We describe the clinical-biological features of 63 cases of variant B chronic lymphocytic leukemia (v-B-CLL), characterized by a mantle cell lymphoma-like immunophenotype, atypical cytomorphology in absence of t(11;14)(q13;q32) in FISH analysis. A historical series of 130 B-CLL was used as comparison. The v-B-CLL were significantly different from the B-CLL in terms of the following clinico-hematological variables: age <70 yrs (p <.001), lymphocytosis <20 x 109/ (p <.001), lymphocyte doubling time < 12 months (p = .02), high serum β2-microglobulin levels (p <.001), and splenomegaly (p = .002). Considering immunophenotipic features, CD38 and CD49d expression were significantly more expressed in v-B-CLL than B-CLL (p <.001); whereas, no statistical difference was observed for ZAP-70 reactivity. Considering the IgVH mutation status, there were more patients mutated in the v-B-CLL group than in the B-CLL group (p = .001). Other significant differences were found about the frequency of the recurrent chromosome alterations, evaluated by means of FISH analysis: trisomy 12 was more frequent in v-B-CLL ( p<.001), while del13q14, considered as a single alteration, was more frequent in B-CLL (p=.008). Gene expression profiling of a panel of 9 v-B-CLL compared with 60 B-CLL samples indicated that the variant group is characterized by a specific molecular pattern of gene expression. In particular we observed the upregulation of tumor protein D52 (TPD52), and that of 6 genes (AFF1, GMPS, PICALM, JUN, REL, RAC2) known to be protooncogenes. Furthermore, we found that upregulated genes with apoptosis related functions (IL-7, HSP90B1, NOTCH2, BECN1, ANXA4, MCL1) are all negative regulators of apoptosis. Microarray analysis revealed that various genes (TRIM38, EEF1D, CASP1, MALT1, RHOH0) involved in the I-kB kinase/NF-kB cascade of the canonical NF-kB signaling pathway, are furtherly upregulated in v-B-CLL. Furthermore, among the genes found differentially expressed in SAM analysis, we observed also the upregulation of CD1c (according to the surface expression of this antigen), OSBPL3 and ITGA4. After a median follow-up of 55 months (range 4-196) and 60 months (range 6-180), 25/42 (59%) v-CLL and 55/93 (59 %) CLL pts were treated. TTT was significant different between 2 groups when the IgVH mutational status was considered (p= .006). Median OS of v-CLL subset was 112 months vs 171 months of CLL subset. When the IgVH mutational status was considered, mutated cases showed a worse OS even if a statistical difference was not observed (p= 0.062). In conclusion, our study identifies, on the basis of a defined CFM-FISH diagnostic approach, a variant form of B-CLL that shows peculiar biological and clinical features that should be considered in the future clinical and prognostic studies. The inclusion of this form in B-CLL study could alter the interpretation of results, especially related to biological markers.

Clinical-biological characterization of variant B chronic lymphocytic leukemia, characterized by a mantle cell lymphoma-like immunophenotype, t(11;14)(q13;q32) negative / A. Ferrario, L. Cro, N. Zucal, M. Lionetti, F. Bertoni, L. Nobili, S. Fabris, K. Todoerti, F. Morabito, G. Cutrona, A. Cortelezzi, A. Guffanti, M. Goldaniga, S. Luminari, L. Marcheselli, M. Ferrarini, A. Neri, G. Lambertenghi Deliliers, L. Baldini. - In: BLOOD. - ISSN 0006-4971. - 114:22(2009), pp. 518-518. ((Intervento presentato al 51. convegno Annual Meeting of the American Society of Hematology tenutosi a New Orleans nel 2009 [10.1182/blood-2009-01-202010].

Clinical-biological characterization of variant B chronic lymphocytic leukemia, characterized by a mantle cell lymphoma-like immunophenotype, t(11;14)(q13;q32) negative

A. Ferrario
Primo
;
M. Lionetti;L. Nobili;S. Fabris;K. Todoerti;A. Cortelezzi;A. Neri;G. Lambertenghi Deliliers
Penultimo
;
L. Baldini
Ultimo
2009

Abstract

We describe the clinical-biological features of 63 cases of variant B chronic lymphocytic leukemia (v-B-CLL), characterized by a mantle cell lymphoma-like immunophenotype, atypical cytomorphology in absence of t(11;14)(q13;q32) in FISH analysis. A historical series of 130 B-CLL was used as comparison. The v-B-CLL were significantly different from the B-CLL in terms of the following clinico-hematological variables: age <70 yrs (p <.001), lymphocytosis <20 x 109/ (p <.001), lymphocyte doubling time < 12 months (p = .02), high serum β2-microglobulin levels (p <.001), and splenomegaly (p = .002). Considering immunophenotipic features, CD38 and CD49d expression were significantly more expressed in v-B-CLL than B-CLL (p <.001); whereas, no statistical difference was observed for ZAP-70 reactivity. Considering the IgVH mutation status, there were more patients mutated in the v-B-CLL group than in the B-CLL group (p = .001). Other significant differences were found about the frequency of the recurrent chromosome alterations, evaluated by means of FISH analysis: trisomy 12 was more frequent in v-B-CLL ( p<.001), while del13q14, considered as a single alteration, was more frequent in B-CLL (p=.008). Gene expression profiling of a panel of 9 v-B-CLL compared with 60 B-CLL samples indicated that the variant group is characterized by a specific molecular pattern of gene expression. In particular we observed the upregulation of tumor protein D52 (TPD52), and that of 6 genes (AFF1, GMPS, PICALM, JUN, REL, RAC2) known to be protooncogenes. Furthermore, we found that upregulated genes with apoptosis related functions (IL-7, HSP90B1, NOTCH2, BECN1, ANXA4, MCL1) are all negative regulators of apoptosis. Microarray analysis revealed that various genes (TRIM38, EEF1D, CASP1, MALT1, RHOH0) involved in the I-kB kinase/NF-kB cascade of the canonical NF-kB signaling pathway, are furtherly upregulated in v-B-CLL. Furthermore, among the genes found differentially expressed in SAM analysis, we observed also the upregulation of CD1c (according to the surface expression of this antigen), OSBPL3 and ITGA4. After a median follow-up of 55 months (range 4-196) and 60 months (range 6-180), 25/42 (59%) v-CLL and 55/93 (59 %) CLL pts were treated. TTT was significant different between 2 groups when the IgVH mutational status was considered (p= .006). Median OS of v-CLL subset was 112 months vs 171 months of CLL subset. When the IgVH mutational status was considered, mutated cases showed a worse OS even if a statistical difference was not observed (p= 0.062). In conclusion, our study identifies, on the basis of a defined CFM-FISH diagnostic approach, a variant form of B-CLL that shows peculiar biological and clinical features that should be considered in the future clinical and prognostic studies. The inclusion of this form in B-CLL study could alter the interpretation of results, especially related to biological markers.
Settore MED/15 - Malattie del Sangue
American Society of Hematology
http://abstracts.hematologylibrary.org/cgi/content/abstract/114/22/1259?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=lionetti&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/146032
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