Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Haertelstrasse 16-18, 04107 Leipzig, Germany.
J Theor Biol. 2010 May 21;264(2):287-300. doi: 10.1016/j.jtbi.2009.12.032. Epub 2010 Jan 18.
Intensification of cytotoxic chemotherapy enhances the outcome of several malignancies but is limited by haematotoxicity. While neutropenia and anaemia can be treated with supportive growth factor applications, thrombocytopenia remains a dose-limiting side effect due to the lack of clinically approved pharmaceutical growth factors. Hence, it is necessary to assess the degree of thrombocytopenia of newly designed intensified regimens in the planning phase of a clinical trial. We present a simple ordinary differential equations model of thrombopoiesis under chemotherapy which maps the dynamics of stem cells, CFU-Mk, megakaryocytes and platelets in spleen and circulation. Major regulatory cytokine of thrombopoiesis is thrombopoietin (TPO) whose production and consumption is explicitly modelled. TPO acts by increasing the number of mitoses of CFU-Mk and increasing the mass and maturation of megakaryocytes. Chemotherapy is modelled by a drug-dose and cell-stage specific acute cell loss. Most of the cell kinetic parameters of the model were taken from literature. Parameters regarding TPO regulation and chemotherapy toxicity were estimated by fitting the predictions of the model to time series data of platelets received from large clinical data sets of patients under seven different chemotherapies. We obtained a good agreement between model and data for all scenarios. Parameter estimates were biologically plausible throughout. For validation, the model also explains data of TPO and platelet dynamics after thrombopheresis taken from literature. We used the model to make clinically relevant predictions. Regarding thrombocytopenia we estimated that the CHOP regimen for the treatment of high-grade non-Hodgkin's lymphoma can be time-intensified to a cycle duration of 12 days while the time-intensified CHOEP regimen would result in severe cumulative toxicity. We conclude that our proposed model proved validity for both, different chemotherapeutic regimens and thrombopheresis as well. It is useful to assess the thrombocytopenic risk in the planning phase of a clinical trial.
细胞毒性化疗的强化增强了几种恶性肿瘤的疗效，但受到血液毒性的限制。虽然中性粒细胞减少症和贫血可以用支持性生长因子治疗，但由于缺乏临床批准的药物生长因子，血小板减少症仍然是一个剂量限制的副作用。因此，在临床试验的规划阶段，有必要评估新设计的强化方案的血小板减少程度。我们提出了一个简单的化疗下血小板生成的常微分方程模型，该模型描述了干细胞、CFU-Mk、巨核细胞和血小板在脾脏和循环中的动态。血小板生成的主要调节细胞因子是血小板生成素（TPO），其产生和消耗被明确建模。TPO 通过增加 CFU-Mk 的有丝分裂次数以及增加巨核细胞的质量和成熟度来发挥作用。化疗通过药物剂量和细胞阶段特异性急性细胞损失来建模。该模型的大多数细胞动力学参数均来自文献。关于 TPO 调节和化疗毒性的参数是通过将模型的预测拟合到来自 7 种不同化疗方案的大量患者临床数据集的血小板时间序列数据来估计的。对于所有情况，模型与数据之间都有很好的一致性。参数估计在整个过程中都是合理的。为了验证，该模型还解释了文献中从血小板生成术获得的 TPO 和血小板动力学的数据。我们使用该模型进行了临床相关的预测。关于血小板减少症，我们估计治疗高级非霍奇金淋巴瘤的 CHOP 方案可以将周期时间缩短至 12 天，而强化的 CHOEP 方案则会导致严重的累积毒性。我们得出结论，我们提出的模型不仅对不同的化疗方案而且对血小板生成术都具有有效性。它可用于在临床试验规划阶段评估血小板减少症的风险。
