The combination of complex karyotype subtypes and IGHV mutational status identifies new prognostic and predictive groups in chronic lymphocytic leukaemia

Andrea Visentin,Francesca Romana Mauro,Robin Foà,Laura Bonaldi,Annalisa Martines,Maurizio A Nanni ,Monica Facco,Eleonora Volta,Antonio Cuneo,Anna Guarini,Edoardo Scomazzon,Ilaria Del Giudice,Francesco Cavazzini,Gian Matteo Rigolin,Stefano Pravato,Gianpietro Semenzato,Maurizio Cavallari,Silvia Imbergamo,Maria Antonella Bardi,Federica Frezzato,Livio Trentin

doi:10.1038/s41416-019-0502-x

Abstract

BackgroundComplex karyotype (CK) is a heterogeneous category with a negative impact in chronic lymphocytic leukaemia (CLL). Our group has recently reported that CK patients with major structural abnormalities (i.e. CK2) are characterised by a worse prognosis, as compared to other lesions within CK(CK1).MethodsWe performed a multicentre retrospective study to test whether the combination of CK subtypes with IGHV status could be a relevant prognostic and predictive tool.ResultsAmong 522 patients 13% harboured CK2, 41% CK1 and/or U-IGHV (U-CK1) and 46% M-IGHV without any CK subtypes (M-noCK). After a median follow-up of 5.8 years, CK2 patients had the shortest TTFT (5-year TTFT 31%, 39 and 81%, p < 0.0001) and OS (5-year OS 67%, 85 and 93%, p < 0.0001) as compared to U-CK1 or M-noCK cases, regardless of TP53 abnormalities. CK2 patients also had the worst outcome after chemoimmunotherapy. In fact, the median TTNT after FCR or BR was 1.86 and 4.79 years for CK2 and U-CK1, but not reached for M-noCK patients (p < 0.0005).ConclusionsWe herein suggest that the combined assessment of the IGHV mutational status and CK subtypes refines the prognostication of CLL, allowing to identify M-IGHV patients without any CK subtypes who are characterised by an indolent disease and excellent outcome after chemoimmunotherapy.

Highlights

Complex karyotype (CK) is a heterogeneous category with a negative impact in chronic lymphocytic leukaemia (CLL)
Chromosome banding analysis in CLL is capable of identifying chromosomal abnormalities that are missed by fluorescence in situ hybridisation (FISH) analysis, sometimes fulfilling the criteria of CK.[4,18,27,28]
The combination of immunoglobulin heavy chain (IGHV) mutational status with data derived from chromosome banding analysis allows to identify a subset of patients characterised by M-IGHV without any CK subtypes with a very indolent disease, 90% alive after 10 years of follow-up, who can achieve logterm remission after a short-course of chemoimmunotherapy

Summary

Introduction

Complex karyotype (CK) is a heterogeneous category with a negative impact in chronic lymphocytic leukaemia (CLL). Complex karyotype (CK), defined by the presence of at least three chromosome lesions in the same clone, is detectable in 14–34% of CLL cases[4,5,6,7] and is emerging as a new negative prognostic biomarker associated with an adverse outcome[4,8] and worse response to chemoimmunotherapy[5,9] as well as to novel agents,[10,11] regardless of the CLL-IPI score, unmutated IGHV genes and 11q/17p deletions.[6] the CK itself is a heterogeneous quantitative and qualitative cytogenetic category that includes numerical (i.e. monosomies and trisomies) and structural abnormalities (i.e. balanced and unbalanced translocations, marker chromosomes, isochromosomes, deletions, insertions and additions).

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