Background and Aim: CLL is a chronic disease with heterogeneous clinical course. While a subset of patients requires early treatment others are followed without treatment for many years. Cytogenetic aberrations have major impact on the prognosis. The aim of this study was to evaluate 1) the frequency of gain of additional chromosome aberrations during the course of the disease (clonal evolution,CE) 2) the pattern of genetic abnormalities acquired during the CE 3) the association between genetic parameters at diagnosis and CE and 4) the impact of CE on clinical outcome. An additional aim was to compare monitoring by interphase FISH (IP-FISH) or chromosome banding analysis (CBA). Patients and Methods: Two different cohorts were evaluated: A) 363 CLL patients who were analyzed during the course of their disease at least at 2 time points by IP-FISH. In this cohort only patients were enrolled who were analyzed at each time point with the complete FISH panel using probes for 13q14 (D13S25, D13S319), 11q22 (ATM), 17p (TP53), 6q21/6q23, chromosome 12 centromer and IGH -CCND1. B) 245 CLL patients who were evaluated by CBA at least at 2 time points. 179 cases were included in both cohorts. Results: In cohort A 954 FISH analyses were performed in 363 cases (mean: 2.6, range: 2–14). The median time between the first and the last evaluation was 21.1 months (range 1.0–68.9 months). Overall, in 42 of 363 patients (11.6%) clonal evolution was observed, 9.3% of untreated and 16.8% of treated patients showed clonal evolution (p=0.05). The most frequently acquired abnormality was a 17p deletion detected in 12/42 (28.6%) cases, followed by deletion of 13q14 and 11q22 (9 cases each, 21.5%). In 6/131 (4.6%) cases with heterozygous 13q14 deletion at first analysis a homozygous 13q14 deletion was observed during follow up. In 290 of 363 the IGHV mutation status was available. An unmutated IGHV status tended to be associated with clonal evolution, 26/35 (74.3%) cases with and 147/255 (57.6%) patients without clonal evolution showed an unmutated IGHV status (p=0.067). No association between any specific abnormality detected by FISH and clonal evolution was observed. The median time between first FISH analysis and the first detection of clonal evolution was 25 months (range 2–65 months). In cohort B 618 CBA were performed in 245 cases (mean: 2.5, range: 2–8). The median time between the first and the last evaluation was 18.8 months (range 1.0–68.9 months). In 73 patients (30.0%) clonal evolution was observed. The most frequently acquired abnormality was loss of 17p detected in 26 cases, followed by deletion of 13q (n=21), and 11q (n=8). Other recurrent aberrations occurring during CE were gains of 8q (n=14), 13q (n=11), 17q (n=8), 1q (n=7), 3q (n=6), 16q (n=6), 4q (n=5), 1p (n=5), 9q (n=4), 15q (n=4), losses of 8p (n=10), 9q (n=8), 8q (n=7), 9p (n=7), 6q (n=7), 1q (n=6), 6p (n=5), 1p (n=5), 10q (n=4), 7q (n=3) and 14q32-rearrangement (n=6) with different partners (2p11, 4p16, 10p11, 2x 8q24, 19q13). In 202 of 245 patients the IGHV mutation status was available. An unmutated IGHV status was significantly more frequent in cases with as compared to patients without CE (44/62 (71.0%) vs 75/140 (53.6%), p=0.021). The median time between first CBA and the first detection of clonal evolution was 21 months (range 1–65 months). Clonal evolution was observed in 7/48 (14.6%) patients with normal karyotype, in 48/159 (30.2%) cases with non-complex aberrant karyotype and in 18/38 (47.4%) patients with complex karyotype (≥ 3 abnormalities) (p=0.04 for normal vs non-complex aberrant and p=0.056 for non-complex aberrant vs complex). For 135 of 245 cases clinical data with respect to treatment was available (45 cases with and 90 without CE). 33/45 (73%) patients with and 52/90 (57.8%) without clonal evolution had received treatment. A tendency towards a shorter overall survival was observed in patients with as compared to patients without CE detected by CBA (alive at 10 yrs 75.4% vs 93.5%). Conclusions: 1. Chromosome banding analysis detects clonal evolution more frequently than IP-FISH (30.0% vs 11.6%). 2. Clonal evolution occurs more frequently in patients with an unmutated IGHV status and an aberrant karyotype with the highest frequency in patients with complex karyotype. 3. Sequential analyses by FISH and CBA seem reasonable as especially 17p abnormalities occur frequently during the course of the disease, which impacts on treatment decisions.
Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
Asterisk with author names denotes non-ASH members.