IN CHRONIC LYMPHOCYTIC LEUKAEMIA WITH COMPLEX KARYOTYPE, MAJOR STRUCTURAL ABNORMALITIES IDENTI- FY A SUBSET OF PATIENTS WITH INFERIOR OUTCOME AND DISTINCT BIOLOGIC CHARACTERISTICS

Introduction: In CLL the complex karyotype (CK) is a negative prog- nostic factor associated with an inferior outcome and a worse response to treatment, including novel agents. The CK is a heterogeneous cyto- genetic category, including numerical and structural abnormalities. We investigated whether in CLL with CK the presence of numerical or struc- tural chromosomal abnormalities could be associated with distinct clin- ical or biologic features. Methods: 90 untreated CLL patients with CK diagnosed and treated between 2000 and 2017 according to NCI criteria were included. CK was defined in the presence of ≥3 clonal aberrations. The prognostic rel- evance of monosomies, trisomies, deletions, balanced translocations, unbalanced rearrangements and ≥5 abnormalities was then analysed and correlated to clinical and biological parameters including IGHV muta- tional status and mutations affecting NOTCH1, SF3B1, BIRC3 and TP53 genes. We then analysed the mRNA expression profiles of 23 patients with (n=11) and without (n=12) unbalanced rearrangements. Results: The median age was 67.4 years. The median follow-up was 51.3 months. In multivariate analysis, age >65 years (p=0.038) and unbalanced rearrangements (p=0.025) were associated with a worse overall survival. Patients with unbalanced rearrangements had a lower incidence of 11q deletion (p=0.029) and trisomies (p=0.006) and a higher incidence of TP53 aberrations (p=0.014), monosomies (p=0.004) and a karyotype with ≥5 abnormalities (p=0.003). When considering time to first treatment, in multivariate analysis, advanced stage (p=0.001), unmu- tated IGHV (p=0.034) and unbalanced rearrangements (p=0.043) were associated with a negative prognostic impact. The analysis of mRNA expression profiles identified 160 differentially expressed genes (p <0.1, fold change cut-off >2.0). Using a combined set of genes, a clear-cut separation of the analysed samples was obtained (Figure 1). The presence of unbalanced rearrangements was associated with a deregulation of genes involved in cell cycle control and DNA damage response. Among these, TRPM4, RASGRF1, CTTBP2 and SLAMF1 may be of interest as they may have possible prognostic and therapeutic implications. Conclusions: We have shown that CLL patients with unbalanced rearrangements may represent a subset of very high-risk CLL patients with distinct clinical and biologic characteristics. These patients should to be identified at the time of treatment and could be considered upfront for alternative treatments, including combinations of novel agents.