Predicting Minimal Residual Disease In Acute Myeloid Leukemia Through Stochastic Modeling Of Clonality

Event-free and overall survival remains poor for acute myeloid leukemia (AML). Chemo-resistant clones contributing to relapse of the disease arise from minimal residual disease (MRD) rather than resulting from newly acquired mutations during or after chemotherapy. MRD is the presence of measurable leukemic cells using non-morphologic assays. It is considered a strong predictor of relapse. The dynamics of clones comprising MRD is poorly understood and is considered influenced by a form of Darwinian selection. We propose a stochastic model based on a multitype (multi-clone) age-dependent Markov branching process to study how random events in MRD contribute to the heterogeneity in response to treatment in a cohort of six patients from The Cancer Genome Atlas database with whole genome sequencing data at two time points. Our model offers a more accurate understanding of how relapse arises and which properties allow a leukemic clone to thrive in the Darwinian competition among leukemic and normal hematopoietic clones. The model suggests a quantitative relationship between MRD and time to relapse and therefore may aid clinicians in determining when and how to implement treatment changes to postpone or prevent the time to relapse.