Disease response and durability of remission are very heterogeneous in patients with acute myeloid leukaemia (AML). There is increasing evidence that the individual risk of early relapse can be predicted based on the initial treatment response. However, it is unclear how such a correlation is linked to functional aspects of AML progression and treatment. We suggest a mathematical model in which leukaemia-initiating cells and normal/healthy haematopoietic stem and progenitor cells reversibly change between an active state characterized by proliferation and chemosensitivity and a quiescent state, in which the cells do not divide, but are also insensitive to chemotherapy. Applying this model to 275 molecular time courses of nucleophosmin 1-mutated patients, we conclude that the differential chemosensitivity of the leukaemia-initiating cells together with the cells’ intrinsic proliferative capacity is sufficient to reproduce both, early relapse as well as long-lasting remission. We can, furthermore, show that the model parameters associated with individual chemosensitivity and proliferative advantage of the leukaemic cells are closely linked to the patients’ time to relapse, while a reliable prediction based on early response only is not possible based on the currently available data. Although we demonstrate with our approach, that the complete response data is sufficient to quantify the aggressiveness of the disease, further investigations are necessary to study how an intensive early sampling strategy may prospectively improve risk assessment and help to optimize individual treatments.

中文翻译：

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对细胞毒疗法的不同反应解释了急性髓系白血病患者的治疗动态：来自数学建模方法的见解

急性髓系白血病 (AML) 患者的疾病反应和缓解持续时间非常不同。越来越多的证据表明，早期复发的个体风险可以根据初始治疗反应进行预测。然而，尚不清楚这种相关性如何与 AML 进展和治疗的功能方面相关联。我们提出了一个数学模型，其中白血病起始细胞和正常/健康的造血干细胞和祖细胞在以增殖和化学敏感性为特征的活跃状态和细胞不分裂但对化学疗法不敏感的静止状态之间可逆地变化. 将此模型应用于核磷蛋白 1 突变患者的 275 个分子时间过程，我们得出结论，白血病起始细胞的不同化学敏感性以及细胞的内在增殖能力足以重现早期复发和长期缓解。此外，我们可以证明，与白血病细胞的个体化学敏感性和增殖优势相关的模型参数与患者的复发时间密切相关，而基于当前可用数据仅基于早期反应的可靠预测是不可能的. 尽管我们用我们的方法证明了完整的反应数据足以量化疾病的侵袭性，但仍有必要进行进一步的调查，以研究密集的早期采样策略如何前瞻性地改善风险评估并帮助优化个体治疗。