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Schuetz, C.* ; Gerke, J.S.* ; Ege, M.J. ; Walter, J.* ; Kusters, M.* ; Worth, A.* ; Kanakry, J.A.* ; Dimitrova, D.* ; Wolska-Kuśnierz, B.* ; Chen, K.* ; Unal, E.* ; Karakukcu, M.* ; Pashchenko, O.* ; Leiding, J.* ; Kawai, T.* ; Amrolia, P.J.* ; Berghuis, D.* ; Buechner, J.* ; Buchbinder, D.* ; Cowan, M.J.* ; Gennery, A.R.* ; Güngör, T.* ; Heimall, J.* ; Miano, M.* ; Meyts, I.* ; Morris, E.C.* ; Riviere, J.* ; Sharapova, S.O.* ; Shaw, P.J.* ; Slatter, M.* ; Hönig, M.* ; Veys, P.* ; Fischer, A.* ; Cavazzana, M.* ; Moshous, D.* ; Schulz, A.* ; Albert, M.H.* ; Puck, J.M.* ; Lankester, A.C.* ; Notarangelo, L.D.* ; Neven, B.*

Hypomorphic RAG deficiency: Impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Blood 141, 713-724 (2023)
Postprint DOI PMC
Open Access Gold (Paid Option)
Patients with hypomorphic mutations in RAG1 or RAG2 genes present as either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïveCD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Infections; autoimmunity; damage prior HSCT; In patients with; Stem-cell Transplantation; Severe Combined Immunodeficiency; Autoimmunity; Mutations; Outcomes
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 141, Issue: 7, Pages: 713-724 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Asthma and Allergy Prevention (IAP)
Grants
Rosemarie-Germscheid-Stiftung
California Institute of Regenerative Medicine (CIRM)
Jeffrey Modell Foundation
Lisa and Douglas Goldman Fund
Division of Intramural Research, National Institutes of Health, National Institute of Allergy and Infectious Diseases
Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health
Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases