Molecular-Based Ecosystem to Improve Personalized Medicine in Chronic Myelomonocytic Leukemia
Abstract
PURPOSE Chronic myelomonocytic leukemia (CMML) is a rare myeloid neoplasm characterized by clinical heterogeneity and is associated with poor outcomes. To date, limited molecular information has been incorporated into disease classification and risk stratification. We aimed to integrate genomic features into the clinical decision-making process for CMML. PATIENTS AND METHODS We analyzed a retrospective cohort of 3013 patients with CMML (training set) and a prospective population of 516 patients (validation set). Using an innovative framework for multimodal data analysis, we developed molecular-based disease taxonomy and prognostication. RESULTS Unsupervised clustering identified nine entities with distinct genomic features and outcomes ( P < .001), including splicing machinery, transcription factors, signal transduction and tyrosine kinase pathways aberrations, and high-risk molecular signatures. Notably, 15% of patients showed molecular/clinical overlap with other myeloid neoplasms. We integrated molecular and clinical information to build the international CMML Prognostic Scoring System (iCPSS), incorporating mutations in nine genes together with hematologic parameters and cytogenetic abnormalities. The iCPSS identified five groups with distinct probability of overall and leukemia-free survival in both training and validation cohorts ( P < .001), outperforming existing prognostic models. Importantly, 55% of patients were reassigned to higher or lower risk groups by the iCPSS. Decision analysis demonstrated that iCPSS could refine the optimal timing of allogeneic transplantation at the individual level; compared with conventional prognostic tools, iCPSS-based decision modeling changed transplantation strategy in 31% of cases, resulting in a significant gain-in-life expectancy for eligible patient population ( P < .001). A federated learning platform was implemented to enable continuous, privacy-preserving model update across multiple centers. CONCLUSION Molecular information improves CMML classification and prognostication, supports more effective clinical decision making, and potentially refines the design of clinical trials.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (128)
Luca Lanino
3Yale University, New Haven, United States
Anthony M. Hunter
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
Nico Gagelmann
From the Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Marie Robin
9Hôpital Saint Louis (APHP), Service d'hématologie, Paris, France
Daniele Dall'Olio
12University of Bologna, Bologna, Italy
Alice Flamigni
MOX, Department of Mathematics, Politecnico di Milano, Milan, Italy
Claudia Sala
Carmelo Gurnari
1Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, OH
Yu-Hung Wang
1University of Manchester, Manchester, United Kingdom
Lisa Pleyer
Blanca Xicoy
3Hematology Service, Institut Català d'Oncologia. Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucèmia Josep Carreras, Badalona, Spain
Guillermo Montalban-Bravo
Lee-Yung Shih
12School of Medicine, Chang Gung University, Taoyuan, Taiwan
Ali Alsugair
1Mayo Clinic, Hematology, Rochester, United States
Saubia Fathima
1Mayo Clinic, Hematology, Rochester, United States
Caterina Gregorio
Cesare Rollo
Laura Palomo
9ICO-Hospital Germans Trias i Pujol, Institut de Recerca contra la Leucèmia Josep Carreras (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
Anne Sophie Platzbecker
1Else Kroener Fresenius Center for Digital Health, Faculty of Medicine and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
Gianluca Asti
Raphaël Itzykson
6Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France
David A. Sallman
6Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
Piero Fariselli
Wolfgang Kern
40MLL Munich Leukemia Laboratory, Munich, Germany
Guillermo Garcia-Manero
Uwe Platzbecker
Francesc Sole
8Institut de Recerca Contra la Leucèmia Josep Carreras, Barcelona, Spain
Maria Diez-Campelo
11Hospital Clínico Universitario de Salamanca, Salamanca, Spain
Jaroslaw Maciejewski
1Department of Translational Hematology and Oncology Research, Cleveland, United States
Rafael Bejar
Felicitas Thol
Nicolaus Kröger
From the Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Michael Savona
7Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, United States
Pierre Fenaux
Guillermo Sanz
26Hospital Universitario y Politécnico La Fe, Hematology Department, Valencia, Spain
Shahram Kordasti
Valeria Santini
7DMSC University of Florence, AOUC, MDS Unit, Hematology, Florence, Italy
Michaela Fontenay
7Université Paris Cité and Assistance Publique-Hôpitaux de Paris Centre, Hôpital Cochin, Paris, France
Amer M. Zeidan
Rami S. Komrokji
H. Lee Moffitt Cancer Center, Tampa, Florida, United States
Torsten Haferlach
7Munich Leukemia Laboratory, Munich, Germany
Ulrich Germing
Gastone Castellani
Saverio D'Amico
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Mrinal Patnaik
5Mayo Clinic, Rochester, United States
Francesca Ieva
Eric Solary
3Gustave Roussy, Paris, France
Ayalew Tefferi
4Mayo Clinic, Scottsdale, United States
Eric Padron
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Matteo Giovanni Della Porta
Tamanna Haque
4Memorial Sloan Kettering Cancer Center, New York, United States
Omar Abdel-Wahab
Molecular Pharmacology Program, Sloan Kettering Institute
Klaus Geissler
Alex Bataller
2Division of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Alexandre Bazinet
1The University of Texas MD Anderson Cancer Center, Houston, United States
Manja Meggendorfer
46Munich Leukemia Laboratory, Munich, Germany
Mirco Quintavalla
Alessandro Bruseghini
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Elisabetta Sauta
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Luciana Carota
11Bologna Univerisity, Department of Medical and Surgical Sciences, Bologna, Italy
Tiziana Sanavia
Lorenzo Dall'Olio
Erica Travaglino
8Pathology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Lurdes Zamora
3Hematology Service, Institut Català d'Oncologia. Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucèmia Josep Carreras, Badalona, Spain
David Quintela
Andres Jerez
1Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Hematologic Genetic Diagnosis and Counseling Unit, Barcelona, Spain
Elena Cornejo
Paloma Garcia Martin
11Hospital Universitario Clínico San Cecilio, Hematology, Granada, Spain
Marina Díaz-Beyá
7Hospital Clínic Barcelona, Hematopathology Section, Barcelona, Spain
Alejandro Avendano Pita
Veronica Roldan
Dolly Viviana Fiallo Suarez
21Hospital Dr. Negrín, Las Palmas de Gran Canaria, Spain
Estefania Cerezo Velasco
Marisa Calabuig
1Hospital Clínico Universitario-INCLIVA, Hematology Department, Valencia, Spain
Esperanza Such
Laboratory of Cytogenetics and Molecular Biology. Hospital Universitari i Politècnic La Fe, Valencia, Spain
Cristina Castilla-Llorente
6Institut Gustave Roussy, Villejuif, France
Claude E. Bulabois
Laetitia Souchet
Hussein Awada
4Cleveland Clinic Foundation, Cleveland, United States
Massimo Bernardi
Patrizia Chiusolo
6Section of Hematology, Department of Radiological and Hematological Sciences, Catholic University, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Antonio Curti
2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy
Luisa Giaccone
Carlo Finelli
10IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Ilaria Casetti
Francesco Onida
22ASST Fatebenefratelli-Sacco, University Milan, Milan, Italy
Lorenza Maria Borin
3Fondazione IRCCS San Gerardo dei Tintori, Hematology, Monza, Italy
Matilde Yung Follo
Angela Consagra
30University of Florence, MDS Unit, Hematology, AOU Careggi - Department of Experimental and Clinical Medicine, Florence, Italy
Francesco Passamonti
University of Milan, Milan
Elisa Diral
24San Raffaele Scientific Institute, Department of Hematology, Milan, Italy
Vladan Vucinic
15University Hospital Leipzig, Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, Leipzig, Germany
Gregorio M. Bergonzi
Maria Teresa Voso
Hsin-An Hou
10National Taiwan University Hospital, Taipei, Taiwan
Wen-Chien Chou
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Chi-Yuan Yao
Chien-Chin Lin
National Taiwan University Hospital, Taipei, Taiwan
Hwei-Fang Tien
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Alessia Campagna
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Marta Ubezio
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Antonio Russo
Gabriele Todisco
Giulia Maggioni
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Cristina A. Tentori
Alessandro Buizza
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Ivan Ferrari
Maria Di Matteo
Alessandra Crespi
2IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
Giulia Figini
2IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
Camilla Delponte
Francesco Pesce
31Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy
Matteo Zampini
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Elena Riva
Mattia Delleani
2Train s.r.l., Milan, Italy
Eleonora Iascone
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Laura Crisafulli
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Francesca Ficara
Denise Ventura
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Nicole Pinocchio
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Matteo Brindisi
1IRCCS Humanitas Research Hospital, AI Center, Rozzano, Italy
Armando Santoro
IRCCS Humanitas Research Hospital, Milan
Ahmad Kiwan
4Yale University, New Haven, United States
Jennifer VanOudenhove
Najla H. Al Ali
Timothy A. Graubert
Swapna Thota
University of Tennessee HSC, Memphis, Tennessee, United States
Elizabeth Griffiths
8Roswell Park Comprehensive Cancer Center, Buffalo, United States