Venetoclax plus azacitidine (ven/aza) is a new standard of care for adult Acute Myeloid Leukemia (AML) patients who are not candidates for intensive therapies. Risk stratification approaches have been proposed to identify patients with favorable, intermediate, and adverse therapeutic outcomes following ven/aza and other lower intensive therapies. However, most have been developed for retrospective data analyses and have limitations in their application to upfront risk stratification of newly diagnosed patients. Here, we describe an AML risk model, termed the Refined Risk Model (RRM), that is specific for ven/aza, addresses important real-world considerations and utilizes pathology features that have the potential to be available relatively quickly-and-broadly following diagnosis. The RRM was developed and internally validated using a single center cohort of 316 AML patients from the University of Colorado treated upfront with ven/aza, and then externally validated on an AML cohort from a nationwide electronic health record-derived de-identified AML database. The RRM effectively stratified patients into Adverse, Intermediate, and Favorable groups across both the internal and external cohorts; it performed well in subsets with or without allogeneic transplant recipients, demonstrated tolerance to missing data, and showed numerical performance comparable to or exceeding the existing alternatives such as the European Leukemia Network (ELN 2022) and molecular prognostic risk signature (mPRS) models. These findings suggest that the RRM may have potential application in defining the prognostic mortality risk for newly diagnosed AML patients, which may help guide clinical trial design and execution as well as other important elements of AML clinical decision support.

Both CAS and MB are employees of and hold equity in OncoVerity. In addition, CAS is a consultant to RefinedScience. All other authors declare no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was a retrospective analysis utilizing a limited data set. Study approval and a full HIPAA waiver of consent was granted by the Colorado Multiple Institutional Review Board (approval number 23-2059)

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This retrospective study was approved by CU internal review board (IRB) and used a limited dataset with a waiver of consent from the CU IRB. The raw, individual patient data are protected and not available due to data privacy laws. The processed data are available at reasonable request to the corresponding author. The Flatiron Health data that supported the findings of this study were originated by and are the property of Flatiron Health, Inc., which has restrictions prohibiting the authors from making the data set publicly available. Requests for data sharing by license or by permission for the specific purpose of replicating results in this manuscript can be submitted to PublicationsDataAccess@flatiron.com.