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

Does shining a spotlight on XIAP deficiency bring the role of allogeneic HCT into better focus?

“…1 Another recent sizable report from Japan in 2021 also indicates higher survival rates of 85% (n 5 26). 9 These data, plus a recent observation of greater than 90% survival in patients with XIAP deficiency who did not develop acute graft-versus-host disease, 6 support optimism regarding allogeneic HCT in the current era. The survival estimates for conservatively treated patients and patients who have received a transplant do not account for disease morbidity associated with long-term symptomatic XIAP deficiency or the impact of possible long-term morbidity that can be associated with allogeneic HCT complications.…”

“…Patients fare poorly with fully myeloablative conditioning regimens, and murine studies and clinical observation both demonstrate that XIAP deficiency confers increased risk of severe graft-versus-host disease. [5][6][7][8] Patients with XIAP deficiency would ideally be risk-stratified soon after diagnosis to determine who should be optimally considered for allogeneic HCT versus who should be followed initially with conservative medical management. There are many challenges surrounding outcome stratification, and it is always difficult to compare outcomes between conservatively managed patients and those treated with allogeneic HCT, given that patients presenting at a young age with severe phenotypes tend to be the patients most often considered for allogeneic HCT.…”

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

“…However, encouraging data on monogeneic diseases manifesting with severe IBD [e.g. X‐linked inhibitor of apoptosis (XIAP) deficiency 108 and homozygous loss of function mutations in interleukin‐10 (IL10) and IL10 receptors (IL10R) 109 ] pave the way for the potential use of allogeneic HSCT as an effective treatment option for the most severe, treatment‐refractory cases of polygeneic IBD. Further trials are needed to explore benefits and reduce treatment‐related toxicity in children undergoing autologous or allogeneic HSCT for IBD.…”

“…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 …”

“…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.…”