Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
- Ludwig Maximilian University of Munich
- University of South Florida
- Johns Hopkins University
- Great Ormond Street Hospital for Children NHS Trust
- National Cancer Institute (NCI)
- Children's Memorial Health Institute
- University of Utah
- Erciyes University
- Pirogov Russian National Research Medical University
- Leiden University
- University of Oslo
- University of California at Irvine
- University of California at San Francisco
- Newcastle University
- University of Zurich
- Children's Hospital of Philadelphia (CHOP)
- University of Pennsylvania
- IRCCS Istituto Giannina Gaslini - Genova
- KU Leuven
- Royal Free London NHS Foundation Trust
- University of Sydney
- Great North Children's Hospital
- Ulm University
- Université Paris Cité
- College de France
- Necker–Enfants Malades Hospital
- Imagine Institute
Abstract
Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with 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 naïve CD4+ 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.
Details
Original language | English |
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Pages (from-to) | 713-724 |
Number of pages | 12 |
Journal | Blood |
Volume | 141 |
Issue number | 7 |
Publication status | Published - 16 Feb 2023 |
Peer-reviewed | Yes |
External IDs
PubMed | 36279417 |
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ORCID | /0009-0003-6519-0482/work/146166633 |
Keywords
ASJC Scopus subject areas
Keywords
- Infant, Newborn, Humans, Tissue Donors, T-Lymphocytes, Hematopoietic Stem Cell Transplantation/adverse effects, Early Diagnosis, Cost of Illness, Graft vs Host Disease/diagnosis, Retrospective Studies, Unrelated Donors, Transplantation Conditioning