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

Schuetz, C.; Gerke, J.; Ege, M.; Walter, J.; Kusters, M.; Worth, A.; Kanakry, J.A.; Dimitrova, D.; Wolska-Kuśnierz, B.; Chen, K.; ÜNAL, EKREM; 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.; Rivière, J.; Sharapova, S.O.; Shaw, P.J.; Slatter, M.; Honig, 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.

doi:10.1182/blood.2022017667

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

Atıf İçin Kopyala

Schuetz C., Gerke J., Ege M., Walter J., Kusters M., Worth A., ...Daha Fazla

Blood, cilt.141, sa.7, ss.713-724, 2023 (SCI-Expanded)

Yayın Türü: Makale / Tam Makale
Cilt numarası: 141 Sayı: 7
Basım Tarihi: 2023
Doi Numarası: 10.1182/blood.2022017667
Dergi Adı: Blood
Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
Sayfa Sayıları: ss.713-724
Anahtar Kelimeler: Infections, autoimmunity, damage prior HSCT, In patients with
Erciyes Üniversitesi Adresli: Evet

Özet

© 2022 The American Society of HematologyPatients 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.