Publications (45) View all
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Article: Clinical implications of the molecular genetics of chronic lymphocytic leukemia.
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ABSTRACT: Genetics and molecular genetics have contributed to clarify the biological bases of the clinical heterogeneity of chronic lymphocytic leukemia. In recent years, our knowledge of the molecular genetics of chronic lymphocytic leukemia has significantly broadened, offering potential new clinical implications. Mutations of TP53 and ATM add prognostic information independently of fluorescence in situ hybridization cytogenetic stratification. In addition, next generation sequencing technologies have allowed previously unknown genomic alterations in chronic lymphocytic leukemia to be identified. Mutations of NOTCH1, SF3B1 and BIRC3 have been associated with short time to progression and survival. Each of these lesions recognizes a different distribution across different clinical phases and biological subgroups of the disease. The clinical implications of these molecular lesions are in some instances well established, such as in the case of patients with TP53 disruption, who should be considered for alternative therapies/allogeneic stem cell transplant upfront, or in patients with ATM disruption, who are candidates to rituximab-based immunochemotherapy. On the contrary, NOTCH1, SF3B1 and BIRC3 mutations appear to have a specific significance, the clinical value of which is currently being validated, i.e. association to Richter syndrome transformation for NOTCH1 mutations, and short progression-free survival after treatment for SF3B1 mutations. Certainly, these new lesions have helped clarify the molecular bases of chronic lymphocytic leukemia aggressiveness beside TP53 disruption. This review covers the recent advancements in our understanding of the molecular genetics of chronic lymphocytic leukemia and discusses how they are going to translate into clinical implications for patient management.Haematologica 05/2013; 98(5):675-85. · 6.42 Impact Factor -
Article: IgD cross-linking induces gene expression profiling changes and enhances apoptosis in chronic lymphocytic leukemia cells.
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ABSTRACT: Gene profile and functional changes upon IgD cross-linking were evaluated in chronic lymphocytic leukemia (CLL). Microarrays highlighted responsiveness to IgD in all cases, independently of clinico-biological characteristics. Stimulated samples exhibited the down-regulation of transcripts of B-cell receptor signaling and cell-adhesion at 24h and the up-modulation of differentiation and apoptosis genes at 48h. A significant increase in apoptosis upon ligation was also documented. Furthermore, comparison between IgD and IgM stimulation displayed a differential transcriptional/functional response. In conclusion, CLL respond to IgD displaying expression changes and cell-death enhancement, indicating the apoptosis induction via-IgD as an alternative approach for CLL management.Leukemia research 01/2013; · 2.36 Impact Factor -
Article: Identification of molecular and functional patterns of p53 alterations in chronic lymphocytic leukemia patients in different phases of the disease.
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ABSTRACT: We analyzed TP53 mutations in 483 chronic lymphocytic leukemia patients at different phases of the disease and found a higher incidence of mutations at the later phases and a distinctive mutation profile in each phase. p53 function evaluated by immunoblotting and flow cytometry after cell irradiation was impaired in 28/109 cases. Three phenotipycally different dysfunctions were observed: type I, associated with heterozygous missense TP53 mutations - typically present at diagnosis - and partially resistant to radiation-induced killing; type II and III, with a higher incidence of microdeletions, nonsense mutations and bi-allelic TP53 defects - common in progressive and chemoresistant cases - and a complete radioresistance. Furthermore, in 4/28 patients, all chemoresistant, we found p53 dysfunctions without TP53 mutations. In chronic lymphocytic leukemia patients, a disease phase-specific variability in the p53 mutation profile and function takes place, and both analyses could be useful to guide treatment choices.Haematologica 09/2012; · 6.42 Impact Factor -
Article: Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial.
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ABSTRACT: The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re-evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow-up, investigator-assessed complete response (CR) rate (21·0% vs 10·8%), median progression-free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non-responders. However, patients with objective response or a CR experienced a significantly longer OS than non-responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first-line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.British Journal of Haematology 08/2012; 159(1):67-77. · 4.94 Impact Factor -
Article: Monoclonal B-cell lymphocytosis: a reappraisal of its clinical implications.
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ABSTRACT: Monoclonal B-cell lymphocytosis (MBL) is a recently defined medical condition that displays biological similarities to chronic lymphocytic leukemia (CLL), the most common subtype of adult leukemia in the Western world. MBL may be diagnosed in individuals with a normal lymphocyte count via a screening assay (screening MBL) or through the clinical evaluation of lymphocytosis (clinical MBL). Clinical MBL, which resembles CLL with a good prognosis, has attracted considerable interest because of its clinical and biological implications. The biological profile of clinical MBL appears indistinguishable from that of CLL for a large variety of markers. Differential diagnosis between clinical MBL and CLL is mainly based on peripheral blood B-cell counts. The 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria changed the definition of CLL to a B-cell count ≥ 5.0 × 10(9)/L to eliminate overlap between CLL and MBL. However, this cut-off is arbitrary, and recent studies suggest that a B-cell count of 10.0-11.0 × 10(9)/L may represent the threshold that best predicts time to first treatment. After a diagnosis of clinical MBL, patients should be educated about appropriate monitoring and follow-up keeping in mind that, with time and counseling, most patients will understand that clinical MBL and CLL represent a continuum.Leukemia & lymphoma 02/2012; 53(9):1660-5. · 2.40 Impact Factor
