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The Day 14 bone marrow biopsy (D14 BMB) has historically been a key tool for early treatment response assessment in acute myeloid leukemia (AML), particularly following intensive chemotherapy. Traditionally, a blast count of <5% at D14 is associated with higher complete remission (CR) rates and improved overall survival (OS), while persistent disease often prompts re-induction therapy. However, emerging evidence suggests that while re-induction may increase CR rates, it does not consistently improve OS and is associated with significant morbidity. With the emergence of venetoclax-based and other targeted therapies, the traditional role of D14 BMB is being reconsidered, as these agents exhibit slower response kinetics, making later assessments and measurable residual disease (MRD) monitoring more reliable for treatment adaptation. This review critically examines the prognostic utility of D14 BMB in AML, its relevance across different treatment modalities, and its correlation with long-term outcomes. By synthesizing current evidence, we explore whether D14 BMB remains a valuable clinical tool or if a paradigm shift toward later assessments and MRD-guided decision-making is warranted in modern AML therapy.