Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster I
Hematology Disease Topics & Pathways:
autoimmune hemolytic anemia, Diseases, Immune Disorders, immunodeficiency
Methods: To assemble a highly annotated and curated patient database, we retrospectively collected detailed clinical information of AIHA in patients with RAG deficiency through multi-national collaboration and reviewed all published cases with RAG deficiency and concurrent AIHA from PubMed between 2001 and 2021.
Results: We identified 74 patients with RAG deficiency who developed AIHA during their disease course, and characteristics of the cohort are shown in the Table. Of our own case series (n = 20), the median age at clinical and molecular diagnosis was 1.6 and 2.3 years, respectively. There was a slight predominance of female patients (53.7%). RAG1 mutations were found in 75.0% of cases, and CID-G/AI (55.0%) was the predominant clinical phenotype with a median RAG1 activity of 19.3%. AIHA was typically preceded by viral infections (55.0%) and presented with severe symptomatic anemia (median hemoglobin 6.4 g/dL), with recurrent episodes (median 2), and required multiple units of transfusion support (median 5 units). Most cases were warm AIHA with IgG autoantibodies (92.9%) detected by Coombs tests. In parallel, anti-cytokine autoantibodies against IFNα (85.7%), IFNω (57.1%), and IL12 (28.6%) were frequently found in these patients. Despite the use of high-dose corticosteroid (85.0%) and intravenous immunoglobulin (68.8%), more than half of them required additional immunosuppressive treatment (52.6%), and ultimately, 15 (75%) patients underwent allogeneic stem cell transplant. Among them, refractory cytopenias were the indication of transplant in seven patients. Cases reported in the literature (n = 54) had a similar clinical profile to our cohort; therefore, they were combined for further analysis (n = 74). We found a unique immunological profile of patients fulfilled the diagnosis of Evans syndrome (n = 34, 45.9%), including a trend of more female patients (65.5 vs. 42.9%, p = 0.062), a higher frequency of positive Coombs test (96.7 vs. 75.0%, p = 0.023), lower total lymphocyte (median 1009 vs. 2120/µL, p = 0.015), CD8+ (median 102 vs. 226/µL, p = 0.004), CD56+ cell counts (median 209 vs. 382/µL, p = 0.005), and more cases underwent allogeneic stem cell transplant (75.0 vs. 45.9%, p = 0.014). In the combined cohort, the 10-year overall survival was 55.4%, and allogeneic stem cell transplant was associated with reduced mortality (31.7 vs. 57.1%, p = 0.036).
Conclusion: Patients with RAG deficiency often experience severe, recurrent, and treatment-refractory cytopenias, including AIHA during their disease course. Those with Evans syndrome demonstrated a unique immunological profile with reduced numbers of cytotoxic cells, which required further mechanistic investigations. Multiple lines of AIHA-directed therapies are typically required, and allogeneic stem cell transplant, if indicated, may improve the long-term outcomes in this population.
Disclosures: Westermann-Clark: Amgen,: Consultancy; Pfizer,: Consultancy; Novartis: Consultancy; BMS/Celgene/: Consultancy; Juno: Consultancy; , Kite/Gilead: Consultancy, Research Funding; Precision Biosciences,: Consultancy; Jazz,: Consultancy, Research Funding; Beigene: Consultancy; Adaptive,: Consultancy; Century Therapeutics: Consultancy; Autolus: Consultancy. Walter: Regeneron: Consultancy; Enzyvant: Consultancy; UptoDate: Other: Medical Writer; Pharmig: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Consultancy; Grifols: Consultancy; Octapharma: Research Funding; ADMA Biologicals: Consultancy; MustangBio: Research Funding; Chiesi: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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