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

Background: Complex 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). Methods: We performed a multicentre retrospective study to test whether the combination of CK subtypes with IGHV status could be a relevant prognostic and predictive tool. Results: Among 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). Conclusions: We 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.