Abstract

<div>Abstract<p><b>Purpose:</b> Del17p13 predicts poor outcome and chemorefractoriness in chronic lymphocytic leukemia (CLL). Conversely, it is unknown whether <i>TP53</i> mutations carry any prognostic value independent of del17p13. We tested the independent prognostic value of <i>TP53</i> mutations in CLL.</p><p><b>Experimental Design:</b> The study was based on a consecutive series of 308 CLL. DNA sequencing of <i>TP53</i> exons 2 to 10 and del17p13 interphase fluorescence <i>in situ</i> hybridization were done at CLL diagnosis. Study end points were survival and chemorefractoriness.</p><p><b>Results:</b> At diagnosis, <i>TP53</i> mutations (<i>n</i> = 32) occurred in 31 of 308 (10.0%) patients. Of all CLL showing <i>TP53</i> disruption by either mutation and/or deletion (<i>n</i> = 44), 10 cases (22.7%) showed <i>TP53</i> mutations in the absence of del17p13. Multivariate analysis selected <i>TP53</i> mutations (hazard ratio, 3.20; <i>P</i> = 0.002) as an independent predictor of overall survival after adjustment for del17p13. Also, multivariate analysis selected <i>TP53</i> mutations (hazard ratio, 3.97; <i>P</i> < 0.001) as an independent predictor of chemorefractoriness after adjustment for del17p13. Compared with cases without <i>TP53</i> alterations, CLL harboring any type of <i>TP53</i> disruption (mutation only, del17p13 only, or both mutation and del17p13) uniformly displayed a high prevalence of unfavorable prognosticators and poor outcome. Analysis of sequential CLL samples showed the acquisition of new or additional <i>TP53</i> alterations at the time of chemorefractoriness.</p><p><b>Conclusions:</b> These data show that (<i>a</i>) <i>TP53</i> mutations are an independent predictor of short survival and chemorefractoriness, and (<i>b</i>) that CLL presenting with <i>TP53</i> mutations without del17p13 fare as poorly as CLL carrying del17p13. Because CLL harboring <i>TP53</i> mutations without del17p13 are currently not recognized by conventional diagnostic strategies, these results may be relevant for a comprehensive prognostic characterization of CLL.</p></div>

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