Banck Jan Christoph, Görlich Dennis
Institute of Biostatistics and Clinical Research, Westfälische Wilhelms-Universität Münster, Münster, Germany.
Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.
BMC Syst Biol. 2019 Jan 31;13(1):18. doi: 10.1186/s12918-019-0684-0.
Clinical integration of systems biology approaches is gaining in importance in the course of digital revolution in modern medicine. We present our results of the analysis of an extended mathematical model describing abnormal human hematopoiesis. The model is able to describe the course of an acute myeloid leukemia including its treatment. In first-line treatment of acute myeloid leukemia, the induction chemotherapy aims for a rapid leukemic cell reduction. We consider combinations of cytarabine and anthracycline-like chemotherapy. Both substances are widely used as standard treatment to achieve first remission. In particular, we compare two scenarios: a single-induction course with 7 days cytarabine and 3 day of anthracycline-like treatment (7 + 3) with a 7 + 3 course and a bone marrow evaluation that leads, in case of insufficient leukemic cell reduction, to the provision of a second chemotherapy course. Three scenarios, based on the leukemias growth kinetics (slow, intermediate, fast), were analyzed. We simulated different intensity combinations for both therapy schemata (7 + 3 and 7 + 3 + evaluation).
Our model shows that within the 7 + 3 regimen a wider range of intensity combinations result in a complete remission (CR), compared to 7 + 3 + evaluation (fast: 64.3% vs 46.4%; intermediate: 63.7% vs 46.7%; slow: 0% vs 0%). Additionally, the number of simulations resulting in a prolonged CR was higher within the standard regimen (fast: 59.8% vs 40.1%; intermediate: 48.6% vs 31.0%; slow: 0% vs 0%). On the contrary, the 7 + 3 + evaluation regimen allows CR and prolonged CR by lower chemotherapy intensities compared to 7 + 3. Leukemic pace has a strong impact on treatment response and especially on specific effective doses. As a result, faster leukemias are characterized by superior treatment outcomes and can be treated effectively with lower treatment intensities.
We could show that 7 + 3 treatment has considerable more chemotherapy combinations leading to a first CR. However, the 7 + 3 + evaluation regimen leads to CR for lower therapy intensity and presumably less side effects. An additional evaluation can be considered beneficial to control therapy success, especially in low dose settings. The treatment success is dependent on leukemia growth dynamics. The determination of leukemic pace should be a relevant part of a personalized medicine.
在现代医学的数字革命进程中，系统生物学方法的临床整合正变得愈发重要。我们展示了对一个描述人类异常造血的扩展数学模型的分析结果。该模型能够描述急性髓系白血病的病程及其治疗过程。在急性髓系白血病的一线治疗中，诱导化疗旨在迅速减少白血病细胞。我们考虑阿糖胞苷和蒽环类化疗药物的联合使用。这两种药物都被广泛用作实现首次缓解的标准治疗药物。特别是，我们比较了两种情况：一种是7天阿糖胞苷和3天蒽环类治疗的单诱导疗程（7 + 3），另一种是7 + 3疗程以及在白血病细胞减少不足时进行骨髓评估并提供第二个化疗疗程的情况。基于白血病生长动力学（缓慢、中等、快速）分析了三种情况。我们模拟了两种治疗方案（7 + 3和7 + 3 + 评估）的不同强度组合。
我们的模型表明，与7 + 3 + 评估方案相比，在7 + 3方案中，更广泛的强度组合可导致完全缓解（CR）（快速型：64.3%对46.4%；中等型：63.7%对46.7%；缓慢型：0%对0%）。此外，在标准方案中导致CR延长的模拟次数更多（快速型：59.8%对40.1%；中等型：48.6%对31.0%；缓慢型：0%对0%）。相反，与7 + 3相比，7 + 3 + 评估方案通过较低的化疗强度即可实现CR和CR延长。白血病进展速度对治疗反应尤其是对特定有效剂量有强烈影响。因此，进展较快的白血病具有更好的治疗效果，并且可以用较低的治疗强度有效治疗。
我们可以证明，7 + 3治疗有更多可导致首次CR的化疗组合。然而，7 + 3 + 评估方案以较低的治疗强度实现CR，并且可能副作用更少。额外的评估可被认为有助于控制治疗效果，尤其是在低剂量情况下。治疗效果取决于白血病的生长动态。确定白血病进展速度应是个性化医疗的一个相关部分。
