Mechanism of treatment-free remission in patients with chronic myeloid leukemia revealed by a computational model of CML evolution

Abstract

In the past few years, international treatment guidelines for chronic myeloid leukemia (CML) have incorporated recommendations for attempting discontinuation of treatment with tyrosine kinase inhibitors (TKIs) outside of the setting of a clinical trial with the aim of treatment-free remission (TFR). Multiple clinical studies have shown consistent results that 40%-50% patients can achieve long-term TFR after TKI discontinuation, and most relapse patients undergo molecular recurrence within 6 months after TKI discontinuation, however the underling mechanisms remain unclear. To understand the mechanism of TFR in patients with CML, we consider the competition between leukemia stem cell and bone marrow microenvironment, and develop a mathematical model to investigate the CML progression dynamics. Model simulations are consistent with clinical observation of CML progression, and reveal a mechanism of dimorphic response after TKI discontinuation. Our model predicts that neoplasitic microenvironment is significant for CML occurrence and progression. We furthermore discuss the prediction of TFR based on the change rates of microenvironment index and leukemia stem cells ratio prior TKI discontinuation.