Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia Running title: CD49d and prognosis in CLL

CD49d/α4-integrin is variably expressed in chronic lymphocytic leukemia (CLL). We evaluated its relevance as independent prognosticator for overall survival (OS) and time-to-treatment (TTT) in a series of 303 (232 for TTT) CLL, in comparison with other biological or clinical prognosticators (CD38, ZAP-70, IGHV gene status, cytogenetic abnormalities, soluble CD23, β2-microglobulin, Rai-staging). Flow cytometric detection of CD49d was stable and reproducible, and the chosen cut-off (30% CLL cells) easily discriminated CD49d from CD49d cases. CD49d, whose expression was strongly associated with that of CD38 (p=2.2x10) and ZAP-70 (p=2.6x10), or with IGHV mutations (p=1.1x10), was independent prognosticator for OS along with IGHV mutational status (CD49d hazard ratio, HRCD49d=3.52, p=0.02; HRIGHV=6.53, p=0.0004) or, if this parameter was omitted, with ZAP-70 (HRCD49d=3.72, p=0.002; HRZAP-70=3.32, p=0.0091). CD49d was also a prognosticator for TTT (HR=1.74, p=0.007) and refined the impact of all the other factors. Notably, a CD49d phenotype, while not changing the outcome of good prognosis (ZAP-70, mutated-IGHV) CLL, was necessary to correctly prognosticate the shorter TTT of ZAP-70 (HR=3.12; p=0.023) or unmutated-IGHV (HR=2.95; p=0.002) cases. These findings support the introduction of CD49d detection in routine prognostic assessment of CLL patients, and suggest both pathogenetic and therapeutic implications for CD49d expression in CLL. only. For personal use at PENN STATE UNIVERSITY on February 23, 2013. bloodjournal.hematologylibrary.org From