Risk Prognostication After Hypomethylating Agents Combined With Venetoclax in AML: The PRISM Risk Model.

Lachowiez CA, Zeidner JF, Othman J, Kaempf A, Yun S, Heiblig M, Heuser M, Shahswar R, Madero Marroquin R, Cannova JM, Žučenka A, Marvin-Peek J, Senapati J, Abaza Y, Swaroop A, Zacheo I, Monaco F, Belhabri A, Tauveron-Jalenques U, Tavernier E, Carré M, Aspas Requena G, Cook RJ, Traer E, Saultz JN, O'Nions J, Basheer F, Laurie J, Handa S, Stein EM, Baer MR, Olin R, Blum W, Schiller G, Lin T, Curran E, Yocum A, Madarang E, Daver N, Kadia TM, Marconi G, Madanat Y, Dillon R, DiNardo CD, Swords R, Arango Ossa JE, Watts J, Loghavi S, Pollyea DA, Bernard E, Patel , Patel AA, Stock W, Drekolias D, Zahra FT, Long N, Swaroop A, Huang Y, Welkie RL (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 44

Pages Range: 2422-2434

Journal Issue: 25

DOI: 10.1200/JCO-26-00347

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, the PRISM-AML Risk Calculator, is publicly available.

Involved external institutions

Oregon Health and Science University (OSHU) United States (USA) (US) UNC Lineberger United States (USA) (US) King’s College London United Kingdom (GB) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) Centre Hospitalier Lyon Sud (CHLS) France (FR) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University of Chicago United States (USA) (US) Memorial Sloan Kettering Cancer Center United States (USA) (US) Sylvester Comprehensive Cancer Center United States (USA) (US) University of Texas MD Anderson Cancer Center United States (USA) (US) University of Colorado Anschutz Medical Campus United States (USA) (US) Institut Gustave-Roussy France (FR) Ospedale Infermi di Rimini Italy (IT) Centre Léon-Bérard (UNICANCER) France (FR) CHU Clermont-Ferrand France (FR) Centre Hospitalier Universitaire de Saint-Étienne (CHU) France (FR) University of Grenoble Alpes (UGA) / Université de Grenoble France (FR) University Hospital of Nimes France (FR) University College London Hospitals (UCLH) United Kingdom (GB) Addenbrooke's Hospital United Kingdom (GB) University Hospitals Sussex NHS Foundation Trust United Kingdom (GB) The Ohio State University Wexner Medical Center (OSUMC) United States (USA) (US) University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) Emory University United States (USA) (US) University of California Los Angeles (UCLA) United States (USA) (US) University of Kansas (KU) United States (USA) (US) University of Cincinnati United States (USA) (US) Columbian College of Arts and Sciences United States (USA) (US) Vilnius University / Vilniaus universitetas Lithuania (LT) Northwestern University United States (USA) (US) University of Bologna / Università di Bologna Italy (IT) University of Texas Southwestern Medical Center (UT Southwestern) United States (USA) (US) Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST) Italy (IT)

How to cite

APA:

Lachowiez, C.A., Zeidner, J.F., Othman, J., Kaempf, A., Yun, S., Heiblig, M.,... Welkie, R.L. (2026). Risk Prognostication After Hypomethylating Agents Combined With Venetoclax in AML: The PRISM Risk Model. Journal of Clinical Oncology, 44(25), 2422-2434. https://doi.org/10.1200/JCO-26-00347

MLA:

Lachowiez, Curtis A., et al. "Risk Prognostication After Hypomethylating Agents Combined With Venetoclax in AML: The PRISM Risk Model." Journal of Clinical Oncology 44.25 (2026): 2422-2434.

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