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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.

Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication., Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed., Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations ( SF3B1 , SRSF2 , and U2AF1 ) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1 - and SRSF2 -related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features., Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis., Competing Interests: Manja MeggendorferEmployment: MLL Munich Leukemia Laboratory Marianna RossiConsulting or Advisory Role: Pfizer, Celgene, IQvia, Janssen Emanuele AngelucciHonoraria: Celgene, Vertex Pharmaceuticals Incorporated (MA) and CRISPR Therapeutics AG (CH)Consulting or Advisory Role: Novartis, Bluebird BioTravel, Accommodations, Expenses: Janssen-Cilag Massimo BernardiHonoraria: CelgeneConsulting or Advisory Role: PfizerTravel, Accommodations, Expenses: Medac, Amgen, Sanofi, Jazz Pharmaceuticals, BioTest, Abbvie, Takeda Lorenza BorinLeadership: CelgeneSpeakers' Bureau: GenzymeTravel, Accommodations, Expenses: Genzyme Benedetto BrunoHonoraria: Jazz Pharmaceuticals, Novartis, AmgenResearch Funding: Amgen Valeria SantiniHonoraria: Celgene/Bristol-Myers Squibb, Novartis, Janssen-CilagConsulting or Advisory Role: Celgene/Bristol-Myers Squibb, Novartis, Menarini, Takeda, PfizerResearch Funding: CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Celgene Andrea BacigalupoHonoraria: Pfizer, Therakos, Novartis, Sanofi, Jazz Pharmaceuticals, Riemser, Merck Sharp & Dohme, Janssen-Cilag, Gilead Sciences, Kiadis Pharma, Astellas PharmaConsulting or Advisory Role: Novartis, Kiadis Pharma, Gilead Sciences, Astellas PharmaSpeakers' Bureau: Pfizer, Therakos, Novartis, Sanofi, Riemser, Merck Sharp & Dohme, Adienne, Jazz PharmaceuticalsTravel, Accommodations, Expenses: Sanofi, Therakos, Jazz Pharmaceuticals Maria Teresa VosoHonoraria: Celgene/Jazz, AbbvieConsulting or Advisory Role: Celgene/JazzSpeakers' Bureau: CelgeneResearch Funding: Celgene Esther OlivaHonoraria: Celgene, Novartis, Amgen, Alexion PharmaceuticalsConsulting or Advisory Role: Amgen, Celgene, NovartisSpeakers' Bureau: Celgene, NovartisPatents, Royalties, Other Intellectual Property: Royalties for QOL-E instrument Francesco PassamontiSpeakers' Bureau: Novartis, AOP Orphan Pharmaceuticals Niccolò BolliConsulting or Advisory Role: JanssenSpeakers' Bureau: Celgene, Amgen Alessandro RambaldiHonoraria: Amgen, OmerosConsulting or Advisory Role: Amgen, Omeros, Novartis, Astellas Pharma, Jazz PharmaceuticalsTravel, Accommodations, Expenses: Celgene Wolfgang KernEmployment: MLL Munich Leukemia LaboratoryLeadership: MLL Munich Leukemia LaboratoryStock and Other Ownership Interests: MLL Munich Leukemia Laboratory Shahram KordastiHonoraria: Beckman Coulter, GWT-TUD, Alexion PharmaceuticalsConsulting or Advisory Role: Syneos HealthResearch Funding: Celgene, Novartis Guillermo SanzHonoraria: CelgeneConsulting or Advisory Role: Abbvie, Celgene, Helsinn Healthcare, Janssen, Roche, Amgen, Boehringer Ingelheim, Novartis, TakedaSpeakers' Bureau: TakedaResearch Funding: CelgeneTravel, Accommodations, Expenses: Celgene, Takeda, Gilead Sciences, Roche Pharma AG Armando SantoroConsulting or Advisory Role: Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer AG, MSD, Sanofi, ArQuleSpeakers' Bureau: Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer AG, MSD Uwe PlatzbeckerHonoraria: Celgene/JazzConsulting or Advisory Role: Celgene/JazzResearch Funding: Amgen, Janssen, Novartis, BerGenBio, CelgenePatents, Royalties, Other Intellectual Property: part of a patent for a TFR-2 antibody (Rauner et al. Nature Metabolics 2019)Travel, Accommodations, Expenses: Celgene Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene Torsten HaferlachEmployment: MLL Munich Leukemia LaboratoryLeadership: MLL Munich Leukemia LaboratoryConsulting or Advisory Role: IlluminaNo other potential conflicts of interest were reported.

5-Azacytidine is an effective therapy in high risk MDS and oligoblastic AML. This "real life" analysis was made on 185 patients treated with 5-azacytidine in 10 centers afferent to REL ("Rete Ematologica Lombarda"), a network in Lombardia region. The aim was to assess the influence of disease and comorbidity risk assessments on the survival. The results confirm the utility of 5-azacitidine in prolonging OS regardless of advanced age and the presence of comorbidities. They also encourage an early treatment since patients with IPSS-R High risk MDS have better outcome with respect to Very High risk ones. According to the IPSS cytogenetic risk, there was no difference in the outcome between Intermediate and High risk patients. Nevertheless, a poorer cytogenetic risk, according to the IPSS-R cytogenetic stratification, negatively influenced the outcome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The World Health Organization classification of myelodysplastic syndromes (MDS) is based on morphological evaluation of marrow dysplasia. We performed a systematic review of cytological and histological data from 1150 patients with peripheral blood cytopenia. We analyzed the frequency and discriminant power of single morphological abnormalities. A score to define minimal morphological criteria associated to the presence of marrow dysplasia was developed. This score showed high sensitivity/specificity (>90%), acceptable reproducibility and was independently validated. The severity of granulocytic and megakaryocytic dysplasia significantly affected survival. A close association was found between ring sideroblasts and SF3B1 mutations, and between severe granulocytic dysplasia and mutation of ASXL1, RUNX1, TP53 and SRSF2 genes. In myeloid neoplasms with fibrosis, multilineage dysplasia, hypolobulated/multinucleated megakaryocytes and increased CD34+ progenitors in the absence of JAK2, MPL and CALR gene mutations were significantly associated with a myelodysplastic phenotype. In myeloid disorders with marrow hypoplasia, granulocytic and/or megakaryocytic dysplasia, increased CD34+ progenitors and chromosomal abnormalities are consistent with a diagnosis of MDS. The proposed morphological score may be useful to evaluate the presence of dysplasia in cases without a clearly objective myelodysplastic phenotype. The integration of cytological and histological parameters improves the identification of MDS cases among myeloid disorders with fibrosis and hypocellularity.

Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible., (© 2014 by The American Society of Hematology.)

To analyze the unpredicted event of hematological improvement (HI) during iron-chelation therapy (ICT), we reviewed a series of 53 myelodysplastic patients with transfusion dependency in a retrospective study involving 8 centers afferent to the "Rete Ematologica Lombarda". According to the IWG response criteria published in the year 2000, we observed erythroid responses in 19 patients (35.1%), 5 major (9.2%) and 14 minor (25.9%). In the assessable patients, platelet response was 8/13 (61%) and neutrophil response was 13/17 (76.4%). Only in patients with erythroid improvement, multilineage responses were observed. Apparently, patients with greater erythropoiesis dysfunction may take more advantage., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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