Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of TP53/ATM FISH deletions

Abstract

Genomic complexity identified by chromosome banding analysis (CBA) predicts a worse clinical outcome in CLL patients treated either with standard or new treatments. Herein, we analyzed the clinical impact of complex karyotypes (CK) with or without high-risk FISH deletions (ATM and/or TP53, HR-FISH) in a cohort of 1045 untreated MBL/CLL patients. In all, 99/1045 (9.5%) patients displayed a CK. Despite ATM and TP53 deletions were more common in CK (25% vs 7%; P < 0.001; 40% vs 5%; P < 0.001, respectively), only 44% (40/90) patients with TP53 deletions showed a CK. CK group showed a significant higher two-year cumulative incidence of treatment (48% vs 20%; P < 0.001), as well as a shorter overall survival (OS) (79 mo vs not reached; P < 0.001). When patients were categorized regarding CK and HR-FISH, those with both characteristics showed the worst median OS (52 mo) being clearly distinct from those non-CK and non-HR-FISH (median not reached), but no significant differences were detected between cases with only CK or HR-FISH. Both CK and TP53 deletion remained statistically significant in the multivariate analysis for OS. In conclusion, CK group is globally associated with advanced disease and poor prognostic markers. Further investigation in larger cohorts with CK lacking HR-FISH is needed to elucidate which mechanisms underlie the poor outcome of this subgroup.

Cytogenetic landscape in 1012 newly diagnosed chronic lymphocytic leukemia

“…7 However, CK remained a heterogeneous group. 5 In our series, we could define 4 CK groups according to their FISH status.…”

“…Approximately one third of CK displayed TP53 loss, one third ATM 9 Other data showed that CK cases had a comparable OS as pts exhibiting TP53 loss (whatever CBA result), and pts cumulating CK and TP53 loss had the lower overall survival. 5 Here we could define two supplementary subgroups of CK pts, CK without HR-FISH and CK with ATM loss, which represented 67% of CK cases remained to be clinically investigated.…”

The percentage of cells with 17p deletion and the size of 17p deletion subclones show prognostic significance in chronic lymphocytic leukemia

“… More than 20 metaphases were analyzed. Complex karyotype (CK) was defined as ≥3 chromosome aberrations detected in at least two metaphases …”

Molecular pathogenesis of chronic lymphocytic leukaemia

“…Similar studies have also shown that the presence of a complex karyotype is associated with a worse prognosis (Jaglowski et al , ; Travella et al , ) and poorer treatment response rates, even in the current era of novel therapies (Thompson et al , ). More recently, a complex karyotype was shown to be associated with poor outcome in the absence of mutations of TP53 or ATM (Puiggros et al , ) and was an independent prognostic marker in a prospective study of patients receiving chlorambucil based chemo‐immunotherapy (Herling et al , ). Furthermore, Baliakas et al () have demonstrated that a threshold for defining complex karyotype of 5 or more chromosomal lesions is associated with mutations of TP53 and, perhaps due to this association, an aggressive clinical course.…”