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1. Synthetic Data Generation by Artificial Intelligence to Accelerate Research and Precision Medicine in Hematology

Author

D'Amico, S, Dall'Olio, D, Sala, C, Dall'Olio, L, Sauta, E, Zampini, M, Asti, G, Lanino, L, Maggioni, G, Campagna, A, Ubezio, M, Russo, A, Bicchieri, M, Riva, E, Tentori, C, Travaglino, E, Morandini, P, Savevski, V, Santoro, A, Prada-Luengo, I, Krogh, A, Santini, V, Kordasti, S, Platzbecker, U, Diez-Campelo, M, Fenaux, P, Haferlach, T, Castellani, G, Della Porta, M, D'Amico S., Dall'Olio D., Sala C., Dall'Olio L., Sauta E., Zampini M., Asti G., Lanino L., Maggioni G., Campagna A., Ubezio M., Russo A., Bicchieri M. E., Riva E., Tentori C. A., Travaglino E., Morandini P., Savevski V., Santoro A., Prada-Luengo I., Krogh A., Santini V., Kordasti S., Platzbecker U., Diez-Campelo M., Fenaux P., Haferlach T., Castellani G., Della Porta M. G., D'Amico, S, Dall'Olio, D, Sala, C, Dall'Olio, L, Sauta, E, Zampini, M, Asti, G, Lanino, L, Maggioni, G, Campagna, A, Ubezio, M, Russo, A, Bicchieri, M, Riva, E, Tentori, C, Travaglino, E, Morandini, P, Savevski, V, Santoro, A, Prada-Luengo, I, Krogh, A, Santini, V, Kordasti, S, Platzbecker, U, Diez-Campelo, M, Fenaux, P, Haferlach, T, Castellani, G, Della Porta, M, D'Amico S., Dall'Olio D., Sala C., Dall'Olio L., Sauta E., Zampini M., Asti G., Lanino L., Maggioni G., Campagna A., Ubezio M., Russo A., Bicchieri M. E., Riva E., Tentori C. A., Travaglino E., Morandini P., Savevski V., Santoro A., Prada-Luengo I., Krogh A., Santini V., Kordasti S., Platzbecker U., Diez-Campelo M., Fenaux P., Haferlach T., Castellani G., and Della Porta M. G.

Abstract

PURPOSE: Synthetic data are artificial data generated without including any real patient information by an algorithm trained to learn the characteristics of a real source data set and became widely used to accelerate research in life sciences. We aimed to (1) apply generative artificial intelligence to build synthetic data in different hematologic neoplasms; (2) develop a synthetic validation framework to assess data fidelity and privacy preservability; and (3) test the capability of synthetic data to accelerate clinical/translational research in hematology. METHODS: A conditional generative adversarial network architecture was implemented to generate synthetic data. Use cases were myelodysplastic syndromes (MDS) and AML: 7,133 patients were included. A fully explainable validation framework was created to assess fidelity and privacy preservability of synthetic data. RESULTS: We generated MDS/AML synthetic cohorts (including information on clinical features, genomics, treatment, and outcomes) with high fidelity and privacy performances. This technology allowed resolution of lack/incomplete information and data augmentation. We then assessed the potential value of synthetic data on accelerating research in hematology. Starting from 944 patients with MDS available since 2014, we generated a 300% augmented synthetic cohort and anticipated the development of molecular classification and molecular scoring system obtained many years later from 2,043 to 2,957 real patients, respectively. Moreover, starting from 187 MDS treated with luspatercept into a clinical trial, we generated a synthetic cohort that recapitulated all the clinical end points of the study. Finally, we developed a website to enable clinicians generating high-quality synthetic data from an existing biobank of real patients. CONCLUSION: Synthetic data mimic real clinical-genomic features and outcomes, and anonymize patient information. The implementation of this technology allows to increase the scientific

Published
2023

2. Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

Author

Sauta, E, Robin, M, Bersanelli, M, Travaglino, E, Meggendorfer, M, Zhao, L, Caballero Berrocal, J, Sala, C, Maggioni, G, Bernardi, M, Di Grazia, C, Vago, L, Rivoli, G, Borin, L, D'Amico, S, Tentori, C, Ubezio, M, Campagna, A, Russo, A, Mannina, D, Lanino, L, Chiusolo, P, Giaccone, L, Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Nibourel, O, Bicchieri, M, Bolli, N, Rambaldi, A, Passamonti, F, Savevski, V, Santoro, A, Germing, U, Kordasti, S, Santini, V, Diez-Campelo, M, Sanz, G, Sole, F, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, Della Porta, M, Sauta, Elisabetta, Robin, Marie, Bersanelli, Matteo, Travaglino, Erica, Meggendorfer, Manja, Zhao, Lin-Pierre, Caballero Berrocal, Juan Carlos, Sala, Claudia, Maggioni, Giulia, Bernardi, Massimo, Di Grazia, Carmen, Vago, Luca, Rivoli, Giulia, Borin, Lorenza, D'Amico, Saverio, Tentori, Cristina Astrid, Ubezio, Marta, Campagna, Alessia, Russo, Antonio, Mannina, Daniele, Lanino, Luca, Chiusolo, Patrizia, Giaccone, Luisa, Voso, Maria Teresa, Riva, Marta, Oliva, Esther Natalie, Zampini, Matteo, Riva, Elena, Nibourel, Olivier, Bicchieri, Marilena, Bolli, Niccolo', Rambaldi, Alessandro, Passamonti, Francesco, Savevski, Victor, Santoro, Armando, Germing, Ulrich, Kordasti, Shahram, Santini, Valeria, Diez-Campelo, Maria, Sanz, Guillermo, Sole, Francesc, Kern, Wolfgang, Platzbecker, Uwe, Ades, Lionel, Fenaux, Pierre, Haferlach, Torsten, Castellani, Gastone, Della Porta, Matteo Giovanni, Sauta, E, Robin, M, Bersanelli, M, Travaglino, E, Meggendorfer, M, Zhao, L, Caballero Berrocal, J, Sala, C, Maggioni, G, Bernardi, M, Di Grazia, C, Vago, L, Rivoli, G, Borin, L, D'Amico, S, Tentori, C, Ubezio, M, Campagna, A, Russo, A, Mannina, D, Lanino, L, Chiusolo, P, Giaccone, L, Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Nibourel, O, Bicchieri, M, Bolli, N, Rambaldi, A, Passamonti, F, Savevski, V, Santoro, A, Germing, U, Kordasti, S, Santini, V, Diez-Campelo, M, Sanz, G, Sole, F, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, Della Porta, M, Sauta, Elisabetta, Robin, Marie, Bersanelli, Matteo, Travaglino, Erica, Meggendorfer, Manja, Zhao, Lin-Pierre, Caballero Berrocal, Juan Carlos, Sala, Claudia, Maggioni, Giulia, Bernardi, Massimo, Di Grazia, Carmen, Vago, Luca, Rivoli, Giulia, Borin, Lorenza, D'Amico, Saverio, Tentori, Cristina Astrid, Ubezio, Marta, Campagna, Alessia, Russo, Antonio, Mannina, Daniele, Lanino, Luca, Chiusolo, Patrizia, Giaccone, Luisa, Voso, Maria Teresa, Riva, Marta, Oliva, Esther Natalie, Zampini, Matteo, Riva, Elena, Nibourel, Olivier, Bicchieri, Marilena, Bolli, Niccolo', Rambaldi, Alessandro, Passamonti, Francesco, Savevski, Victor, Santoro, Armando, Germing, Ulrich, Kordasti, Shahram, Santini, Valeria, Diez-Campelo, Maria, Sanz, Guillermo, Sole, Francesc, Kern, Wolfgang, Platzbecker, Uwe, Ades, Lionel, Fenaux, Pierre, Haferlach, Torsten, Castellani, Gastone, and Della Porta, Matteo Giovanni

Abstract

Purpose: Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M. Methods: A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed. Results: IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score. Conclusion: IPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevan

Published
2023

3. A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study

Author

Maggioni, G, Bersanelli, M, Travaglino, E, Alfonso Piérola, A, Kasprzak, A, Sangerman Montserrat, A, Sauta, E, Sala, C, Matteuzzi, T, Meggendorfer, M, Gnocchi, M, Zhao, L, Astrid Tentori, C, Nachtkamp, K, Dall'Olio, D, Mosca, E, Ubezio, M, Campagna, A, Russo, A, Rivoli, G, Bernardi, M, Borin, L, Teresa Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Saba, E, D'Amico, S, Lanino, L, Tinterri, B, Re, F, Bicchieri, M, Giordano, L, Angelotti, G, Morandini, P, Sophie Kubasch, A, Passamonti, F, Rambaldi, A, Savevski, V, Santoro, A, A van de Loosdrecht, A, Brogi, A, Santini, V, Kordasti, S, Sanz, G, Sole, F, Gattermann, N, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, Germing, U, Diez-Campelo, M, G Della Porta, M, Giulia Maggioni, Matteo Bersanelli, Erica Travaglino, Ana Alfonso Piérola, Annika Kasprzak, Arnan Sangerman Montserrat, Elisabetta Sauta, Claudia Sala, Tommaso Matteuzzi, Manja Meggendorfer, Matteo Gnocchi, Lin-Pierre Zhao, Cristina Astrid Tentori, Kathrin Nachtkamp, Daniele Dall'Olio, Ettore Mosca, Marta Ubezio, Alessia Campagna, Antonio Russo, Giulia Rivoli, Massimo Bernardi, Lorenza Borin, Maria Teresa Voso, Marta Riva, Esther Oliva, Matteo Zampini, Elena Riva, Elena Saba, Saverio D'Amico, Luca Lanino, Benedetta Tinterri, Francesca Re, Marilena Bicchieri, Laura Giordano, Giovanni Angelotti, Pierandrea Morandini, Anne Sophie Kubasch, Francesco Passamonti, Alessandro Rambaldi, Victor Savevski, Armando Santoro, Arjan A van de Loosdrecht, Alice Brogi, Valeria Santini, Shahram Kordasti, Guillermo Sanz, Francesc Sole, Norbert Gattermann, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Ulrich Germing, Maria Diez-Campelo, Matteo G Della Porta, Maggioni, G, Bersanelli, M, Travaglino, E, Alfonso Piérola, A, Kasprzak, A, Sangerman Montserrat, A, Sauta, E, Sala, C, Matteuzzi, T, Meggendorfer, M, Gnocchi, M, Zhao, L, Astrid Tentori, C, Nachtkamp, K, Dall'Olio, D, Mosca, E, Ubezio, M, Campagna, A, Russo, A, Rivoli, G, Bernardi, M, Borin, L, Teresa Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Saba, E, D'Amico, S, Lanino, L, Tinterri, B, Re, F, Bicchieri, M, Giordano, L, Angelotti, G, Morandini, P, Sophie Kubasch, A, Passamonti, F, Rambaldi, A, Savevski, V, Santoro, A, A van de Loosdrecht, A, Brogi, A, Santini, V, Kordasti, S, Sanz, G, Sole, F, Gattermann, N, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, Germing, U, Diez-Campelo, M, G Della Porta, M, Giulia Maggioni, Matteo Bersanelli, Erica Travaglino, Ana Alfonso Piérola, Annika Kasprzak, Arnan Sangerman Montserrat, Elisabetta Sauta, Claudia Sala, Tommaso Matteuzzi, Manja Meggendorfer, Matteo Gnocchi, Lin-Pierre Zhao, Cristina Astrid Tentori, Kathrin Nachtkamp, Daniele Dall'Olio, Ettore Mosca, Marta Ubezio, Alessia Campagna, Antonio Russo, Giulia Rivoli, Massimo Bernardi, Lorenza Borin, Maria Teresa Voso, Marta Riva, Esther Oliva, Matteo Zampini, Elena Riva, Elena Saba, Saverio D'Amico, Luca Lanino, Benedetta Tinterri, Francesca Re, Marilena Bicchieri, Laura Giordano, Giovanni Angelotti, Pierandrea Morandini, Anne Sophie Kubasch, Francesco Passamonti, Alessandro Rambaldi, Victor Savevski, Armando Santoro, Arjan A van de Loosdrecht, Alice Brogi, Valeria Santini, Shahram Kordasti, Guillermo Sanz, Francesc Sole, Norbert Gattermann, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Ulrich Germing, Maria Diez-Campelo, and Matteo G Della Porta

Abstract

BACKGROUND: Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. METHODS: In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Düsseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. FINDINGS: The study included 7792 (58·7%) men and 5492 (41·3%) women. 10 906 (82·1%) patients were White, and race was not reported for 2378 (17·9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0·0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0·0062 in the IWG-PM cohort; IDH2 p<0·0001 in EuroMDS vs p=0·042 in IWG-PM; TET2 p=0·031 vs p=0·035; U2AF1 p=0·033 vs p<0·0001) and mutations in two genes were enriched in women (DNMT3A p<0·000

Published
2023

4. Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

Author

Sauta, E., Robin, M., Bersanelli, M., Travaglino, E., Meggendorfer, M., Zhao, L. -P., Caballero Berrocal, J. C., Sala, C., Maggioni, G., Bernardi, M., Di Grazia, C., Vago, L., Rivoli, G., Borin, L., D'Amico, S., Tentori, C. A., Ubezio, M., Campagna, A., Russo, A., Mannina, D., Lanino, L., Chiusolo, Patrizia, Giaccone, L., Voso, Maria Teresa, Riva, M., Oliva, E. N., Zampini, M., Riva, E., Nibourel, O., Bicchieri, M., Bolli, N., Rambaldi, A., Passamonti, F., Savevski, V., Santoro, A., Germing, U., Kordasti, S., Santini, V., Diez-Campelo, M., Sanz, G., Sole, F., Kern, W., Platzbecker, U., Ades, L., Fenaux, P., Haferlach, T., Castellani, G., Della Porta, M. G., Chiusolo P. (ORCID:0000-0002-1355-1587), Voso M. T., Sauta, E., Robin, M., Bersanelli, M., Travaglino, E., Meggendorfer, M., Zhao, L. -P., Caballero Berrocal, J. C., Sala, C., Maggioni, G., Bernardi, M., Di Grazia, C., Vago, L., Rivoli, G., Borin, L., D'Amico, S., Tentori, C. A., Ubezio, M., Campagna, A., Russo, A., Mannina, D., Lanino, L., Chiusolo, Patrizia, Giaccone, L., Voso, Maria Teresa, Riva, M., Oliva, E. N., Zampini, M., Riva, E., Nibourel, O., Bicchieri, M., Bolli, N., Rambaldi, A., Passamonti, F., Savevski, V., Santoro, A., Germing, U., Kordasti, S., Santini, V., Diez-Campelo, M., Sanz, G., Sole, F., Kern, W., Platzbecker, U., Ades, L., Fenaux, P., Haferlach, T., Castellani, G., Della Porta, M. G., Chiusolo P. (ORCID:0000-0002-1355-1587), and Voso M. T.

Abstract

PURPOSEMyelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M.METHODSA total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed.RESULTSIPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively).In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk.Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score.CONCLUSIONIPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may

Published
2023

5. The genetics of myelodysplastic syndromes: Clinical relevance

Author

Chiereghin, C, Travaglino, E, Zampini, M, Saba, E, Saitta, C, Riva, E, Bersanelli, M, Della Porta, M, Chiereghin C., Travaglino E., Zampini M., Saba E., Saitta C., Riva E., Bersanelli M., Della Porta M. G., Chiereghin, C, Travaglino, E, Zampini, M, Saba, E, Saitta, C, Riva, E, Bersanelli, M, Della Porta, M, Chiereghin C., Travaglino E., Zampini M., Saba E., Saitta C., Riva E., Bersanelli M., and Della Porta M. G.

Abstract

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

Published
2021

6. Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes

Author

Della Porta, M G, Travaglino, E, Boveri, E, Ponzoni, M, Malcovati, L, Papaemmanuil, E, Rigolin, G M, Pascutto, C, Croci, G, Gianelli, U, Milani, R, Ambaglio, I, Elena, C, Ubezio, M, Da Via’, M C, Bono, E, Pietra, D, Quaglia, F, Bastia, R, Ferretti, V, Cuneo, A, Morra, E, Campbell, P J, Orazi, A, Invernizzi, R, and Cazzola, M

Published
2015
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7. Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes

Author

Porta, Della MG, Travaglino, E, Boveri, E, Ponzoni, M, Malcovati, L, Papaemmanuil, E, Rigolin, G M, Pascutto, C, Croci, G, Gianelli, U, Milani, R, Ambaglio, I, Elena, C, Ubezio, M, Da Viaʼ, M C, Bono, E, Pietra, D, Quaglia, F, Bastia, R, Ferretti, V, Cuneo, A, Morra, E, Campbell, P J, Orazi, A, Invernizzi, R, and Cazzola, M

Published
2015
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8. Clinical relevance of clonal hematopoiesis in persons aged >= 80 years

Author

Rossi, M, Meggendorfer, M, Zampini, M, Tettamanti, M, Riva, E, Travaglino, E, Bersanelli, M, Mandelli, S, Galbussera, AA, Mosca, E, Saba, E, Chiereghin, C, Manes, N, Milanesi, C, Ubezio, M, Morabito, L, Peano, C, Solda, G, Asselta, R, Duga, S, Selmi, C, De Santis, M, Malik, K, Maggioni, G, Bicchieri, M, Campagna, A, Tentori, CA, Russo, A, Civilini, E, Allavena, P, Piazza, R, Corrao, G, Sala, C, Termanini, A, Giordano, L, Detoma, P, Malabaila, A, Sala, L, Rosso, S, Zanetti, R, Saitta, C, Condorelli, G, Passamonti, F, Santoro, A, Francesc Solé, Platzbecker, U, Fenaux, P, Bolli, N, Castellani, G, Kern, W, Vassiliou, GS, Haferlach, T, Lucca, U, and Della Porta, MG

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged >= 80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged >= 80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged >= 80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency >= 0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged >= 80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged >= 80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged >= 80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Published
2021

9. Clinical relevance of clonal hematopoiesis in persons aged ≥80 years

Author

Rossi, M, Meggendorfer, M, Zampini, M, Tettamanti, M, Riva, E, Travaglino, E, Bersanelli, M, Mandelli, S, Galbussera, A, Mosca, E, Saba, E, Chiereghin, C, Manes, N, Milanesi, C, Ubezio, M, Morabito, L, Peano, C, Soldà, G, Asselta, R, Duga, S, Selmi, C, De Santis, M, Malik, K, Maggioni, G, Bicchieri, M, Campagna, A, Tentori, C, Russo, A, Civilini, E, Allavena, P, Piazza, R, Corrao, G, Sala, C, Termanini, A, Giordano, L, Detoma, P, Malabaila, A, Sala, L, Rosso, S, Zanetti, R, Saitta, C, Condorelli, G, Passamonti, F, Santoro, A, Sole, F, Platzbecker, U, Fenaux, P, Bolli, N, Castellani, G, Kern, W, Vassiliou, G, Haferlach, T, Lucca, U, Della Porta, M, Rossi, Marianna, Meggendorfer, Manja, Zampini, Matteo, Tettamanti, Mauro, Riva, Emma, Travaglino, Erica, Bersanelli, Matteo, Mandelli, Sara, Galbussera, Alessia Antonella, Mosca, Ettore, Saba, Elena, Chiereghin, Chiara, Manes, Nicla, Milanesi, Chiara, Ubezio, Marta, Morabito, Lucio, Peano, Clelia, Soldà, Giulia, Asselta, Rosanna, Duga, Stefano, Selmi, Carlo, De Santis, Maria, Malik, Karolina, Maggioni, Giulia, Bicchieri, Maria Elena, Campagna, Alessia, Tentori, Cristina Astrid, Russo, Antonio, Civilini, Efrem, Allavena, Paola, Piazza, Rocco, Corrao, Giovanni, Sala, Claudia, Termanini, Alberto, Giordano, Laura, Detoma, Paolo, Malabaila, Aurelio, Sala, Luca, Rosso, Stefano, Zanetti, Roberto, Saitta, Claudia, Riva, Elena, Condorelli, Gianluigi, Passamonti, Francesco, Santoro, Armando, Sole, Francesc, Platzbecker, Uwe, Fenaux, Pierre, Bolli, Niccolo, Castellani, Gastone, Kern, Wolfgang, Vassiliou, George, Haferlach, Torsten, Lucca, Ugo, Della Porta, Matteo G, Rossi, M, Meggendorfer, M, Zampini, M, Tettamanti, M, Riva, E, Travaglino, E, Bersanelli, M, Mandelli, S, Galbussera, A, Mosca, E, Saba, E, Chiereghin, C, Manes, N, Milanesi, C, Ubezio, M, Morabito, L, Peano, C, Soldà, G, Asselta, R, Duga, S, Selmi, C, De Santis, M, Malik, K, Maggioni, G, Bicchieri, M, Campagna, A, Tentori, C, Russo, A, Civilini, E, Allavena, P, Piazza, R, Corrao, G, Sala, C, Termanini, A, Giordano, L, Detoma, P, Malabaila, A, Sala, L, Rosso, S, Zanetti, R, Saitta, C, Condorelli, G, Passamonti, F, Santoro, A, Sole, F, Platzbecker, U, Fenaux, P, Bolli, N, Castellani, G, Kern, W, Vassiliou, G, Haferlach, T, Lucca, U, Della Porta, M, Rossi, Marianna, Meggendorfer, Manja, Zampini, Matteo, Tettamanti, Mauro, Riva, Emma, Travaglino, Erica, Bersanelli, Matteo, Mandelli, Sara, Galbussera, Alessia Antonella, Mosca, Ettore, Saba, Elena, Chiereghin, Chiara, Manes, Nicla, Milanesi, Chiara, Ubezio, Marta, Morabito, Lucio, Peano, Clelia, Soldà, Giulia, Asselta, Rosanna, Duga, Stefano, Selmi, Carlo, De Santis, Maria, Malik, Karolina, Maggioni, Giulia, Bicchieri, Maria Elena, Campagna, Alessia, Tentori, Cristina Astrid, Russo, Antonio, Civilini, Efrem, Allavena, Paola, Piazza, Rocco, Corrao, Giovanni, Sala, Claudia, Termanini, Alberto, Giordano, Laura, Detoma, Paolo, Malabaila, Aurelio, Sala, Luca, Rosso, Stefano, Zanetti, Roberto, Saitta, Claudia, Riva, Elena, Condorelli, Gianluigi, Passamonti, Francesco, Santoro, Armando, Sole, Francesc, Platzbecker, Uwe, Fenaux, Pierre, Bolli, Niccolo, Castellani, Gastone, Kern, Wolfgang, Vassiliou, George, Haferlach, Torsten, Lucca, Ugo, and Della Porta, Matteo G

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Published
2021

14. Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

Author

Papaemmanuil, E., Cazzola, M., Boultwood, J., Malcovati, L., Vyas, P., Bowen, D., Pellagatti, A., Wainscoat, J. S., Hellstrom-Lindberg, E., Gambacorti-Passerini, C., Godfrey, A. L., Rapado, I., Cvejic, A., Rance, R., McGee, C., Ellis, P., Mudie, L. J., Stephens, P. J., McLaren, S., Massie, C. E., Tarpey, P. S., Varela, I., Nik-Zainal, S., Davies, H. R., Shlien, A., Jones, D., Raine, K., Hinton, J., Butler, A. P., Teague, J. W., Baxter, E. J., Score, J., Galli, A., Della Porta, M. G., Travaglino, E., Groves, M., Tauro, S., Munshi, N. C., Anderson, K. C., El-Naggar, A., Fischer, A., Mustonen, V., Warren, A. J., Cross, N. C.P., Green, A. R., Futreal, P. A., Stratton, M. R., and Campbell, P. J.

Published
2011
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17. IMarine - IMarine data infrastructure enabling software

Author

Antoniadis A., Cirillo R., Formisano C., Fortunati L., Gerbesiotis J., Lelii L., Panagiotis L., Savini A., Simeoni F., and Travaglino E.

Subjects
i-Marine Project, Security, gCube, Maven, H.3.7 Digital Libraries, Enabling Software, Workflow, Process Execution Engine
Abstract

iMarine Data Infrastructure Enabling Software contains the description of software and pointers to the documentation and artifacts of the related components that comprise the e-Infrastructure Management suite delivered from M11 to M24

Published
2013

18. Inappropriately low hepcidin levels in patients with myelodysplastic syndrome carrying a somatic mutation of SF3B1

Author

Ambaglio, I., Malcovati, L., Papaemmanuil, E., Laarakkers, C.M., Della Porta, M.G., Galli, A., Da Via, M.C., Bono, E., Ubezio, M., Travaglino, E., Albertini, R., Campbell, P.J., Swinkels, D.W., Cazzola, M., Ambaglio, I., Malcovati, L., Papaemmanuil, E., Laarakkers, C.M., Della Porta, M.G., Galli, A., Da Via, M.C., Bono, E., Ubezio, M., Travaglino, E., Albertini, R., Campbell, P.J., Swinkels, D.W., and Cazzola, M.

Abstract

Contains fulltext : 118639.pdf (publisher's version ) (Open Access), Somatic mutations of the RNA splicing machinery have been recently identified in myelodysplastic syndromes. In particular, a strong association has been found between SF3B1 mutation and refractory anemia with ring sider-oblasts, a condition characterized by ineffective erythropoiesis and parenchymal iron overload. We studied the relationship between SF3B1 mutation, erythroid activity and hepcidin levels in myelodysplastic syndrome patients. Erythroid activity was evaluated through the proportion of marrow erythroblasts, soluble transferrin receptor and serum growth differentiation factor 15. Significant relationships were found between SF3B1 mutation and marrow erythroblasts (P=0.001), soluble transferrin receptor (P=0.003) and serum growth differentiation factor 15 (P=0.033). Serum hepcidin varied considerably, and multivariable analysis showed that the hepcidin to ferritin ratio, a measure of adequacy of hepcidin levels relative to body iron stores, was inversely related to the SF3B1 mutation (P=0.013). These observations suggest that patients with SF3B1 mutation have inappropriately low hepcidin levels, which may explain their propensity to parenchymal iron loading.

Published
2013

19. Twenty-one cases of blastic plasmacytoid dendritic cell neoplasm: focus on biallelic locus 9p21.3 deletion

Author

Lucioni, M, Novara, F, Fiandrino, G, Riboni, R, Fanoni, D, Arra, M, Venegoni, L, Nicola, M, Dallera, E, Arcaini, L, Onida, F, Vezzoli, P, Travaglino, E, Boveri, E, Zuffardi, O, Paulli, M, Berti, E, BERTI, EMILIO, Lucioni, M, Novara, F, Fiandrino, G, Riboni, R, Fanoni, D, Arra, M, Venegoni, L, Nicola, M, Dallera, E, Arcaini, L, Onida, F, Vezzoli, P, Travaglino, E, Boveri, E, Zuffardi, O, Paulli, M, Berti, E, and BERTI, EMILIO

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive malignancy derived from precursors of plasmacytoid dendritic cells. We analyzed 21 cases with array-based comparative genomic hybridization (aCGH). Complete or partial chromosomal losses largely outnumbered the gains, with common deleted regions involving 9p21.3 (CDKN2A/CDKN2B), 13q13.1-q14.3 (RB1), 12p13.2-p13.1 (CDKN1B), 13q11-q12 (LATS2), and 7p12.2 (IKZF1) regions. CDKN2A/CDKN2B deletion was confirmed by FISH. This scenario argues for disruption of cell cycle at G1/S transition, representing a genetic landmark of BPDCN, and possibly contributing to its pathogenesis. Statistical analysis of overall survival in our series highlighted an association of poor outcome with biallelic loss of locus 9p21.3. We suggest that, in the absence of reliable parameters for predicting prognosis in BPDCN other than age, tumor stage, and/or clinical presentation, simple methods, such as FISH for CDKN2A/CDKN2B, could help to identify the most aggressive cases. © 2011 by The American Society of Hematology.

Published
2011

20. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts

Author

Papaemmanuil, E, Cazzola, M, Boultwood, J, Malcovati, L, Vyas, P, Bowen, D, Pellagatti, A, Wainscoat, J, Hellstrom Lindberg, E, GAMBACORTI PASSERINI, C, Godfrey, A, Rapado, I, Cvejic, A, Rance, R, Mcgee, C, Ellis, P, Mudie, L, Stephens, P, Mclaren, S, Massie, C, Tarpey, P, Varela, I, Nik Zainal, S, Davies, H, Shlien, A, Jones, D, Raine, K, Hinton, J, Butler, A, Teague, J, Baxter, E, Score, J, Galli, A, Della Porta, M, Travaglino, E, Groves, M, Tauro, S, Munshi, N, Anderson, K, El Naggar, A, Fischer, A, Mustonen, V, Warren, A, Cross, N, Green, A, Futreal, P, Stratton, M, Campbell, P, Chronic Myeloid Disorders Working Group of the International Cancer Genome, C, Wainscoat, JS, Godfrey, AL, McGee, C, Mudie, LJ, Stephens, PJ, McLaren, S, Massie, CE, Tarpey, PS, Davies, HR, Butler, AP, Teague, JW, Baxter, EJ, Della Porta, MG, Munshi, NC, Anderson, KC, Warren, AJ, Cross, NC, Green, AR, Futreal, PA, Stratton, MR, Campbell, PJ, Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, GAMBACORTI PASSERINI, CARLO, Papaemmanuil, E, Cazzola, M, Boultwood, J, Malcovati, L, Vyas, P, Bowen, D, Pellagatti, A, Wainscoat, J, Hellstrom Lindberg, E, GAMBACORTI PASSERINI, C, Godfrey, A, Rapado, I, Cvejic, A, Rance, R, Mcgee, C, Ellis, P, Mudie, L, Stephens, P, Mclaren, S, Massie, C, Tarpey, P, Varela, I, Nik Zainal, S, Davies, H, Shlien, A, Jones, D, Raine, K, Hinton, J, Butler, A, Teague, J, Baxter, E, Score, J, Galli, A, Della Porta, M, Travaglino, E, Groves, M, Tauro, S, Munshi, N, Anderson, K, El Naggar, A, Fischer, A, Mustonen, V, Warren, A, Cross, N, Green, A, Futreal, P, Stratton, M, Campbell, P, Chronic Myeloid Disorders Working Group of the International Cancer Genome, C, Wainscoat, JS, Godfrey, AL, McGee, C, Mudie, LJ, Stephens, PJ, McLaren, S, Massie, CE, Tarpey, PS, Davies, HR, Butler, AP, Teague, JW, Baxter, EJ, Della Porta, MG, Munshi, NC, Anderson, KC, Warren, AJ, Cross, NC, Green, AR, Futreal, PA, Stratton, MR, Campbell, PJ, Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, and GAMBACORTI PASSERINI, CARLO

Abstract

BACKGROUND: Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. METHODS: We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. RESULTS: We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. CONCLUSIONS: Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes

Published
2011

21. Inappropriately low hepcidin levels in patients with myelodysplastic syndrome carrying a somatic mutation of SF3B1

Author

Ambaglio, I., primary, Malcovati, L., additional, Papaemmanuil, E., additional, Laarakkers, C. M., additional, Della Porta, M. G., additional, Galli, A., additional, Da Via, M. C., additional, Bono, E., additional, Ubezio, M., additional, Travaglino, E., additional, Albertini, R., additional, Campbell, P. J., additional, Swinkels, D. W., additional, and Cazzola, M., additional

Published
2013
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22. Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis

Author

Broseus, J., primary, Florensa, L., additional, Zipperer, E., additional, Schnittger, S., additional, Malcovati, L., additional, Richebourg, S., additional, Lippert, E., additional, Cermak, J., additional, Evans, J., additional, Mounier, M., additional, Raya, J. M., additional, Bailly, F., additional, Gattermann, N., additional, Haferlach, T., additional, Garand, R., additional, Allou, K., additional, Besses, C., additional, Germing, U., additional, Haferlach, C., additional, Travaglino, E., additional, Luno, E., additional, Pinan, M. A., additional, Arenillas, L., additional, Rozman, M., additional, Perez Sirvent, M. L., additional, Favre, B., additional, Guy, J., additional, Alonso, E., additional, Ahwij, N., additional, Jerez, A., additional, Hermouet, S., additional, Maynadie, M., additional, Cazzola, M., additional, and Girodon, F., additional

Published
2012
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24. SomaticSF3B1Mutation in Myelodysplasia with Ring Sideroblasts

Author

Papaemmanuil, E., primary, Cazzola, M., additional, Boultwood, J., additional, Malcovati, L., additional, Vyas, P., additional, Bowen, D., additional, Pellagatti, A., additional, Wainscoat, J.S., additional, Hellstrom-Lindberg, E., additional, Gambacorti-Passerini, C., additional, Godfrey, A.L., additional, Rapado, I., additional, Cvejic, A., additional, Rance, R., additional, McGee, C., additional, Ellis, P., additional, Mudie, L.J., additional, Stephens, P.J., additional, McLaren, S., additional, Massie, C.E., additional, Tarpey, P.S., additional, Varela, I., additional, Nik-Zainal, S., additional, Davies, H.R., additional, Shlien, A., additional, Jones, D., additional, Raine, K., additional, Hinton, J., additional, Butler, A.P., additional, Teague, J.W., additional, Baxter, E.J., additional, Score, J., additional, Galli, A., additional, Della Porta, M.G., additional, Travaglino, E., additional, Groves, M., additional, Tauro, S., additional, Munshi, N.C., additional, Anderson, K.C., additional, El-Naggar, A., additional, Fischer, A., additional, Mustonen, V., additional, Warren, A.J., additional, Cross, N.C.P., additional, Green, A.R., additional, Futreal, P.A., additional, Stratton, M.R., additional, and Campbell, P.J., additional

Published
2011
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25. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS)

Author

Malcovati, L., primary, Della Porta, M. G., additional, Strupp, C., additional, Ambaglio, I., additional, Kuendgen, A., additional, Nachtkamp, K., additional, Travaglino, E., additional, Invernizzi, R., additional, Pascutto, C., additional, Lazzarino, M., additional, Germing, U., additional, and Cazzola, M., additional

Published
2011
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27. Risk stratification based on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome

Author

Della Porta, M. G., primary, Malcovati, L., additional, Strupp, C., additional, Ambaglio, I., additional, Kuendgen, A., additional, Zipperer, E., additional, Travaglino, E., additional, Invernizzi, R., additional, Pascutto, C., additional, Lazzarino, M., additional, Germing, U., additional, and Cazzola, M., additional

Published
2010
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28. Immunophenotypic, cytogenetic and functional characterization of circulating endothelial cells in myelodysplastic syndromes

Author

Della Porta, M G, primary, Malcovati, L, additional, Rigolin, G M, additional, Rosti, V, additional, Bonetti, E, additional, Travaglino, E, additional, Boveri, E, additional, Gallì, A, additional, Boggi, S, additional, Ciccone, M, additional, Pramparo, T, additional, Mazzini, G, additional, Invernizzi, R, additional, Lazzarino, M, additional, and Cazzola, M, additional

Published
2007
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37. P-41 Aberrant mitochondrial iron distribution and maturation arrest characterizes early erythroid precursors in low-risk myelodysplastic syndromes

Author

Tehranchi, R., primary, Invernizzi, R., additional, Grandien, A., additional, Zhivotovsky, B., additional, Fadeel, B., additional, Forsblom, A.-M., additional, Travaglino, E., additional, Samuelsson, J., additional, Cazzola, M., additional, Wibom, R., additional, and Hellström-Lindberg, E., additional

Published
2005
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40. ANALYSIS OF THE MITOCHONDRIAL FERRITIN PHYSIOPATHOLOGICAL ROLE IN SIDEROBLASTIC ERYTHROPOIESIS

Author

Invernizzi, R., Della Porta, M. G., Rosti, V., Galli, A., Travaglino, E., Santambrogio, P., Marseglia, C., Matti, V., LUCA MALCOVATI, Bergamaschi, G., Cazzola, M., Levi, S., Invernizzi, R., Della Porta, M. G., Rosti, V., Galli, A., Travaglino, E., Santambrogio, P., Marseglia, C., Matti, V., Malcovati, L., Bergamaschi, G., Cazzola, M., and Levi, SONIA MARIA ROSA

47. Clinical relevance of clonal hematopoiesis in persons aged ≥80 years

Author

Aurelio Malabaila, Maria De Santis, Paolo Detoma, Erica Travaglino, Alessia A. Galbussera, Elena Saba, Emma Riva, Rocco Piazza, Marta Ubezio, Maria Elena Bicchieri, Armando Santoro, Gianluigi Condorelli, Matteo Bersanelli, Sara Mandelli, Chiara Chiereghin, George S. Vassiliou, Stefano Duga, Paola Allavena, Francesco Passamonti, Efrem Civilini, Claudia Sala, Matteo Zampini, Luca Sala, Giovanni Corrao, Francesc Solé, Uwe Platzbecker, Karolina Malik, Ettore Mosca, N. Manes, Matteo G. Della Porta, Ugo Lucca, Alessia Campagna, Claudia Saitta, Mauro Tettamanti, Torsten Haferlach, Gastone Castellani, Wolfgang Kern, Laura Giordano, Clelia Peano, Giulia Soldà, Cristina Astrid Tentori, Giulia Maggioni, Stefano Rosso, Manja Meggendorfer, Roberto Zanetti, Chiara Milanesi, Elena Riva, Rosanna Asselta, Pierre Fenaux, Alberto Termanini, Marianna Rossi, Niccolo Bolli, Carlo Selmi, Lucio Morabito, Antonio Russo, Rossi M., Meggendorfer M., Zampini M., Tettamanti M., Riva E., Travaglino E., Bersanelli M., Mandelli S., Antonella Galbussera A., Mosca E., Saba E., Chiereghin C., Manes N., Milanesi C., Ubezio M., Morabito L., Peano C., Solda G., Asselta R., Duga S., Selmi C., De Santis M., Malik K., Maggioni G., Bicchieri M., Campagna A., Tentori C.A., Russo A., Civilini E., Allavena P., Piazza R., Corrao G., Sala C., Termanini A., Giordano L., Detoma P., Malabaila A., Sala L., Rosso S., Zanetti R., Saitta C., Condorelli G., Passamonti F., Santoro A., Sole F., Platzbecker U., Fenaux P., Bolli N., Castellani G., Kern W., Vassiliou G.S., Haferlach T., Lucca U., Della Porta M.G., Rossi, M, Meggendorfer, M, Zampini, M, Tettamanti, M, Riva, E, Travaglino, E, Bersanelli, M, Mandelli, S, Galbussera, A, Mosca, E, Saba, E, Chiereghin, C, Manes, N, Milanesi, C, Ubezio, M, Morabito, L, Peano, C, Soldà, G, Asselta, R, Duga, S, Selmi, C, De Santis, M, Malik, K, Maggioni, G, Bicchieri, M, Campagna, A, Tentori, C, Russo, A, Civilini, E, Allavena, P, Piazza, R, Corrao, G, Sala, C, Termanini, A, Giordano, L, Detoma, P, Malabaila, A, Sala, L, Rosso, S, Zanetti, R, Saitta, C, Condorelli, G, Passamonti, F, Santoro, A, Sole, F, Platzbecker, U, Fenaux, P, Bolli, N, Castellani, G, Kern, W, Vassiliou, G, Haferlach, T, Lucca, U, and Della Porta, M

Subjects
Oncology, Male, Myeloid, Coronary Disease, Biochemistry, Arthritis, Rheumatoid, hemic and lymphatic diseases, aged adult, 80 and over, follow-up, cytopenia, Age Factor, Aged, 80 and over, Myeloid Neoplasia, medicine.diagnostic_test, Age Factors, leukemia, vascular disease, Hematology, anemia, myeloid neoplasms, Leukemia, Haematopoiesis, medicine.anatomical_structure, Leukemia, Myeloid, hematopoiesi, Female, Human, medicine.medical_specialty, Anemia, Immunology, Myelodysplastic Syndrome, Myeloid Neoplasm, Internal medicine, medicine, clonal hematopoiesis, Humans, mean corpuscular volume analyse, Clinical significance, coronary heart disease, Red blood cell indices, Cytopenia, business.industry, mutational screening, Cell Biology, medicine.disease, Myelodysplastic Syndromes, Mutation, Clonal Hematopoiesi, business, hematologic neoplasm
Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Published
2021

48. A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes

Author

Giulia Maggioni, Matteo Bersanelli, Erica Travaglino, Ana Alfonso Piérola, Annika Kasprzak, Arnan Sangerman Montserrat, Elisabetta Sauta, Claudia Sala, Tommaso Matteuzzi, Manja Meggendorfer, Matteo Gnocchi, Lin-Pierre Zhao, Cristina Astrid Tentori, Kathrin Nachtkamp, Daniele Dall'Olio, Ettore Mosca, Marta Ubezio, Alessia Campagna, Antonio Russo, Giulia Rivoli, Massimo Bernardi, Lorenza Borin, Maria Teresa Voso, Marta Riva, Esther Oliva, Matteo Zampini, Elena Riva, Elena Saba, Saverio D'Amico, Luca Lanino, Benedetta Tinterri, Francesca Re, Marilena Bicchieri, Laura Giordano, Giovanni Angelotti, Pierandrea Morandini, Anne Sophie Kubasch, Francesco Passamonti, Alessandro Rambaldi, Victor Savevski, Armando Santoro, Arjan A. van de Loosdrecht, Alice Brogi, Valeria Santini, Shahram Kordasti, Guillermo Sanz, Francesc Sole, Norbert Gattermann, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Ulrich Germing, Maria Diez-Campelo, Matteo G. Della Porta, Hematology, AII - Cancer immunology, AII - Inflammatory diseases, CCA - Cancer biology and immunology, Maggioni, G, Bersanelli, M, Travaglino, E, Alfonso Piérola, A, Kasprzak, A, Sangerman Montserrat, A, Sauta, E, Sala, C, Matteuzzi, T, Meggendorfer, M, Gnocchi, M, Zhao, L, Astrid Tentori, C, Nachtkamp, K, Dall'Olio, D, Mosca, E, Ubezio, M, Campagna, A, Russo, A, Rivoli, G, Bernardi, M, Borin, L, Teresa Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Saba, E, D'Amico, S, Lanino, L, Tinterri, B, Re, F, Bicchieri, M, Giordano, L, Angelotti, G, Morandini, P, Sophie Kubasch, A, Passamonti, F, Rambaldi, A, Savevski, V, Santoro, A, A van de Loosdrecht, A, Brogi, A, Santini, V, Kordasti, S, Sanz, G, Sole, F, Gattermann, N, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, Germing, U, Diez-Campelo, M, and G Della Porta, M

Subjects
Malalties hematològiques, Hematologic diseases, Myelodysplastic Syndrome, Factors sexuals en les malalties, Sex factors in disease, sex, Hematology, personalized medicine, Settore MED/15
Abstract

Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p

Published
2023

49. Real-World Validation of Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

Author

Elisabetta Sauta, Marie Robin, Matteo Bersanelli, Erica Travaglino, Manja Meggendorfer, Lin-Pierre Zhao, Juan Carlos Caballero Berrocal, Claudia Sala, Giulia Maggioni, Massimo Bernardi, Carmen Di Grazia, Luca Vago, Giulia Rivoli, Lorenza Borin, Saverio D'Amico, Cristina Astrid Tentori, Marta Ubezio, Alessia Campagna, Antonio Russo, Daniele Mannina, Luca Lanino, Patrizia Chiusolo, Luisa Giaccone, Maria Teresa Voso, Marta Riva, Esther Natalie Oliva, Matteo Zampini, Elena Riva, Olivier Nibourel, Marilena Bicchieri, Niccolo’ Bolli, Alessandro Rambaldi, Francesco Passamonti, Victor Savevski, Armando Santoro, Ulrich Germing, Shahram Kordasti, Valeria Santini, Maria Diez-Campelo, Guillermo Sanz, Francesc Sole, Wolfgang Kern, Uwe Platzbecker, Lionel Ades, Pierre Fenaux, Torsten Haferlach, Gastone Castellani, Matteo Giovanni Della Porta, Sauta, E, Robin, M, Bersanelli, M, Travaglino, E, Meggendorfer, M, Zhao, L, Caballero Berrocal, J, Sala, C, Maggioni, G, Bernardi, M, Di Grazia, C, Vago, L, Rivoli, G, Borin, L, D'Amico, S, Tentori, C, Ubezio, M, Campagna, A, Russo, A, Mannina, D, Lanino, L, Chiusolo, P, Giaccone, L, Voso, M, Riva, M, Oliva, E, Zampini, M, Riva, E, Nibourel, O, Bicchieri, M, Bolli, N, Rambaldi, A, Passamonti, F, Savevski, V, Santoro, A, Germing, U, Kordasti, S, Santini, V, Diez-Campelo, M, Sanz, G, Sole, F, Kern, W, Platzbecker, U, Ades, L, Fenaux, P, Haferlach, T, Castellani, G, and Della Porta, M

Subjects
Cancer Research, Oncology, Myelodysplastic Syndrome, MDS, IPSS-M, Hematology, Settore MED/15
Abstract

PURPOSE Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M. METHODS A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed. RESULTS IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively). In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk. Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score. CONCLUSION IPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score.

Published
2023

50. The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Author

Erica Travaglino, Elena Riva, Chiara Chiereghin, Matteo Bersanelli, Claudia Saitta, Matteo G. Della Porta, Matteo Zampini, Elena Saba, Chiereghin, C, Travaglino, E, Zampini, M, Saba, E, Saitta, C, Riva, E, Bersanelli, M, and Della Porta, M

Subjects
0301 basic medicine, Cohesin complex, DNA repair, disease classification, Review, QH426-470, Gene mutation, Biology, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Genotype, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), gene mutations, Myelodysplastic syndromes, medicine.disease, Phenotype, myelodysplastic syndrome, 030104 developmental biology, Myelodysplastic Syndromes, 030220 oncology & carcinogenesis, Mutation, DNA methylation, prognosis
Abstract

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

Published
2021

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