76 results on '"Rossi, Davide"'
Search Results
2. IELSG38: phase II trial of front-line chlorambucil plus subcutaneous rituximab induction and maintenance in mucosa-associated lymphoid tissue lymphoma
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Stathis, Anastasios, primary, Pirosa, Maria Cristina, additional, Orsucci, Lorella, additional, Feugier, Pierre, additional, Tani, Monica, additional, Ghesquières, Hervé, additional, Musuraca, Gerardo, additional, Rossi, Francesca Gaia, additional, Merli, Francesco, additional, Guièze, Romain, additional, Gyan, Emmanuel, additional, Gini, Guido, additional, Marino, Dario, additional, Gressin, Remy, additional, Morschhauser, Franck, additional, Cavallo, Federica, additional, Palombi, Francesca, additional, Conconi, Annarita, additional, Tessoulin, Benoît, additional, Tilly, Hervé, additional, Zanni, Manuela, additional, Cabras, Maria Giuseppina, additional, Capochiani, Enrico, additional, Califano, Catello, additional, Celli, Melania, additional, Pulsoni, Alessandro, additional, Angrilli, Francesco, additional, Occhini, Ubaldo, additional, Casasnovas, René-Olivier, additional, Cartron, Guillaume, additional, Devizzi, Liliana, additional, Haioun, Corinne, additional, Liberati, Anna Marina, additional, Houot, Roch, additional, Merli, Michele, additional, Pietrantuono, Giuseppe, additional, Re, Francesca, additional, Spina, Michele, additional, Landi, Francesco, additional, Cavalli, Franco, additional, Bertoni, Francesco, additional, Rossi, Davide, additional, Ielmini, Nicoletta, additional, Borgo, Elena, additional, Luminari, Stefano, additional, Zucca, Emanuele, additional, and Thieblemont, Catherine, additional
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- 2024
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3. The immunomodulatory molecule TIGIT is expressed by chronic lymphocytic leukemia cells and contributes to anergy
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Arruga, Francesca, primary, Rubin, Marta, additional, Papazoglou, Despoina, additional, Iannello, Andrea, additional, Ioannou, Nikolaos, additional, Moia, Riccardo, additional, Rossi, Davide, additional, Gaidano, Gianluca, additional, Coscia, Marta, additional, Laurenti, Luca, additional, D’Arena, Giovanni, additional, Allan, John N., additional, Furman, Richard R., additional, Vaisitti, Tiziana, additional, Ramsay, Alan G., additional, and Deaglio, Silvia, additional
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- 2023
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4. Comparative analysis of targeted next-generation sequencing panels for the detection of gene mutations in chronic lymphocytic leukemia: an ERIC multi-center study
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Sutton, Lesley-Ann, Ljungström, Viktor, Enjuanes, Anna, Cortese, Diego, Skaftason, Aron, Tausch, Eugen, Kozubik, Katerina Stano, Nadeu, Ferran, Armand, Marine, Malcikova, Jikta, Djureinovic, Tatjana, Forster, Jade, Davis, Zadie, Oscier, David, Rossi, Davide, Ghia, Paolo, Strefford, Jonathan C., Pospisilova, Sarka, Stilgenbauer, Stephan, Davi, Frederic, Campo, Elias, Stamatopoulos, Kostas, Rosenquist, Richard, Karolinska Institutet [Stockholm], Uppsala University, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Ulm (UUlm), Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), University of Southampton, Oncology Institute of Southern Switzerland (IOSI), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), IRCCS Ospedale San Raffaele [Milan, Italy], Karolinska University Hospital [Stockholm], Sutton, Lesley-Ann, Ljungström, Viktor, Enjuanes, Anna, Cortese, Diego, Skaftason, Aron, Tausch, Eugen, Stano Kozubik, Katerina, Nadeu, Ferran, Armand, Marine, Malcikova, Jikta, Pandzic, Tatjana, Forster, Jade, Davis, Zadie, Oscier, David, Rossi, Davide, Ghia, Paolo, Strefford, Jonathan C, Pospisilova, Sarka, Stilgenbauer, Stephan, Davi, Frederic, Campo, Elia, Stamatopoulos, Kosta, and Rosenquist, Richard
- Subjects
Cytogenetics and Molecular Genetics ,[SDV]Life Sciences [q-bio] ,Mutation ,Next-generation sequencing ,High-Throughput Nucleotide Sequencing ,Humans ,Chronic Lymphocytic Leukemia ,Hematology ,Hematologi ,Genomics ,Precision Medicine ,Leukemia, Lymphocytic, Chronic, B-Cell ,Article - Abstract
International audience; Next-generation sequencing (NGS) has transitioned from research to clinical routine, yet the comparability of different technologies for mutation profiling remains an open question. We performed a European multicenter (n=6) evaluation of three amplicon-based NGS assays targeting 11 genes recurrently mutated in chronic lymphocytic leukemia. Each assay was assessed by two centers using 48 pre-characterized chronic lymphocytic leukemia samples; libraries were sequenced on the Illumina MiSeq instrument and bioinformatics analyses were centralized. Across all centers the median percentage of target reads ≥100x ranged from 94.2- 99.8%. In order to rule out assay-specific technical variability, we first assessed variant calling at the individual assay level i.e., pairwise analysis of variants detected amongst partner centers. After filtering for variants present in the paired normal sample and removal of PCR/sequencing artefacts, the panels achieved 96.2% (Multiplicom), 97.7% (TruSeq) and 90% (HaloPlex) concordance at a variant allele frequency (VAF) >0.5%. Reproducibility was assessed by looking at the inter-laboratory variation in detecting mutations and 107 of 115 (93% concordance) mutations were detected by all six centers, while the remaining eight variants (7%) were undetected by a single center. Notably, 6 of 8 of these variants concerned minor subclonal mutations (VAF 5%, after rigorous validation, the use of unique molecular identifiers may be necessary to reach a higher sensitivity and ensure consistent and accurate detection of low-frequency variants.
- Published
- 2020
5. Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis
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Arribas, Alberto J., primary, Napoli, Sara, additional, Cascione, Luciano, additional, Sartori, Giulio, additional, Barnabei, Laura, additional, Gaudio, Eugenio, additional, Tarantelli, Chiara, additional, Mensah, Afua Adjeiwaa, additional, Spriano, Filippo, additional, Zucchetto, Antonella, additional, Rossi, Francesca M, additional, Rinaldi, Andrea, additional, Castro de Moura, Manuel, additional, Jovic, Sandra, additional, Bordone-Pittau, Roberta, additional, Di Veroli, Alessandra, additional, Stathis, Anastasios, additional, Cruciani, Gabriele, additional, Stussi, Georg, additional, Gattei, Valter, additional, Brown, Jennifer R., additional, Esteller, Manel, additional, Zucca, Emanuele, additional, Rossi, Davide, additional, and Bertoni, Francesco, additional
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- 2022
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6. Marginal zone lymphoma: present status and future perspectives
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Cheah, Chan Y., primary, Zucca, Emanuele, additional, Rossi, Davide, additional, and Habermann, Thomas M., additional
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- 2022
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7. Reply to Aron P. Kater et al.
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Moia, Riccardo, primary, Gaidano, Gianluca, additional, and Rossi, Davide, additional
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- 2020
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8. A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia
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Cohen, Jared A., primary, Rossi, Francesca Maria, additional, Zucchetto, Antonella, additional, Bomben, Riccardo, additional, Terzi-di-Bergamo, Lodovico, additional, Rabe, Kari G., additional, Degan, Massimo, additional, Steffan, Agostino, additional, Polesel, Jerry, additional, Santinelli, Enrico, additional, Innocenti, Idanna, additional, Cutrona, Giovanna, additional, D’Arena, Giovanni, additional, Pozzato, Gabriele, additional, Zaja, Francesco, additional, Chiarenza, Annalisa, additional, Rossi, Davide, additional, Di Raimondo, Francesco, additional, Laurenti, Luca, additional, Gentile, Massimo, additional, Morabito, Fortunato, additional, Neri, Antonino, additional, Ferrarini, Manlio, additional, Fegan, Christopher D., additional, Pepper, Christopher J., additional, Del Poeta, Giovanni, additional, Parikh, Sameer A., additional, Kay, Neil E., additional, and Gattei, Valter, additional
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- 2019
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9. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study
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Ferrero, Simone, primary, Rossi, Davide, additional, Rinaldi, Andrea, additional, Bruscaggin, Alessio, additional, Spina, Valeria, additional, Eskelund, Christian W., additional, Evangelista, Andrea, additional, Moia, Riccardo, additional, Kwee, Ivo, additional, Dahl, Christina, additional, Di Rocco, Alice, additional, Stefoni, Vittorio, additional, Diop, Fary, additional, Favini, Chiara, additional, Ghione, Paola, additional, Mahmoud, Abdurraouf Mokhtar, additional, Schipani, Mattia, additional, Kolstad, Arne, additional, Barbero, Daniela, additional, Novero, Domenico, additional, Paulli, Marco, additional, Zamò, Alberto, additional, Jerkeman, Mats, additional, da Silva, Maria Gomes, additional, Santoro, Armando, additional, Molinari, Annalia, additional, Ferreri, Andres, additional, Grønbæk, Kirsten, additional, Piccin, Andrea, additional, Cortelazzo, Sergio, additional, Bertoni, Francesco, additional, Ladetto, Marco, additional, and Gaidano, Gianluca, additional
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- 2019
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10. HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia
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Griggio, Valentina, primary, Vitale, Candida, additional, Todaro, Maria, additional, Riganti, Chiara, additional, Kopecka, Joanna, additional, Salvetti, Chiara, additional, Bomben, Riccardo, additional, Bo, Michele Dal, additional, Magliulo, Daniela, additional, Rossi, Davide, additional, Pozzato, Gabriele, additional, Bonello, Lisa, additional, Marchetti, Monia, additional, Omedè, Paola, additional, Kodipad, Ahad Ahmed, additional, Laurenti, Luca, additional, Del Poeta, Giovanni, additional, Mauro, Francesca Romana, additional, Bernardi, Rosa, additional, Zenz, Thorsten, additional, Gattei, Valter, additional, Gaidano, Gianluca, additional, Foà, Robin, additional, Massaia, Massimo, additional, Boccadoro, Mario, additional, and Coscia, Marta, additional
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- 2019
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11. Novel insights into the genetics and epigenetics of MALT lymphoma unveiled by next generation sequencing analyses
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Cascione, Luciano, primary, Rinaldi, Andrea, additional, Bruscaggin, Alessio, additional, Tarantelli, Chiara, additional, Arribas, Alberto J., additional, Kwee, Ivo, additional, Pecciarini, Lorenza, additional, Mensah, Afua A., additional, Spina, Valeria, additional, Chung, Elaine Y.L., additional, di Bergamo, Lodovico Terzi, additional, Dirnhofer, Stephan, additional, Tzankov, Alexandar, additional, Miranda, Roberto N., additional, Young, Ken H., additional, Traverse-Glehen, Alexandra, additional, Gaidano, Gianluca, additional, Swerdlow, Steven H., additional, Gascoyne, Randy, additional, Rabadan, Raul, additional, Ponzoni, Maurilio, additional, Bhagat, Govind, additional, Rossi, Davide, additional, Zucca, Emanuele, additional, and Bertoni, Francesco, additional
- Published
- 2019
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12. Liquid biopsy in lymphoma
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Rossi, Davide, primary, Spina, Valeria, additional, Bruscaggin, Alessio, additional, and Gaidano, Gianluca, additional
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- 2019
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13. The novel CD19-targeting antibody-drug conjugate huB4-DGN462 shows improved anti-tumor activity compared to SAR3419 in CD19-positive lymphoma and leukemia models
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Hicks, Stuart W., primary, Tarantelli, Chiara, additional, Wilhem, Alan, additional, Gaudio, Eugenio, additional, Li, Min, additional, Arribas, Alberto J., additional, Spriano, Filippo, additional, Bordone, Roberta, additional, Cascione, Luciano, additional, Lai, Katharine C., additional, Qiu, Qifeng, additional, Taborelli, Monica, additional, Rossi, Davide, additional, Stussi, Georg, additional, Zucca, Emanuele, additional, Stathis, Anastasios, additional, Sloss, Callum M., additional, and Bertoni, Francesco, additional
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- 2019
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14. The Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) demonstrated synergies with other anti-lymphoma targeted agents
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Tarantelli, Chiara, primary, Zhang, Lu, additional, Curti, Elisabetta, additional, Gaudio, Eugenio, additional, Spriano, Filippo, additional, Priebe, Valdemar, additional, Cascione, Luciano, additional, Arribas, Alberto J., additional, Zucca, Emanuele, additional, Rossi, Davide, additional, Stathis, Anastasios, additional, and Bertoni, Francesco, additional
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- 2019
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15. The involvement of microRNA in the pathogenesis of Richter syndrome
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Van Roosbroeck, Katrien, primary, Bayraktar, Recep, additional, Calin, Steliana, additional, Bloehdorn, Johannes, additional, Dragomir, Mihnea Paul, additional, Okubo, Keishi, additional, Bertilaccio, Maria Teresa Sabrina, additional, Zupo, Simonetta, additional, You, M. James, additional, Gaidano, Gianluca, additional, Rossi, Davide, additional, Chen, Shih-Shih, additional, Chiorazzi, Nicholas, additional, Thompson, Philip A., additional, Ferrajoli, Alessandra, additional, Bertoni, Francesco, additional, Stilgenbauer, Stephan, additional, Keating, Michael J., additional, and Calin, George A., additional
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- 2018
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16. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia
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Baliakas, Panagiotis, primary, Moysiadis, Theodoros, additional, Hadzidimitriou, Anastasia, additional, Xochelli, Aliki, additional, Jeromin, Sabine, additional, Agathangelidis, Andreas, additional, Mattsson, Mattias, additional, Sutton, Lesley-Ann, additional, Minga, Eva, additional, Scarfò, Lydia, additional, Rossi, Davide, additional, Davis, Zadie, additional, Villamor, Neus, additional, Parker, Helen, additional, Kotaskova, Jana, additional, Stalika, Evangelia, additional, Plevova, Karla, additional, Mansouri, Larry, additional, Cortese, Diego, additional, Navarro, Alba, additional, Delgado, Julio, additional, Larrayoz, Marta, additional, Young, Emma, additional, Anagnostopoulos, Achilles, additional, Smedby, Karin E., additional, Juliusson, Gunnar, additional, Sheehy, Oonagh, additional, Catherwood, Mark, additional, Strefford, Jonathan C., additional, Stavroyianni, Niki, additional, Belessi, Chrysoula, additional, Pospisilova, Sarka, additional, Oscier, David, additional, Gaidano, Gianluca, additional, Campo, Elias, additional, Haferlach, Claudia, additional, Ghia, Paolo, additional, Rosenquist, Richard, additional, and Stamatopoulos, Kostas, additional
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- 2018
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17. Age-related clonal hematopoiesis and monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia: a new association?
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Condoluci, Adalgisa, primary and Rossi, Davide, additional
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- 2018
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18. Circulating tumor DNA as a liquid biopsy in plasma cell dyscrasias
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Gerber, Bernhard, primary, Manzoni, Martina, additional, Spina, Valeria, additional, Bruscaggin, Alessio, additional, Lionetti, Marta, additional, Fabris, Sonia, additional, Barbieri, Marzia, additional, Ciceri, Gabriella, additional, Pompa, Alessandra, additional, Forestieri, Gabriela, additional, Lerch, Erika, additional, Servida, Paolo, additional, Bertoni, Francesco, additional, Zucca, Emanuele, additional, Ghielmini, Michele, additional, Cortelezzi, Agostino, additional, Cavalli, Franco, additional, Stussi, Georg, additional, Baldini, Luca, additional, Rossi, Davide, additional, and Neri, Antonino, additional
- Published
- 2018
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19. Mutational status of IGHV is the most reliable prognostic marker in trisomy 12 chronic lymphocytic leukemia
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Bulian, Pietro, primary, Bomben, Riccardo, additional, Bo, Michele Dal, additional, Zucchetto, Antonella, additional, Rossi, Francesca Maria, additional, Degan, Massimo, additional, Pozzo, Federico, additional, Bittolo, Tamara, additional, Bravin, Vanessa, additional, D’Agaro, Tiziana, additional, Cerri, Michaela, additional, Chiarenza, Annalisa, additional, Chaffee, Kari G., additional, Condoluci, Adalgisa, additional, D’Arena, Giovanni, additional, Spina, Michele, additional, Zaja, Francesco, additional, Pozzato, Gabriele, additional, Di Raimondo, Francesco, additional, Rossi, Davide, additional, Poeta, Giovanni Del, additional, Gaidano, Gianluca, additional, Shanafelt, Tait D., additional, and Gattei, Valter, additional
- Published
- 2017
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20. Mutations in the 3′ untranslated region of NOTCH1 are associated with low CD20 expression levels chronic lymphocytic leukemia
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Bittolo, Tamara, primary, Pozzo, Federico, additional, Bomben, Riccardo, additional, D’Agaro, Tiziana, additional, Bravin, Vanessa, additional, Bulian, Pietro, additional, Rossi, Francesca Maria, additional, Zucchetto, Antonella, additional, Degan, Massimo, additional, Macor, Paolo, additional, D’Arena, Giovanni, additional, Chiarenza, Annalisa, additional, Zaja, Francesco, additional, Pozzato, Gabriele, additional, Di Raimondo, Francesco, additional, Rossi, Davide, additional, Gaidano, Gianluca, additional, Del Poeta, Giovanni, additional, Gattei, Valter, additional, and Dal Bo, Michele, additional
- Published
- 2017
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21. Integration of B-cell receptor-induced ERK1/2 phosphorylation and mutations of SF3B1 gene refines prognosis in treatment-naïve chronic lymphocytic leukemia
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Cavallini, Chiara, primary, Visco, Carlo, additional, Putta, Santosh, additional, Rossi, Davide, additional, Mimiola, Elda, additional, Purvis, Norman, additional, Lovato, Ornella, additional, Perbellini, Omar, additional, Falisi, Erika, additional, Facco, Monica, additional, Trentin, Livio, additional, Romanelli, Maria G., additional, Semenzato, Gianpietro, additional, Ambrosetti, Achille, additional, Gaidano, Gianluca, additional, Pizzolo, Giovanni, additional, Cesano, Alessandra, additional, and Scupoli, Maria T., additional
- Published
- 2016
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22. Clinical impact of small subclones harboring NOTCH1 , SF3B1 or BIRC3 mutations in chronic lymphocytic leukemia
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Rasi, Silvia, primary, Khiabanian, Hossein, additional, Ciardullo, Carmela, additional, Terzi-di-Bergamo, Lodovico, additional, Monti, Sara, additional, Spina, Valeria, additional, Bruscaggin, Alessio, additional, Cerri, Michaela, additional, Deambrogi, Clara, additional, Martuscelli, Lavinia, additional, Biasi, Alessandra, additional, Spaccarotella, Elisa, additional, De Paoli, Lorenzo, additional, Gattei, Valter, additional, Foà, Robin, additional, Rabadan, Raul, additional, Gaidano, Gianluca, additional, and Rossi, Davide, additional
- Published
- 2016
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23. Aberrant somatic hypermutation in transformation of follicular lymphoma and chronic lymphocytic leukemia to diffuse large B-cell lymphoma
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Rossi, Davide, Berra, Eva, Cerri, Michaela, Deambrogi, Clara, Barbieri, Caterina, Franceschetti, Silvia, Lunghi, Monia, Conconi, Annarita, Paulli, Marco, Matolcsy, Andras, Pasqualucci, Laura, Daniela Capello, and Gaidano, Gianluca
- Subjects
Gene Rearrangement ,Neoplastic ,Leukemia ,Lymphoma, B-Cell ,Lymphoma ,B-Lymphocyte ,B-Cell ,Follicular ,Cell Transformation ,Somatic Hypermutation ,Leukemia, Lymphocytic, Chronic, B-Cell ,Lymphocytic ,Gene Frequency ,Humans ,Chronic ,Immunoglobulin ,Cell Transformation, Neoplastic ,Somatic Hypermutation, Immunoglobulin ,Gene Rearrangement, B-Lymphocyte ,Lymphoma, Follicular - Abstract
The molecular mechanisms involved in histologic transformation of follicular lymphoma (FL) and B-chronic lymphocytic leukemia (B-CLL) to diffuse large B-cell lymphoma (DLBCL) are heterogeneous and largely unknown. Here we explored whether aberrant somatic hypermutation, leading to the acquisition of new mutations in PIM-1, PAX-5, RhoH/TTF and c-MYC genes, is involved in transformation from FL or B-CLL to DLBCL. Eighteen sequential pairs of FL/DLBCL (n=9) and B-CLL/DLBCL (n=9) were investigated. Our findings demonstrate that acquisition of novel mutations due to aberrant somatic hypermutation was associated with DLBCL transformation in 5/9 (55.5%) cases of FL and 2/9 (22.2%) cases of B-CLL.
- Published
- 2006
24. Comparative analysis of targeted next-generation sequencing panels for the detection of gene mutations in chronic lymphocytic leukemia: an ERIC multi-center study.
- Author
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Sutton LA, Ljungström V, Enjuanes A, Cortese D, Skaftason A, Tausch E, Stano Kozubik K, Nadeu F, Armand M, Malcikova J, Pandzic T, Forster J, Davis Z, Oscier D, Rossi D, Ghia P, Strefford JC, Pospisilova S, Stilgenbauer S, Davi F, Campo E, Stamatopoulos K, Rosenquist R, and On Behalf Of The European Research Initiative On Cll Eric
- Subjects
- High-Throughput Nucleotide Sequencing, Humans, Mutation, Reproducibility of Results, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Next-generation sequencing (NGS) has transitioned from research to clinical routine, yet the comparability of different technologies for mutation profiling remains an open question. We performed a European multicenter (n=6) evaluation of three amplicon-based NGS assays targeting 11 genes recurrently mutated in chronic lymphocytic leukemia. Each assay was assessed by two centers using 48 pre-characterized chronic lymphocytic leukemia samples; libraries were sequenced on the Illumina MiSeq instrument and bioinformatics analyses were centralized. Across all centers the median percentage of target reads ≥100x ranged from 94.2- 99.8%. In order to rule out assay-specific technical variability, we first assessed variant calling at the individual assay level i.e., pairwise analysis of variants detected amongst partner centers. After filtering for variants present in the paired normal sample and removal of PCR/sequencing artefacts, the panels achieved 96.2% (Multiplicom), 97.7% (TruSeq) and 90% (HaloPlex) concordance at a variant allele frequency (VAF) >0.5%. Reproducibility was assessed by looking at the inter-laboratory variation in detecting mutations and 107 of 115 (93% concordance) mutations were detected by all six centers, while the remaining eight variants (7%) were undetected by a single center. Notably, 6 of 8 of these variants concerned minor subclonal mutations (VAF <5%). We sought to investigate low-frequency mutations further by using a high-sensitivity assay containing unique molecular identifiers, which confirmed the presence of several minor subclonal mutations. Thus, while amplicon-based approaches can be adopted for somatic mutation detection with VAF >5%, after rigorous validation, the use of unique molecular identifiers may be necessary to reach a higher sensitivity and ensure consistent and accurate detection of low-frequency variants.
- Published
- 2021
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25. Targeting CD205 with the antibody drug conjugate MEN1309/OBT076 is an active new therapeutic strategy in lymphoma models.
- Author
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Gaudio E, Tarantelli C, Spriano F, Guidetti F, Sartori G, Bordone R, Arribas AJ, Cascione L, Bigioni M, Merlino G, Fiascarelli A, Bressan A, Adjeiwaa Mensah A, Golino G, Lucchini R, Bernasconi E, Rossi D, Zucca E, Stussi G, Stathis A, Boyd RS, Dusek RL, Bisht A, Attanasio N, Rohlff C, Pellacani A, Binaschi M, and Bertoni F
- Subjects
- Antibodies, Monoclonal pharmacology, Antigens, CD20, Apoptosis, Cell Line, Tumor, Humans, Rituximab therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Immunoconjugates pharmacology, Immunoconjugates therapeutic use, Lymphoma drug therapy
- Abstract
Antibody drug conjugates represent an important class of anti-cancer drugs in both solid tumors and hematological cancers. Here, we report preclinical data on the anti-tumor activity of the first-in-class antibody drug conjugate MEN1309/OBT076 targeting CD205. The study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination and validation experiments on in vivo models. CD205 was first shown frequently expressed in lymphomas, leukemias and multiple myeloma by immunohistochemistry on tissue microarrays. Anti-tumor activity of MEN1309/OBT076 as single agent was then shown across 42 B-cell lymphoma cell lines with a median IC50 of 200 pM and induction of apoptosis in 25/42 (59.5%) of the cases. The activity appeared highly correlated with its target expression. After in vivo validation as the single agent, the antibody drug conjugate synergized with the BCL2 inhibitor venetoclax, and the anti-CD20 monoclonal antibody rituximab. The first-in-class antibody drug targeting CD205, MEN1309/OBT076, demonstrated strong pre-clinical anti-tumor activity in lymphoma, warranting further investigations as a single agent and in combination.
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- 2020
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26. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study.
- Author
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Ferrero S, Rossi D, Rinaldi A, Bruscaggin A, Spina V, Eskelund CW, Evangelista A, Moia R, Kwee I, Dahl C, Di Rocco A, Stefoni V, Diop F, Favini C, Ghione P, Mahmoud AM, Schipani M, Kolstad A, Barbero D, Novero D, Paulli M, Zamò A, Jerkeman M, da Silva MG, Santoro A, Molinari A, Ferreri A, Grønbæk K, Piccin A, Cortelazzo S, Bertoni F, Ladetto M, and Gaidano G
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Mutation, Prognosis, Prospective Studies, Transplantation, Autologous, DNA-Binding Proteins genetics, Hematopoietic Stem Cell Transplantation, Lymphoma, Mantle-Cell diagnosis, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell genetics, Neoplasm Proteins genetics, Tumor Suppressor Protein p53 genetics
- Abstract
In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase 3 trial (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of KMT2D and disruption of TP53 by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding KMT2D mutations and TP53 disruption to the MIPI-c backbone, we derived a new prognostic index, the "MIPI-genetic" ("MIPI- g"). The "MIPI-g" improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that TP53 disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring KMT2D mutations share the same poor outcome as patients harboring TP53 disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. ( Trial registered at clinicaltrials.gov identifier: NCT02354313 )., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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27. A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia.
- Author
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Cohen JA, Rossi FM, Zucchetto A, Bomben R, Terzi-di-Bergamo L, Rabe KG, Degan M, Steffan A, Polesel J, Santinelli E, Innocenti I, Cutrona G, D'Arena G, Pozzato G, Zaja F, Chiarenza A, Rossi D, Di Raimondo F, Laurenti L, Gentile M, Morabito F, Neri A, Ferrarini M, Fegan CD, Pepper CJ, Del Poeta G, Parikh SA, Kay NE, and Gattei V
- Subjects
- Humans, Italy, Laboratories, Mutation, Prognosis, United Kingdom, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy
- Abstract
We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia (CLL) developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count >32.0x10
3 /microliter, 1 point. Low-, intermediate- and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144 / 395 / 540 / 322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage CLL, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 CLL being performed at the time of diagnosis to aid prognosis and treatment, particularly in today's chemofree era., (Copyright© 2020 Ferrata Storti Foundation.)- Published
- 2020
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- View/download PDF
28. HIF-1α is over-expressed in leukemic cells from TP53 -disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia.
- Author
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Griggio V, Vitale C, Todaro M, Riganti C, Kopecka J, Salvetti C, Bomben R, Bo MD, Magliulo D, Rossi D, Pozzato G, Bonello L, Marchetti M, Omedè P, Kodipad AA, Laurenti L, Del Poeta G, Mauro FR, Bernardi R, Zenz T, Gattei V, Gaidano G, Foà R, Massaia M, Boccadoro M, and Coscia M
- Subjects
- Animals, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Mice, Phosphatidylinositol 3-Kinases genetics, Tumor Microenvironment, Tumor Suppressor Protein p53 genetics, Von Hippel-Lindau Tumor Suppressor Protein, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study, we demonstrate that CLL cells from TP53 -disrupted ( TP53
dis ) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the TP53dis subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of HIF-1A mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53dis tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53dis leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL., (Copyright© 2020 Ferrata Storti Foundation.)- Published
- 2020
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29. Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia.
- Author
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Diop F, Moia R, Favini C, Spaccarotella E, De Paoli L, Bruscaggin A, Spina V, Terzi-di-Bergamo L, Arruga F, Tarantelli C, Deambrogi C, Rasi S, Adhinaveni R, Patriarca A, Favini S, Sagiraju S, Jabangwe C, Kodipad AA, Peroni D, Mauro FR, Giudice ID, Forconi F, Cortelezzi A, Zaja F, Bomben R, Rossi FM, Visco C, Chiarenza A, Rigolin GM, Marasca R, Coscia M, Perbellini O, Tedeschi A, Laurenti L, Motta M, Donaldson D, Weir P, Mills K, Thornton P, Lawless S, Bertoni F, Poeta GD, Cuneo A, Follenzi A, Gattei V, Boldorini RL, Catherwood M, Deaglio S, Foà R, Gaidano G, and Rossi D
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Baculoviral IAP Repeat-Containing 3 Protein, Cyclophosphamide therapeutic use, Humans, Mutation, Prognosis, Retrospective Studies, Rituximab therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3 -mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3 -mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P <0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P <0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P =0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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- View/download PDF
30. The involvement of microRNA in the pathogenesis of Richter syndrome.
- Author
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Van Roosbroeck K, Bayraktar R, Calin S, Bloehdorn J, Dragomir MP, Okubo K, Bertilaccio MTS, Zupo S, You MJ, Gaidano G, Rossi D, Chen SS, Chiorazzi N, Thompson PA, Ferrajoli A, Bertoni F, Stilgenbauer S, Keating MJ, and Calin GA
- Subjects
- Adult, Aged, Animals, Apoptosis, Cell Proliferation, Cell Transformation, Neoplastic genetics, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Mice, Mice, Inbred NOD, Mice, SCID, Middle Aged, Prognosis, Syndrome, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor genetics, Cell Transformation, Neoplastic pathology, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Leukemia, Lymphocytic, Chronic, B-Cell pathology, MicroRNAs genetics
- Abstract
Richter syndrome is the name given to the transformation of the most frequent type of leukemia, chronic lymphocytic leukemia, into an aggressive lymphoma. Patients with Richter syndrome have limited response to therapies and dismal survival. The underlying mechanisms of transformation are insufficiently understood and there is a major lack of knowledge regarding the roles of microRNA that have already proven to be causative for most cases of chronic lymphocytic leukemia. Here, by using four types of genomic platforms and independent sets of patients from three institutions, we identified microRNA involved in the transformation of chronic lymphocytic leukemia to Richter syndrome. The expression signature is composed of miR-21, miR-150, miR-146b and miR-181b, with confirmed targets significantly enriched in pathways involved in cancer, immunity and inflammation. In addition, we demonstrated that genomic alterations may account for microRNA deregulation in a subset of cases of Richter syndrome. Furthermore, network analysis showed that Richter transformation leads to a complete rearrangement, resulting in a highly connected microRNA network. Functionally, ectopic overexpression of miR-21 increased proliferation of malignant B cells in multiple assays, while miR-150 and miR-26a were downregulated in a chronic lymphocytic leukemia xenogeneic mouse transplantation model. Together, our results suggest that Richter transformation is associated with significant expression and genomic loci alterations of microRNA involved in both malignancy and immunity., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
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- View/download PDF
31. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia.
- Author
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Baliakas P, Moysiadis T, Hadzidimitriou A, Xochelli A, Jeromin S, Agathangelidis A, Mattsson M, Sutton LA, Minga E, Scarfò L, Rossi D, Davis Z, Villamor N, Parker H, Kotaskova J, Stalika E, Plevova K, Mansouri L, Cortese D, Navarro A, Delgado J, Larrayoz M, Young E, Anagnostopoulos A, Smedby KE, Juliusson G, Sheehy O, Catherwood M, Strefford JC, Stavroyianni N, Belessi C, Pospisilova S, Oscier D, Gaidano G, Campo E, Haferlach C, Ghia P, Rosenquist R, and Stamatopoulos K
- Subjects
- Aged, Aged, 80 and over, Chromosome Aberrations, Female, Humans, Immunogenetics, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Mutation, Neoplasm Staging, Prognosis, Time-to-Treatment, Biomarkers, Tumor, Disease Susceptibility, Leukemia, Lymphocytic, Chronic, B-Cell etiology, Leukemia, Lymphocytic, Chronic, B-Cell mortality
- Abstract
Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL., (Copyright © 2019 Ferrata Storti Foundation.)
- Published
- 2019
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- View/download PDF
32. Integration of B-cell receptor-induced ERK1/2 phosphorylation and mutations of SF3B1 gene refines prognosis in treatment-naïve chronic lymphocytic leukemia.
- Author
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Cavallini C, Visco C, Putta S, Rossi D, Mimiola E, Purvis N, Lovato O, Perbellini O, Falisi E, Facco M, Trentin L, Romanelli MG, Semenzato G, Ambrosetti A, Gaidano G, Pizzolo G, Cesano A, and Scupoli MT
- Subjects
- ADP-ribosyl Cyclase 1 genetics, ADP-ribosyl Cyclase 1 immunology, Disease Progression, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains metabolism, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Mitogen-Activated Protein Kinase 1 immunology, Mitogen-Activated Protein Kinase 3 immunology, Mutation, Phosphoproteins immunology, Phosphorylation, Prognosis, RNA Splicing Factors immunology, Receptor, Notch1 genetics, Receptor, Notch1 immunology, Receptors, Antigen, B-Cell immunology, Signal Transduction, Survival Analysis, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 immunology, Gene Expression Regulation, Leukemic, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Mitogen-Activated Protein Kinase 1 genetics, Mitogen-Activated Protein Kinase 3 genetics, Phosphoproteins genetics, RNA Splicing Factors genetics, Receptors, Antigen, B-Cell genetics
- Published
- 2017
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- View/download PDF
33. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors.
- Author
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Sutton LA, Young E, Baliakas P, Hadzidimitriou A, Moysiadis T, Plevova K, Rossi D, Kminkova J, Stalika E, Pedersen LB, Malcikova J, Agathangelidis A, Davis Z, Mansouri L, Scarfò L, Boudjoghra M, Navarro A, Muggen AF, Yan XJ, Nguyen-Khac F, Larrayoz M, Panagiotidis P, Chiorazzi N, Niemann CU, Belessi C, Campo E, Strefford JC, Langerak AW, Oscier D, Gaidano G, Pospisilova S, Davi F, Ghia P, Stamatopoulos K, and Rosenquist R
- Subjects
- Complementarity Determining Regions genetics, Cytogenetic Analysis, Female, Gene Frequency, Gene Rearrangement, B-Lymphocyte, Genes, Immunoglobulin, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Joining Region genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Polymorphism, Single Nucleotide, Prognosis, Biomarkers, Tumor, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Mutation, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell metabolism
- Abstract
We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
- Full Text
- View/download PDF
34. Innovation in the prognostication of chronic lymphocytic leukemia: how far beyond TP53 gene analysis can we go?
- Author
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Pospisilova S, Sutton LA, Malcikova J, Tausch E, Rossi D, Montserrat E, Moreno C, Stamatopoulos K, Gaidano G, Rosenquist R, and Ghia P
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Alleles, Biomarkers, Tumor metabolism, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Class I Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases metabolism, Gene Expression, Gene Frequency, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Molecular Targeted Therapy, Piperidines, Prognosis, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Purines therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Quinazolinones therapeutic use, Sulfonamides therapeutic use, Tumor Suppressor Protein p53 deficiency, Antineoplastic Agents therapeutic use, Biomarkers, Tumor genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Tumor Suppressor Protein p53 genetics
- Published
- 2016
- Full Text
- View/download PDF
35. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia.
- Author
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Del Principe MI, Dal Bo M, Bittolo T, Buccisano F, Rossi FM, Zucchetto A, Rossi D, Bomben R, Maurillo L, Cefalo M, De Santis G, Venditti A, Gaidano G, Amadori S, de Fabritiis P, Gattei V, and Del Poeta G
- Subjects
- Adult, Aged, Aged, 80 and over, Chlorambucil administration & dosage, Disease-Free Survival, Female, Humans, Male, Middle Aged, Predictive Value of Tests, Prednisolone administration & dosage, Retrospective Studies, Rituximab administration & dosage, Survival Rate, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Proto-Oncogene Proteins c-bcl-2 blood, bcl-2-Associated X Protein blood
- Abstract
In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
- Full Text
- View/download PDF
36. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients.
- Author
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Tedeschi A, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortelezzi A, Nador G, Scarfò L, Cairoli R, Frustaci AM, Dalceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Massaia M, Gaidano G, and Montillo M
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclophosphamide administration & dosage, Cyclophosphamide adverse effects, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Pentostatin administration & dosage, Pentostatin adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Published
- 2015
- Full Text
- View/download PDF
37. The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study.
- Author
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Rossi D, Bruscaggin A, La Cava P, Galimberti S, Ciabatti E, Luminari S, Rigacci L, Tucci A, Pulsoni A, Bertoldero G, Vallisa D, Rusconi C, Spina M, Arcaini L, Angrilli F, Stelitano C, Merli F, Gaidano G, Federico M, and Palumbo GA
- Subjects
- Aged, Antibiotics, Antineoplastic administration & dosage, Antibiotics, Antineoplastic therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Doxorubicin administration & dosage, Doxorubicin therapeutic use, Female, Humans, Kaplan-Meier Estimate, Lymphoma, Follicular diagnosis, Lymphoma, Follicular drug therapy, Lymphoma, Follicular mortality, Male, Middle Aged, MutL Protein Homolog 1, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Polymorphism, Single Nucleotide, Prognosis, Receptors, IgG genetics, Treatment Failure, Treatment Outcome, Adaptor Proteins, Signal Transducing genetics, Genotype, Lymphoma, Follicular genetics, Nuclear Proteins genetics
- Abstract
Though most follicular lymphoma biomarkers rely on tumor features, the host genetic background may also be relevant for outcome. Here we aimed at verifying the contribution of candidate polymorphisms of FCγ receptor, DNA repair and detoxification genes to prognostic stratification of follicular lymphoma treated with immunochemotherapy. The study was based on 428 patients enrolled in the FOLL05 prospective trial that compared three standard-of-care regimens (rituximab-cyclophosphamide-vincristine-prednisone versus rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone versus rituximab-fludarabine-mitoxantrone) for the first line therapy of advanced follicular lymphoma. Polymorphisms were genotyped on peripheral blood DNA samples. The primary endpoint was time to treatment failure. Polymorphisms of FCGR2A and FCGR3A, which have been suggested to influence the activity of rituximab as a single agent, did not affect time to treatment failure in the pooled analysis of the three FOLL05 treatment arms that combined rituximab with chemotherapy (P=0.742, P=0.252, respectively). These results were consistent even when the analysis was conducted by intention to treat, indicating that different chemotherapy regimens and loads did not interact differentially with the FCGR2A and FCGR3A genotypes. The genotype of MLH1, which regulates the genotoxic effect of doxorubicin, significantly affected time to treatment failure in patients in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone arm (P=0.001; q<0.1), but not in arms in which patients did not receive doxorubicin (i.e., the rituximab-cyclophosphamide-vincristine-prednisone and rituximab-fludarabine-mitoxantrone arms). The impact of MLH1 on time to treatment failure was independent after adjusting for the Follicular Lymphoma International Prognostic Index and other potential confounding variables by multivariate analysis. These data indicate that MLH1 genotype is a predictor of failure to benefit from rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone treatment in advanced follicular lymphoma and confirm that FCGR2A and FCGR3A polymorphisms have no impact when follicular lymphoma is treated with rituximab plus chemotherapy (clinicaltrials.gov identifier: NCT00774826)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2015
- Full Text
- View/download PDF
38. The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection.
- Author
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Arcaini L, Rossi D, Lucioni M, Nicola M, Bruscaggin A, Fiaccadori V, Riboni R, Ramponi A, Ferretti VV, Cresta S, Casaluci GM, Bonfichi M, Gotti M, Merli M, Maffi A, Arra M, Varettoni M, Rattotti S, Morello L, Guerrera ML, Sciarra R, Gaidano G, Cazzola M, and Paulli M
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, DNA-Binding Proteins, Female, Follow-Up Studies, Hepacivirus isolation & purification, Hepatitis C mortality, Hepatitis C pathology, Hepatitis C virology, Humans, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Large B-Cell, Diffuse virology, Male, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local virology, Polymerase Chain Reaction, Prognosis, RNA-Binding Proteins, Survival Rate, Hepatitis C genetics, Homeodomain Proteins genetics, Lymphoma, Large B-Cell, Diffuse genetics, Mutation genetics, Neoplasm Recurrence, Local genetics, Nuclear Proteins genetics, Receptor, Notch1 genetics, Receptor, Notch2 genetics
- Abstract
Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lymphoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%-56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%-77%) for those without these genetic lesions. By univariate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome., (Copyright© Ferrata Storti Foundation.)
- Published
- 2015
- Full Text
- View/download PDF
39. Bendamustine and subcutaneous alemtuzumab combination is an effective treatment in relapsed/refractory chronic lymphocytic leukemia patients.
- Author
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Montillo M, Tedeschi A, Gaidano G, Coscia M, Petrizzi VB, Orlandi E, Cascavilla N, Ghia P, Motta M, Gallamini A, Frustaci AM, Rossi D, De Paoli L, Nichelatti M, Morra E, and Massaia M
- Subjects
- Adolescent, Adult, Aged, Alemtuzumab, Bendamustine Hydrochloride, Drug Administration Schedule, Drug Combinations, Female, Humans, Injections, Intravenous, Injections, Subcutaneous, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Recurrence, Survival Analysis, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Alkylating therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Nitrogen Mustard Compounds therapeutic use
- Published
- 2014
- Full Text
- View/download PDF
40. MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis.
- Author
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Benner A, Mansouri L, Rossi D, Majid A, Willander K, Parker A, Bond G, Pavlova S, Nückel H, Merkel O, Ghia P, Montserrat E, Kaderi MA, Rosenquist R, Gaidano G, Dyer MJ, Söderkvist P, Linderholm M, Oscier D, Tvaruzkova Z, Pospisilova S, Dührsen U, Greil R, Döhner H, Stilgenbauer S, and Zenz T
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Young Adult, Databases, Factual trends, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins c-mdm2 genetics
- Abstract
A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies., (Copyright© Ferrata Storti Foundation.)
- Published
- 2014
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41. HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 base pair (rs66554220) polymorphism.
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Rizzo R, Audrito V, Vacca P, Rossi D, Brusa D, Stignani M, Bortolotti D, D'Arena G, Coscia M, Laurenti L, Forconi F, Gaidano G, Mingari MC, Moretta L, Malavasi F, and Deaglio S
- Subjects
- Female, Gene Expression, HLA-G Antigens metabolism, Humans, Immunophenotyping, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Lymphocyte Count, Male, Prognosis, RNA, Messenger genetics, RNA, Messenger metabolism, HLA-G Antigens genetics, HLA-G Antigens immunology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Polymorphism, Genetic, Tumor Escape genetics, Tumor Escape immunology
- Abstract
This work investigates the possibility that HLA-G, a molecule modulating innate and adaptive immunity, is part of an immune escape strategy of chronic lymphocytic leukemia cells. A 14 base pair insertion/deletion polymorphism (rs66554220) in the 3'-untranslated region of HLA-G influences mRNA stability and protein expression. The analysis of a cohort of patients with chronic lymphocytic leukemia confirmed that del/del individuals are characterized by higher levels of surface and soluble HLA-G than subjects with the other two genotypes. In line with its role in immunomodulation, the percentage of regulatory T lymphocytes is higher in del/del patients than in patients with the other genotypes and correlates with the amounts of surface or soluble HLA-G. Furthermore, addition of sHLA-G-rich plasma from patients with chronic lymphocytic leukemia induces natural killer cell apoptosis and impairs natural killer cell lysis, with effects proportional to the amount of soluble HLA-G added. Lastly, the presence of an HLA-G 14 base pair polymorphism is of prognostic value, with del/del patients showing reduced overall survival, as compared to those with other genotypes. These results suggest that: (i) the HLA-G 14 base pair polymorphism influences the levels of surface and soluble HLA-G expression, and (ii) the over-expression of HLA-G molecules contributes to creating tolerogenic conditions.
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- 2014
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42. Outcome prediction of diffuse large B-cell lymphomas associated with hepatitis C virus infection: a study on behalf of the Fondazione Italiana Linfomi.
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Merli M, Visco C, Spina M, Luminari S, Ferretti VV, Gotti M, Rattotti S, Fiaccadori V, Rusconi C, Targhetta C, Stelitano C, Levis A, Ambrosetti A, Rossi D, Rigacci L, D'Arco AM, Musto P, Chiappella A, Baldini L, Bonfichi M, and Arcaini L
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Female, Hepatitis C virology, Humans, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse drug therapy, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Patient Outcome Assessment, Prognosis, Retrospective Studies, Treatment Outcome, Young Adult, Hepatitis C complications, Lymphoma, Large B-Cell, Diffuse complications, Lymphoma, Large B-Cell, Diffuse mortality
- Abstract
A specific prognostication score for hepatitis C virus-positive diffuse large B-cell lymphomas is not available. For this purpose, the Fondazione Italiana Linfomi (FIL, Italian Lymphoma Foundation) carried out a multicenter retrospective study on a large consecutive series of patients with hepatitis C virus-associated diffuse large B-cell lymphoma to evaluate the prognostic impact of clinical and virological features and to develop a specific prognostic score for this subset of patients. All prognostic evaluations were performed on 535 patients treated with an anthracycline-based induction regimen (with rituximab in 255 cases). Severe hepatotoxicity was observed in 14% of patients. The use of rituximab was not associated with increased rate of severe hepatotoxicity. Three-year overall survival and progression-free survival were 71% and 55%, respectively. At multivariate analysis, ECOG performance status of 2 or over, serum albumin below 3.5 g/dL and HCV-RNA viral load over 1000 KIU/mL retained prognostic significance. We combined these 3 factors in a new "HCV Prognostic Score" able to discriminate 3 risk categories with different overall and progression-free survival (low=0; intermediate=1; high-risk ≥2 factors; P<0.001). This score retained prognostic value in the subgroups of patients treated with and without rituximab (P<0.001). The new score performed better than the International Prognostic Index at multivariate analysis and Harrel C-statistic. With the use of three readily available factors (performance status, albumin level and HCV-RNA viral load), the new "HCV Prognostic Score" is able to identify 3 risk categories with different survival, and may be a useful tool to predict the outcome of hepatitis C virus-associated diffuse large B-cell lymphomas.
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- 2014
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43. High XBP1 expression is a marker of better outcome in multiple myeloma patients treated with bortezomib.
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Gambella M, Rocci A, Passera R, Gay F, Omedè P, Crippa C, Corradini P, Romano A, Rossi D, Ladetto M, Boccadoro M, and Palumbo A
- Subjects
- Aged, Bortezomib, Disease-Free Survival, Female, Humans, Male, Regulatory Factor X Transcription Factors, Survival Rate, X-Box Binding Protein 1, Antineoplastic Agents administration & dosage, Biomarkers, Tumor biosynthesis, Boronic Acids administration & dosage, DNA-Binding Proteins biosynthesis, Gene Expression Regulation, Neoplastic drug effects, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, Multiple Myeloma mortality, Neoplasm Proteins biosynthesis, Pyrazines administration & dosage, Transcription Factors biosynthesis
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- 2014
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44. The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia.
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Brusa D, Serra S, Coscia M, Rossi D, D'Arena G, Laurenti L, Jaksic O, Fedele G, Inghirami G, Gaidano G, Malavasi F, and Deaglio S
- Subjects
- Adult, Age Factors, Aged, B7-H1 Antigen genetics, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes pathology, Cell Communication, Cell Differentiation, Cell Proliferation, Disease Progression, Female, Gene Expression, Humans, Immunologic Memory, Interferon-gamma biosynthesis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Middle Aged, Programmed Cell Death 1 Receptor genetics, Protein Binding, T-Lymphocyte Subsets pathology, B7-H1 Antigen metabolism, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Programmed Cell Death 1 Receptor metabolism, T-Lymphocyte Subsets metabolism
- Abstract
Chronic lymphocytic leukemia is marked by profound defects in T-cell function. Programmed death-1 is a receptor involved in tumor-mediated immunosuppression through binding of the PD-L1 ligand. Multiparametric flow cytometry and immunohistochemistry were used to study PD-1/PD-L1 expression. Functional assays were used to determine the involvement of the PD-1/PD-L1 axis in T-cell responses. PD-1 expression by CD4(+) and CD8(+) T lymphocytes was significantly higher in 117 chronic lymphocytic leukemia patients than in 33 donors of a comparable age. CD4(+) and CD8(+) T lymphocytes from chronic lymphocytic leukemia patients displayed increased numbers of effector memory and terminally differentiated cells, respectively, when compared to controls. The number of effector memory CD4(+) and terminally differentiated CD8(+) lymphocytes positively associated with a more advanced stage of disease, treatment requirements and unfavorable genomic aberrations. Furthermore, leukemic lymphocytes expressed higher levels of PD-L1 than circulating B lymphocytes from normal donors. PD-1 and PD-L1 surface expression spiked in proliferating T and B lymphocytes, suggesting that this interaction works efficiently in activated environments. Within chronic lymphocytic leukemia proliferation centers in the lymph node, CD4(+)/PD-1(+) T lymphocytes were found to be in close contact with PD-L1(+) chronic lymphocytic leukemia cells. Lastly, functional experiments using recombinant soluble PD-L1 and blocking antibodies indicated that this axis contributes to the inhibition of IFN-γ production by CD8(+) T cells. These observations suggest that pharmacological manipulation of the PD-1/PD-L1 axis may contribute to restoring T-cell functions in the chronic lymphocytic leukemia microenvironment.
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- 2013
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45. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials.
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Bringhen S, Mateos MV, Zweegman S, Larocca A, Falcone AP, Oriol A, Rossi D, Cavalli M, Wijermans P, Ria R, Offidani M, Lahuerta JJ, Liberati AM, Mina R, Callea V, Schaafsma M, Cerrato C, Marasca R, Franceschini L, Evangelista A, Teruel AI, van der Holt B, Montefusco V, Ciccone G, Boccadoro M, San Miguel J, Sonneveld P, and Palumbo A
- Subjects
- Age Factors, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cause of Death, Female, Humans, Male, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Neoplasm Staging, Prognosis, Proportional Hazards Models, Randomized Controlled Trials as Topic, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Multiple Myeloma mortality
- Abstract
Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46-60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20-1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51-2.70; P<0.001), in those who experienced grade 3-4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75-3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12-2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.
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- 2013
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46. Clinical implications of the molecular genetics of chronic lymphocytic leukemia.
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Foà R, Del Giudice I, Guarini A, Rossi D, and Gaidano G
- Subjects
- Genetic Heterogeneity, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- 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.
- Published
- 2013
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47. Multiple myeloma shows no intra-disease clustering of immunoglobulin heavy chain genes.
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Ferrero S, Capello D, Svaldi M, Boi M, Gatti D, Drandi D, Rossi D, Barbiero S, Mantoan B, Mantella E, Zanni M, Ghione P, Larocca A, Passera R, Bertoni F, Gattei V, Forconi F, Laurenti L, Del Poeta G, Marasca R, Cortelazzo S, Gaidano G, Palumbo A, Boccadoro M, and Ladetto M
- Subjects
- B-Lymphocytes immunology, B-Lymphocytes pathology, Complementarity Determining Regions chemistry, Complementarity Determining Regions immunology, Data Mining, Databases, Nucleic Acid, Humans, Multigene Family immunology, Multiple Myeloma immunology, Myeloma Proteins chemistry, Myeloma Proteins immunology, Sequence Analysis, DNA, Somatic Hypermutation, Immunoglobulin immunology, Complementarity Determining Regions genetics, Genes, Immunoglobulin Heavy Chain immunology, Multiple Myeloma genetics, Myeloma Proteins genetics
- Abstract
Background: Characterization of the immunoglobulin gene repertoire has improved our understanding of the immunopathogenesis of lymphoid tumors. Early B-lymphocyte precursors of multiple myeloma are known to exist and might be susceptible to antigenic drive., Design and Methods: To verify this hypothesis, we collected a database of 345 fully readable multiple myeloma immunoglobulin sequences. We characterized the immunoglobulin repertoire, analyzed the somatic hypermutation load, and investigated for stereotyped receptor clusters., Results: Compared to the normal immunoglobulin repertoire, multiple myeloma displayed only modest differences involving only a few genes, showing that the myeloma immunoglobulin repertoire is the least skewed among mature B-cell tumors. Median somatic hypermutation load was 7.8%; median length of complementarity determining-region 3 was 15.5 amino acids. Clustering analysis showed the absence of myeloma specific clusters and no similarity with published chronic lymphocytic leukemia or lymphoma subsets., Conclusions: Analysis of multiple myeloma immunoglobulin repertoire does not support a pathogenetic role for antigen selection in this tumor.
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- 2012
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48. Nuclear factor-κB dysregulation in splenic marginal zone lymphoma: new therapeutic opportunities.
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Arcaini L and Rossi D
- Subjects
- Humans, Lymphoma, B-Cell, Marginal Zone genetics, Lymphoma, B-Cell, Marginal Zone metabolism, Receptors, Antigen, B-Cell metabolism, Signal Transduction, Splenic Neoplasms genetics, Splenic Neoplasms metabolism, Toll-Like Receptors metabolism
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- 2012
- Full Text
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49. NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL.
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Del Giudice I, Rossi D, Chiaretti S, Marinelli M, Tavolaro S, Gabrielli S, Laurenti L, Marasca R, Rasi S, Fangazio M, Guarini A, Gaidano G, and Foà R
- Subjects
- Aged, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Middle Aged, Mutation Rate, Prognosis, Survival Analysis, Chromosomes, Human, Pair 12, Gene Expression Profiling, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation, Receptor, Notch1 genetics, Transcription, Genetic, Trisomy
- Abstract
Trisomy 12, the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), confers an intermediate prognosis. In our cohort of 104 untreated patients carrying +12, NOTCH1 mutations occurred in 24% of cases and were associated to unmutated IGHV genes (P=0.003) and +12 as a sole cytogenetic abnormality (P=0.008). NOTCH1 mutations in +12 CLL associated with an approximately 2.4 fold increase in the risk of death, a significant shortening of survival (P<0.01) and proved to be an independent predictor of survival in multivariate analysis. Analogous to +12 CLL with TP53 disruption or del(11q), NOTCH1 mutations in +12 CLL conferred a significantly worse survival compared to that of +12 CLL with del(13q) or +12 only. The overrepresentation of cell cycle/proliferation related genes of +12 CLL with NOTCH1 mutations suggests the biological contribution of NOTCH1 mutations to determine a poor outcome. NOTCH1 mutations refine the intermediate prognosis of +12 CLL.
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- 2012
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50. ATM and chronic lymphocytic leukemia: mutations, and not only deletions, matter.
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Rossi D and Gaidano G
- Subjects
- Ataxia Telangiectasia Mutated Proteins, Female, Humans, Male, Alleles, Cell Cycle Proteins genetics, DNA-Binding Proteins genetics, Disease Progression, Gene Expression Profiling, Germ-Line Mutation, Heterozygote, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Loss of Heterozygosity, Protein Serine-Threonine Kinases genetics, Tumor Suppressor Proteins genetics
- Published
- 2012
- Full Text
- View/download PDF
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