Predicting Minimal Residual Disease in Acute Myeloid Leukemia through Stochastic Modeling of Clonality

Abstract

Event-free and overall survival remains poor for acute myeloid leukemia (AML). Chemoresistant 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. Author summaryRelapse affects about 50% of AML patients who achieved remission after treatment, and the prognosis of relapsed AML is poor. Current evidence has shown that in many patients, mutations giving rise to relapse are already present at diagnosis and remain in small numbers in remission, defined as the minimal residual disease (MRD). We propose a mathematical model to analyze how MRD develops into relapse, and how random events in MRD may affect the patient's fate. This work may aid clinicians in predicting the range of outcomes of chemotherapy, given mutational data at diagnosis. This can help in choosing treatment strategies that reduce the risk of relapse.

Beyond Deterministic Models in Drug Discovery and Development

“…Fluctuations also become less meaningful when the value of K increases, since the noise increases by the square root of cell the number and, therefore, for long periods of time, it fluctuates on a scale of ffiffiffi ffi K p . This model behavior could be useful to characterize the minimal residual disease (MRD) and how it can develop into the complete cure of the patient or into a relapse, as demonstrated in [41], where the authors showed how random events in MRD may affect the patient's fate. This work may aid clinicians in choosing treatment strategies that reduce the risk of relapse.…”