A Molecular-Based Ecosystem to Improve Personalized Medicine in Patients with Chronic Myelomonocytic Leukemia (CMML)
Authors: Lanino Luca , Hunter Anthony M. , Gagelmann Nico , Robin Marie , Sala Claudia , Dall'Olio Daniele , Gurnari Carmelo , Dall'Olio Lorenzo , Wang Yu-Hung , Pleyer Lisa , Xicoy Blanca , Montalban-Bravo Guillermo , Shih Lee-Yung , Haque Tamanna , Abdel-Wahab Omar , Geissler Klaus , Bataller Alex , Bazinet Alexandre , Meggendorfer Manja , Casetti Ilaria Carola , Sauta Elisabetta , Travaglino Erica , Palomo Laura , Zamora Lurdes , Quintela David , Jerez Andres , Cornejo Elena , Garcia Martin Paloma , Díaz-Beyá Marina , Avendaño Pita Alejandro , Roldan Veronica , Fiallo Suarez Dolly Viviana , Cerezo Velasco Estefania , Calabuig Marisa , Such Esperanza , Sanz Guillermo , Kubasch Anne Sophie , Castilla-Llorente Cristina , Bulabois Claude-Éric , Souchet Laetitia , Awada Hussein , Bernardi Massimo , Chiusolo Patrizia , Curti Antonio , Giaccone Luisa , Onida Francesco , Borin Lorenza Maria , Passamonti Francesco , Diral Elisa , Vucinic Vladan , Bergonzi Gregorio Maria , Voso Maria Teresa , Hou Hsin-An , Chou Wen-Chien , Yao Chi-Yuan , Lin Chien-Chin , Tien Hwei-Fang , Campagna Alessia , Ubezio Marta , Russo Antonio , Todisco Gabriele , Maggioni Giulia , Tentori Cristina Astrid , Buizza Alessandro , Asti Gianluca , Zampini Matteo , Riva Elena , Delleani Mattia , Consagra Angela , Ficara Francesca , Santoro Armando , Carota Luciana , Sanavia Tiziana , Rollo Cesare , Kiwan Ahmad , VanOudenhove Jennifer , Fariselli Piero , Al Ali Najla H. , Sallman David , Kern Wolfgang , Garcia-Manero Guillermo , Thota Swapna , Griffiths Elizabeth A. , Follo Matilde Yung , Finelli Carlo , Platzbecker Uwe , Sole Francesc , Diez-Campelo Maria , Maciejewski Jaroslaw , Bejar Rafael , Thol Felicitas R. , Kröger Nicolaus , Fenaux Pierre , Itzykson Raphael , Graubert Timothy Aaron , Fontenay Michaela , Zeidan Amer M. , Komrokji Rami S. , Santini Valeria , Haferlach Torsten , Germing Ulrich , D'Amico Saverio , Castellani Gastone , Patnaik Mrinal M. , Solary Eric , Padron Eric , Della Porta Matteo Giovanni 
Published: December 2024

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&lt;.001), and median leukemia-free survival (LFS) ranging from 210 to 18 months (P&lt;.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&lt;.001) and identified groups of patients with different probabilities of disease relapse, ranging from 9% to 62% (P&lt;.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.