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Recent evidence suggests that complex karyotype (CK) defined by the presence of >= 3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with >= 5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and 112,119 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hyper-mutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with 112,119, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with >= 5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.

Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosomebanding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL. © 2019 by The American Society of Hematology.

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptorimmunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggeststhat B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never beenexplored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn.Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogeneticdata were available. These patients were followed up in 15 academic institutions throughout Europe (in CzechRepublic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collectedbetween June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptorimmunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressingunmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome ofour analysis was time to fi rst treatment, defi ned as the time between diagnosis and date of fi rst treatment.Findings 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 majorsubsets. Stereotyped subsets showed signifi cant diff erences in terms of age, sex, disease burden at diagnosis,CD38 expression, and cytogenetic aberrations of prognostic signifi cance. Patients within a specifi c subset generallyfollowed the same clinical course, whereas patients in diff erent stereotyped subsets—despite having the sameimmunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status—showedsubstantially diff erent times to fi rst treatment. By integrating B-cell receptor immunoglobulin stereotypy (forsubsets 1, 2, and 4) into the well established Döhner cytogenetic prognostic model, we showed these, whichcollectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separateclinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2).Interpretation The molecular classifi cation of chronic lymphocytic leukaemia based on B-cell receptorimmunoglobulin stereotypy improves the Döhner hierarchical model and refi nes prognostication beyondimmunoglobulin mutational status, with potential implications for clinical decision making, especially withinprospective clinical trials.Funding European Union; General Secretariat for Research and Technology of Greece; AIRC; Italian Ministry ofHealth; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on ChronicLymphocytic Leukemia; Nordic Cancer Union; Swedish Cancer Society; Swedish Research Council; and NationalCancer Institute (NIH).

We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P

An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2.Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL. © 2015 by The American Society of Hematology 10.1182/blood-2014-09-600874.

Background: About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptorimmunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggeststhat B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never beenexplored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn.Methods: For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogeneticdata were available. These patients were followed up in 15 academic institutions throughout Europe (in CzechRepublic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collectedbetween June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptorimmunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressingunmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome ofour analysis was time to fi rst treatment, defi ned as the time between diagnosis and date of fi rst treatment.Findings: 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 majorsubsets. Stereotyped subsets showed signifi cant diff erences in terms of age, sex, disease burden at diagnosis,CD38 expression, and cytogenetic aberrations of prognostic signifi cance. Patients within a specifi c subset generallyfollowed the same clinical course, whereas patients in diff erent stereotyped subsets-despite having the sameimmunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status-showedsubstantially diff erent times to fi rst treatment. By integrating B-cell receptor immunoglobulin stereotypy (forsubsets 1, 2, and 4) into the well established Döhner cytogenetic prognostic model, we showed these, whichcollectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separateclinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2).Interpretation: The molecular classifi cation of chronic lymphocytic leukaemia based on B-cell receptorimmunoglobulin stereotypy improves the Döhner hierarchical model and refi nes prognostication beyondimmunoglobulin mutational status, with potential implications for clinical decision making, especially withinprospective clinical trials.