Background. Study of myeloid neoplasms (MN) has been rapidly transformed by genome characterization. Gene mutations have been reported to influence disease phenotype and risk of disease progression, and the evaluation of mutational status can provide valuable insights to improve the decision-making process. In this international study, we evaluated the clinical impact of mutational screening in patients with CMML, which is characterized by significant clinical and genomic heterogeneity, including a substantial proportion of patients with poor outcomes and unmet needs. Currently, only limited molecular information has been incorporated into CMML classification and prognostication.

Methods. We retrospectively collected 3182 CMML patients. We used MOSAIC, an AI-based framework for multimodal analysis in rare cancers (PMID: 38875514) to develop innovative, molecular-based tools for classification and prognostication. An independent validation of the results on 516 prospectively collected patients was performed.

Results. Bayesian Networs and Hierarchical Dirichlet Processes were used to identify genomic associations and define a CMML molecular classification. We identified 11 clusters with distinct clinical and genomic features, including splicing machinery, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures (i.e., AML-like and TP53 mutations). Up to 15% of patients showed clear genomic overlap with other MN. Importantly, extensive multi-color flow cytometry on T lymphocytes, NK and myeloid cells (BD FACSymphony A5 Cell Analyzer) revealed specific immunologic and inflammation signatures associated with molecular subgroups.

We then integrated molecular and clinical information to build an international CMML Prognostic Scoring System (iCPSS). We assessed the performance of different statistical and AI-based methods; L1-penalized Cox Model resulted as the best performing method. Selected features included hematological parameters (WBC, Hb, PLT and marrow blasts), cytogenetic abnormalities, and mutations in 10 genes (ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SETBP1, STAG2, TET2, TP53, U2AF1). By Bayesian thresholds optimization, we identified 5 risk classes (i.e., very-low, low, intermediate, high and very-high) with median overall survival (OS) ranging from 99 to 9 months (P<.001), and median leukemia-free survival (LFS) ranging from 210 to 18 months (P<.001). iCPSS provided better patient discrimination across all clinical endpoints compared to currently available prognostic tools, with a Concordance Index (CI) for OS of 0.75 versus 0.62-0.64, respectively. Notably, compared to available scoring systems, up to 40% of patients were reassigned to higher or lower risk classes by the iCPSS. External validation on an independent prospective cohort confirmed that the performance of iCPSS is superior to existing prognostic models (CI for OS 0.71 vs 0.54-0.61, respectively)

To demonstrate the clinical utility of iCPSS, we focused on 753 patients who underwent allogeneic stem cell transplantation (HSCT). In multivariable analysis, iCPSS stratified the probability of OS post-HSCT (P<.001) and identified groups of patients with different probabilities of disease relapse, ranging from 9% to 62% (P<.001). We employed a clinical- and genomic-based decision support system (PMID: 38723212) to determine the optimal timing of HSCT. Preliminary analyses indicated that higher-risk patients according to iCPSS (i.e., intermediate, high, and very high) benefit from an immediate HSCT strategy. Lower-risk patients (i.e., very low and low) had life expectancy maximized with delayed HSCT. Modeling decision analysis using iCPSS compared to conventional scores, resulted in a change in transplantation policy for a significant proportion of patients (up to 25%).

Conclusion. Molecular information significantly improves the classification of CMML patients, providing a basis for refining diagnostic boundaries with other MN and for a more rational inclusion of patients in clinical trials. The iCPSS demonstrated superior performance over currently available scoring systems and improved HSCT decision making process.

Disclosures

Hunter:GSK: Consultancy, Honoraria; PharmaEssentia: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Sobi​ (formerly CTI biopharma): Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Cogent Biosciences: Research Funding; Ascentage Pharma: Research Funding; Syntrix Biosystems: Research Funding; Novartis: Research Funding; PharmaEssentia: Research Funding. Robin:Novartis: Other: research support; Abbvie: Other: research support; Medac: Other: research support; Neovii: Other: research support. Pleyer:BMS: Honoraria; AbbVie: Honoraria; Otsuka: Honoraria. Xicoy:BMS: Honoraria. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Shih:PhamaEssentia: Honoraria; Novartis, Taiwan: Research Funding; GSK: Honoraria; Celgene: Research Funding. Abdel-Wahab:Minovia Therapeutics: Consultancy, Research Funding; Codify Therapeutics: Consultancy, Current equity holder in private company, Research Funding; Nurix Therapeutics: Research Funding. Geissler:Otsuka: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Beigene: Honoraria; Celgene: Honoraria; BMS: Honoraria. Jerez:Aztrazeneca: Research Funding; GILEAD: Research Funding; Novartis: Consultancy; BMS: Consultancy. Díaz-Beyá:BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Abbvie: Consultancy. Sanz:Novartis, BMS, J&J, Takeda, Amgen, Menarini, Bayer, Pfizer: Other; BMS: Research Funding; AstraZeneca, GSK: Consultancy, Honoraria; Novartis, ExCellera: Speakers Bureau. Kubasch:BMS: Honoraria; Curis: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Curti:Pfizer: Honoraria, Research Funding; Menarini stemline: Honoraria; Abbvie: Honoraria; Jazz Pharmaceutics: Honoraria. Giaccone:Abbvie: Honoraria. Onida:Menarini-stemline: Speakers Bureau; kyowa: Speakers Bureau; MEDAC: Speakers Bureau; takeda: Speakers Bureau. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vucinic:Gilead/Kite, Janssen, BMS Celgene, Novartis: Consultancy, Honoraria; Amgen: Honoraria, Other: Travel grant. Voso:Celgene/BMS: Other: Research support, Advisory Board, Speakers Bureau; Astra Zeneca: Speakers Bureau; Abbvie: Speakers Bureau; Syros: Other: Advisory Board; Jazz: Other: Advisory Board, Speakers Bureau; Astellas: Speakers Bureau; Novartis: Other: Research support, Speakers Bureau. Hou:Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding; PharmaEssentia: Consultancy, Honoraria, Other: Travel fees; Synmosa: Consultancy, Honoraria, Other: Travel fees; Panco healthcare Co: Consultancy, Honoraria, Other: Travel fees; AstraZeneca: Consultancy, Honoraria, Other: Travel fees; Novartis: Consultancy, Honoraria, Other: Travel fees; IQVIA: Consultancy, Honoraria, Other: Travel fees; Astellas: Consultancy, Other: Travel fees, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel fees, Research Funding; CSL Behring: Consultancy, Honoraria, Other: Travel fees; Sandoz: Consultancy, Honoraria, Other: Travel fees; TSH Biopharm: Consultancy, Honoraria, Other: Travel fees; Lotus: Consultancy, Honoraria, Other: Travel fees; Kirin: Consultancy, Honoraria, Other: Travel fees; Johnson & Johnson: Consultancy, Honoraria, Other: Travel fees; Eli Lilly: Consultancy, Honoraria, Other: Travel fees; BMS: Consultancy, Honoraria, Other: Travel fees, Research Funding; GSK: Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel fees; Kirin: Research Funding; Zuellig Pharma: Consultancy, Honoraria, Other: Travel fees; Ono: Consultancy, Honoraria, Other: Travel fees; Roche: Consultancy, Honoraria, Other: Travel fees; Chugai: Consultancy, Honoraria, Other: Travel fees; TTY Biopharm Company: Consultancy, Honoraria, Other: Travel fees ; Merck Sharp & Dohme: Consultancy, Honoraria, Other: Travel fees; Takeda: Consultancy, Honoraria, Other: Travel fees; Daiichi Sankyo: Consultancy, Honoraria, Other: Travel fees; BeiGene: Consultancy, Honoraria, Other: Travel fees; PharmaEssentia: Research Funding. Santoro:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Abb-vie: Speakers Bureau; Incyte: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arqule: Speakers Bureau; Sanofi: Consultancy; Roche: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EISAI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Beigene: Speakers Bureau; Astrazeneca: Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau. Sallman:Abbvie: Consultancy; Agios: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere, LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Curis: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Aprea: Research Funding; Astex: Other: Personal fees; Merck: Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding; Astex: Research Funding; AbbVie: Research Funding; Helsinn: Other: Personal fees; Amphivena: Research Funding; Genentech: Other: Personal fees. Thota:Sobi Inc, Novartis, Alexion, pharmaessentia: Membership on an entity's Board of Directors or advisory committees. Griffiths:Partner Therapeutics: Consultancy; Picnic Health: Consultancy; Astex Pharmaceuticals/Taiho Oncology/Otsuka: Consultancy, Research Funding; MDS International Foundation: Honoraria; Alexion Pharmaceuticals/ AstraZeneca Rare Disease: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Blueprint Medicines: Research Funding; Celldex Pharmaceuticals: Research Funding; CTI Biopharma: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; MedscapeLive: Honoraria; MediCom Worldwide: Honoraria; Novartis: Consultancy, Research Funding; AAMDS: Honoraria; Abbvie: Consultancy; Servier: Consultancy; MJH Health: Honoraria; Physicians Educational Resource: Honoraria; ASH: Honoraria; NextCure: Research Funding; Apellis Pharmaceuticals: Consultancy, Research Funding; Takeda Oncology: Consultancy. Finelli:Celgene BMS: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Platzbecker:Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Diez-Campelo:SYROS: Membership on an entity's Board of Directors or advisory committees; ASTEX/OTSUKA: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL TO MEETINGS; GSK: 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; BLUEPRINT MEDICINES: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board fees; Gilead: Other: Travel reimbursement; HEMAVAN: Membership on an entity's Board of Directors or advisory committees; CURIS: Membership on an entity's Board of Directors or advisory committees; AGIOS: Consultancy, Membership on an entity's Board of Directors or advisory committees; KEROS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau. Bejar:Aptose Biosciences: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Thol:Astellas: Honoraria; Rigel: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kröger:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Neovii: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Therakos: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; DKMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Provirex: Consultancy. Fenaux:Agios: Research Funding; AbbVie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Astex: Research Funding; Servier: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding. Itzykson:Abbvie: Research Funding; Advesya: Research Funding. Zeidan:Agios: Consultancy, Honoraria; Akeso Pharma: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Schroedinger: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Treadwell: Consultancy, Honoraria; Medus: Consultancy, Honoraria; Hikma: Consultancy, Honoraria; Vinerx: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Sumitomo: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Geron: Consultancy, Honoraria, Research Funding; Shattuck Labs: Research Funding; Kura: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Keros: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding; Notable: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Lava Therapeutics: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Faron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria. Komrokji:DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Research Funding; Keros: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy; Servio: Honoraria; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; Servio: Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Santini:Ascentage, AbbVie, Bristol Myers Squibb, CTI BioPharma, Geron, Gilead, Novartis, Servier, Syros Pharmaceuticals: Other: Advisory Board. Germing:JAZZ: Research Funding; Novatis: Honoraria; BMS: Honoraria; BMS: Research Funding; Abbvie: Research Funding. Patnaik:Solu therapeutics: Research Funding; Kura Oncology: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Epigenetix: Research Funding; Polaris: Research Funding; StemLine: Research Funding. Solary:PEPKON: Research Funding; NOVARTIS: Speakers Bureau. Della Porta:Bristol Myers Squibb: Consultancy.

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