of severe treatment-related toxicities like respiratory distress syndrome or life-threatening bleeding was high (25% and 23%, respectively). 108 In summary, further characterisation of genetic components of paediatric ADs will evolve our understanding, and direct appropriate treatment, including allogeneic HSCT, which is a standard of care according to EBMT guidelines. 118 'Standard' autologous HSCT is clearly ineffective in these patients as a means of long-term cure.…”

“…A further recent study on children with XIAP deficiency, a rare genetic disease which causes severe autoimmunity such as treatment‐refractory IBD and life‐threatening sHLH, reports encouraging survival data after allogeneic HSCT following reduced‐intensity or reduced‐toxicity conditioning. Forty children and young adults with a median age at HSCT of 6.5 years (0.45–27) reached an overall survival rate of 74% and a rate of event‐free survival of 64% at two years post transplant, but the incidence of severe treatment‐related toxicities like respiratory distress syndrome or life‐threatening bleeding was high (25% and 23%, respectively) 108 …”