Background. The clinical heterogeneity of chronic lymphocytic leukemia (CLL) requires parameters to stratify patients into prognostic subgroups to adapt treatment ranging from ‘watch and wait’ to allogeneic stem cell transplantation. Different parameters such as lymphocyte doubling time, b-2 microglobulin, CD38 and ZAP-70 expression, immunoglobulin variable heavy chain (IgVH) mutation status and genetic abnormalities have been integrated in clinical practice. By using fluorescence in situ hybridization (FISH), cytogenetic abnormalities can be found in approximately 80% of patients. Aims. In the present study, we performed FISH analysis to detect the major cytogenetic alterations in a series of patients in Binet stage A included in the prospective multicenter O-CLL1 GISL study started in April 2007. Methods. Molecular markers characterization and FISH analyses were previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. GCC, 2008). Results. Up to date, 275 patients have been enrolled in the trial and FISH data concerning trisomy 12 and 13q14, 17p13, 11q23 deletions were available in 192 patients. At least one abnormality was found in 131/192 (68.2%) patients. The most frequent abnormality was del(13)(q14) (100/192, 52%), followed by trisomy 12 (25/192, 13%) (in one case accompanied by 17p13 deletion), del(17)(p13) (6/192, 3%) and del(11)(q22.3) (10/192, 5%). 13q14 deletion was found as a sole abnormalities in 90 patients; in the remaining cases, it was combined with del(17)(p13) (3 pts), trisomy 12 (1 pts) and del(11q)(22.3) (6 pts). Among patients with 13q14 deletions, 71 were monoallelic, 7/100 biallelic, whereas 22 showed combined biallelic and monoallelic deletion patterns. We also analyzed the relationship between each single abnormality and CD38 and ZAP-70 expression, and IgVH mutational status. In particular, the CD38 percentages were 8.4±1.8 (mean value±SD), 19.5±2.8, 45.1±7.1, 30.3±8.4, 52.9±9.9 for del(13)(q14), normal, trisomy 12, del(11)(q22) and del(17)(p13) FISH alterations (p<0.0001), respectively. The percentages of IgVH mutations significantly (p<0.0001) correlated with cytogenetic alterations; namely, 5.3±0.4 for cases with del(13q14), 4.6±0.6 in normal, 1.8±0.6 in trisomy 12, 0.2±0.1 in del(11)(q22) and 1.6±1.7 in the 4 cases with del(17p13). Similarly, a significantly (p=0.0005) lower mean value of ZAP-70 expression was accounted in del(13q14) (29.7±2.3) as compared with normal cases (34.6±3.2), trisomy 12 (43.8±5.4), del(11)(q22) (55.9±9.7) and del(17)(p13) (54.8±11.8). Based on a scoring system in which 1 point was assigned to each unfavorable biomarker (i.e. CD38, ZAP-70 or IgVH mutational status) we stratified our series in three different groups from 0 to 3 according to the absence or presence of one, two or all three biomarkers. Similarly, cytogenetic abnormalities were clustered in 3 risk groups [i.e. low del(13)(q14) and normal; intermediate (trisomy 12); and high risk del(11)(q22) and del(17)(p13)] as suggested by others. Interestingly, 72/77 cases scoring 0 for the biomarkers, gathered in the low FISH group. Conversely, out of the 13 cases with high FISH risk, 10 cluster in scoring 2-3. Conclusions. Our preliminary results indicate that in Binet stage A CLL patients at diagnosis cytogenetic abnormalities with an expected negative clinical impact are relatively few (16/192, 8%) but significantly associated with prognostic biomarkers which negatively predict the clinical outcome in CLL.

RELATIONSHIP BETWEEN CYTOGENETIC ANOMALIES AND BIOMARKERS IN BINET STAGE A PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AT DIAGNOSIS: PRELIMINARY RESULTS OF A PROSPECTIVE, MULTICENTER O-CLL1 GISL STUDY / Fabris, ; G., Cutrona; M., Gentile; S., Matis; E. A., Pesce; F., Di Raimondo; A., Musolino; M., Gobbi; N., Di Rienzo; F. R., Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; S., Zupo; C., Mammi; L., Baldini; F., Angrilli; G., Quintana; U., Consoli; G., Bertoldero; E., Iannitto; P., Di Tonno; A., Fragasso; S., Molica; P., Musto; M. C., Cox; G., Festini; V., Callea; Sacchi, Stefano; A., Cortelezzi; G., Lambertenghi Deliliers. - In: HAEMATOLOGICA. - ISSN 1592-8721. - ELETTRONICO. - 94:(2009), pp. 372-372. ((Intervento presentato al convegno nd tenutosi a Berlin nel June 4-7, 2009.

RELATIONSHIP BETWEEN CYTOGENETIC ANOMALIES AND BIOMARKERS IN BINET STAGE A PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AT DIAGNOSIS: PRELIMINARY RESULTS OF A PROSPECTIVE, MULTICENTER O-CLL1 GISL STUDY

SACCHI, Stefano;
2009-01-01

Abstract

Background. The clinical heterogeneity of chronic lymphocytic leukemia (CLL) requires parameters to stratify patients into prognostic subgroups to adapt treatment ranging from ‘watch and wait’ to allogeneic stem cell transplantation. Different parameters such as lymphocyte doubling time, b-2 microglobulin, CD38 and ZAP-70 expression, immunoglobulin variable heavy chain (IgVH) mutation status and genetic abnormalities have been integrated in clinical practice. By using fluorescence in situ hybridization (FISH), cytogenetic abnormalities can be found in approximately 80% of patients. Aims. In the present study, we performed FISH analysis to detect the major cytogenetic alterations in a series of patients in Binet stage A included in the prospective multicenter O-CLL1 GISL study started in April 2007. Methods. Molecular markers characterization and FISH analyses were previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. GCC, 2008). Results. Up to date, 275 patients have been enrolled in the trial and FISH data concerning trisomy 12 and 13q14, 17p13, 11q23 deletions were available in 192 patients. At least one abnormality was found in 131/192 (68.2%) patients. The most frequent abnormality was del(13)(q14) (100/192, 52%), followed by trisomy 12 (25/192, 13%) (in one case accompanied by 17p13 deletion), del(17)(p13) (6/192, 3%) and del(11)(q22.3) (10/192, 5%). 13q14 deletion was found as a sole abnormalities in 90 patients; in the remaining cases, it was combined with del(17)(p13) (3 pts), trisomy 12 (1 pts) and del(11q)(22.3) (6 pts). Among patients with 13q14 deletions, 71 were monoallelic, 7/100 biallelic, whereas 22 showed combined biallelic and monoallelic deletion patterns. We also analyzed the relationship between each single abnormality and CD38 and ZAP-70 expression, and IgVH mutational status. In particular, the CD38 percentages were 8.4±1.8 (mean value±SD), 19.5±2.8, 45.1±7.1, 30.3±8.4, 52.9±9.9 for del(13)(q14), normal, trisomy 12, del(11)(q22) and del(17)(p13) FISH alterations (p<0.0001), respectively. The percentages of IgVH mutations significantly (p<0.0001) correlated with cytogenetic alterations; namely, 5.3±0.4 for cases with del(13q14), 4.6±0.6 in normal, 1.8±0.6 in trisomy 12, 0.2±0.1 in del(11)(q22) and 1.6±1.7 in the 4 cases with del(17p13). Similarly, a significantly (p=0.0005) lower mean value of ZAP-70 expression was accounted in del(13q14) (29.7±2.3) as compared with normal cases (34.6±3.2), trisomy 12 (43.8±5.4), del(11)(q22) (55.9±9.7) and del(17)(p13) (54.8±11.8). Based on a scoring system in which 1 point was assigned to each unfavorable biomarker (i.e. CD38, ZAP-70 or IgVH mutational status) we stratified our series in three different groups from 0 to 3 according to the absence or presence of one, two or all three biomarkers. Similarly, cytogenetic abnormalities were clustered in 3 risk groups [i.e. low del(13)(q14) and normal; intermediate (trisomy 12); and high risk del(11)(q22) and del(17)(p13)] as suggested by others. Interestingly, 72/77 cases scoring 0 for the biomarkers, gathered in the low FISH group. Conversely, out of the 13 cases with high FISH risk, 10 cluster in scoring 2-3. Conclusions. Our preliminary results indicate that in Binet stage A CLL patients at diagnosis cytogenetic abnormalities with an expected negative clinical impact are relatively few (16/192, 8%) but significantly associated with prognostic biomarkers which negatively predict the clinical outcome in CLL.
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Fabris, ; G., Cutrona; M., Gentile; S., Matis; E. A., Pesce; F., Di Raimondo; A., Musolino; M., Gobbi; N., Di Rienzo; F. R., Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; S., Zupo; C., Mammi; L., Baldini; F., Angrilli; G., Quintana; U., Consoli; G., Bertoldero; E., Iannitto; P., Di Tonno; A., Fragasso; S., Molica; P., Musto; M. C., Cox; G., Festini; V., Callea; Sacchi, Stefano; A., Cortelezzi; G., Lambertenghi Deliliers
RELATIONSHIP BETWEEN CYTOGENETIC ANOMALIES AND BIOMARKERS IN BINET STAGE A PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AT DIAGNOSIS: PRELIMINARY RESULTS OF A PROSPECTIVE, MULTICENTER O-CLL1 GISL STUDY / Fabris, ; G., Cutrona; M., Gentile; S., Matis; E. A., Pesce; F., Di Raimondo; A., Musolino; M., Gobbi; N., Di Rienzo; F. R., Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; S., Zupo; C., Mammi; L., Baldini; F., Angrilli; G., Quintana; U., Consoli; G., Bertoldero; E., Iannitto; P., Di Tonno; A., Fragasso; S., Molica; P., Musto; M. C., Cox; G., Festini; V., Callea; Sacchi, Stefano; A., Cortelezzi; G., Lambertenghi Deliliers. - In: HAEMATOLOGICA. - ISSN 1592-8721. - ELETTRONICO. - 94:(2009), pp. 372-372. ((Intervento presentato al convegno nd tenutosi a Berlin nel June 4-7, 2009.
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