MRD intervention in AML: A new therapeutic horizon

Acute myeloid leukemia (AML) is a polyclonal malignancy marked by high relapse rates despite initial morphologic remission. Although measurable residual disease (MRD) is an established prognostic tool, increasing evidence supports a role for pre-emptive, MRD-directed therapy. AML monitoring is hampered by absence of a universal MRD marker, necessitating a more personalized approach. NPM1 is suited to an MRD-directed strategy as the mutation is AML-defining and monitoring methods highly sensitive. Critically, rising NPM1mut levels portend clinical relapse with high fidelity and recent studies demonstrate that venetoclax-based regimens induce rapid and deep MRD responses in a high proportion of patients with NPM1mut MRD relapse. The range of MRD-directed treatment options are expanding and include FLT3 and menin inhibitors for MRD relapse driven by FLT3-ITD and KMT2A rearrangements, respectively. To overcome the logistical issue of multiple MRD markers and associated therapies, we have developed a multi-target, multi-arm platform trial named INTERCEPT. Novel features include the potential to adaptively expand the range of MRD markers and directed therapies, seamless transition of patients from a local to centralized MRD monitoring framework, a clinical decision rules approach to allocate treatment in a hierarchical and pre-specified manner, creation of parallel protocol appendices to enable multiple industry partners to co-exist with commercial independence, and development of approaches to minimize the "MRD relapse to treatment" time interval. The future success of MRD-directed therapy will depend on rapid diagnostic turnaround, coordinated logistics and innovative clinical trial designs able to keep pace with advances in MRD-detection technologies and associated targeted therapies.