Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia: Clinical and biologic correlations

Abstract

To clarify whether karyotype aberrations (KA) involving regions not covered by the standard fluorescence in situ hybridization (FISH) panel have independent prognostic relevance, we evaluated KA by conventional cytogenetics in a learning cohort (LC; n = 166) and a validation cohort (VC; n = 250) of untreated chronic lymphocytic leukemia (CLL) patients. In the VC, novel mitogens were used to improve metaphase generation and TP53, NOTCH1, and SF3B1 mutations were assessed. KA undetected by FISH were found in 35 and 35% of the cases in the LC and VC, respectively. In addition to FISH, KA allowed reclassification of 23 and 26% of cases in the LC and VC, respectively, into a higher cytogenetic risk group. By multivariate analysis, both in the LC and VC, KA other than isolated 13q deletion correlated with a shorter time to first treatment (TFT; P < 0.001 and 0.003, respectively), while a complex karyotype predicted a worse overall survival (OS, P = 0.015 and 0.010, respectively). In the VC, where a comprehensive biologic assessment was performed, a shorter TFT was also predicted by stage (P < 0.001), IGHV mutational status (P = 0.05), and del(17p)/TP53 mutations (P = 0.033) while stage (P = 0.023) and del(17p)/TP53 mutations (P = 0.024) independently predicted a shorter OS. FISH results did not independently impact on TFT and OS, in the LC and VC cohorts; this was also the case for NOTCH1 and SF3B1 mutations in the VC. We suggest that in CLL, conventional karyotyping with novel mitogens could be more effective than FISH for the detection of KA allowing for a more precise refinement of prognosis.

In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI

“…8 All patients were diagnosed and treated according to National Cancer Institute criteria. 9 The study was approved by the local ethics committee.…”

“…13 Furthermore, with the use of effective mitogens, cytogenetic abnormalities and, in particular, CK recently emerged as one of the novel biomarkers associated with an inferior outcome [4][5][6][7][8]12,20 and with the development of chemorefractoriness. 21 In conclusion, we showed for the first time that comorbidities and CK were associated with a worse outcome independently of CLL-IPI.…”

“Identifying High-Risk Chronic Lymphocytic Leukemia: A Pathogenesis-Oriented Appraisal of Prognostic and Predictive Factors in Patients Treated With Chemotherapy With or Without Immunotherapy.”

“…The presence of chromosome aberrations was predictive of an inferior outcome in those patients without detectable aberrations by fluorescence in situ hybridization (FISH) 93. Unbalanced chromosome translocations, frequently occurring in the context of complex karyotype, were shown to be independent prognostic factors in a study94 and complex karyotype predicted for a shorter TTFT71 and OS95 by multivariable analysis. The prognostic value of complex karyotype was also demonstrated in relapsed/refractory CLL patients treated with ibrutinib-based regimens, where this parameter showed a stronger impact on the outcome than del(17p) 96.…”

“…Telomere length proved a reproducible predictor of the outcome but the detection method is not standardized yet, even if a recent study confirmed the reproducibility of results obtained with monochrome multiplex Q-PCR (MMQ-PCR) and single telomere length analysis (STELA), opening the way for the assay standardisation 56. Complex karyotype as detected by stimulation with novel mitogens66 may represent a novel predictor of unfavourable outcome 71,95–97. While simple measures of disease burden such as stage and lymphocytosis do not play a role anymore as prognostic markers, host characteristics such as poor PS and advanced age still play a relevant role in predicting OS.…”

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

“…Moreover, the complex karyotype emerged as an independent predictor of inferior time to first treatment (TTFT) and shorter overall survival (OS) in patients investigated at diagnosis [29] or at disease progression [30] and in relapsed/refractory CLL treated with ibrutinib [31]. …”