Presence of Unbalanced Chromosomal Translocations Independently Predicts for Treatment Failure, Short Treatment-Free (TFS) and Overall Survival (OS) in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients Treated with Cladribine.

Chromosomal translocations have recently emerged as an important prognostic indicator in B-CLL (Mayr et al, Blood 2006). Until now however, their value had neither been determined in patients undergoing homogeneous treatment, nor compared to that of IgVH mutational status, another major prognostic factor in B-CLL. Sixty-five B-CLL pts treated with cladribine-containing regimens were included in the present analysis. All had been investigated by conventional cytogenetic analysis using TPA as a mitogen, interphase FISH (tested loci: 11q/ATM, 12cen, 17p/P53, 13q/RB1&/D13S319), IgVH mutational status and P53 mutational screening prior to inclusion. Translocations (n= 45) were detected in 42 % of the pts, and included both balanced (n=12) and unbalanced (n=33) types. Pts with translocations were more heavily pretreated (P=.05) and presented with significantly higher incidence of complex aberrations (P<.001), 17p aberrations (P<.001) and P53 gene mutations (P<.001). IgVH genes were mutated in 43% and unmutated in 57% of the pts. The presence of unbalanced translocations was associated with significant lower response rate (P=0.004), shorter median TFS (7 vs. 36 months, logrank 22.72, P<.004) and median OS (13 vs. 69 months, logrank 16.51, P<.001), as compared to patients without translocation. In multivariate analysis, translocations, especially the unbalanced subtypes, were significantly associated with the risk of therapeutic failure (P<.000, OR: 7.6) and short TFS (P<.000, HR: 2.12). In addition, the presence of unbalanced translocations proved to be the prognostic marker with the highest negative impact on OS (P=.013, HR: 4.4). Other prognostic factors independently associated with OS were abnormal cytogenetics, high LDH, prior treatment with alkylating agents, and age. IgVH mutational status was independently associated with risk of failure and TFS, but not OS. Interestingly, the presence of translocation(s) had strong negative impact on TFS and OS in IgVH mutated pts, whereas it did not modify outcome in unmutated ones. In conclusion, in B-CLL patients treated with cladribine, the presence of chromosomal translocations is a strong prognostic indicator. This indicates that conventional cytogenetics remains an important tool in defining individual B-CLL patient’s risk.