p 53 Aberrations do not predict individual response to fludarabine in patients with B-cell chronic lymphocytic leukaemia in advanced stages

In recent years, genetic factors have been established as important predictors of disease progression and survival in patients with chronic lymphocytic leukaemia (CLL), and they have implications for the risk-adapted clinical management of CLL, particularly in younger patients (Dohner et al, 2000; Krober et al, 2002; Lin et al, 2002; Stilgenbauer et al, 2002; Shanafelt et al, 2004). These biologic markers are currently being incorporated into clinical use as adjuncts to the classical staging systems. Genetic aberrations that modify the expression of p53 (deletions and mutations) are independent poor prognostic factors in CLL (Stilgenbauer et al, 2002). Growing evidence has implicated aberrant promoter methylation in the molecular pathogenesis of several human cancers (Esteller et al, 2001). In vitro studies have demonstrated the expected correlation between hypermethylation in the promoter region of p53 and a decrease in the transcription of this gene (Mass & Wang, 1997; Schroeder & Mass, 1997; Pogribny et al, 2000; Pogribny & James, 2002; Agirre et al, 2003a), however, only a few studies have been carried out in human malignancies. To date, the role of aberrant promoter methylation in B-CLL has not been investigated exhaustively, and widespread studies have been mainly restricted to the p15 and p16 genes (Baur et al, 1999; Rossi et al, 2004). In many countries fludarabine is an approved first-line therapy treatment for CLL, which achieves superior remission rates when compared with traditional first-line therapies, such as the chlorambucil and anthracyline-based regimens. The drug is equally effective in early and advanced disease, and in younger and older patients with CLL (Keating et al, 1998; Rai et al, 2000; Leporrier et al, 2001; O’Brien et al, 2001; Leporrier, 2004; Montserrat, 2004). The presence of either mutations or deletions of the p53 gene has been reported to predict Mikel Valgañón, Pilar Giraldo, Xabier Agirre, Marı́a J. Larráyoz, Araceli Rubio-Martinez, Daniel Rubio-Felix, Marı́a J. Calasanz and Marı́a D. Odero Department of Genetics, University of Navarra, Pamplona, Fundación Estudio Hematologı́a y Hemoterapia de Aragón (FEHHA), Zaragoza, and Division of Oncology, School of Medicine, University of Navarra and Foundation for Applied Medical Research, Pamplona, Spain