Multimodal Artificial Intelligence Fusion Models to Predict Response to Venetoclax and Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia

Venetoclax and azacitidine (ven-aza) is a standard of care therapy for newly diagnosed acute myeloid leukemia (AML) patients unfit to receive intensive therapy, and may also be appropriate for certain fit patients. Models predicting response to ven-aza currently focus predominantly on genetics. Here, we present two multimodal fusion models: a custom ResNet-34-based model and a pathology foundation model fine-tuned for bone marrow smear (BMS) images that combine clinical and genetic variables with whole slide images. Training on 193 newly diagnosed AML patients who received ven-aza, we obtained an area-under-the-receiver-operating-characteristic (AUROC) of 0.79 and 0.82 for the ResNet-based and fine-tuned foundation models in a heldout test set, and 0.76 and 0.73 in an external validation set, predicting best response to this therapy. Sensitivity analysis showed that fusing image data with clinical and genetic variables outperformed training on either modality alone. In univariable and multivariable analyses, image-based classification was an independent predictive marker, second only in effect size to IDH1/2 mutation status, outperforming other genetic alterations. Image-based explainability showed high model attention on myeloblasts, suggesting previously unrecognized cell-specific patterns associated with response. Our findings suggest BMS images complement genetic biomarkers to refine outcome prediction in ven-aza treatment and incentivize AI-supported outcome prediction, including bone marrow morphology.