Model-Based Optimal AML Consolidation Treatment.

Abstract

Neutropenia is an adverse event commonly arising during intensive chemotherapy of acute myeloid leukemia (AML). It is often associated with infectious complications. Mathematical modeling, simulation, and optimization of the treatment process would be a valuable tool to support clinical decision making, potentially resulting in less severe side effects and deeper remissions. However, until now, there has been no validated mathematical model available to simulate the effect of chemotherapy treatment on white blood cell (WBC) counts and leukemic cells simultaneously. We developed a population pharmacokinetic/pharmacodynamic (PK/PD) model combining a myelosuppression model considering endogenous granulocyte-colony stimulating factor (G-CSF), a PK model for cytarabine (Ara-C), a subcutaneous absorption model for exogenous G-CSF, and a two-compartment model for leukemic blasts. This model was fitted to data of 44 AML patients during consolidation therapy with a novel Ara-C plus G-CSF schedule from a phase II controlled clinical trial. Additionally, we were able to optimize treatment schedules with respect to disease progression, WBC nadirs, and the amount of Ara-C and G-CSF. The developed PK/PD model provided good prediction accuracies and an interpretation of the interaction between WBCs, G-CSF, and blasts. For 14 patients (those with available bone marrow blast counts), we achieved a median 4.2-fold higher WBC count at nadir, which is the most critical time during consolidation therapy. The simulation results showed that relative bone marrow blast counts remained below the clinically important threshold of 5%, with a median of 60% reduction in Ara-C. These in silico findings demonstrate the benefits of optimized treatment schedules for AML patients. Until 2017, no new drug had been approved for the treatment of AML, fostering the optimal use of currently available drugs.