A matter of debate in chronic lymphocytic leukemia: Is the occurrence of autoimmune disorders an indicator of chronic lymphocytic leukemia therapy?

Purpose of Review: Autoimmune cytopenia is a noninfrequent complication of chronic lymphocytic leukemia (CLL) classified into simple and complex autoimmunity, on the basis of the absence or the concomitance of disease progression. Simple-refractory and complex autoimmunity indicate the need of treatment. Here, we review the epidemiology and the biological mechanisms that account for CLL-associated autoimmune disorders and discuss their prognostic relevance and the indication of treatment. Recent Findings: Autoimmune disorders can complicate CLL at any stage and even occur in the preleukemic monoclonal B lymphocytosis. CLL cells can act as antigen-presenting cells, possibly inducing the formation of autoreactive T helper cells (through the production of B-cell activator factor and a proliferation-inducing ligand) and nonfunctional T regulatory cells (via CD27-CD70 interaction). Further, nonmalignant lymphocytes may stimulate via CD154-mediated mechanism both tumor growth and the development of autoimmunity, especially after fludarabine-based regimens of therapy. CLL cells tend to produce monoclonal polyreactive autoantibodies suggesting that autoantigen stimulation via B-cell receptor signaling may affect the natural history of CLL. Though the results of multivariate analysis do not allow to separate autoimmune disorders developing in CLL from conventional prognostic factors, the pathogenetic intertwining between autoimmunity and malignant transformation indicates the importance of defining whether the occurrence of autoimmunity in CLL might be considered an autonomous prognostic indicator that influences treatment decisions. Summary: Simple-refractory and complex autoimmunity are independent indicators of therapy for CLL. Further, epidemiological and biological studies will help clarifying the prognostic and possibly also the pathogenetic significance of simple autoimmunity.