Background. The inclusion of gene mutations and chromosomal abnormalities in the 2022 WHO and ICC Classifications of MDS has enhanced diagnostic precision and is expected to improve clinical decision-making process. Although these two systems share similarities, clinically relevant discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. In this study on behalf of the International Consortium for MDS (icMDS), we adopted a data-driven approach to provide a harmonization roadmap between the 2022 WHO and ICC classification for MDS. A modified Delphi Process consensus approach is currently ongoing among icMDS experts to finalize a harmonized MDS classification scheme.

Methods. We analyzed retrospective international cohorts of patients with a diagnosis of MDS (n=7017) and AML (n=1002) according to WHO 2016 criteria. Hierarchical Dirichlet Processes were applied to define clusters capturing broad dependencies among all gene mutations and cytogenetic abnormalities. To investigate the features of importance and their impact on the clustering process, we employed the SHapley Additive exPlanations approach (SHAP). This allowed to define harmonized labels for each clinical entity. The clinical relevance of the unsupervised clustering was assessed through the analysis of phenotypic features and outcomes among each group. ( Blood 2022;140: 9828-9830)

Results. Patients' characteristics are summarized in Table 1. We identified 9 clusters, defined by specific genomic features. The cluster of highest hierarchical importance was characterized by biallelic inactivation of TP53 (biTP53). According to SHAP analysis, bi TP53 was defined as 2 or more TP53 mutations, or 1 mutation with copy number loss or cnLOH. Most patients assigned to bi TP53 cluster had TP53 VAF>10% (77.9%) and complex karyotype (70.1%). Assignment to bi TP53 cluster was irrespective of blast count. Patients with monoallelic TP53 mutation segregated into other clusters. Hierarchically, the second cluster included patients with del(5q). SHAP analysis highlighted 5q deletion alone, or with one other chromosomal abnormality other than -7, and absence of bi TP53, as the most relevant features. Most of these patients had blast counts <5% (88.1%). The third distinct cluster included patients with SF3B1 mutations (in the absence of concurrent del(7q), abn3q26.2, complex karyotype or RUNX1 mutation). Most patients with MDS and SF3B1 mutation had <5% blasts (94.2%). Common co-mutated variants in the SF3B1 cluster included mutant DNMT3A (25.2%) and TET2 (38.3%).

Morphologically defined MDS cases (i.e., not meeting criteria for bi TP53, del(5q) or SF3B1) were preferentially assigned to the following additional clusters: SF3B1 and concurrent higher-risk mutations (e.g., RUNX1 and ASXL1); SRSF2 and concomitant TET2 mutations; U2AF1 mutations with del(20q), del(7q) or -7; SRSF2 with TET2 mutations and co-mutational patterns including RUNX1 and ASXL1; and AML-like genomic signatures. Our analyses suggest that morphologically defined MDS is characterized by a large heterogeneity in terms of mutation profiles, not entirely captured by the presence of unilineage versus multilineage dysplasia, percentage of bone marrow blasts, and presence of hypocellularity and fibrosis.

To better investigate the continuum between high risk MDS (i.e., patients with ≥10% blasts) and AML, an exploratory comparison was made using a cohort of AML (defined according to WHO 2016) patients analyzed using the same statistical methods. Only a partial overlap in genetic signatures was observed between MDS with ≥10% blasts and AML. However, similarities were observed between the AML-like MDS clusters (characterized by mutant NPM1, bZIP CEBPA, and Core Binding Factor abnormalities) and AML clusters defined by the same genetic signature, thus supporting the classification of these entities as AML, irrespective of blast count.

Conclusion. Our study demonstrated the utility of a data-driven approach based on advanced statistical methods to generate a harmonized classification for MDS. Table 2 shows a provisional, hierarchical classification algorithm. Further refinement of entity labels and classification criteria is the subject of the ongoing modified Delphi Process consensus approach among icMDS experts.

Fenaux:Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; French MDS Group: Honoraria. Platzbecker:BMS: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Research Funding; Silence Therapeutics: Consultancy, Honoraria, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Syros: Consultancy, Honoraria, Research Funding; BeiGene: Research Funding; Merck: Research Funding; AbbVie: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; medical writing support, Research Funding; Fibrogen: Research Funding; Servier: Consultancy, Honoraria, Research Funding; Curis: Consultancy, Research Funding; Janssen Biotech: Consultancy, Research Funding; Roche: Research Funding. Santini:BMS, Abbvie, Geron, Gilead, CTI, Otsuka, servier, janssen, Syros: Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Other: Travel expense reimbursement; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board fees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Chan:AbbVie: Honoraria; BMS: Honoraria. Xie:Moffitt Cancer Center: Current Employment; Novartis: Speakers Bureau. Brunner:Keros Therapeutics: Consultancy; Taiho: Consultancy; Agios: Consultancy, Research Funding; AstraZeneca: Research Funding; Celgene/BMS: Consultancy, Research Funding; GSK: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy; Takeda: Consultancy; Gilead: Consultancy. Kuykendall:BMS: Consultancy, Research Funding; Blueprint: Consultancy, Research Funding, Speakers Bureau; Imago: Consultancy; Incyte: Consultancy; GSK: Consultancy; Prelude: Research Funding; CTI: Consultancy; AbbVie: Consultancy; Sierra Oncology: Research Funding; Protagonist Therapeutics, Inc.: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; Novartis: Consultancy. Buckstein:Abbvie: Honoraria; Taiho: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Carraway:Takeda: Other; BMS: Consultancy, Research Funding, Speakers Bureau; Daiichi: Consultancy; Stemline Therapeutics: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau; Genentech: Consultancy; Novartis: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau; Astex Pharmaceuticals: Other; AbbVie: Other; Celgene: Research Funding; Agios: Consultancy, Speakers Bureau; Syndax: Other: DSMB. DeZern:Sobi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Caribou: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Appellis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Griffiths:Apellis Pharmaceuticals: Consultancy, Research Funding; Taiho Oncology: Consultancy; AAMDSIF: Honoraria; Physicians Educational Resource: Honoraria; S. Karger Publishing: Honoraria; Abbvie: Consultancy; Artis Ventures: Membership on an entity's Board of Directors or advisory committees; MediCom Worldwide, Inc.: Honoraria; American Society of Hematology: Honoraria; Vera and Joseph Dresner Foundation: Membership on an entity's Board of Directors or advisory committees; Celldex Therapeutics: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; NextCure, Inc: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; CTI Biopharma: Consultancy; MDS International Foundation: Honoraria; Blueprint Medicines, Inc: Research Funding; Partner Therapeutics: Consultancy; Medscape: Honoraria; Astex Pharmaceuticals: Research Funding; Takeda Oncology: Consultancy; AstraZeneca Rare Disease: Consultancy, Research Funding; Picnic Health: Membership on an entity's Board of Directors or advisory committees. Lancet:AbbVie Inc.: Consultancy; Atheneum: Consultancy; BerGenBio / DAVA Oncology: Consultancy; Boxer Capital: Consultancy; Celgene: Consultancy, Research Funding; Globe Life Sciences: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MD Anderson: Consultancy; MEDTalks: Consultancy; Novartis: Consultancy; Peer Voice: Consultancy; Servier: Consultancy; Tegus: Consultancy; The Dedham Group: Consultancy. Loghavi:Caris Diagnostics: Consultancy; Blueprint Medicine: Consultancy; Abbvie: Consultancy; Gerson Lehrman Group: Consultancy; QualWorld: Consultancy; Guidepoint: Consultancy; Recordati/ EUSA Pharma: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding; Amgen: Research Funding; Abbvie: Current equity holder in publicly-traded company. Odenike:BMS/Celgene, Novartis, Rigel, Servier, Taiho ; DSMB-Kymera therapeutics: Membership on an entity's Board of Directors or advisory committees; ABBVIE, Astrazeneca, Agios, Aprea, Astex, BMS/Celgene, CTI, Daiichi, Incyte, Janssen, Kartos, Novartis, NS-Pharma and Oncotherapy Sciences: Research Funding. Padron:Kura: Research Funding; Incyte: Research Funding; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pharmaessentia: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees; Gillead: Membership on an entity's Board of Directors or advisory committees. Patnaik:Epigenetix: Research Funding; Kura: Research Funding; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; StemLine: Research Funding. Roboz:Janssen: Consultancy, Research Funding; Bluebird bio: Consultancy; Astellas: Consultancy; Actinium: Consultancy; BMS: Consultancy; Blueprint: Consultancy; Agios: Consultancy; AZ: Consultancy; Jazz: Consultancy; MEI: Consultancy; Mesoblast: Consultancy; Amgen: Consultancy; GSK: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Jasper: Consultancy; Pfizer: Consultancy; Syndax: Consultancy; Takeda: Consultancy. Stahl:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: GME activity ; Clinical care options: Other: GME activity ; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Haymarket Media: Other: GME activity ; GSK: Membership on an entity's Board of Directors or advisory committees; Boston Consulting: Consultancy; Kymera: Membership on an entity's Board of Directors or advisory committees; Dedham group: Consultancy; Curis Oncology: Other: GME activity . Sekeres:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Kurome: Consultancy, Current holder of stock options in a privately-held company. Savona:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie Inc.: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron Corporation: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology, Inc.: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Patents & Royalties; ALX Oncology: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding. Sweet:Gilead: Consultancy; Bristol Myers Squibb: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; Arog: Consultancy; Novartis: Consultancy; Curis: Consultancy; Pfizer: Consultancy; Mablytics: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Nkarta: Consultancy; Incyte: Research Funding; BeiGene: Current Employment. Sallman:AbbVie, Affimed Gmbh, Gilead, Incyte, Intellisphere, LLC, Molecular Partners AG, PGEN Therapeutics, Inc., Takeda, Zentalis; Advisory board for AvenCell, BlueBird Bio, BMS, Intellia, Jasper Therapeutics, Kite, Magenta Therapeutics, NKARTA, Novartis, Orbita: Consultancy; Aprea, Jazz: Research Funding. Hourigan:Foundation of the NIH AML MRD Biomarkers Consortium: Research Funding. Wei:Beigene: Consultancy, Honoraria; Aculeus: Consultancy; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Syndax: Research Funding; Servier: Consultancy, Honoraria, Patents & Royalties: MCL1 use, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Shoreline: Consultancy; Astra Zeneca: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Borate:RUNX1 Foundation: Honoraria; Kura: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Incyte: Other; Jazz: Other: Research; Pfizer: Other: Research; Genentech: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Research. Efficace:AbbVie: Consultancy; Incyte: Consultancy; Syros: Consultancy. Daver:Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Agios: Consultancy; Shattuck Labs: Consultancy; Syndax: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy; ImmunoGen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy; FATE: Research Funding; Trovagene: Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; AROG: Consultancy; AbbVie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kronos Bio: Research Funding. Garcia-Manero:Genentech: Research Funding; Bristol Myers Squibb: Other: Medical writing support, Research Funding; AbbVie: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Current Employment, Other: Equity Ownership. Scheinberg:AbbVie: Consultancy, Other: Speaker; Alexion: Consultancy, Other: Scientific presentations/speaker; Alnylam: Research Funding; Amgen: Consultancy, Other: Scientific presentations/speaker; AstraZeneca: Consultancy, Other: Scientific presentations/speaker, Research Funding; BioCryst: Consultancy, Research Funding; BMS: Other: Speaker; Janssen: Consultancy, Other: Scientific presentations/speaker; Novartis: Consultancy, Other: Scientific presentations, Research Funding, Speakers Bureau; Pfizer: Consultancy, Other: Speaker, Research Funding; F. Hoffmann-La Roche Ltd,: Consultancy, Other: Scientific presentations, Research Funding; Viracta: Research Funding. Miyazaki:Novartis: Honoraria; Celgene: Honoraria; Dainippon-Sumitomo: Honoraria; Nipponshinnyaku: Honoraria; Chugai: Honoraria; Otsuka: Honoraria; Astellas: Honoraria; Kyowa-Kirin: Honoraria. Kulasekararaj:Samsung: Consultancy; Achillion: Consultancy; BioCryst: Consultancy; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cluzeau:Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Syros: Speakers Bureau; Keros: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Incyte: Speakers Bureau. Kordasti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Beckman Coulter: Honoraria. van de Loosdrecht:Roche: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan:Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Astex: Research Funding; Shattuck Labs: Research Funding; Foran: Consultancy, Research Funding; Syros: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Komrokji:AbbVie, CTI biopharma, Jazz, Pharma Essentia, Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy; Rigel, Taiho, DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Della Porta:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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