In-silico comparison of two induction regimens (7 + 3 vs 7 + 3 plus additional bone marrow evaluation) in acute myeloid leukemia treatment

Abstract

BackgroundClinical 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).ResultsOur 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (10.1186/s12918-019-0684-0) contains supplementary material, which is available to authorized users.

Computational Reconstruction of Clonal Hierarchies From Bulk Sequencing Data of Acute Myeloid Leukemia Samples

“…The clinical course of the disease shows a significant among-patient variability which can only be partially predicted based on currently existing risk-stratifications ( Stiehl et al, 2014 , 2015 , 2020 ; Döhner et al, 2017 ; Wang et al, 2017 ; Roloff and Griffiths, 2018 ). To better understand the mechanism of relapse and to identify patients at risk, a quantitative understanding of clonal dynamics is required ( Ding et al, 2012 ; Cancer Genome Atlas Research Network, 2013 ; Stiehl et al, 2014 ; Greif et al, 2018 ; Banck and Görlich, 2019 ; Cocciardi et al, 2019 ; Lorenzi et al, 2019 ; Ediriwickrema et al, 2020 ).…”

“…From the computational side, a range of tools have been developed to fit models and extract quantitative information from data in the context of AML ( Attolini et al, 2010 ; Nobile et al, 2019 ) and other cancers, see e.g., ( Roth et al, 2014 ; Caravagna et al, 2020 ) for statistical approaches using variant allele frequencies, ( Attolini et al, 2010 ) for a population-based model and ( Nobile et al, 2019 ) for xenotransplant data. These approaches are complemented by process-based models ( Stiehl et al, 2014 , 2016 ; Rahman et al, 2018 ; Banck and Görlich, 2019 ; Dinh et al, 2019 , 2020 ; Salichos et al, 2020 ).…”

Computational reconstruction of clonal hierarchies from bulk sequencing data of acute myeloid leukemia samples

“…Mathematical and computational models are important to link genetic data to functional cell properties such as proliferation and self-renewal of leukemic stem cells, both of which are of prognostic relevance [9,11,12,13,14,18,19].…”

“…LSC at relapse are characterized by a slow proliferation rate and a further increase of the self-renewal fraction [9,19]. Computer simulations and model analysis indicate that increased self-renewal leads to a competitive advantage of the respective clones and that clones appearing later in the course of the disease have a higher self-renewal compared to clones emerging earlier [9,13,14,19,22].…”

“…Mathematical and computational models are important to link genetic data to functional cell properties such as proliferation and self-renewal of leukemic stem cells, both of which are of prognostic relevance [9,11,12,13,14,18,19]. Such models allow to estimate which leukemic cell properties correspond to the clinical course of an individual patient and to link the estimates to mutation data [9,11,12].…”