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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. Topic: AS01-Diagnosis/AS01c-Molecular aberrations (cytogenetic, genetic, gene expression): A CARTOGRAPHY OF UBA1 GENE TESTING, EPIDEMIOLOGY AND CLINICAL-GENOMIC CHARACTERISTICS: THE VEXAS/MDS ITALIAN EXPERIENCE

Author

Gurnari, C., primary, Pascale, M.R., additional, Vitale, A., additional, Diral, E., additional, Galossi, E., additional, Falconi, G., additional, Bruno, A., additional, Crisafulli, F., additional, Frassi, M., additional, Cattaneo, C., additional, Bertoli, D., additional, Bernardi, M., additional, Condorelli, A., additional, Morsia, E., additional, Crisà, E., additional, Triggianese, P., additional, Brussino, L., additional, Battipaglia, G., additional, Bindoli, S., additional, Sfriso, P., additional, Caroni, F., additional, Olivieri, A., additional, Kordasti, S., additional, Albano, F., additional, Pane, F., additional, Musto, P., additional, Bocchia, M., additional, Lugli, E., additional, Rambaldi, A., additional, Greco, R., additional, Franceschini, F., additional, Ciceri, F., additional, Cantarini, L., additional, and Voso, M.T., additional

Published
2023
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3. TARGETING THE DEFECTIVE COA PATHWAY TO IMPROVE ERYTHROPOIESIS IN SF3B1-MUTANT MDS-RS PATIENTS

Author

Philippe, C., primary, Mian, S., additional, Maniati, E., additional, Protopapa, P., additional, Bergot, T., additional, Piganeau, M., additional, Nemkov, T., additional, Di Bella, D., additional, Morales, V., additional, Finch, A., additional, D’Alessandro, A., additional, Bianchi, K., additional, Wang, J., additional, Gallipoli, P., additional, Kordasti, S., additional, Kubasch, A.S., additional, Cross, M., additional, Platzbecker, U., additional, Wiseman, D., additional, Bonnet, D., additional, Bernard, D., additional, Gribben, J., additional, and Rouault-Pierre, K., additional

Published
2023
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6. Clinical application of flow cytometry in patients with unexplained cytopenia and suspected myelodysplastic syndrome: A report of the European LeukemiaNet International MDS-Flow Cytometry Working Group.

Author

Loosdrecht, A.A. van de, Kern, W., Porwit, A., Valent, P., Kordasti, S., Cremers, E., Alhan, C., Duetz, C., Dunlop, A., Hobo, W.A., Preijers, F.W., Wagner-Ballon, O., Chapuis, N., Fontenay, M., Bettelheim, P., Eidenschink-Brodersen, L., Font, P., Johansson, U., Loken, M.R., Marvelde, J.G. Te, Matarraz, S., Ogata, K., Oelschlaegel, U., Orfao, A., Psarra, K., Subirá, D., Wells, D.A., Béné, M.C., Porta, M.G. Della, Burbury, K., Bellos, F., Velden, V.H. van der, Westers, Theresia M., Saft, L., Ireland, R., Loosdrecht, A.A. van de, Kern, W., Porwit, A., Valent, P., Kordasti, S., Cremers, E., Alhan, C., Duetz, C., Dunlop, A., Hobo, W.A., Preijers, F.W., Wagner-Ballon, O., Chapuis, N., Fontenay, M., Bettelheim, P., Eidenschink-Brodersen, L., Font, P., Johansson, U., Loken, M.R., Marvelde, J.G. Te, Matarraz, S., Ogata, K., Oelschlaegel, U., Orfao, A., Psarra, K., Subirá, D., Wells, D.A., Béné, M.C., Porta, M.G. Della, Burbury, K., Bellos, F., Velden, V.H. van der, Westers, Theresia M., Saft, L., and Ireland, R.

Abstract

01 januari 2023, Item does not contain fulltext, This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients.

Published
2023

7. Flow cytometric analysis of myelodysplasia: Pre-analytical and technical issues-Recommendations from the European LeukemiaNet.

Author

Velden, V.H. van der, Preijers, F.W., Johansson, U., Westers, Theresia M., Dunlop, A., Porwit, A., Béné, M.C., Valent, P., Marvelde, J. Te, Wagner-Ballon, O., Oelschlaegel, U., Saft, L., Kordasti, S., Ireland, R., Cremers, E., Alhan, C., Duetz, C., Hobo, W.A., Chapuis, N., Fontenay, M., Bettelheim, P., Eidenshink-Brodersen, L., Font, P., Loken, M.R., Matarraz, S., Ogata, K., Orfao, A., Psarra, K., Subirá, D., Wells, D.A., Porta, M.G. Della, Burbury, K., Bellos, F., Weiß, E., Kern, W., Loosdrecht, A. van de, Velden, V.H. van der, Preijers, F.W., Johansson, U., Westers, Theresia M., Dunlop, A., Porwit, A., Béné, M.C., Valent, P., Marvelde, J. Te, Wagner-Ballon, O., Oelschlaegel, U., Saft, L., Kordasti, S., Ireland, R., Cremers, E., Alhan, C., Duetz, C., Hobo, W.A., Chapuis, N., Fontenay, M., Bettelheim, P., Eidenshink-Brodersen, L., Font, P., Loken, M.R., Matarraz, S., Ogata, K., Orfao, A., Psarra, K., Subirá, D., Wells, D.A., Porta, M.G. Della, Burbury, K., Bellos, F., Weiß, E., Kern, W., and Loosdrecht, A. van de

Abstract

01 januari 2023, Item does not contain fulltext, BACKGROUND: Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress has been made in the FCM field concerning technical issues (including software and hardware) and pre-analytical procedures. METHODS: Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group. RESULTS: We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies. CONCLUSIONS: These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice.

Published
2023

8. Multiparameter flow cytometry in the evaluation of myelodysplasia: Analytical issues: Recommendations from the European LeukemiaNet/International Myelodysplastic Syndrome Flow Cytometry Working Group.

Author

Porwit, A., Béné, M.C., Duetz, C., Matarraz, S., Oelschlaegel, U., Westers, Theresia M., Wagner-Ballon, O., Kordasti, S., Valent, P., Preijers, F.W., Alhan, C., Bellos, F., Bettelheim, P., Burbury, K., Chapuis, N., Cremers, E., Porta, M.G. Della, Dunlop, A., Eidenschink-Brodersen, L., Font, P., Fontenay, M., Hobo, W., Ireland, R., Johansson, U., Loken, M.R., Ogata, K., Orfao, A., Psarra, K., Saft, L., Subira, D., Marvelde, J. Te, Wells, D.A., Velden, V.H. van der, Kern, W., Loosdrecht, A.A. van de, Porwit, A., Béné, M.C., Duetz, C., Matarraz, S., Oelschlaegel, U., Westers, Theresia M., Wagner-Ballon, O., Kordasti, S., Valent, P., Preijers, F.W., Alhan, C., Bellos, F., Bettelheim, P., Burbury, K., Chapuis, N., Cremers, E., Porta, M.G. Della, Dunlop, A., Eidenschink-Brodersen, L., Font, P., Fontenay, M., Hobo, W., Ireland, R., Johansson, U., Loken, M.R., Ogata, K., Orfao, A., Psarra, K., Saft, L., Subira, D., Marvelde, J. Te, Wells, D.A., Velden, V.H. van der, Kern, W., and Loosdrecht, A.A. van de

Abstract

01 januari 2023, Item does not contain fulltext, Multiparameter flow cytometry (MFC) is one of the essential ancillary methods in bone marrow (BM) investigation of patients with cytopenia and suspected myelodysplastic syndrome (MDS). MFC can also be applied in the follow-up of MDS patients undergoing treatment. This document summarizes recommendations from the International/European Leukemia Net Working Group for Flow Cytometry in Myelodysplastic Syndromes (ELN iMDS Flow) on the analytical issues in MFC for the diagnostic work-up of MDS. Recommendations for the analysis of several BM cell subsets such as myeloid precursors, maturing granulocytic and monocytic components and erythropoiesis are given. A core set of 17 markers identified as independently related to a cytomorphologic diagnosis of myelodysplasia is suggested as mandatory for MFC evaluation of BM in a patient with cytopenia. A myeloid precursor cell (CD34(+) CD19(-) ) count >3% should be considered immunophenotypically indicative of myelodysplasia. However, MFC results should always be evaluated as part of an integrated hematopathology work-up. Looking forward, several machine-learning-based analytical tools of interest should be applied in parallel to conventional analytical methods to investigate their usefulness in integrated diagnostics, risk stratification, and potentially even in the evaluation of response to therapy, based on MFC data. In addition, compiling large uniform datasets is desirable, as most of the machine-learning-based methods tend to perform better with larger numbers of investigated samples, especially in such a heterogeneous disease as MDS.

Published
2023

9. 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

10. 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

11. 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

14. P013 - Topic: AS01-Diagnosis/AS01c-Molecular aberrations (cytogenetic, genetic, gene expression): A CARTOGRAPHY OF UBA1 GENE TESTING, EPIDEMIOLOGY AND CLINICAL-GENOMIC CHARACTERISTICS: THE VEXAS/MDS ITALIAN EXPERIENCE

Author

Gurnari, C., Pascale, M.R., Vitale, A., Diral, E., Galossi, E., Falconi, G., Bruno, A., Crisafulli, F., Frassi, M., Cattaneo, C., Bertoli, D., Bernardi, M., Condorelli, A., Morsia, E., Crisà, E., Triggianese, P., Brussino, L., Battipaglia, G., Bindoli, S., Sfriso, P., Caroni, F., Olivieri, A., Kordasti, S., Albano, F., Pane, F., Musto, P., Bocchia, M., Lugli, E., Rambaldi, A., Greco, R., Franceschini, F., Ciceri, F., Cantarini, L., and Voso, M.T.

Published
2023
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16. 42P Independent prognostic value of flow cytometry (FCM) in myelodysplastic syndromes (MDS): Composition of a prognostic FCM-score for overall survival

Author

Santaolalla, A., primary, Oelschlaegel, U., additional, Timms, J., additional, Winter, S., additional, Parker, P., additional, Harrison, C.N., additional, Westers, T.M., additional, van de Loosdrecht, A.A., additional, van Hemelrijck, M., additional, Platzbecker, U., additional, and Kordasti, S., additional

Published
2022
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17. P990: T CELL RESPONSE AND OMICRON VARIANT NEUTRALISATION FOLLOWING VACCINATION AGAINST SARS-COV-2 IN PATIENTS WITH CHRONIC MYELOID DISORDERS

Author

Harrington, P., primary, Saunders, J., additional, Saha, C., additional, Sheikh, A., additional, Dillon, R., additional, Raj, K., additional, Cadman-Davies, L., additional, Lechmere, T., additional, Khan, H., additional, Woodley, C., additional, Asirvatham, S., additional, Curto-Garcia, N., additional, O’Sullivan, J., additional, Kordasti, S., additional, Radia, D., additional, McLornan, D., additional, Malim, M., additional, Doores, K., additional, Harrison, C., additional, and de Lavallade, H., additional

Published
2022
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19. Predicting progression-free survival after systemic therapy in advanced head and neck cancer: Bayesian regression and model development

Author

Mustapha, R., Flores-Borja, F., Alfano, G., Ng, K., Weitsman, G., Dolcetti, L., Mohamed, A.A., Vicencio, J.M., Galazi, M., Opzoomer, J.W., Arnold, J.N., Thavaraj, S., Kordasti, S., Doyle, Jana, Greenberg, Jon, Dillon, M.T., Harrington, K.J., Forster, M., Coolen, A.C.C., Ng, Tony, Mustapha, R., Flores-Borja, F., Alfano, G., Ng, K., Weitsman, G., Dolcetti, L., Mohamed, A.A., Vicencio, J.M., Galazi, M., Opzoomer, J.W., Arnold, J.N., Thavaraj, S., Kordasti, S., Doyle, Jana, Greenberg, Jon, Dillon, M.T., Harrington, K.J., Forster, M., Coolen, A.C.C., and Ng, Tony

Abstract

Contains fulltext : 288117.pdf (Publisher’s version ) (Open Access)

Published
2022

20. A Crohn's disease-associated IL2RA enhancer variant determines the balance of T cell immunity by regulating responsiveness to IL-2 signaling.

Author

Goldberg R., Clough J.N., Roberts L.B., Sanchez J., Kordasti S., Petrov N., Hertweck A., Lorenc A., Jackson I., Tasker S., Appios A., Omer O., Parkes M., Prescott N., Jenner R.G., Irving P.M., Lord G.M., Goldberg R., Clough J.N., Roberts L.B., Sanchez J., Kordasti S., Petrov N., Hertweck A., Lorenc A., Jackson I., Tasker S., Appios A., Omer O., Parkes M., Prescott N., Jenner R.G., Irving P.M., and Lord G.M.

Abstract

BACKGROUND AND AIMS: Differential responsiveness to interleukin (IL)-2 between effector CD4+ T cells (Teff) and regulatory T cells (Treg) is a fundamental mechanism of immunoregulation. The single nucleotide polymorphism rs61839660, located within IL2RA (CD25), has been associated with the development of Crohn's disease. We sought to identify the T cell immune phenotype of IBD patients who carry this SNP. METHOD(S): Teff and Treg were isolated from individuals homozygous (TT), heterozygous (CT) or wild type (CC) for the minor allele at rs61839660, and used for phenotyping (flow cytometry, Cytometry Time Of Flight) functional assays or T cell receptor (TCR) sequencing. Phosphorylation of signal transducer and activator of transcription 5 (STAT5) was assessed in response to IL-2, IL-7 and in the presence of basiliximab, a monoclonal antibody directed against CD25. Teff proinflammatory cytokine expression levels were assessed by reverse transcription quantitative polymerase chain reaction after IL-2 and/or TCR stimulation. RESULT(S): Presence of the minor T allele enhances CD25 expression leading to increased STAT5 phosphorylation and proinflammatory cytokine transcript expression by Teff in response to IL-2 stimulation in vitro. Teff from TT individuals demonstrate a more activated gut homing phenotype. TCR sequencing analysis suggests that TT patients may have a reduced clonal capacity to mount an optimal regulatory T cell response. CONCLUSION(S): rs61839660 regulates the responsiveness of T cells to IL-2 signaling by modulating CD25 expression. As low dose IL-2 is being trialed as a selective Treg modulator in CD, these findings highlight the potential for adverse effects in patients with this genotype.Copyright © The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn's and Colitis Organisation.

Published
2021

21. Flow cytometric analysis of myelodysplasia: Pre-analytical and technical issues-Recommendations from the European LeukemiaNet

Author

van der Velden, VHJ, Preijers, F, Johansson, U, Westers, TM, Dunlop, A, Porwit, A, Bene, MC, Valent, P, te Marvelde, J, Wagner-Ballon, O, Oelschlaegel, U, Saft, L, Kordasti, S, Ireland, R, Cremers, E, Alhan, C, Duetz, C, Hobo, W, Chapuis, N, Fontenay, M, Bettelheim, P, Eidenshink-Brodersen, L, Font, P, Loken, MR, Matarraz, S, Ogata, K, Orfao, A, Psarra, K, Subira, D, Wells, DA, Della Porta, MG, Burbury, K, Bellos, F, Weiss, E, Kern, W, van de Loosdrecht, A, van der Velden, VHJ, Preijers, F, Johansson, U, Westers, TM, Dunlop, A, Porwit, A, Bene, MC, Valent, P, te Marvelde, J, Wagner-Ballon, O, Oelschlaegel, U, Saft, L, Kordasti, S, Ireland, R, Cremers, E, Alhan, C, Duetz, C, Hobo, W, Chapuis, N, Fontenay, M, Bettelheim, P, Eidenshink-Brodersen, L, Font, P, Loken, MR, Matarraz, S, Ogata, K, Orfao, A, Psarra, K, Subira, D, Wells, DA, Della Porta, MG, Burbury, K, Bellos, F, Weiss, E, Kern, W, and van de Loosdrecht, A

Abstract

BACKGROUND: Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress has been made in the FCM field concerning technical issues (including software and hardware) and pre-analytical procedures. METHODS: Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group. RESULTS: We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies. CONCLUSIONS: These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice.

Published
2021

22. Clinical application of flow cytometry in patients with unexplained cytopenia and suspected myelodysplastic syndrome: A report of the European LeukemiaNet International MDS-Flow Cytometry Working Group

Author

Loosdrecht, AA, Kern, W, Porwit, A, Valent, P, Kordasti, S, Cremers, E, Alhan, C, Duetz, C, Dunlop, A, Hobo, W, Preijers, F, Wagner-Ballon, O, Chapuis, N, Fontenay, M, Bettelheim, P, Eidenschink-Brodersen, L, Font, P, Johansson, U, Loken, MR, Marvelde, JG, Matarraz, S, Ogata, K, Oelschlaegel, U, Orfao, A, Psarra, K, Subira, D, Wells, DA, Bene, MC, Della Porta, MG, Burbury, K, Bellos, F, van der Velden, VHJ, Westers, TM, Saft, L, Ireland, R, Loosdrecht, AA, Kern, W, Porwit, A, Valent, P, Kordasti, S, Cremers, E, Alhan, C, Duetz, C, Dunlop, A, Hobo, W, Preijers, F, Wagner-Ballon, O, Chapuis, N, Fontenay, M, Bettelheim, P, Eidenschink-Brodersen, L, Font, P, Johansson, U, Loken, MR, Marvelde, JG, Matarraz, S, Ogata, K, Oelschlaegel, U, Orfao, A, Psarra, K, Subira, D, Wells, DA, Bene, MC, Della Porta, MG, Burbury, K, Bellos, F, van der Velden, VHJ, Westers, TM, Saft, L, and Ireland, R

Abstract

This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients.

Published
2021

23. Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group

Author

Westers, T M, Ireland, R, Kern, W, Alhan, C, Balleisen, J S, Bettelheim, P, Burbury, K, Cullen, M, Cutler, J A, Della Porta, M G, Dräger, A M, Feuillard, J, Font, P, Germing, U, Haase, D, Johansson, U, Kordasti, S, Loken, M R, Malcovati, L, te Marvelde, J G, Matarraz, S, Milne, T, Moshaver, B, Mufti, G J, Ogata, K, Orfao, A, Porwit, A, Psarra, K, Richards, S J, Subirá, D, Tindell, V, Vallespi, T, Valent, P, van der Velden, V H J, de Witte, T M, Wells, D A, Zettl, F, Béné, M C, and van de Loosdrecht, A A

Published
2012
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26. Factors affecting COVID-19 outcomes in cancer patients: A first report from Guy’s Cancer Centre in London

Author

Russell, B, primary, Moss, C, additional, Papa, S, additional, Irshad, S, additional, Ross, P, additional, Spicer, J, additional, Kordasti, S, additional, Crawley, D, additional, Wylie, H, additional, Cahill, F, additional, Haire, A, additional, Zaki, K, additional, Rahman, F, additional, Sita-Lumsden, A, additional, Josephs, D, additional, Enting, D, additional, Lei, M, additional, Ghosh, S, additional, Harrison, C, additional, Swampillai, A, additional, Sawyer, E, additional, Dsouza, A, additional, Gomberg, S, additional, Fields, P, additional, Wrench, D, additional, Raj, K, additional, Gleeson, M, additional, Bailey, K, additional, Dillon, R, additional, Streetley, M, additional, Rigg, A, additional, Sullivan, R, additional, Dolly, S, additional, and Van Hemelrijck, M, additional

Published
2020
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30. Prospective study of rabbit antithymocyte globulin and ciclosporin for aplastic anemia from the EBMT Severe Aplastic Anemia Working Party

Author

Marsh JC, Bacigalupo A, Schrezenmeier H, Tichelli A, Passweg JR, Killick SB, Warren AJ, Foukaneli T, Aljurf M, Al Zahrani HA, Schafhausen P, Roth A, Franzke A, Brummendorf TH, Dufour C, Oneto R, Sedgwick P, Barrois A, Kordasti S, Elebute MO, Mufti GJ, Socie G., RISITANO, ANTONIO MARIA, Marsh, Jc, Bacigalupo, A, Schrezenmeier, H, Tichelli, A, Risitano, ANTONIO MARIA, Passweg, Jr, Killick, Sb, Warren, Aj, Foukaneli, T, Aljurf, M, Al Zahrani, Ha, Schafhausen, P, Roth, A, Franzke, A, Brummendorf, Th, Dufour, C, Oneto, R, Sedgwick, P, Barrois, A, Kordasti, S, Elebute, Mo, Mufti, Gj, and Socie, G.

Published
2012

32. Rationale for the clinical application of flow cytometry in patients with myelodysplastic syndromes: position paper of an International Consortium and the European LeukemiaNet Working Group

Author

Loosdrecht, A.A. van de, Ireland, R., Kern, W., Della Porta, M.G., Alhan, C., Balleisen, J.S., Bettelheim, P., Bowen, D.T., Burbury, K., Eidenschink, L., Cazzola, M., Chu, S.S., Cullen, M., Cutler, J.A., Drager, A.M., Feuillard, J., Fenaux, P., Font, P., Germing, U., Haase, D., Hellstrom-Lindberg, E., Johansson, U., Kordasti, S., Loken, M.R., Malcovati, L., Marvelde, J.G. Te, Matarraz, S., Milne, T., Moshaver, B., Mufti, G.J., Nikolova, V., Ogata, K., Oelschlaegel, U., Orfao, A., Ossenkoppele, G.J., Porwit, A., Platzbecker, U., Preijers, F.W.M.B., Psarra, K., Richards, S.J., Subira, D., Seymour, J.F., Tindell, V., Vallespi, T., Valent, P., Velden, V.H. van der, Wells, D.A., Witte, T.J.M. de, Zettl, F., Bene, M.C., Westers, T.M., Loosdrecht, A.A. van de, Ireland, R., Kern, W., Della Porta, M.G., Alhan, C., Balleisen, J.S., Bettelheim, P., Bowen, D.T., Burbury, K., Eidenschink, L., Cazzola, M., Chu, S.S., Cullen, M., Cutler, J.A., Drager, A.M., Feuillard, J., Fenaux, P., Font, P., Germing, U., Haase, D., Hellstrom-Lindberg, E., Johansson, U., Kordasti, S., Loken, M.R., Malcovati, L., Marvelde, J.G. Te, Matarraz, S., Milne, T., Moshaver, B., Mufti, G.J., Nikolova, V., Ogata, K., Oelschlaegel, U., Orfao, A., Ossenkoppele, G.J., Porwit, A., Platzbecker, U., Preijers, F.W.M.B., Psarra, K., Richards, S.J., Subira, D., Seymour, J.F., Tindell, V., Vallespi, T., Valent, P., Velden, V.H. van der, Wells, D.A., Witte, T.J.M. de, Zettl, F., Bene, M.C., and Westers, T.M.

Abstract

Item does not contain fulltext, An international working group within the European LeukemiaNet gathered, aiming to determine the role of flow cytometry (FC) in myelodysplastic syndromes (MDS). It was agreed that FC has a substantial application in disease characterization, diagnosis and prognosis. FC may also be useful in predicting treatment responses and monitoring novel and standard therapeutic regimens. In this article the rationale is discussed that flow cytometry should be integrated as a part of diagnostic and prognostic scoring systems in MDS.

Published
2013

33. Standardization of flow cytometry in myelodysplastic syndromes: a report from an international consortium and the European LeukemiaNet Working Group.

Author

Westers, T.M., Ireland, R., Kern, W., Alhan, C., Balleisen, J.S., Bettelheim, P., Burbury, K., Cullen, M., Cutler, J.A., Porta, M.G. Della, Drager, A.M., Feuillard, J., Font, P., Germing, U., Haase, D., Johansson, U., Kordasti, S., Loken, M.R., Malcovati, L., Marvelde, J.G. Te, Matarraz, S., Milne, T., Moshaver, B., Mufti, G.J., Ogata, K., Orfao, A., Porwit, A., Psarra, K., Richards, S.J., Subira, D., Tindell, V., Vallespi, T., Valent, P., Velden, V.H. van der, Witte, T.J.M. de, Wells, D.A., Zettl, F., Bene, M.C., Loosdrecht, A.A. van de, Westers, T.M., Ireland, R., Kern, W., Alhan, C., Balleisen, J.S., Bettelheim, P., Burbury, K., Cullen, M., Cutler, J.A., Porta, M.G. Della, Drager, A.M., Feuillard, J., Font, P., Germing, U., Haase, D., Johansson, U., Kordasti, S., Loken, M.R., Malcovati, L., Marvelde, J.G. Te, Matarraz, S., Milne, T., Moshaver, B., Mufti, G.J., Ogata, K., Orfao, A., Porwit, A., Psarra, K., Richards, S.J., Subira, D., Tindell, V., Vallespi, T., Valent, P., Velden, V.H. van der, Witte, T.J.M. de, Wells, D.A., Zettl, F., Bene, M.C., and Loosdrecht, A.A. van de

Abstract

1 juli 2012, Item does not contain fulltext, Flow cytometry (FC) is increasingly recognized as an important tool in the diagnosis and prognosis of myelodysplastic syndromes (MDS). However, validation of current assays and agreement upon the techniques are prerequisites for its widespread acceptance and application in clinical practice. Therefore, a working group was initiated (Amsterdam, 2008) to discuss and propose standards for FC in MDS. In 2009 and 2010, representatives from 23, mainly European, institutes participated in the second and third European LeukemiaNet (ELN) MDS workshops. In the present report, minimal requirements to analyze dysplasia are refined. The proposed core markers should enable a categorization of FC results in cytopenic patients as 'normal', 'suggestive of', or 'diagnostic of' MDS. An FC report should include a description of validated FC abnormalities such as aberrant marker expression on myeloid progenitors and, furthermore, dysgranulopoiesis and/or dysmonocytopoiesis, if at least two abnormalities are evidenced. The working group is dedicated to initiate further studies to establish robust diagnostic and prognostic FC panels in MDS. An ultimate goal is to refine and improve diagnosis and prognostic scoring systems. Finally, the working group stresses that FC should be part of an integrated diagnosis rather than a separate technique.

Published
2012

36. 137 Standardization of flow cytometry in myelodysplastic syndromes: A report from an international consortium and the European LeukemiaNet Working Group

Author

Westers, T.M., primary, Ireland, R., additional, Kern, W., additional, Alhan, C., additional, Balleisen, J.S., additional, Béné, M.C., additional, Bettelheim, P., additional, Burbury, K., additional, Cullen, M., additional, Cutler, J.A., additional, Porta, M.G. Della, additional, Drager, A.M., additional, Feuillard, J., additional, Font, P., additional, Germing, U., additional, Haase, D., additional, Johansson, U., additional, Kordasti, S., additional, Loken, M.R., additional, Malcovati, L., additional, te Marvelde, J.G., additional, Matarraz, S., additional, Milne, T., additional, Moshaver, B., additional, Mufti, G.J., additional, Ogata, K., additional, Orfao, A., additional, Porwit, A., additional, Psarra, K., additional, Richards, S.J., additional, Subirá, D., additional, Tindell, V., additional, Vallespi, T., additional, Valent, P., additional, van der Velden, V.H., additional, de Witte, T.M., additional, Wells, D.A., additional, Zettl, F., additional, and van de Loosdrecht, A.A., additional

Published
2011
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37. Imbalance of effector and regulatory CD4 T cells is associated with graft-versus-host disease after hematopoietic stem cell transplantation using a reduced intensity conditioning regimen and alemtuzumab

Author

Matthews, K., primary, Lim, Z., additional, Afzali, B., additional, Pearce, L., additional, Abdallah, A., additional, Kordasti, S., additional, Pagliuca, A., additional, Lombardi, G., additional, Madrigal, J. A., additional, Mufti, G. J., additional, and Barber, L. D., additional

Published
2009
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40. 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

41. 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

43. Data-driven, harmonised classification system for myelodysplastic syndromes: a consensus paper from the International Consortium for Myelodysplastic Syndromes.

Author

Komrokji RS, Lanino L, Ball S, Bewersdorf JP, Marchetti M, Maggioni G, Travaglino E, Al Ali NH, Fenaux P, Platzbecker U, Santini V, Diez-Campelo M, Singh A, Jain AG, Aguirre LE, Tinsley-Vance SM, Schwabkey ZI, Chan O, Xie Z, Brunner AM, Kuykendall AT, Bennett JM, Buckstein R, Bejar R, Carraway HE, DeZern AE, Griffiths EA, Halene S, Hasserjian RP, Lancet J, List AF, Loghavi S, Odenike O, Padron E, Patnaik MM, Roboz GJ, Stahl M, Sekeres MA, Steensma DP, Savona MR, Taylor J, Xu ML, Sweet K, Sallman DA, Nimer SD, Hourigan CS, Wei AH, Sauta E, D'Amico S, Asti G, Castellani G, Delleani M, Campagna A, Borate UM, Sanz G, Efficace F, Gore SD, Kim TK, Daver N, Garcia-Manero G, Rozman M, Orfao A, Wang SA, Foucar MK, Germing U, Haferlach T, Scheinberg P, Miyazaki Y, Iastrebner M, Kulasekararaj A, Cluzeau T, Kordasti S, van de Loosdrecht AA, Ades L, Zeidan AM, and Della Porta MG

Abstract

The WHO and International Consensus Classification 2022 classifications of myelodysplastic syndromes enhance diagnostic precision and refine decision-making processes in these diseases. However, some discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. We adopted a data-driven approach to provide a harmonisation between these two classification systems. We investigated the importance of genomic features and their effect on the cluster assignment process to define harmonised entity labels. A panel of expert haematologists, haematopathologists, and data scientists who are members of the International Consortium for Myelodysplastic Syndromes was formed and a modified Delphi consensus process was adopted to harmonise morphologically defined categories without a distinct genomic profile. The panel held regular online meetings and participated in a two-round survey using an online voting tool. We identified nine clusters with distinct genomic features. The cluster of highest hierarchical importance was characterised by biallelic TP53 inactivation. Cluster assignment was irrespective of blast count. Individuals with monoallelic TP53 inactivation were assigned to other clusters. Hierarchically, the second most important group included myelodysplastic syndromes with del(5q). Isolated del(5q) and less than 5% of blast cells in the bone marrow were the most relevant label-defining features. The third most important cluster included myelodysplastic syndromes with mutated SF3B1. The absence of isolated del(5q), del(7q)/-7, abn3q26.2, complex karyotype, RUNX1 mutations, or biallelic TP53 were the basis for a harmonised label of this category. Morphologically defined myelodysplastic syndrome entities showed large genomic heterogeneity that was not efficiently captured by single-lineage versus multilineage dysplasia, marrow blasts, hypocellularity, or fibrosis. We investigated the biological continuum between myelodysplastic syndromes with more than 10% bone marrow blasts and acute myeloid leukaemia, and found only a partial overlap in genetic features. After the survey, myelodysplastic syndromes with low blasts (ie, less than 5%) and myelodysplastic syndromes with increased blasts (ie, 5% or more) were recognised as disease entities. Our data-driven approach can efficiently harmonise current classifications of myelodysplastic syndromes and provide a reference for patient management in a real-world setting., Competing Interests: Declaration of interests UG reports speaker honoraria from Novartis, AbbVie, and BMS; and institutional research support from BMS, AbbVie, and Jazz Pharmaceuticals. FE reports consultancy or advisory roles for AbbVie, Incyte, Syros, Novartis, and Jazz Pharmaceuticals. SH reports research support from STORM Therapeutics and AstraZeneca. EAG reports honoraria from AAMDS, MedscapeLIVE!, MediCom Worldwide, MJH Life Sciences, ASH, MDS International Foundation, and Physicians’ Education Resource; consulting fees from AbbVie, Alexion, Apellis, Takeda Oncology, Astex/Taiho Oncology, Alexion/AstraZeneca Rare Disease, Celgene/BMS, CTI BioPharma, Novartis, Partner Therapeutics, Picnic Health, and Servier; and research funding from Alexion, Apellis, Astex /Otsuka/Taiho Oncology, Blueprint Medicines, Celldex Therapeutics, Genentech, and NextCure. MAS reports participation on advisory boards for BMS, Kurome, Schrödinger, and Karyopharm. MD-C reports participation on a data safety monitoring board or advisory board for BMS, Novartis, Blueprint Medicines, GSK, Agios, Hemavan, Syros, Keros, Curis, and Astex/Otsuka; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events for BMS, Novartis, and Keros. UP reports research support and honoraria from BMS, Geron, Curis, AbbVie, and Janssen. RBe reports employment or equity from Aptose Biosciences; participation on advisory boards for BMS, Servier, NeoGenomics, and Geron; being Data Monitoring Committee Chair for Gilead, Ipsen, and Keros; and consultancy for TenSixteen. YM reports honoraria from Nippon Shinyaku, BMS, Novartis, Sumitomo Pharma, Kyowa Kirin, AbbVie, Daiichi Sankyo, Takeda, Janssen, Astellas, Pfizer, Eisai, and Otsuka; and research funding from Chugai. AED reports participation on advisory boards, consultancy, or honoraria from Celgene/BMS, Agios, Novartis, Astellas, and Gilead; and participation on clinical trial committees or data safety monitoring boards for Novartis, AbbVie, Kura, Geron, Servier, Keros, and Celgene/BMS. DPS reports employment by Ajax Therapeutics; former employment by Novartis; and minor equity in Arrowhead and Bluebird. TKK reports consultancy for Agenus and ImmunoBiome. AK reports research support from Novartis and BMS; consulting fees from Alexion, Novartis, Amgen, Agios, Pfizer, Samsung, Celgene, F Hoffmann-La Roche, and Sobi; honoraria from Alexion, Novartis, Pfizer, Amgen, Samsung, Celgene, F Hoffmann-La Roche, BMS, Sobi, and Silence Therapeutics; and speakers fees from Alexion, Novartis, Amgen, Pfizer, Celgene, F Hoffmann-La Roche, and Sobi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Published
2024
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44. Identification of an immune-related genes signature in lung adenocarcinoma to predict survival and response to immune checkpoint inhibitors.

Author

Davoodi-Moghaddam Z, Jafari-Raddani F, Kordasti S, and Bashash D

Subjects
Humans, Prognosis, Male, Female, Biomarkers, Tumor genetics, Middle Aged, Lymphocytes, Tumor-Infiltrating immunology, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Aged, Transcriptome, Mutation, Computational Biology methods, Immune Checkpoint Inhibitors therapeutic use, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung mortality, Adenocarcinoma of Lung immunology, Adenocarcinoma of Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms mortality, Lung Neoplasms immunology, Lung Neoplasms pathology
Abstract

Background: Although advances in immune checkpoint inhibitor (ICI) research have provided a new treatment approach for lung adenocarcinoma (LUAD) patients, their survival is still unsatisfactory, and there are issues in the era of response prediction to immunotherapy., Methods: Using bioinformatics methods, a prognostic signature was constructed, and its predictive ability was validated both in the internal and external datasets (GSE68465). We also explored the tumor-infiltrating immune cells, mutation profiles, and immunophenoscore (IPS) in the low-and high-risk groups., Results: As far as we are aware, this is the first study which introduces a novel prognostic signature model using BIRC5, CBLC, S100P, SHC3, ANOS1, VIPR1, LGR4, PGC, and IGKV4.1. According to multivariate analysis, the 9-immune-related genes (IRGs) signature provided an independent prognostic factor for the overall survival (OS). The low-risk group had better OS, and the tumor mutation burden (TMB) was significantly lower in this group. Moreover, the risk scores were negatively associated with the tumor-infiltrating immune cells, like CD8 + T cells, macrophages, dendritic cells, and NK cells. In addition, the IPS were significantly higher in the low-risk group as they had higher gene expression of immune checkpoints, suggesting that ICIs could be a promising treatment option for low-risk LUAD patients., Conclusion: The combination of these 9-IRGs not only could efficiently predict overall survival of LUAD patients but also show a powerful association with the expression of immune checkpoints and response to ICIs based on IPS; hoping this model paves the way for better stratification and management of patients in clinical practice., (© 2024. The Author(s).)

Published
2024
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45. ImmCellTyper facilitates systematic mass cytometry data analysis for deep immune profiling.

Author

Sun J, Choy D, Sompairac N, Jamshidi S, Mishto M, and Kordasti S

Subjects
Humans, Software, Cluster Analysis, Flow Cytometry methods, Single-Cell Analysis methods, Data Analysis
Abstract

Mass cytometry is a cutting-edge high-dimensional technology for profiling marker expression at the single-cell level, advancing clinical research in immune monitoring. Nevertheless, the vast data generated by cytometry by time-of-flight (CyTOF) poses a significant analytical challenge. To address this, we describe ImmCellTyper (https://github.com/JingAnyaSun/ImmCellTyper), a novel toolkit for CyTOF data analysis. This framework incorporates BinaryClust, an in-house developed semi-supervised clustering tool that automatically identifies main cell types. BinaryClust outperforms existing clustering tools in accuracy and speed, as shown in benchmarks with two datasets of approximately 4 million cells, matching the precision of manual gating by human experts. Furthermore, ImmCellTyper offers various visualisation and analytical tools, spanning from quality control to differential analysis, tailored to users' specific needs for a comprehensive CyTOF data analysis solution. The workflow includes five key steps: (1) batch effect evaluation and correction, (2) data quality control and pre-processing, (3) main cell lineage characterisation and quantification, (4) in-depth investigation of specific cell types; and (5) differential analysis of cell abundance and functional marker expression across study groups. Overall, ImmCellTyper combines expert biological knowledge in a semi-supervised approach to accurately deconvolute well-defined main cell lineages, while maintaining the potential of unsupervised methods to discover novel cell subsets, thus facilitating high-dimensional immune profiling., Competing Interests: JS, DC, NS, SJ, MM, SK No competing interests declared, (© 2024, Sun, Choy et al.)

Published
2024
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46. Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes.

Author

Tentori CA, Gregorio C, Robin M, Gagelmann N, Gurnari C, Ball S, Caballero Berrocal JC, Lanino L, D'Amico S, Spreafico M, Maggioni G, Travaglino E, Sauta E, Meggendorfer M, Zhao LP, Campagna A, Savevski V, Santoro A, Al Ali N, Sallman D, Sole F, Garcia-Manero G, Germing U, Kroger N, Kordasti S, Santini V, Sanz G, Kern W, Platzbecker U, Diez-Campelo M, Maciejewski JP, Ades L, Fenaux P, Haferlach T, Zeidan AM, Castellani G, Komrokji R, Ieva F, and Della Porta MG

Subjects
Humans, Middle Aged, Male, Retrospective Studies, Female, Aged, Adult, Time Factors, Decision Support Systems, Clinical, Genomics, Decision Support Techniques, Risk Assessment, Young Adult, Myelodysplastic Syndromes therapy, Myelodysplastic Syndromes genetics, Hematopoietic Stem Cell Transplantation methods, Transplantation, Homologous
Abstract

Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M)., Patients and Methods: We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies., Results: Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy ( P = .001)., Conclusion: These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

Published
2024
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47. Development of a natural language processing pipeline for assessment of cardiovascular risk in myeloproliferative neoplasms.

Author

Duminuco A, Au Yeung J, Vaghela R, Virdee S, Woodley C, Asirvatham S, Curto-Garcia N, Sriskandarajah P, O'Sullivan J, de Lavallade H, Radia D, Kordasti S, Palumbo G, Harrison C, and Harrington P

Abstract

Competing Interests: Hugues de Lavallade has received research grants and honoraria from Incyte and honoraria from Novartis and Pfizer. Claire Harrison has received speaker fees from Novartis, Jannsen, CTI, Celgene, Medscape and has served on the Advisory Board for Incyte, CTI, Sierra Oncology, Novartis, Celgene, Roche, AOP pharma, Geron and Astra Zenica, and is an Editor of HemaSphere. Patrick Harrington has received research funding from GSK, BMS, Novartis, Incyte, AOP, and Constellation and honoraria from GSK, Incyte, and Novartis.

Published
2024
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48. Mutations in the splicing factor SF3B1 are linked to frequent emergence of HLA-DR low/neg monocytes in lower-risk myelodysplastic neoplasms.

Author

Winter S, Schneider M, Oelschlaegel U, Maggioni G, Riva E, Raddi MG, Bencini S, Peruzzi B, Choy D, Antunes Dos Reis R, Güse E, Lischer C, Vera J, Timms JA, Sompairac N, Sockel K, Poloni A, Tunger A, Della Porta MG, Santini V, Schmitz M, Platzbecker U, and Kordasti S

Subjects
Humans, RNA Splicing Factors genetics, Myelodysplastic Syndromes genetics, Monocytes metabolism, Phosphoproteins genetics, Mutation, HLA-DR Antigens genetics
Published
2024
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49. Immune-monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium.

Author

Tentori CA, Zhao LP, Tinterri B, Strange KE, Zoldan K, Dimopoulos K, Feng X, Riva E, Lim B, Simoni Y, Murthy V, Hayes MJ, Poloni A, Padron E, Cardoso BA, Cross M, Winter S, Santaolalla A, Patel BA, Groarke EM, Wiseman DH, Jones K, Jamieson L, Manogaran C, Daver N, Gallur L, Ingram W, Ferrell PB, Sockel K, Dulphy N, Chapuis N, Kubasch AS, Olsnes AM, Kulasekararaj A, De Lavellade H, Kern W, Van Hemelrijck M, Bonnet D, Westers TM, Freeman S, Oelschlaegel U, Valcarcel D, Raddi MG, Grønbæk K, Fontenay M, Loghavi S, Santini V, Almeida AM, Irish JM, Sallman DA, Young NS, van de Loosdrecht AA, Adès L, Della Porta MG, Cargo C, Platzbecker U, and Kordasti S

Abstract

Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies., Competing Interests: Shahram Kordasti: Novartis: Advisory Board, Speakers bureau, Alexion: Speakers bureau, Beckman Coulter: Speakers bureau, MorphoSys: Research Support (none is related to this publication). Wolfgang Kern declares part‐ownership of MLL Munich Leukemia Laboratory. Austin Kulasekararaj: Research support (to institution): Celgene/BMS and Novartis. Speaker's fees: Alexion/AstraZeneca, Akari, Apellis, Celgene/BMS, Novartis, Pfizer, Ra Pharma/UCB, Roche, SOBI. Scientific advisory board: Alexion/Astra Zeneca, Apellis, Amgen, Agios, Biocryst, Celgene/BMS, Novartis, Pfizer, Regeneron, Roche, SOBI, Janssen, Samsung and Novo Nordisk (none is related to this publication)., (© 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Published
2024
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50. Uncommon Presentation of Sarcoidosis with Severe Thrombocytopenia and Hemorrhagic Diathesis.

Author

Lame D, Pianelli M, Kordasti S, Morsia E, Olivieri A, and Poloni A

Abstract

Sarcoidosis, a multi-organ system disease, often presents insidiously. Thrombocytopenia in sarcoidosis is frequent because of hypersplenism, granulomas infiltrating the bone marrow, or immune thrombocytopenia (ITP). The diagnosis of ITP relies on exclusionary criteria, given the absence of a definitive laboratory diagnostic feature. In the era prior to modern ITP management, sarcoidosis-associated ITP was known to manifest severely, often showing resistance to treatment and an increased risk of mortality. In this case, we present a young male who was admitted to a district hospital's emergency room, displaying symptoms of hematuria, gingival bleeding, and a petechial rash. Blood tests revealed severe thrombocytopenia with a platelet count of 0, while all other metabolic and serological exams returned normal results. Infectious and autoimmune causes were ruled out, and a bone marrow examination excluded any hematological disorder. Initial management, including platelet transfusion and presumptive treatment for ITP with dexamethasone and Human Immunoglobulin IV (IVIG), failed to improve the patient's platelet count or alleviate the hemorrhagic diathesis. Second-line therapy with Rituximab and Methylprednisolone was initiated with no benefit. Considering the hemorrhagic signs and the delayed response of Rituximab, we shifted to third-line therapy with Romiplostim at the maximal dose and continued Methylprednisolone. The platelet count recovered completely after the second Romiplostim administration (over 350 × 10 9 platelets/L) and Methylprednisolone was rapidly tapered. To further study the causes of thrombocytopenia a total body CT scan was performed and it identified non-homogeneously hypodense tissue in the bilateral hilar area extending medially to the subcarinal area, suggesting possible lymphatic origin and raising suspicion of sarcoidosis. Further investigations, including Angiotensin Converting Enzyme (ACE) titration, bronchoscopy, bronchoalveolar lavage, and EndoBronchial UltraSound-guided TransBronchial Needle Aspiration (EBUS-TBNA), confirmed the diagnosis of sarcoidosis. Despite a mild restrictive insufficiency noted in spirometry, the patient remained asymptomatic with only a mild respiratory insufficiency, and hence, was enlisted for follow-up. As for the ITP, the platelet count remained normal over a year. Notably, while sarcoidosis onset often predates ITP onset by an average of 48 months, in our case the onset of the two diseases was simultaneously. Our case adds valuable information to the limited body of knowledge regarding the treatment of sarcoidosis-associated ITP.

Published
2024
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