Autoimmune Cytopenias in Chronic Lymphocytic Leukemia: Focus on Molecular Aspects

Abstract

Autoimmune cytopenias, particularly autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), complicate up to 25% of chronic lymphocytic leukemia (CLL) cases. Their occurrence correlates with a more aggressive disease with unmutated VHIG status and unfavorable cytogenetics (17p and 11q deletions). CLL lymphocytes are thought to be responsible of a number of pathogenic mechanisms, including aberrant antigen presentation and cytokine production. Moreover, pathogenic B-cell lymphocytes may induce T-cell subsets imbalance that favors the emergence of autoreactive B-cells producing anti-red blood cells and anti-platelets autoantibodies. In the last 15 years, molecular insights into the pathogenesis of both primary and secondary AIHA/ITP has shown that autoreactive B-cells often display stereotyped B-cell receptor and that the autoantibodies themselves have restricted phenotypes. Moreover, a skewed T-cell repertoire and clonal T cells (mainly CD8+) may be present. In addition, an imbalance of T regulatory-/T helper 17-cells ratio has been involved in AIHA and ITP development, and correlates with various cytokine genes polymorphisms. Finally, altered miRNA and lnRNA profiles have been found in autoimmune cytopenias and seem to correlate with disease phase. Genomic studies are limited in these forms, except for recurrent mutations of KMT2D and CARD11 in cold agglutinin disease, which is considered a clonal B-cell lymphoproliferative disorder resulting in AIHA. In this manuscript, we review the most recent literature on AIHA and ITP secondary to CLL, focusing on available molecular evidences of pathogenic, clinical, and prognostic relevance.

Keywords: Evans' syndrome; autoimmune hemolytic anemia; chronic lymphocytic leukemia; immune thrombocytopenia; molecular.

Figure 1

Autoimmune cytopenias (AIC) in chronic lymphocytic leukemia (CLL): the heterogeneity of onset imposes different management in each context.

Figure 2

The changing border between primary and secondary autoimmune cytopenias (AIC). Immune dysregulation is more profound in AIC secondary to systemic autoimmune diseases and immune deficiencies, than in AIC secondary to infections. Likewise, a higher burden of somatic mutations is more typical of bone marrow failures (BMF) and lymphoproliferative disorders (chronic lymphocytic leukemia, CLL; non-Hodgkin lymphomas, NHL), than in cold agglutinin disease (CAD) and syndrome (CAS). The increasing availability of genomic testing will improve the diagnostic sensitivity, moving upward the border between primary and secondary AIC.