Papers by Silvia Zibellini
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Clinical Lymphoma and Myeloma, 2007
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Blood, Dec 6, 2014
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Blood, Jan 6, 2016
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with vari... more Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least one somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15 to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1 and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified four categories with signi...
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Leukemia and Lymphoma, May 1, 2007
Hairy cell leukaemia (HCL) is a rare acquired disorder of B cell origin [1-3]. Besides sporadic c... more Hairy cell leukaemia (HCL) is a rare acquired disorder of B cell origin [1-3]. Besides sporadic cases, HCL may affect different relatives of the same family. Familial aggregation of HCL has been reported in 13 families with 28 affected relatives [4],[5]. Although familial HCL is ...
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Clinical Lymphoma Myeloma, 2009
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Leukemia research reports, 2015
Primary resistance to tyrosine-kinase inhibitors (TKIs) is quite uncommon in chronic-phase Chroni... more Primary resistance to tyrosine-kinase inhibitors (TKIs) is quite uncommon in chronic-phase Chronic Myeloid Leukemia (CML) and related to still poorly understood mechanisms, as ABL mutations are rarely detected in primary resistant patients. We report the challenging case of a CML patient who was resistant to multiple TKIs because of different emerging ABL mutations and became pregnant while on Nilotinib therapy despite repeated and clear discouragement to conceive. She decided to continue with her pregnancy, showing an admirable and incredible perseverance in the pursuit of her personal aims.
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Leukemia Research Reports, 2015
Primary resistance to tyrosine-kinase inhibitors (TKIs) is quite uncommon in chronic-phase Chroni... more Primary resistance to tyrosine-kinase inhibitors (TKIs) is quite uncommon in chronic-phase Chronic Myeloid Leukemia (CML) and related to still poorly understood mechanisms, as ABL mutations are rarely detected in primary resistant patients. We report the challenging case of a CML patient who was resistant to multiple TKIs because of different emerging ABL mutations and became pregnant while on Nilotinib therapy despite repeated and clear discouragement to conceive. She decided to continue with her pregnancy, showing an admirable and incredible perseverance in the pursuit of her personal aims.
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Human Pathology, 2009
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Clinical Lymphoma Myeloma and Leukemia, 2011
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Leukemia & Lymphoma, 2007
Hairy cell leukaemia (HCL) is a rare acquired disorder of B cell origin [1-3]. Besides sporadic c... more Hairy cell leukaemia (HCL) is a rare acquired disorder of B cell origin [1-3]. Besides sporadic cases, HCL may affect different relatives of the same family. Familial aggregation of HCL has been reported in 13 families with 28 affected relatives [4],[5]. Although familial HCL is ...
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Leukemia & Lymphoma, 2013
We characterized immunoglobulin heavy chain (IGH) gene rearrangements and searched for clusters o... more We characterized immunoglobulin heavy chain (IGH) gene rearrangements and searched for clusters of stereotyped B-cell receptors in 123 patients with Waldenström macroglobulinemia (WM; n = 59) or immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) (n = 64). A productive monoclonal IGHV-D-J rearrangement was obtained in 99/123 patients (80%). Immunoglobulin heavy chain variable (IGHV) genes were mutated in 94/99 patients (95%) with a median somatic hypermutation rate of 6.7% (2.1-14.5). Compared with the normal B-cell repertoire, patients with WM/IgM-MGUS showed an over-representation of the IGHV3 subgroup (83% vs. 55%, p < 0.0001) and an under-representation of IGHV1 (7% vs. 14%, p = 0.04) and IGHV4 (7% vs. 23%, p = 0.0001) subgroups. At the gene level, in WM/IgM-MGUS there was an over-representation of IGHV3-23 (24% vs. 12%, p = 0.0003), IGHV3-64 (3% vs. < 1%, p = 0.003), IGHV3-7 (12% vs. 4%, p = 0.0001) and IGHV3-74 (9% vs. 2%, p < 0.0001), while IGHV4-39 was never used (0 vs. 5%, p = 0.03). Intra-WM/IgM-MGUS search for HCDR3 similarity showed no association fulfilling criteria for stereotyped receptors. WM/IgM-MGUS sequences were unrelated to known chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL) or mantle cell lymphoma (MCL) subsets. In conclusion, the IGHV gene usage in WM and IgM-MGUS is remarkably biased as compared to the normal B-cell repertoire. WM and IgM-MGUS-specific HCDR3 clusters do not occur with a frequency detectable with currently available databases, not supporting a B-cell receptor-driven pathogenesis in WM and IgM-MGUS.
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Hematological Oncology, 2013
This study analyzed 140 patients with isolated del13q14 on interphase FISH (I-FISH), to identify ... more This study analyzed 140 patients with isolated del13q14 on interphase FISH (I-FISH), to identify subsets with a different progression risk and to assess the acquisition of additional chromosomal abnormalities (clonal evolution) in treatment-naïve del13q14 patients. A monoallelic deletion (del13qx1) was detected in 123 cases (88%), a biallelic deletion (del13qx2) in eight and a mosaic of monoallelic and biallelic deletions (del13qx1/del13qx2) in nine. In 33% of cases, deletion encompassed the Rb1 locus The median percentage of abnormal nuclei was 50% (15%-96%), and it was higher in patients with a biallelic/mosaic pattern in comparison with patients with monoallelic deletion. Sixty two patients (44%) have been treated; 5-year treatment free survival rate was 56% and the median treatment free survival was 65 months. The baseline percentage of deleted nuclei, as a continuous variable, was related to progression (HR: 1.02; p = 0.001). According to deletion burden, three groups were identified: 64 cases (46%) had <50% deleted nuclei, 47 (33%) had 50-69% deleted nuclei, and 29 (21%) had ≥70% deleted nuclei. The 5-year untreated rate was 70.5% , 52.6% and 28.7% (p < 0.0001), respectively. In multivariate analysis using IGHV mutational status, presence of a nullisomic clone, CD38 expression and percentage of deleted nuclei as covariates, only IGHV mutational status and the percentage of deleted nuclei were independent risk factors for treatment. In 103 patients serially monitored by I-FISH before starting any treatment, we observed a significant increase in the proportion of del13q14 cells, and this increase affected the risk of subsequent treatment requirement (HR 2.54, p = 0.001). The appearance of a new clone was detected in 16 patients (15.5%) and chromosome 13 was involved in 14 of them. I-FISH monitoring proves worthwhile for a dynamic risk stratification and for planning clinical surveillance.
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Haematologica, 2011
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Haematologica, 2013
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Clinical Lymphoma and Myeloma, 2009
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British Journal of Haematology, 2009
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British Journal of Haematology, 2010
Splenic marginal zone lymphomas (MZL) express mutated (M)) or unmutated (U)) immunoglobulin heavy... more Splenic marginal zone lymphomas (MZL) express mutated (M)) or unmutated (U)) immunoglobulin heavy chain (IGHV) genes. To investigate the IGHV mutational status impact on genetic lesions, this study combined single nucleotide polymorphism-arrays and IGHV sequencing in 83 cases. Clinical features and outcome were similar between U- and M-IGHV cases. Recurrent lesions frequency was higher in U-IGHV cases, including poor prognosticators. Frequencies differed among cases bearing individual IGHV genes or lambda light chains. In conclusion, SMZL comprises subgroups based on genetic abnormalities and immunogenetic status. Genomic lesion frequency differed and was higher in U-IGHV cases, possibly affecting the outcome.
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Blood Cells, Molecules, and Diseases, 2009
Immunoglobulin gene usage and somatic mutation patterns were studied in 59 patients with splenic ... more Immunoglobulin gene usage and somatic mutation patterns were studied in 59 patients with splenic marginal zone lymphoma and were correlated with clinical characteristics. Fifty-nine IGHV rearrangements were amplified. IGHV1, IGHV3, and IGHV4 subgroups accounted for 30%, 56%, and 14% of sequences, respectively. IGHV genes most frequently used were IGHV1-2 (n=12), IGHV3-23 (n=15), IGHV3-30 (n=7) and IGHV4-34 (n=5). IGHV was unmutated in 25%. Villous lymphocytes >10% were detected in 50% of patients belonging to the IGHV1-2 group, in 21% of the IGHV3-23 group, and in no patient of the IGHV3-30 group (p=0.05). Liver involvement was present in 50% of the IGHV3-30 group, in 9% of the IGHV3-23 group, and in no patient of the IGHV1-2 group (p=0.04). HCV-serology was positive in 50% of the IGHV3-30 group, in 7% of the IGHV3-23 group, and in 17% of the IGHV1-2 group (p=0.04). The proportion of intermediate and high risk patients according to the SMZL score was higher in the unmutated respect to the mutated group (69% vs 32%, p=0.05). In conclusion, IGHV rearrangement analysis in splenic marginal zone B-cell lymphoma reveals a non-random preference for use of IGHV1-2, IGHV3-23 and IGHV3-30 genes, whose presence differs according to clinical features and prognostic category.
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Blood, 2013
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Papers by Silvia Zibellini