Development of a Dynamic Counterfactual Risk Stratification Strategy for Newly Diagnosed Patients With AML Treated With Venetoclax and Azacitidine

PURPOSE The objective of this study was to develop a flexible risk stratification strategy for AML that is specific for venetoclax plus azacitidine (ven/aza), addresses real-world data (RWD) issues, and is also adaptable to different use cases. METHODS A series of tunable risk models (RMs) were generated from a dynamic counterfactual machine learning (ML) strategy. These used a range of features from diagnostic AML samples and were tested using objective metrics on a single-institution cohort of 316 newly diagnosed patients treated with ven/aza. RM performance was tested using various model assumptions, data elements, and end points and with applications to an external AML real-world cohort (RWC). RESULTS Favorable, intermediate, and adverse risk groups were identified in a series of ML-based RMs using different assumptions, for genetic-only or genetic-plus-phenotypic data elements and with overall survival and event-free survival as end points. Most RMs demonstrated equitable patient distribution (approximately 20%-40% in each risk group), significant separation between risk strata (log-rank–based P values <0.001), and predictability computed by time-dependent survival AUC values of 0.60-0.70. Similar performance was observed when the proposed RM strategy was adapted and compared with the European Leukemia Net 2022 using the external RWC. CONCLUSION The proposed ML strategy addresses a variety of RWD considerations and is readily tunable through coding and parameter updates for different contexts and use case needs. This strategy represents a novel approach to developing more effective RMs for AML and possibly other diseases.