ZAP‐70 expression is associated with increased risk of autoimmune cytopenias in CLL patients

Abstract

Autoimmune cytopenias (AIC) are frequent in chronic lymphocytic leukemia (CLL) patients, but risk factors and prognostic relevance of these events are controversial. Data about the influence on AIC of biological prognostic markers, as ZAP-70, are scanty. We retrospectively evaluated AIC in 290 CLL patients tested for ZAP-70 expression by immunohistochemistry on bone marrow biopsy at presentation. They were 185 men, median age 63 years, 77.9% Binet stage A, 17.6% B and 4.5% C. AIC occurred in 46 patients (16%): 31 autoimmune hemolytic anemias, 10 autoimmune thrombocytopenias, four Evans syndromes, and one pure red cell aplasia. Of the 46 cases of AIC, 37 (80%) occurred in ZAP-70 positive patients and nine (20%) in ZAP-70 negatives. ZAP-70 expression [Hazard Ratio (HR) = 7.42; 95% confidence interval (CI): 2.49-22.05] and age >65 years (HR = 5.41; 95% CI: 1.67-17.49) resulted independent risk factors for AIC. Among the 136 patients evaluated both for ZAP-70 expression and IGHV status, the occurrence of AIC was higher in ZAP-70 positive/IGHV unmutated cases (35%) than in patients ZAP-70 negative/IGHV mutated (6%) or discordant for the two parameters (4%; P < 0.0001). In ZAP-70 positive patients, occurrence of AIC negatively influenced survival (HR = 1.75; 95% CI: 1.06-2.86). The high risk of developing AIC in ZAP-70 positive CLL, particularly when IGHV unmutated, should be considered in the clinical management.

Immune Thrombocytopenia in Patients with Chronic Lymphocytic Leukemia Is Associated with Stereotyped B-cell Receptors

“…Confirming previous findings, the occurrence of ITP in our series was significantly associated with unmutated IGHV and ZAP-70 positivity (15,17,23,35). A significant group of our patients had available FISH results (325 of 463) which made us possible to investigate on a large scale for the first time the impact of known chromosomal aberrations on ITP occurrence showing that unfavorable lesions, particularly del(11)(q23), were associated with the development of this complication.…”

Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance

“…Ͻ 12 months) correlated with the risk of developing autoimmune cytopenia. More recently, some studies have found an association between autoimmune cytopenia and unfavorable biomarkers, including unmutated IGHV genes, 7,[31][32][33] high expression of CD38 34 or ZAP-70, 7,35 and increased B2M serum levels. 28,29,32 In our series we also found a correlation between increased serum B2M levels, high ZAP-70 or CD38 expression, and autoimmune cytopenia.…”

Non-Hodgkin's Lymphomas

“…180 Patients with advanced disease, unmutated IGHV, increased serum β 2 -microglobulin level, and high expression of ZAP-70 are also at a higher risk of developing AIHA. [181][182][183] ITP in patients with CLL is associated with poorer survival independent of common clinical prognostic variables. In a recent Italian study, high WBC count, unmutated IGHV, and DAT and ZAP-70 positivity were associated with the development of ITP in patients with CLL.…”