Molecular International Prognostic Scoring System for Myelodysplastic Syndromes
Open accessAbstract
BACKGROUND: Risk stratification and therapeutic decision-making for myelodysplastic syndromes (MDS) are based on the International Prognostic Scoring System–Revised (IPSS-R), which considers hematologic parameters and cytogenetic abnormalities. Somatic gene mutations are not yet used in the risk stratification of patients with MDS. METHODS: To develop a clinical-molecular prognostic model (IPSS-Molecular [IPSS-M]), pretreatment diagnostic or peridiagnostic samples from 2957 patients with MDS were profiled for mutations in 152 genes. Clinical and molecular variables were evaluated for associations with leukemia-free survival, leukemic transformation, and overall survival. Feature selection was applied to determine the set of independent IPSS-M prognostic variables. The relative weights of the selected variables were estimated using a robust Cox multivariable model adjusted for confounders. The IPSS-M was validated in an external cohort of 754 Japanese patients with MDS. RESULTS: We mapped at least one oncogenic genomic alteration in 94% of patients with MDS. Multivariable analysis identified TP53multihit, FLT3 mutations, and MLLPTD as top genetic predictors of adverse outcomes. Conversely, SF3B1 mutations were associated with favorable outcomes, but this was modulated by patterns of comutation. Using hematologic parameters, cytogenetic abnormalities, and somatic mutations of 31 genes, the IPSS-M resulted in a unique risk score for individual patients. We further derived six IPSS-M risk categories with prognostic differences. Compared with the IPSS-R, the IPSS-M improved prognostic discrimination across all clinical end points and restratified 46% of patients. The IPSS-M was applicable in primary and secondary/therapy-related MDS. To simplify clinical use of the IPSS-M, we developed an open-access Web calculator that accounts for missing values. CONCLUSIONS: Combining genomic profiling with hematologic and cytogenetic parameters, the IPSS-M improves the risk stratification of patients with MDS and represents a valuable tool for clinical decision-making. (Funded by Celgene Corporation through the MDS Foundation, the Josie Robertson Investigators Program, the Edward P. Evans Foundation, the Projects of National Relevance of the Italian Ministry of University and Research, Associazione Italiana per la Ricerca sul Cancro, the Japan Agency for Medical Research and Development, Cancer Research UK, the Austrian Science Fund, the MEXT [Japanese Ministry of Education, Culture, Sports, Science and Technology] Program for Promoting Research on the Supercomputer Fugaku, the Japan Society for the Promotion of Science, the Taiwan Department of Health, and Celgene Corporation through the MDS Foundation.)
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A recent study identified 92% of TP53 mutant MDS/AML patients to represent a poor risk population.
“with a recent study identifying 92% of TP53 mutant MDS/AML patients to represent a poor risk population.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [13]
There is a strong interplay between VAF, allelic state, and cytogenetic complexity predicting outcomes in mTP53 MDS/AML.
“there is a very strong interplay between VAF, allelic state, and cytogenetic complexity strongly predicting outcomes in this molecular subset”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [13]
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- Authors
- Bernard, E., Tuechler, H., Greenberg, P. L., Hasserjian, R. P., Arango Ossa, J. E., Nannya, Y., Devlin, S. M., Creignou, M., Pinel, P., Monnier, L., Gundem, G., Medina-Martinez, J. S., Domenico, D., Jädersten, M., Germing, U., Sanz, G., van de Loosdrecht, A. A., Kosmider, O., Follo, M. Y., Thol, F., Zamora, L., Pinheiro, R. F., Pellagatti, A., Elias, H. K., Haase, D., Ganster, C., Ades, L., Tobiasson, M., Palomo, L., Della Porta, M. G., Takaori-Kondo, A., Ishikawa, T., Chiba, S., Kasahara, S., Miyazaki, Y., Viale, A., Huberman, K., Fenaux, P., Belickova, M., Savona, M. R., Klimek, V. M., Santos, F. P. S., Boultwood, J., Kotsianidis, I., Santini, V., Solé, F., Platzbecker, U., Heuser, M., Valent, P., Ohyashiki, K., Finelli, C., Voso, M. T., Shih, L.-Y., Fontenay, M., Jansen, J. H., Cervera, J., Gattermann, N., Ebert, B. L., Bejar, R., Malcovati, L., Cazzola, M., Ogawa, S., Hellström-Lindberg, E., & Papaemmanuil, E.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Stanford Cancer Institute (US)
- Massachusetts General Hospital (US)
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York
- Kyoto University (JP)
- Karolinska University Hospital (SE)
- Heinrich Heine University Düsseldorf (DE)
- Instituto de Salud Carlos III (ES)
- Department of Hematology, Amsterdam University Medical Center, Vrije University Medical Center, Amsterdam
- Université Paris Cité (FR)
- University of Bologna (IT)
- Medizinische Hochschule Hannover (DE)
- Josep Carreras Leukaemia Research Institute (ES)
- Universidade Federal do Ceará (BR)
- University of Oxford (GB)
- Universitätsmedizin Göttingen (DE)
- Department of Hematology, Hôpital St Louis, and Paris University, Paris
- Cancer Center, Humanitas Research Hospital & Humanitas University, Milan
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Kobe City Medical Center General Hospital (JP)
- University of Tsukuba (JP)
- Gifu Municipal Hospital (JP)
- Nagasaki University (JP)
- Hôpital Saint-Louis (FR)
- Department of Genomics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic
- Vanderbilt University (US)
- Oncology-Hematology Center, Hospital Israelita Albert Einstein, São Paulo
- Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece
- Azienda Ospedaliero-Universitaria Careggi (IT)
- Leipzig University (DE)
- Ludwig Boltzmann Institute for Hematology and Oncology (AT)
- Tokyo Medical University (JP)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Rome Tor Vergata (IT)
- Chang Gung University (TW)
- Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin and Université de Paris, Université Paris Descartes, Paris
- Radboud University Medical Center (NL)
- Hospital Universitari i Politècnic La Fe (ES)
- Howard Hughes Medical Institute (US)
- Moores Cancer Center (US)
- University of Pavia (IT)
- Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm
- ORCID
- Bernard, Elsa
- Tuechler, Heinz
- Greenberg, Peter L.
- Hasserjian, Robert P.
- Nannya, Yasuhito
- Devlin, Sean M.
- Creignou, Maria
- Gundem, Gunes
- Medina-Martinez, Juan S.
- Domenico, Dylan
- Jädersten, Martin
- Germing, Ulrich
- Sanz, Guillermo
- Kosmider, Olivier
- Follo, Matilde Y.
- Thol, Felicitas
- Zamora, Lurdes
- Pinheiro, Ronald F.
- Pellagatti, Andrea
- Elias, Harold K.
- Ganster, Christina
- Tobiasson, Magnus
- Palomo, Laura
- Ishikawa, Takayuki
- Chiba, Shigeru
- Kasahara, Senji
- Miyazaki, Yasushi
- Viale, Agnes
- Huberman, Kety
- Fenaux, Pierre
- Savona, Michael R.
- Boultwood, Jacqueline
- Santini, Valeria
- Solé, Francesc
- Platzbecker, Uwe
- Heuser, Michael
- Valent, Peter
- Ohyashiki, Kazuma
- Finelli, Carlo
- Voso, Maria Teresa
- Shih, Lee-Yung
- Jansen, Joop H.
- Cervera, José
- Gattermann, Norbert
- Ebert, Benjamin L.
- Bejar, Rafael
- Malcovati, Luca
- Cazzola, Mario
- Ogawa, Seishi
- Papaemmanuil, Elli
- Venue
- NEJM Evidence
- Publisher
- Massachusetts Medical Society
- Published
- 2022-06-28
- Volume
- 1
- Issue
- 7
- Pages
- EVIDoa2200008-EVIDoa2200008
- ISSN
- 2766-5526 (ISSN-L)
- OpenAlex
- W4281727476
- Cited by
- 867
- References
- 25
- Citations by year
- 2026: 162 · 2025: 216 · 2024: 195 · 2023: 216 · 2022: 75
- FWCI
- 127.99
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- NEJM Evidence (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, other-oa)
- Funders
- Japan Society for the Promotion of Science (19H05656)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Epidemiology › Multiple and Secondary Primary Cancers
- Keywords
- myelodysplastic syndrome, IPSS-M, International Prognostic Scoring System, risk stratification, somatic mutations, FLT3 mutation, SF3B1 mutation, leukemia-free survival, leukemic transformation, overall survival, therapy-related MDS, prognostic model, feature selection, Japanese patients
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Humans, Japan, Male, Middle Aged, Mutation, Myelodysplastic Syndromes, Prognosis, Risk Assessment
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