Description:
Autoimmune cytopenias that are chronic, refractory and multi lineage present a challenge in the clinic. However, recent advances exploring their molecular genetic underpinnings have made them more amenable to rationally targeted therapies and forestall end organ damage in the long run. Dr. V. Koneti Rao will discuss diagnosis and management of ALPS-FAS (Autoimmune Lymphoproliferative Syndrome due to FAS variants) and APDS (Activated PI3Kinase Delta Syndrome due to PIK3CD and PIK3R1 genetic variants) including recently licensed targeted treatment for the latter using a PI3Kinsae inhibitor, leniolisib. Dr.Charlotte Cunnigham Rundles will discuss the impact of genetic disorders presenting as CVID (Common Variable Immune Deficiency) affecting multiple organs due to variants in transcription factors, check point inhibitors, chemokines and cytokines. CVID is one of the most common inborn errors of immunity presenting with infections due to insufficient levels of immune globulins and loss of specific antibodies. However, a significant proportion of these patients develop autoimmune multilineage cytopenias and increased susceptibility to malignancies including lymphoma. These conditions may often be the initial manifestation of the underlying immune defect in a patient who has not had significant infections, and these episodes may recur over time. Treatment of the hematologic complications may require frequent and episodic use of corticosteroids, and/or rituximab; splenectomy is discouraged. Genetic associations noted in CVID patients include CTLA4, LRBA, IKZF1, NFKB1 and NFKB2,STAT3 and STAT1 variants that might provide opportunities for targeted therapeutics. Dr.Thierry Lamy will highlight the impact of clonal evolution of T and Nk cells in LGL (large granular lymphocytosis).Large granular lymphocyte (LGL) leukemia is a rare T/NK cell driven chronic lymphoproliferative disease characterized by neutropenia, anemia and autoimmune disorders such as rheumatoid arthritis, Sjogren syndrome, vasculitis, and autoimmune endocrinopathies. Recent advances in the pathogenesis of LGL leukemia have highlighted the implication of STAT3 genetic variants playing a pivotal role in the leukemic cell proliferation and survival, and autoimmunity. The genetic landscape of LGL is afflicted with gene mutations affecting NF-KB pathway (TNFAIP3), epigenome (TET2, KMT2D), and microenvironment (CCL22). Immunosuppressive agents (cyclophosphamide, methotrexate and cyclosporine) constitute the foundation of first line therapy. Recent advances have led to the development of targeted approaches, including JAK-STAT inhibitors, cytokine targeting and hypomethylating agents, opening novel approaches in an otherwise incurable disease.