Laercio DaSilva1, Shannon Swift1, Susan Sansone1, Eva Szabo1,2, Chen Zhao1, Christine Feierabend1, Nisha Patel3, Sebastian Ochoa4, Michail S. Lionakis4, Arun Rajan1,5, Meredith McAdams1
1Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA;
2Lung and Upper Aerodigestive Cancer Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;
3Hematology Section, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD, USA;
4Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;
5Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Correspondence to: Meredith McAdams, MD. Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Building 10, Room 4E-5330, Bethesda, MD 20892, USA. Email: meredith.mcadams@nih.gov.
Background: The autoimmune regulator (AIRE) gene plays a crucial role in the development of immunological self-tolerance. Primary mutations can lead to autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED) whereas decreased expression can be seen in thymomas, both of which are associated with autoimmunity and acquired immunodeficiency. Here we characterize the differences between bone marrow (BM) dyscrasias arising in the setting of primary versus acquired AIRE deficiency.
Methods: We conducted a retrospective review of patients with thymoma or APECED and identified cases with disease or treatment-related biopsy-confirmed BM dyscrasias. We describe clinicopathologic features, management, and outcomes.
Results: Between January 2011 and December 2022, 16 patients [thymoma (n=10); APECED (n=6)] had sufficient data for inclusion. The median age at thymoma diagnosis was 42 (range, 28–72) years, 6 were female, most had World Health Organization (WHO) subtype B histology (B1 n=2, B2 n=2, B2/B3 n=3, B3 n=1, unknown n=2), and 40% (4/10) had a history of paraneoplastic autoimmunity. In contrast, median age at APECED diagnosis was 6 (range, 3–10) years, 4 were female, and 83% (5/6) had 5 or more manifestations of the syndrome. At BM dyscrasia diagnosis, the median age was 48 (33–75) years in thymoma and 25 (range, 3–58) years in APECED, median hemoglobin nadir was 6.9 (range, 5.5–8.3) gm/dL for thymoma and 7.3 (range, 5.0–8.1) gm/dL for APECED, and all patients were red blood cell transfusion dependent. Among patients with thymoma, 70% (7/10) were receiving thymoma-directed therapy. Seven patients presented with anemia alone, 2 with anemia and transfusion-dependent thrombocytopenia, and 1 with anemia and neutropenia. Diagnostic marrows revealed severe erythroid hypoplasia/aplasia alone (n=5), concurrent megakaryocytes hypoplasia/aplasia (n=2), and concurrent decrease in mature granulocytes (n=1). In patients with APECED, 5 presented with anemia alone, and 1 presented with anemia and transfusion-dependent thrombocytopenia. Marrows revealed erythroid hypoplasia/aplasia alone (n=5) and concurrent megakaryocytic aplasia (n=1). Abnormal CD8+ T-cell lymphocytosis was noted in BMs from both thymoma and APECED. Lymphocytic infiltrates were seen in all cases involving >1 cell line and 6 of 10 cases involving erythroid hypoplasia/aplasia alone. Various immunosuppressive treatment approaches were trialed in these patients. Among patients with thymoma, no responses were seen with prednisone (0/3) or intravenous immunoglobulin (0/3). Treatment with cyclosporine A (CsA) achieved transfusion-independence in all patients (8/8), 3 of whom had failed at least one prior line of immunosuppression. In contrast, among APECED patients, no responses were observed with CsA (0/2) or various other immunosuppressive strategies including prednisone (0/1), intravenous immunoglobulin (0/2), rituximab (0/2), mycophenolate mofetil (0/1), tacrolimus (0/2), and antithymocyte globulin (0/2). Responses were only seen with alemtuzumab (4/4), 3 of whom had failed at least one prior line of immunosuppression, and hematopoietic cell transplantation (1/1). Post-CsA BMs in 2 patients with thymoma revealed reduction of lymphoid aggregates and normalization of previously absent cell lines.
Conclusions: AIRE deficiency, both primary and acquired, can be associated with clinically significant, transfusion-dependent BM dyscrasias with potentially serious long-term complications. T-cell directed therapy appears effective and spares patients’ toxicities seen with alternative immunosuppressive agents.
Keywords: Thymoma; autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED); marrow dyscrasia; cyclosporine
