Improved risk assessment in B-cell chronic lymphocytic leukemia based on sex-specific molecular profiling

Abstract

7090 Background: B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease with some patients having an indolent course and others a rapidly progressing one. As underlying molecular mechanisms of differential disease activity, genomic aberrations, the mutational status of the variable region of the immunoglobulin heavy chain (Ig VH) and distinct expression levels of Zap-70 and CD38 have recently been identified, and their capacity to interact with survival and proliferation signals of B-CLL cells has directly been linked to progression and response to therapy. Although male sex has also been identified as risk factor for a more aggressive disease in B-CLL, the molecular basis for this interaction remains elusive. Methods: We compared the prognostic value of the above-mentioned molecular risk factors between female (n=88) and male patients with B-CLL (n=116). Differences in their frequency was evaluated using the Chi-square test. Their impact on treatment-free and overall survival of patients was analyzed using the Kaplan-Meier method and the log-rank test. The prognostic value of each molecular risk parameter in female and male patients was determined using the Cox proportional hazards regression model. Results: High CD38 expression (=30%), unmutated Ig VH gene (=98%) and unfavorable genetic aberrations (i.e. del17p, del11q or tri12) detected in the neoplastic clone identified patients with significantly shortened treatment-free survival, irrespective of the sex of patients. In contrast, Zap70 expression in more than 20% of B-CLL cells was negatively associated with treatment-free survival only in female (RR: 3.5, 95% CI 1.5 –7.9, P=.003) but not in male patients (RR: 1.6, 95% CI 0.9 –2.9, P=.089). In addition, we identified high CD38 expression in T-cells as independent negative prognostic marker in male (RR: 2.8, 95% CI 1.5 –5.0, P=.0006) but not in female patients (RR: 1.9, 95% CI 0.8 –4.6, P=.17). Based on these results we developed a novel sex-adapted algorithm for improved risk assessment in B-CLL. Conclusions: We identified sex-specific differences in the prognostic value of Zap-70 and CD38 in B-CLL. Whether this can be explained by modulation of their specific signaling pathways by sex hormones will have to be addressed in future studies. No significant financial relationships to disclose.