Patient-derived organoids in hematologic malignancies: Fidelity and translation beyond animals

Hematologic patient-derived organoids (PDOs) reconstruct human bone marrow and lymph node microenvironments in 3D, preserving malignant cell states, clonal diversity, and clinically relevant drug responses. Leukemia PDOs artificially mimic the complex bone marrow niche and cytokine dependencies. Lymphoma PDOs recapture immune–stromal interactions and enable testing of targeted and immunotherapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cells. Multiple myeloma PDOs model the bone marrow microenvironment and maintain plasma tumor cell survival cues that drive drug resistance. Across preclinical models, PDOs outperform 2D cultures, spheroids, and xenografts in mechanistic and translational resolution. Converging regulatory support and National Institutes of Health investment position hematologic PDOs as frontline platforms for functional precision oncology. This review highlights current systems, disease-specific advances, quality standards, and future directions.