A proliferation-inducing ligand (APRIL) serum levels predict time to first treatment in patients affected by B-cell chronic lymphocytic leukemia

Abstract

A proliferation-inducing ligand (APRIL), a tumor necrosis factor superfamily member involved in B-lymphocytes differentiation and survival, plays a role in protecting B-Cell Chronic lymphocytic leukemia (B-CLL) cells from apoptosis. Having observed that APRIL serum (sAPRIL) levels were higher in B-CLL patients with CLL at diagnosis as compared to healthy donors (14.61±32.65 vs. 4.19±3.42 ng/mL; P<0.001), we tested the correlation existing in these patients between sAPRIL, clinical-biological parameters and disease progression. sAPRIL levels were measured by ELISA in 130 patients with B-CLL at diagnosis and in 25 healthy donors. sAPRIL levels did not correlate with gender, age, clinical stage, blood cell counts, β2-microglobulin (β2M) levels, ZAP-70 and CD38 expression. Using median sAPRIL natural logarithm (ln) as cutoff, we distinguished two groups of patients (APRIL(LOW) and APRIL(HIGH) ) who were comparable with regard to clinical-biological parameters and overall survival, but different with regard to time to the first treatment (TTFT; P=0.035). According to univariate analysis, high lymphocyte count, high β2M, Binet stage B-C, ZAP-70 expression and ln(sAPRIL) above median were associated with earlier TTFT. Advanced clinical stage, high β2M, ZAP-70 expression and ln(sAPRIL) above median remained independently predictive of shorter TTFT at multivariate analysis. Moreover, sAPRIL increased its prognostic significance when patients were stratified according to independent favorable clinical-biological characteristics (low β2M, stage A and lack of ZAP-70 expression). sAPRIL is a novel indicator of shorter TTFT in B-CLL and a predictor of progression especially in patients otherwise considered at low risk according to validated prognostic factors.