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

Abstract

The current issue of the Journal of Allergy and Clinical Immunology contains an important article by Yang et al titled “Phenotype, genotype, treatment, and survival outcomes in patients with X-Linked inhibitor of apoptosis deficiency.”1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar The authors of this article undertook a much needed and practical effort to study the entire literature on recorded patients, spanning the initial discovery of X-linked inhibitor of apoptosis (XIAP) deficiency in 20062Rigaud S. Fondaneche M.C. Lambert N. Pasquier B. Mateo V. Soulas P. et al.XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.Nature. 2006; 444: 110-114Crossref PubMed Scopus (534) Google Scholar through 2020. They summarized the data on a total of 167 patients from 117 families and were able to shine a spotlight to bring several clinical prognostic points regarding XIAP deficiency into better focus. Can these data be used to help answer the most difficult question raised by patients, families, and clinicians alike regarding the role of allogeneic hematopoietic cell transplantation (HCT)? The question of allogeneic HCT in XIAP deficiency is a difficult one. Since the initial report of XIAP deficiency,2Rigaud S. Fondaneche M.C. Lambert N. Pasquier B. Mateo V. Soulas P. et al.XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.Nature. 2006; 444: 110-114Crossref PubMed Scopus (534) Google Scholar it has been clear that patients may develop life-threatening complications of immune dysregulation. XIAP has several cellular functions, including regulation of apoptosis, mediation of NOD1/2-induced activation of nuclear factor-κB signaling, and regulation of TNF receptor signaling and NLRP3 inflammasome function among others.3Mudde A.C.A. Booth C. Marsh R.A. Evolution of our understanding of XIAP deficiency.Front Pediatr. 2021; 9660520Crossref PubMed Scopus (11) Google Scholar The most common disease manifestations of XIAP deficiency are hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Other complications include splenomegaly, hypogammaglobulinemia, recurrent fevers, infections, hepatitis, arthritis, uveitis, skin abscesses and nonabscess skin problems, and other less common clinical problems.3Mudde A.C.A. Booth C. Marsh R.A. Evolution of our understanding of XIAP deficiency.Front Pediatr. 2021; 9660520Crossref PubMed Scopus (11) Google Scholar There is no standard curative or preventive treatment for patients with XIAP deficiency aside from allogeneic HCT. Treatment is generally symptomatic and based on disease manifestations and symptoms, which can be refractory. In the original discovery cohort reported by Rigaud et al in 2006, 4 of 12 patients with XIAP deficiency had died at the time of publication.2Rigaud S. Fondaneche M.C. Lambert N. Pasquier B. Mateo V. Soulas P. et al.XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.Nature. 2006; 444: 110-114Crossref PubMed Scopus (534) Google Scholar Deaths occurred within a wide range of ages from 0.5 to 40 years and were related mainly to complications of HLH.2Rigaud S. Fondaneche M.C. Lambert N. Pasquier B. Mateo V. Soulas P. et al.XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.Nature. 2006; 444: 110-114Crossref PubMed Scopus (534) Google Scholar An important subsequent comparison of patients with XIAP deficiency and SAP deficiency by Pachlopnik Schmid et al demonstrated that 5 of 22 patients with XIAP deficiency who developed HLH died and 3 of 5 patients with colitis died.4Pachlopnik Schmid J. Canioni D. Moshous D. Touzot F. Mahlaoui N. Hauck F. et al.Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).Blood. 2011; 117: 1522-1529Crossref PubMed Scopus (262) Google Scholar These and other outcomes data could be interpreted to suggest that all patients with XIAP deficiency should be considered for curative treatment with allogeneic HCT. However, some patients with XIAP deficiency have relatively mild phenotypes, and slightly more than half of surviving patients reported by Pachlopnik Schmid et al were clinically well without any treatment at the time of publication of their article.4Pachlopnik Schmid J. Canioni D. Moshous D. Touzot F. Mahlaoui N. Hauck F. et al.Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency).Blood. 2011; 117: 1522-1529Crossref PubMed Scopus (262) Google Scholar To further complicate matters, patients with XIAP deficiency are at particularly high risk of mortality following allogeneic HCT. 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.5Marsh R.A. Rao K. Satwani P. Lehmberg K. Muller I. Li D. et al.Allogeneic hematopoietic cell transplantation for XIAP deficiency: an international survey reveals poor outcomes.Blood. 2013; 121: 877-883Crossref PubMed Scopus (106) Google Scholar, 6Arnold D.E. Nofal R. Wakefield C. Lehmberg K. Wustrau K. Albert M.H. et al.Reduced-intensity/reduced-toxicity conditioning approaches are tolerated in XIAP deficiency but patients fare poorly with acute GVHD.J Clin Immunol. 2022; 22: 36-45Crossref Scopus (5) Google Scholar, 7Toubai T. Rossi C. Oravecz-Wilson K. Liu C. Zajac C. Wu S.J. et al.IAPs protect host target tissues from graft-versus-host disease in mice.Blood Adv. 2017; 1: 1517-1532Crossref PubMed Scopus (14) Google Scholar, 8Muller N. Fischer J.C. Yabal M. Haas T. Poeck H. Jost P.J. XIAP deficiency in hematopoietic recipient cells drives donor T-cell activation and GvHD in mice.Eur J Immunol. 2019; 49: 504-507Crossref PubMed Scopus (9) Google Scholar 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. The article by Yang et al1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar provides some aggregate insights. First, survival rate was comparable among conservatively treated patients (80%-91%) regardless of HLH, IBD, both HLH and IBD, or other phenotype (Table I),1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar implying that consideration of allogeneic HCT should not be limited to only certain indications such as HLH. Again, this should be tempered with the knowledge that younger patients with more severe phenotypes were more likely to be offered allogeneic HCT. Second, survival was significantly worse for conservatively treated patients who presented before the age of 5 years, with approximately 20% mortality by age 10 years,1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar suggesting that patients presenting at younger ages may be optimally treated with allogeneic HCT. Third, a subset of conservatively treated adult patients had a distribution of disease manifestations and outcomes similar to that or the entire group, but survival was worse for patients who continued to develop new manifestations of XIAP deficiency in adulthood (ie, only 33% at age 30 years).1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar Treatment of patients who continue to develop new manifestations over time may optimally include HCT.Table IOutcomes of patients treated conservatively (without allogeneic HCT)1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google ScholarPhenotypeNo. of patientsSurvivalMedian ageMedian time after diagnosisHLH (no IBD)5449/54 (91%)10 y (range 0.2-39 y)4 y (range 0-27 y)IBD (no HLH)2016/20 (80%)17 y (range 1-39 y)14.5 y (range 0-30 y)HLH and IBD108/10 (80%)10 y (range 3-32 y)6.7 (range 1.6-22 y)Other2521/25 (84%)16 y (range 2.3-46 y)14 y (range 1-42 y) Open table in a new tab Lastly, neither type of genetic variant nor amount of protein expression was found to predict outcomes. Yang et al1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar found no clear genotype-phenotype correlations other than association of absent protein with development of splenomegaly at younger ages.1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar Residual protein expression was thoroughly shown to not confer a better prognosis in terms of other manifestations or outcomes, although there was a trend toward earlier age of onset in patients with absent protein.1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar These data are immensely important, and observations about type of pathogenic variant or resulting protein expression should not weigh heavily as part of consideration of HCT. Yang et al1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar also confirm with aggregate data that patients with XIAP deficiency are generally at high risk of allogeneic HCT complications and historical outcomes have been suboptimal. An indication of HLH, active HLH, and use of a fully myeloablative conditioning regimen in patients with HLH adversely affected HCT outcomes.1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar Encouragingly, however, Yang et al1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar noted that the 5-year estimated survival rate following allogeneic HCT was almost 90% in patients reported in 2015-2020 compared with 41% in patients reported in prior years (Table II).1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar Another recent sizable report from Japan in 2021 also indicates higher survival rates of 85% (n = 26).9Ono S. Takeshita K. Kiridoshi Y. Kato M. Kamiya T. Hoshino A. et al.Hematopoietic cell transplantation rescues inflammatory bowel disease and dysbiosis of gut microbiota in XIAP deficiency.J Allergy Clin Immunol Pract. 2021; 9: 3767-3780Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar 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,6Arnold D.E. Nofal R. Wakefield C. Lehmberg K. Wustrau K. Albert M.H. et al.Reduced-intensity/reduced-toxicity conditioning approaches are tolerated in XIAP deficiency but patients fare poorly with acute GVHD.J Clin Immunol. 2022; 22: 36-45Crossref Scopus (5) Google Scholar 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. Future prospective studies are required to better quantify quality of life and freedom from medical interventions in survivors who are treated conservatively or with allogeneic HCT.Table IIOutcomes of patients treated with allogeneic HCT reported before or after 20151Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google ScholarTime period of reportNo. of patientsPhenotype(s)Median age at HCT∗Data applies to all patients in both time frames.Overall survival at 1350 days following HCTMedian time after HCT∗Data applies to all patients in both time frames.2006-20142015-20202822With HLH (n =18)With IBD (n = 5)With HLH + IBD (n = 4)Asymptomatic (n = 1)With HLH (n = 12)With IBD (n = 6)With HLH + IBD (n = 3)With aplastic anemia (n = 1)5 y (range 0.7-19 y)41%89%330 d (range 13-1387 d)∗ Data applies to all patients in both time frames. Open table in a new tab In all, Yang et al1Yang L. Booth C. Speckmann C. Seidel M.G. Worth A.J.J. Kindle G. et al.Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency.J Allergy Clin Immunol. 2022; 150: 456-466Abstract Full Text Full Text PDF Scopus (1) Google Scholar have contributed a practical and valuable summary of more than a decade of clinical experience from the literature. The data and analyses bring several clinical observations into better focus and will serve to improve the care of patients affected by XIAP deficiency. Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiencyJournal of Allergy and Clinical ImmunologyVol. 150Issue 2PreviewX-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency disease caused by XIAP gene mutations. A broad range of phenotype, severity, and age at onset present challenges for patient management. Full-Text PDF