The Combination of Complex Karyotypes' Subtypes and IGHV Mutational Status Provides Prognostic and Predictive Information in Chronic Lymphocytic Leukemia

Abstract INTRODUCTION. Complex karyotype (CK), defined by the presence of at least 3 chromosomal abnormalities, is a heterogeneous cytogenetic category associated with adverse prognosis in several hematologic malignancies. Recently, Rigolin et al. provided evidence that CK with major structural abnormalities (CK2) at chronic lymphocytic leukemia (CLL) diagnosis negatively impact on the time to first treatment (TTFT) and overall survival (OS) (Rigolin GM, BJH 2018). However, it is unknown whether the prognostic strength of CK could be implemented when combined with stable markers such as the IGHV mutational status. In the present study, we assessed the prognostic and predictive role of the combination of CK subtypes and IGHV status in a large CLL series. METHODS. Stimulated cytogenetics with CpG+IL2 was performed in 736 CLL patients in 3 referenced Italian hematological centers. According to Rigolin et al, CK2 cases included unbalanced translocations, addition, insertion, derivative and marker chromosomes. All other CK were classified as type 1 (CK1). An IGHV gene sequence homology >98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). Treatment was initiated according to the iwCLL guidelines. TTFT and OS were calculated from diagnosis to first treatment or death, respectively, or last known follow-up. Survival curves were compared with the log-rank test and p RESULTS. We focused on 520 out of the 736 patients with cytogenetic and IGHV status assessed within 12 months from diagnosis. The median age at diagnosis was 63 years, 322 (62%) were males, 68% at Binet A stage, 45% U-IGHV, 48 harbored TP53 abnormalities, 99 a CK (28 CK1 and 71 CK2), 232 received at least one line of therapy (31% FCR, 16% BR, 8% ibrutinib, 5% chlorambucil-antiCD20, 40% other treatments) and 80 died over a median follow-up of 5.8 years. 71 (14%) harbored CK2, 214 (41%) CK1 or U-IGHV and 235 (45%) M-IGHV without CK2. The former group were characterized by a higher prevalence TP53 (38% vs 8% vs 3%, p The combination of these two markers also provides predictive information after first-line therapy (p CONCLUSIONS. In this study, we demonstrated that the combination of CK subtypes and IGHV status provides important prognostic and predictive data in CLL. Moreover, our model was not inferior to other commonly used prognostic scores. While patients with M-IGHV without any subtypes of CK showed an excellent outcome with chemoimmunotherapy, new alternative therapies should be explored for patients with CK2. Disclosures Visentin: janssen: Consultancy, Honoraria. Rigolin: Gilead: Research Funding. Mauro: abbvie: Other: board member; janssen: Other: board member. Foa: JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Cuneo: Roche: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Trentin: Gilead: Research Funding; Janssen: Research Funding; Abbvie: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees.