IEEE Trans Biomed Eng. 2020 Dec;67(12):3296-3306. doi: 10.1109/TBME.2020.2982749. Epub 2020 Nov 19.
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.
中性粒细胞减少是急性髓细胞白血病（AML）强化化疗中常见的不良反应。它常伴有感染并发症。数学模型、模拟和治疗过程的优化将是支持临床决策的有价值工具，可能会减少更严重的副作用和更深的缓解。然而，到目前为止，还没有经过验证的数学模型可以同时模拟化疗对白细胞（WBC）计数和白血病细胞的影响。
我们开发了一个群体药代动力学/药效学（PK/PD）模型，该模型结合了一个考虑内源性粒细胞集落刺激因子（G-CSF）的骨髓抑制模型、阿糖胞苷（Ara-C）的 PK 模型、外源性 G-CSF 的皮下吸收模型和一个两室模型用于白血病细胞。该模型拟合了来自 II 期对照临床试验的新型 Ara-C 联合 G-CSF 方案巩固治疗的 44 例 AML 患者的数据。此外，我们能够针对疾病进展、WBC 最低点以及 Ara-C 和 G-CSF 的量来优化治疗方案。
所开发的 PK/PD 模型提供了良好的预测准确性，并解释了 WBC、G-CSF 和白血病细胞之间的相互作用。对于 14 名患者（那些有可用的骨髓白血病细胞计数的患者），我们在最低点达到了中位数为 4.2 倍的更高的 WBC 计数，这是巩固治疗中最关键的时间。模拟结果表明，相对骨髓白血病细胞计数保持在临床重要阈值 5%以下，Ara-C 中位数减少了 60%。
这些计算机模拟结果表明了优化 AML 患者治疗方案的益处。
到 2017 年，尚无新药获批用于治疗 AML，这促进了现有药物的最佳使用。
