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1016 Clinical, Immunological Features, Treatments, and Outcomes of Autoimmune Hemolytic Anemia in Patients with RAG Deficiency

Program: Oral and Poster Abstracts
Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster I
Hematology Disease Topics & Pathways:
autoimmune hemolytic anemia, Diseases, Immune Disorders, immunodeficiency
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Chen Wang, MD1*, Bijun Sun, MD2*, Kevin Wu, BSc3*, Jocelyn Farmer, MD, PhD4*, Boglarka Ujhazi, BSc5*, Christoph B. Geier, MD, MSc6*, Sumai Gordon, BSc5*, Emma Westermann-Clark, MD5*, Sinisa Savic, MD, PhD7*, Sargur Ravishankar, MD8*, Karin Chen, MD9*, Cullen M Dutmer, MD10*, Maria G Kanariou, MD11*, Mehdi Adeli, MD12*, Paolo Palma, MD, PhD13*, Carmem Bonfim, MD, PhD14*, Evangelia Lycopoulou, MD15*, Beata Wolska-Kusnierz, PhD16*, Dbaibo Ghassan, MD17*, Jack Bleesing, MD, PhD18*, Despina Moshous, MD, PhD19*, Benedicte Neven, MD20*, Catharina Schuetz, MD21*, Geha Raif, MD22*, Luigi D. Notarangelo, MD23*, Maurizio Miano, MD24*, David K. Buchbinder, MD, MSHS25, Krisztian Csomos, PhD26*, Wenjie Wang, MD2*, Ji-Yang Wang, PhD27*, Xiaochuan Wang, MD2* and Jolan E. Walter, MD, PhD28*

1Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL
2Department of Clinical Immunology, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
3Department of Pediatrics & Medicine, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL
4Department of Allergy & Immunology, Massachusetts General Hospital, Boston, MA
5Department of Pediatric Allergy and Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL
6Department of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany
7St James's University Hospital, University of Leeds, Leeds, United Kingdom
8Sheffield Teaching Hospitals Foundation NHS Trust, Sheffield, United Kingdom
9Division of Immunology, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA
10Section of Allergy & Immunology, Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO
11Department of Immunology and Histocompatibility, Aghia Sophia Children's Hospital, Athens, Greece
12Sidra Medicine, Weill Cornell Medicine-Qatar and Hamad Medical Corporation, Doha, Qatar
13Academic Department of Pediatrics (DPUO), Bambino Gesù Children’s Hospital, Rome, CA, Italy
14Instituto de Pesquisa Pele Pequeno Príncipe/Hospital Infantil Pequeno Principe, Curitiba, Brazil
151st Department of Pediatrics, University of Athens; Aghia Sofia Children's Hospital, Athens, Greece
16Immunology Department, Children's Memorial Health Institute, Warsaw, Poland
17AUBMC Pediatrics, Riad El Solh, American University of Beirut, Beirut, Lebanon
18Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center; Cancer and Blood Diseases Institute, Cincinnati, OH
19Pediatric Immunology, Hematology and Rheumatology Unit, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
20IMAGINE Institute, Université Paris Descartes, Sorbonne Paris Cité, Sorbonne Paris Cité, France
21Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, Ulm, Germany
22Immunology Division, Department of Pediatrics, Harvard Medical School, Boston, MA
23Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD
24Hematology Unit, IRCCS Istituto Giannina Gaslini, Genova, GE, Italy
25Department of Hematology, Children's Hospital of Orange County, Orange, CA
26Division of Allergy and Immunology, Departments of Pediatrics and Medicine, University of South Florida Morsani College of Medicine, Tampa, FL
27Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
28Division of Allergy and Immunology, Departments of Pediatrics, Johns Hopkins All Children's Hospital, St. Petersburg, FL

Background: The clinical features of patients with recombination activating gene (RAG1 and 2) deficiency are diverse, ranging from severe combined immunodeficiency to combined immunodeficiency with granulomatous disease and/or autoimmunity (CID-G/AI). The latter phenotype has been typically associated with hypomorphic mutations, resulting in residual RAG enzymatic activity and frequent autoimmune manifestations. Autoimmune hemolytic anemia (AIHA) is most common, and its development is thought to be due to the breakdown of T/B-cell tolerance, usually triggered by an environmental factor (e.g., viral infection). Its therapeutic response to standard treatment is often unsatisfactory. However, our understanding of this condition is still limited to case reports and small series. Herein, we systematically present clinical, immunological features, treatments, and outcomes of the largest case series of AIHA in RAG deficiency.

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.

*signifies non-member of ASH