We report a female in her late 80s with high-risk pleomorphic mantle cell lymphoma (MCL) harboring germline ATM mutation and 17p deletion who achieved complete metabolic response with zanubrutinib plus rituximab. Serial peripheral blood next-generation sequencing (NGS) during remission revealed emergence of a molecularly distinct pre-leukemic clone characterized by DNMT3A, TET2, and a TP53 point mutation (p.Tyr220Cys)—distinct from the original 17p deletion. Approximately 20 months after MCL diagnosis, she developed acute myeloid leukemia (AML) with FLT3-TKD and NPM1 mutations, confirming transformation of the pre-leukemic clone. Longitudinal VAF tracking demonstrated complete eradication of MCL-associated mutations (ID3, BIRC3) while the myeloid clone expanded. This case provides direct molecular evidence that AML arose from clonal evolution of a pre-existing hematopoietic clone rather than direct MCL transformation, with implications for understanding second malignancies in BTK inhibitor-treated patients.

Acute myeloid leukemia (AML) is predominantly a disease of older adults, with a median age at diagnosis of 68–72 years. Management in this population is complicated by adverse cytogenetic and molecular features, higher rates of secondary disease, and patient-specific factors such as comorbidity and frailty. This narrative review synthesizes the current evidence on risk stratification and treatment of AML in adults aged 60 years and older, with dedicated attention to patients aged 60–75 (“fit” older adults) and those older than 75, including octogenarians. The VIALE-A trial established venetoclax plus azacitidine as standard of care for patients ineligible for intensive chemotherapy (composite complete remission 66.4%; median overall survival 14.7 vs. 9.6 months with azacitidine alone). For fit adults aged 60–75, the choice between intensive chemotherapy and venetoclax-based regimens remains under active investigation, with emerging randomized data suggesting comparable outcomes and a possible advantage for venetoclax-based approaches in adverse-risk disease. Risk stratification has evolved beyond the 2022 European LeukemiaNet (ELN) classification, which was developed in intensively treated cohorts; the 2024 ELN genetic risk classification for less-intensive therapy now provides a framework specific to this population. TP53-mutated AML, including multi-hit disease, remains the dominant unmet need across all treatment modalities. Advances in reduced-intensity conditioning have expanded transplant eligibility into the seventh and eighth decades, and molecularly targeted approaches, including FLT3, IDH1/2, and menin inhibitors, are reshaping frontline and relapsed/refractory therapy. This review covers epidemiology, risk stratification, treatment stratified by age, fitness, and genetic subgroup, the role of transplantation and maintenance therapy, and the limitations of the current evidence base for this heterogeneous population.