Clonal evolution in patients with chronic lymphocytic leukemia

Abstract

Newly acquired genomic abnormalities can arise during the natural history of chronic lymphocytic leukemia (CLL). Reported frequencies range from 17 to 42%, based on several series with small numbers of patients (n ¼ 31-64) and with a limited follow-up (60-83 months) [1][2][3][4]. It has been shown that this complication appears more frequently in patients with unmutated IGVH (immunoglobulin heavy chain variable region) and after treatment. Deletion (del) of 17p13 is unusual as clonal evolution (CE) in untreated patients, and the same thing applies in patients with mutated IGVH. In the present article we report the data obtained in our series, and show that del(17p13) can occur in untreated patients, as well as in those with mutated IGVH.We retrospectively collected data from two Spanish centers. Overall, 81 patients had at least two fluorescence in situ hybridization (FISH) analyses done. The reason for repeated FISH analysis was clinical progression, although in both centers FISH was not performed on a routine basis. The probes used were: LSI p53/LSI ATM and LSI D13S319/ LSI 13q34/CEP 12 multi-color probe sets (Vysis, UK). Standard cut-off level for a deletion was determined as 10% for the probes LSI D13S319, LSI ATM, and LSI p53, and 5% for trisomy 12. A second independent observer analyzed FISH borderline results. Median time of observation after first FISH analysis was 67 months (range 16-111).The baseline characteristics of patients can be seen in Table I. Seventeen out of 81 (21%) patients had CE. In the first FISH analysis, eight out of these 17 (47%) patients had alterations: seven of them (41%) had one alteration [five cases with del(13q14), two cases with trisomy 12] and one case (6%) had two anomalies (13q 7 6 1/11q7). Median observation time between first FISH and the subsequent study with CE was 30 months (range 8-99).Regarding CE itself, 53% of the patients acquired 17p7, while 35% of the cases acquired 11q7, either an anomaly alone or in combination.The details of all the CE cases can be found in Table II, including the treatment between FISH analyses; IGVH data are added, where available.Ten cases with CE had available IGVH data, and four of these were mutated. A germline homology of 98% was used as the cut-off between VH mutated Table I. Clinical characteristics and prior therapy. With CE Without CE n 17 64 Median age (years) (range) 70 (41-80) 68 (45-86) Female (%) 8 (47) 32 (50) Rai III/IV or Binet C (%) 2/14 (14) 13/57 (23) Binet B þ C (%) 4/14 (50) 27/57 (47) Unmutated VH 6/10 NA Number of prior lines (range) 1 (0-6) 1 (0-7) CD38 þ (%) 5/11 (45) 22/53 (41) ZAP70 þ (%) 3/8 (37) 17/45 (38) Follow-up from diagnosis (months) (range) 80 (15-217) 35 (8-183) CE, clonal evolution; NA, not available.

High‐risk clonal evolution in chronic B‐lymphocytic leukemia: single‐center interphase fluorescence in situ hybridization study and review of the literature

“…New high-risk genomic aberrations (11q22 and 17p13 deletion) occurred, respectively, in 8%, 9.4%, 8.2%, 16%, and 5.7% of patients (15)(16)(17)(18)(19). The high percentage of highrisk aberrations in the Loscertales paper can probably be explained by the fact that all patients had progressive disease at second FISH analysis (18). In our study, none of the patients acquired a trisomy 12.…”

“…This study showed CE after a median interval between the two sequential FISH analyses of 40 m with a median follow-up after diagnosis of 89 m. Shanafelt et al (15) observed only one case of CE in 71 patients (1.4%) who got a sequential FISH 2 yr after the baseline analysis, but 17 of 63 patients (23%) showed CE in samples investigated more than 5 yr apart. Median time to CE in the other published series varied between 30 and 64 m (16)(17)(18)(19).…”

“…Loscertales et al . observed high‐risk genomic aberrations as CE in 3/4 patients with mutated IG VH genes .…”

“…High-risk CE seems to occur also as frequently in patients with or without a pre-existing trisomy 12 or 11q deletion. Shanafelt et al showed that ZAP-70-positive patients were four times more likely to experience CE after five or more years of fol- (18).…”

“…Although CLL was not considered as a rapidly proliferating disorder, CE has been reported by conventional karyotyping at the end of the twentieth century (8,(12)(13)(14). At the beginning of the 21st century, several groups confirmed CE with FISH (15)(16)(17)(18)(19).…”