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.)

Cancer Center Humanitas Research Hospital and Humanitas University Milan

Chang Gung Memorial Hospital at Linkou Chang Gung University Taiwan

CIBERONC Instituto de Salud Carlos 3 Madrid

Clinics of Hematology and Medical Oncology University Medical Center Göttingen Germany

Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York

Department of Genomics Institute of Hematology and Blood Transfusion Prague Czech Republic

Department of Hematology Amsterdam University Medical Center Vrije University Medical Center Amsterdam

Department of Hematology and Genetics Unit University Hospital La Fe Valencia Spain

Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan

Department of Hematology Assistance Publique Hôpitaux de Paris Hôpital Cochin and Université de Paris Université Paris Descartes Paris

Department of Hematology Atomic Bomb Disease Institute Nagasaki University Nagasaki Japan

Department of Hematology Democritus University of Thrace Medical School Alexandroupolis Greece

Department of Hematology Faculty of Medicine University of Tsukuba Tsukuba Japan

Department of Hematology Gifu Municipal Hospital Gifu Japan

Department of Hematology Hemostasis Oncology and Stem Cell Transplantation Hannover Medical School Hannover Germany

Department of Hematology Hôpital St Louis and Paris University Paris

Department of Hematology Hospital Universitario y Politécnico La Fe Valencia Spain

Department of Hematology Kobe City Medical Center General Hospital Kobe Japan

Department of Hematology Oncology and Clinical Immunology Heinrich Heine University Düsseldorf Germany

Department of Medical Oncology Howard Hughes Medical Institute Dana Farber Cancer Center Boston

Department of Medicine Center for Hematology and Regenerative Medicine Karolinska Institute Stockholm

Department of Medicine Huddinge Center for Hematology and Regenerative Medicine Karolinska Institutet Karolinska University Hospital Stockholm

Department of Medicine Memorial Sloan Kettering Cancer Center New York

Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt University School of Medicine Nashville

Department of Pathology and Tumor Biology Kyoto University Kyoto Japan

Department of Pathology Massachusetts General Hospital Boston

Division of Hematology and Hemostaseology Department of Internal Medicine 1 Medical University of Vienna Vienna

Division of Hematopoietic Disease Control Institute of Medical Science University of Tokyo Tokyo

Drug Research and Development Center Federal University of Ceara Ceara Brazil

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia Pavia Italy

Health Research Institute La Fe Valencia Spain

Hematology Department Hospital Germans Trias i Pujol Institut Català d'Oncologia Josep Carreras Leukaemia Research Institute Barcelona

Institute for the Advanced Study of Human Biology Kyoto University Kyoto Japan

Institute of Hematology Seràgnoli Istituti di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Integrated Genomics Operation Memorial Sloan Kettering Cancer Center New York

Laboratory of Hematology Department of Laboratory Medicine Radboud University Medical Centre Nijmegen The Netherlands

Ludwig Boltzmann Institute for Hematology and Oncology Medical University of Vienna Vienna

Medical Clinic and Policlinic 1 Hematology and Cellular Therapy University of Leipzig Leipzig Germany

Myelodysplastic syndromes Cooperative Group Gruppo Laziale Mielodisplasie Department of Biomedicine and Prevention Tor Vergata University Rome

Myelodysplastic Syndromes Group Institut de Recerca Contra la Leucèmia Josep Carreras Barcelona

Myelodysplastic syndromes Unit Department of Experimental and Clinical Medicine Hematology Azienda Ospedaliero Universitaria Careggi University of Florence Florence Italy

Oncology Hematology Center Hospital Israelita Albert Einstein São Paulo

Radcliffe Department of Medicine Oxford BRC Haematology Theme University of Oxford Oxford United Kingdom

Stanford University Cancer Institute Stanford CA

Tokyo Medical University Tokyo

University of California San Diego Moores Cancer Center La Jolla CA

Citace poskytuje Crossref.org

Survival and quality of life in patients with lower risk myelodysplastic syndromes exposed to erythropoiesis-stimulating agents: an observational cohort study

Somatic mutations and DNA methylation identify a subgroup of poor prognosis within lower-risk myelodysplastic syndromes

Molecular taxonomy of myelodysplastic syndromes and its clinical implications

Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa

Expression of circular RNAs in myelodysplastic neoplasms and their association with mutations in the splicing factor gene SF3B1