Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune phenomena, particularly autoimmune hemolytic anemia (AIHA). However, there are very few studies analyzing autoimmune cytopenias and its clinical implications in large, unselected series of patients with CLL. We investigated the prevalence, characteristics, and prognostic significance of autoimmune cytopenias in 960 patients with CLL diagnosed at the Hospital Clínic of Barcelona between January 1980 and December 2008. Seventy of 960 (7%) patients presented autoimmune cytopenias, of whom nineteen were detected at diagnosis, three prior to diagnosis and 48 during the course of the disease. Forty-nine patients had AIHA, 20 immune thrombocytopenic purpura (ITP) and one both AIHA and ITP. A clear association was observed between autoimmune cytopenias and poor prognostic variables such as high blood lymphocyte count (p= 0.004), blood lymphocyte doubling time less than 12 months (p= 0.01), increased serum beta-2 microglobulin (p= 0.02), and high expression of ZAP-70 (p=0.02) and CD38 (p=0.07). No statistically significant differences were found in the incidence of AIHA based on treatment modality: fludarabine-based 8/204 (4%)
vs. alkylating agents-based 12/231 (5%). The outcome of patients with autoimmune cytopenias was not significantly different from that of patients without this complication (median survival: 8 years
vs. 9 years; p=ns). Furthermore, no significant differences were observed according to the time at which cytopenia was detected (i.e., before, at diagnosis or after the diagnosis of CLL). Importantly, significant differences in the response rate were observed in the 73 patients with advanced (Binet C stage) disease based on the origin of cytopenia. Whereas 16 of the 19 patients with stage C “immune” disease responded to corticosteroids and as a result switched from stage C to stage A, only 9 of 54 patients with stage C “infiltrative” responded to therapy (p<0.0001). The survival analysis of patients included in this series according to a modified Binet staging system in which stage C “immune” disease is included as a distinct category is shown in the
figure, median survival times being as follows: stage A, 10.2 years, stage B, 5.6 years, stage C “immune”, 7.4 years and stage C “infiltrative” 3.7 years (p<0.0001).
In conclusion, in this large, unselected and single institution series of patients with CLL autoimmune cytopenias correlated with well-known poor prognostic variables but not with treatment modality (i.e. purine analogs vs. alkylating agents). From the prognostic point of view, autoimmune cytopenias did not significantly influenced prognosis in the whole group of patients. Moreover, patients presenting with advanced disease related to an immune mechanism had better prognosis than those in whom advanced stage reflected a high tumor burden only. These results emphasize the importance of determining the origin of cytopenias in patients with CLL for both treatment and prognostic purposes.
