Incidence of Cytogenetic Abnormalities In Newly Diagnosed Binet Stage A CLL and Relationship with Prognostic Biomarkers and with Stereotyped B Cell Receptors: Updated Results on 344 Patients Included In the Prospective O-CLL1 GISL Study.
Authors: Fabris Sonia , Cutrona Giovanna , Gentile Massimo , Matis Serena , Pesce Emanuela Anna , Maura Francesco , Ciceri Gabriella , Raimondo Francesco Di , Musolino Caterina , Gobbi Marco , Renzo Nicola Di , Mauro Francesca Romana , Cantaffa Renato , Brugiatelli Maura , Merli Francesco , Zupo Simonetta , Mammi Caterina , Baldini Luca , Angrilli Francesco , Quintana Gianni , Consoli Ugo , Bertoldero Giovanni , Iannitto Emilio , Tonno Paolo Di , Fragasso Antonio , Molica Stefano , Musto Pellegrino , Cox Maria Cristina , Festini Gainluca , Callea Vincenzo , Sacchi Stefano , Cortelezzi Agostino , Deliliers Giorgio Lambertenghi , Foà Robin , Federico Massimo , Morabito Fortunato , Ferrarini Manlio , Neri Antonino 
Published: October 2019

Abstract
Abstract 4613

Background:
Biologic risk factors such as immunoglobulin variable heavy chain (IgVH) gene mutation status and CD38 and ZAP-70 expression levels, along with genomic aberrations, have been integrated in clinical prognostic evaluation of CLL. Additionaly, CLL subsets expressing a certain stereotyped B-cell receptors have also been indicated to share biological and clinical features.

Aims:
We investigated, by FISH, the incidence of the major cytogenetic alterations (+12 and 13q14, 17p13, 11q23 deletions), their clinical implication and their relationship with prognostic biomarkers in 344 out of 384 Binet A CLLs enrolled in the prospective multicenter O-CLL1 GISL trial. Stereotypy subsets identification have been performed in 324 patients.

Methods:
Molecular markers characterization and FISH protocols were previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. Genes Chromosomes Cancer, 2008), while stereotyped subsets were defined according to Stamatopoulos et al (Blood, 2007) and Murray et al (Blood, 2008).

Results:
At least one abnormality was found in 225/344 (65.4%) cases. The most frequent abnormality was del(13q14), detected in 173 CLLs (50.3%) followed by +12 (44/344;12.8%) (one case harboring 17p13 deletion), del(17p13) (9/344, 2.6%) and del(11q23) (18/344, 5.2%). 13q14 deletion was found as a sole abnormality in 155 (45%) patients; in the remaining cases, it was combined with +12 (3 pts) and 17p13 (4 pts) or 11q23 deletions (11 pts). The 13q deletion was found as a monoallelic deletion in 139/173 (80.3%); the presence of a biallelic deletion (> 20% of interphase nuclei) was found in the remaining 34 cases. No acquisition of new cytogenetic aberrations was evidenced among the 13 CLLs developing progressive disease (range, 6 to 32 months; median, 20 months); in only one case, the proportion of nuclei with 17p13 and 13q14 deletions increased from the time of diagnosis (from 33% to 92%). Biomarkers data were available in all of the patients. CD38 percentages (mean value ± sem) were 7.9±1.3, 15.1±1.9, 51.7±5.5, 22.0±7.8,40.8±13.2, 39.8±7.3 for del(13q14), normal karyotype, +12, del(11q23), del(17p13) and multiple alterations, respectively (p<0.0001). The percentages of IgVH mutations significantly correlated with cytogenetic alterations; namely, 5.7±0.2 for cases with del(13q14), 4.7±0.4 for normal karyotype, 2.3±0.5 for +12, 0.05±0.05 for del(11q23), 2.0±1.1 for del(17p13) and 1.0±0.4 for multiple alterations (p<0.0001). Similarly, a significant correlation was found for ZAP-70 expression: namely 32.9±1.6 for cases with del(13q14), 38.5±2.1 for normal karyotype, 46.4±3.6 for +12, 67.0±8.3 for del(11q22), 41.0±12.8 for del(17p13) and 50.7±5.4 multiple alterations (p<0.0001). Cytogenetic abnormalities were clustered in 3 risk groups [i.e. low del(13q14) and normal; intermediate (+12); and high risk 17p13 and 11q23 deletions] and correlated with a scoring system in which patients were stratified in 4 different groups according to the absence or presence of 1, 2 or 3 biomarkers (Morabito et al., Br. J. Haematol., 2009). Notably, 166/175 cases scoring 0, gathered in the low FISH group, whereas 21/26 high FISH risk cases clustered in scoring 2–3 (p<0.0001). A significantly higher risk of starting treatment was found in high vs. intermediate (p=0.024) and low FISH risk (p=0.001) CLLs. Finally, stereotyped IgVH sequences were found in 108/324 (33%). Unfavorable stereotyped subsets (#1, #2, #3, #7 and #9) were significantly more frequent in CLLs with poor-prognostic aberrations (p=0.0203; RR=3.589).

Conclusions:
Our data indicate that cytogenetic lesions predicting unfavorable prognosis show a relatively low incidence in newly diagnosed Binet stage A CLLs and are significantly associated with negative prognostic biomarkers predictive of disease progression. Our prospective study also confirms the prognostic value of risk FISH categories in predicting the time to the first treatment and revealed a higher rate of unfavorable stereotyped IgVH subsets in patients carrying poor-prognostic genomic aberrations. Finally, preliminary evidence in a limited number of cases indicates that the acquisition of new genetic abnormalities seem to be an infrequent event during disease progression.

Disclosures:
No relevant conflicts of interest to declare.