Modelling post-chemotherapy stem cell dynamics in the bone marrow niche of AML patients

Abstract

Acute myeloid leukemia (AML) is a stem cell-driven malignancy of the blood forming (hematopoietic) system. Despite of high dose chemotherapy with toxic side effects, many patients eventually relapse. The “7+3 regimen”, which consists of 7 days of cytarabine in combination with daunorubicin during the first 3 days, is a widely used therapy protocol. Since peripheral blood cells are easily accessible to longitudinal sampling, significant research efforts have been undertaken to characterize and reduce adverse effects on circulating blood cells. However, much less is known about the impact of the 7+3 regimen on human hematopoietic stem cells and their physiological micro-environments, the so-called stem cell niches. One reason for this is the technical inability to observe human stem cells in vivo and the discomfort related to bone marrow biopsies. To better understand the treatment effects on human stem cells, we consider a mechanistic mathematical model of the stem cell niche before, during and after chemotherapy. The model accounts for different maturation stages of leukemic and hematopoietic cells and considers key processes such as cell proliferation, self-renewal, differentiation and therapy-induced cell death. In the model, hematopoietic (HSCs) and leukemic stem cells (LSCs) compete for a joint niche and respond to both systemic and niche-derived signals. We relate the model to clinical trial data from literature which longitudinally quantifies the counts of hematopoietic stem like (CD34+CD38-ALDH+) cells at diagnosis and after therapy. The proposed model can capture the clinically observed interindividual heterogeneity and reproduce the non-monotonous dynamics of the hematopoietic stem like cells observed in relapsing patients. Our model allows to simulate different scenarios proposed in literature such as therapy-related impairment of the stem cell niche or niche-mediated resistance. Model simulations suggest that during the post-therapy phase a more than 10-fold increase of hematopoietic stem-like cell proliferation rates is required to recapitulate the measured cell dynamics in patients achieving complete remission. We fit the model to data of 7 individual patients and simulate variations of the treatment protocol. These simulations are in line with the clinical finding that G-CSF priming can improve the treatment outcome. Furthermore, our model suggests that a decline of HSC counts during remission might serve as an indication for salvage therapy in patients lacking MRD (minimal residual disease) markers.