Multimodal AI reading of genetic complexity and residual marrow composition in acute promyelocytic leukemia.

Introduction: Acute promyelocytic leukemia (APL) is defined by its genetics, yet interphase fluorescence Methods: We describe two image-derived readouts for a retrospective cohort of patients with APL. A genetic complexity axis classifies the FISH fusion signal pattern and flags any additional cytogenetic abnormality (ACA) beyond the t(15;17), directly from raw, unarranged metaphase spreads. A marrow composition axis extends a cytomorphology pipeline, built on frozen DinoBloom embeddings and a per-cell classification head directly supervised on an annotated subset, from promyelocyte detection to a seven-class differential count. From this composition, we compute a residual hematopoiesis index, the model-estimated fraction of non-leukemic nucleated marrow cells, so that a higher value indicates a larger non-leukemic fraction. The index is a morphology-derived surrogate for residual non-leukemic marrow composition and carries no immune-phenotypic information. The association between the two axes is computed directly from patient-level, out-of-fold branch outputs; a small, three-node fusion module over the two genetic and one composition readout supports only a secondary, exploratory analysis, reported in the Supplementary Material. The cohort held 700 patients with smear, FISH, and karyotype linked per patient, of whom 650 had complete clinical annotation; we evaluated each branch with patient-stratified fivefold cross-validation, five repeats, pooled out-of-fold, and report bootstrap confidence intervals (CIs) over patients. Diagnostic flow cytometry was retrievable for 118 patients, and 80 slides were re-scanned with fields independently re-selected, to check the index against an external measurement and against itself. Results: The fusion-pattern classifier had a macro-averaged F1 of 0.82 across the five signal classes, and the karyotype ACA reader had an area under the curve (AUC) of 0.86. The residual hematopoiesis index had a median of 0.42 (interquartile range, IQR, 0.29 to 0.58) across the cohort, tracked the flow-derived non-blast fraction at a Spearman correlation of 0.80 (95% CI 0.72 to 0.86) in the 118 patients with flow data, and had an intraclass correlation of 0.91 on re-scanned slides. Genetic complexity and the residual hematopoiesis index were associated at a Spearman Conclusion: Image-derived genetic complexity was positively associated with the residual hematopoiesis index, and the association persisted under the adjustments and substitutions applied to it. These findings describe a cross-sectional association in a single-center, retrospective cohort, not a validated diagnostic or risk tool. The residual hematopoiesis index summarizes morphology alone, its agreement with flow cytometry is supportive rather than confirmatory, and the secondary DS analysis drew on a smaller, clinically annotated subset of the cohort rather than on every patient.