An extensive molecular cytogenetic characterization in high-risk chronic lymphocytic leukemia identifies karyotype aberrations and TP53 disruption as predictors of outcome and chemorefractoriness

// Gian Matteo Rigolin 1, * , Luca Formigaro 1, * , Maurizio Cavallari 1 , Francesca Maria Quaglia 1 , Enrico Lista 1 , Antonio Urso 1 , Emanuele Guardalben 1 , Sara Martinelli 1 , Elena Saccenti 1 , Cristian Bassi 2 , Laura Lupini 2 , Maria Antonella Bardi 1 , Eleonora Volta 1 , Elisa Tammiso 1 , Aurora Melandri 1 , Massimo Negrini 2 , Francesco Cavazzini 1, * , Antonio Cuneo 1, * 1 Hematology Section, Department of Medical Sciences, Azienda Ospedaliero-Universitaria, Arcispedale S. Anna, University of Ferrara, Italy 2 Department of Morphology, Surgery and Experimental Medicine, and “Laboratorio per le Tecnologie delle Terapie Avanzate” (LTTA), University of Ferrara, Italy * These authors contributed equally to this work Correspondence to: Gian Matteo Rigolin, email: rglgmt@unife.it Keywords: chronic lymphocytic leukemia, gene somatic mutations, next generation sequencing, karyotype: prognosis Received: September 16, 2016      Accepted: February 21, 2017      Published: March 03, 2017 ABSTRACT We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases. A complex karyotype was present in 21 patients. Mutations were detected in 56 cases and were associated with unmutated IGHV status ( p = 0.040) and complex karyotype ( p = 0.047). TP53 disruption (i.e. TP53 mutations and/or 17p13 deletion by FISH) correlated with the presence of ≥ 2 mutations ( p = 0.001) and a complex karyotype ( p = 0.012). By multivariate analysis, an advanced Binet stage ( p < 0.001) and an unfavorable karyotype ( p = 0.001) predicted a shorter time to first treatment. TP53 disruption ( p = 0.019) and the unfavorable karyotype ( p = 0.028) predicted a worse overall survival. A shorter time to chemorefractoriness was associated with TP53 disruption ( p = 0.001) and unfavorable karyotype ( p = 0.025). Patients with both unfavorable karyotype and TP53 disruption presented a dismal outcome (median overall survival and time to chemorefractoriness of 28.7 and 15.0 months, respectively). In conclusion, karyotype analysis refines risk stratification in high-risk CLL patients and could identify a subset of patients with highly unfavorable outcome requiring alternative treatments.