Risk Prognostication After Hypomethylating Agents Combined With Venetoclax in AML: The PRISM Risk Model
Abstract
PURPOSE As risk stratification for patients with AML treated with lower-intensity venetoclax-based therapy remains suboptimal, we developed and validated a prognostic model integrating clinical, cytogenetic, and molecular features. METHODS We assembled a multinational data set comprising 2,092 adults with newly diagnosed AML treated with hypomethylating agents plus venetoclax (HMA + VEN). One thousand nine hundred eighteen patients with complete data were randomly divided into training (70%) and internal validation (30%) cohorts. Two independent external validation cohorts were assembled (n = 500 and n = 222). Modeling overall survival (OS), Elastic Net regression was applied in 1,000 bootstrap samples from the training cohort to select variables for a Ridge regression, which generated a continuous Prognostic Risk Integration for Survival Modeling (PRISM) score and risk categories based on tertiles (PRISM-3: low, moderate, high). These PRISM indices were then computed for the validation cohorts and compared with the 4-gene classifier (based on mutations in FLT3 -ITD, N/KRAS , and TP53 ). RESULTS PRISM integrated 17 clinical and genomic variables and demonstrated a linear association with OS. PRISM-3 stratified survival consistently across all cohorts (median OS: 25.1-28.8 months for low risk, 12.5-14.7 months for moderate risk, and 5.8-6.7 months for high risk; P < .001). Compared with the 4-gene classifier, PRISM-3 reassigned approximately 40% of patients (and >50% of those with favorable risk) and demonstrated significantly better discrimination in validation cohorts (C-index 0.63-0.65 v 0.59-0.61; P < .05). CONCLUSION PRISM is a validated prognostic model for patients with AML receiving HMA + VEN that improves survival risk stratification beyond current standard tools and supports individualized, risk-adapted clinical decision making. The model is publicly available at prism-aml.com .
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (57)
Curtis A. Lachowiez
Oregon Health & Science University, Portland, Oregon, United States
Joshua F. Zeidner
1Division of Hematology, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
Jad Othman
3The University of Sydney, Sydney, Australia
Andy Kaempf
1Oregon Health & Science University, Division of Hematologic Malignancies, Knight Cancer Institute, Portland, United States
Seongseok Yun
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Maël Heiblig
9Department of Hematology, Centre Hospitalier Universitaire de Lyon, Lyon, France
Michael Heuser
Rabia Shahswar
4Hannover Medical School, Department for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover, Germany
Rafael Madero Marroquin
Joseph M. Cannova
Andrius Zucenka
1Vilnius University, Faculty of Medicine and Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
Jennifer Marvin-Peek
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
Jayastu Senapati
The University of Texas MD Anderson Cancer Center
Yasmin Abaza
19Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Division of Hematology and Oncology, Leukemia Program, Chicago, United States
Irene Zacheo
1919. IRST IRCCS, Meldola, Forlì-Cesena, forlì cesena, Italy
Federica Monaco
11Department of Hematology, Ospedali Infermi, AUSLROMAGNA, Rimini, Italy
Amine Belhabri
19Service d’Hématologie, Centre Léon-Bérard, Lyon, France
Urbain Tauveron-Jalenques
3Centre Hospitalier Universitaire Clermont-Ferrand, Service d'hématologie et thérapie cellulaire, Clermont-Ferrand, France
Emmanuelle Tavernier
Martin Carré
Gaspar Aspas Requena
8CHU Clermont-Ferrand, Department of Hematology, Clermont-Ferrand, France
Rachel J. Cook
Elie Traer
Oregon Health & Science University, Portland, Oregon, United States
Jennifer N. Saultz
Jenny O'Nions
13Department of Hematology, University College London Hospital NHS Foundation Trust, London, United Kingdom
Faisal Basheer
13Addenbrooke's Hospital, Department of Haematology, Cambridge, United Kingdom
John Laurie
14University Hospitals Sussex NHS Foundation Trust, Worthing, United Kingdom
Shivani Handa
The Ohio State University, Columbus, Ohio, United States
Eytan M. Stein
Leukemia Service Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA
Maria R. Baer
10University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
Rebecca Olin
1University of California, San Francisco, Hematology, Blood and Marrow Transplantation, and Cellular Therapy Program, San Francisco, United States
William Blum
Emory University, Atlanta, Georgia, United States
Gary Schiller
7David Geffen School of Medicine at UCLA, Los Angeles, United States
Tara Lin
20University of Kansas Cancer Center, Westwood, United States
Emily Curran
University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
Ashley Yocum
14Blood Cancer United, Washington, United States
Ellen Madarang
2University of Miami Miller School of Medicine, Leukemia Service, Department of Medicine, Miami, United States
Naval Daver
1The University of Texas MD Anderson Cancer Center, Houston, TX
Tapan M. Kadia
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Giovanni Marconi
31Hematology Unit, Ospedale S. Maria delle Croci, University of Bologna, Ravenna, Italy
Yazan Madanat
Richard Dillon
5King's College London, London, United Kingdom
Courtney D. DiNardo
Department of Leukemia The University of Texas MD Anderson Cancer Center Houston Texas USA
Ronan Swords
OHSU Knight Cancer Institute Center for Hematologic Malignancies, Portland, Oregon, United States
Juan E. Arango Ossa
Justin Watts
2Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Medicine, Miami, United States
Sanam Loghavi
Daniel A. Pollyea
4Division of Hematology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO
Elsa Bernard
2Institut Gustave Roussy, Computational Clinical Oncology Lab, UMR 981, Villejuif, France
Anand A. Patel
4Department of Medicine, The University of Chicago, Chicago, IL
Wendy Stock
Dimitrios Drekolias
Moffitt Cancer Cancer and Research Institute, Tampa, Florida, United States
Fatima Tuz Zahra
1H. Lee Moffitt Cancer Center, Tampa, United States
Nicola Long
1Oregon Health & Science University, Division of Hematologic Malignancies, Knight Cancer Institute, Portland, United States
Alok Swaroop
Ying Huang
Rina Li Welkie