Mutation-Defined Strategies in Younger AML and the Limits of Paradigm Applicability

The experts discuss application of mutation-driven treatment approaches to younger, fit patients with AML and clarify where current low-intensity paradigms do and do not apply. The panel begins by noting that certain mutation subsets, such as KMT2A rearrangements and NPM1 mutations, were explicitly excluded from some landmark trials (including the PARADIGM study referenced later), simplifying initial treatment choices for these groups. Because their disease biology responds differently, these patients often require distinct induction models from the general AML population under consideration in PARADIGM.

The discussion then shifts to FLT3-mutated AML, a well-recognized proliferative subset. The speakers underscore that these patients were also not included in PARADIGM and historically demonstrate substantial benefit from intensive induction combined with FLT3 inhibitors. Although older patients may not experience the same magnitude of benefit, the prevailing consensus remains that younger, FLT3-mutated individuals should continue receiving intensive induction followed by targeted inhibition, often proceeding to allogeneic transplantation regardless of initial response.

Panelists also describe how accumulating institutional experience, such as data from the Colorado group, shows that certain mutations have suboptimal responses to azacitidine–venetoclax regimens. This reinforces that mutation biology should anchor treatment selection more strongly than age alone. The segment highlights the importance of avoiding overgeneralization; although low-intensity regimens are expanding rapidly, they are not appropriate for every mutation subset.

They then discuss the QuANTUM-like trial, evaluating intensive chemotherapy plus targeted inhibitors versus azacitidine–venetoclax in younger, induction-eligible patients. This trial is seen as essential for clarifying whether optimized intensive chemo or lower-intensity venetoclax-based therapies perform better in biologically aggressive disease.

Overall, mutation-defined AML, especially FLT3, KMT2A, and NPM1 subsets, still requires strategic use of intensive therapy and targeted agents. These cases highlight the limits of applying low-intensity induction universally and demonstrate why nuanced, mutation-driven treatment remains essential.