Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact

Abstract

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 +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.

Graphical abstract

Figure 1.

Kaplan-Meier curves for OS. (A) Patients with CK (≥3 aberrations, red line) vs non-CK cases (0-2 aberrations, blue line) in the entire cohort. The observed crossover can be explained by the few “events” at the tail of the CK curve, where mostly censored cases are included. (B) Patients with FISH-normal/idel(13q) detected by FISH who carry CK (≥3 aberrations, red line) vs non-CK FISH-normal/idel(13q) cases (blue line). (C) Patients with CK and +12,+19 (red line) vs CLL with CK (green line) and the remaining non-CK CLL (blue line). (D) Patients with CK and +12,+19 carrying mutated IGHV genes (M-CLL, blue line) vs the remaining M-CLL with CK (red line).

Figure 2.

Different biological profiles and clinical outcome among patients with CK (≥3 aberrations [abs]) depending on the number of chromosomal abnormalities. (A) Frequency of U-CLL (unmutated IGHV genes), TP53abs (deletion of chromosome 17p and/or TP53 mutations), del(11q) (deletion of chromosome 11q), and normal-FISH/idel(13q) (normal FISH or isolated deletion of chromosome 13q according to Döhner hierarchical model). Patients with CK and ≥5 aberrations (high-CK) are enriched for U-CLL and TP53abs compared with CK patients with 3 aberrations (low-CK) and those with 4 aberrations (intermediate-CK). Patients with normal-FISH(idel(13q) are detected within all CK groups. (B-D) Kaplan-Meier curves for OS. (B) All patients with CK in the entire cohort. Low-CK, intermediate-CK, and high-CK cases are represented with the blue, red, and green lines, respectively. (C) Patients without TP53abs. High-CK patients exhibit the shortest OS (purple line), whereas there is no difference between low-CK (red line), intermediate-CK (green line), and the remaining non-CK CLL (blue line). (D) Patients with TP53abs. The number of aberrations aggravates the clinical outcome, with high-CK (purple line) exhibiting the shortest OS.

Figure 3.

Distribution of chromosome gains and losses as well as chromosomal breakpoints in the CKs of the present series within 3 aberrations (low-CK), 4 aberrations (intermediate-CK), and ≥5 aberrations (high-CK). (A) 3 aberrations (low-CK); (B) 4 aberrations (intermediate-CK); (C) ≥5 aberrations (high-CK). Gains, right green bars; losses, left red bars; translocation breakpoints, right blue bars adjacent to chromosomes. Ideograms were prepared with the CYDAS software package, freely available at www.cydas.org.

Figure 4.

Kaplan-Meier curves based on a hierarchical model for OS incorporating CK, TP53abs (deletion of chromosome 17p and/or TP53 mutations), and the expression of somatically hypermutated (M-CLL) or unmutated (U-CLL) immunoglobulin heavy variable genes (IGHV). High-CK (≥5 aberrations, red line) exhibits the shortest OS followed by cases with TP53abs and 3 or 4 aberrations (low-CK and intermediate-CK, respectively; low-CK/intermediate-CK/TP53abs, green line), non-CK cases with TP53abs (non-CK/TP53abs, purple line), and non-CK/non-TP53abs cases with unmutated IGHV genes (non-CK/non-TP53abs/U-CLL, black line). Patients with the longest OS are those with non-CK/TP53abs and mutated IGHV genes (M-CLL), as well as patients with CK and +12,+19 (non-CK/non-TP53abs/M-CLL–CK,+12,+19, blue line). P values for all pair comparisons are provided with an inset table in which the colored cells indicate the respective subgroups based on the color of each Kaplan-Meier curve.