Mathematical models for cytarabine-derived myelosuppression in acute myeloid leukaemia

Abstract

We investigate the personalisation and prediction accuracy of mathematical models for white blood cell (WBC) count dynamics during consolidation treatment using intermediate or high-dose cytarabine (Ara-C) in acute myeloid leukaemia (AML). Ara-C is the clinically most relevant cytotoxic agent for AML treatment. We extend a mathematical model of myelosuppression and a pharmacokinetic model of Ara-C with different hypotheses of Ara-C’s pharmacodynamic effects. We cross-validate the 12 model variations using dense WBC count measurements from 23 AML patients. Surprisingly, the prediction accuracy remains satisfactory in each of the models despite different modelling hypotheses. Therefore, we compare average clinical and calculated WBC recovery times for different Ara-C schedules as a successful methodology for model discrimination. As a result, a new hypothesis of a secondary pharmacodynamic effect on the proliferation rate seems plausible. Furthermore, we demonstrate the impact of treatment timing on subsequent nadir values based on personalised predictions as a possibility for influencing/controlling myelosuppression.

Model-Based Simulation of Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

“…Given this good correspondence between cross-validated data and simulations, we felt encouraged to compare simulations of different treatment protocols as specified in Table 2. Note, however, that generalizations of mathematical models personalized for data from one protocol to another have to be considered with extreme care (compare the discussion for acute myeloid leukemia models by Jost et al (2019)). The impact of model variations on the outcome of simulation studies is usually significant.…”

Model-Based Optimal AML Consolidation Treatment

“…Nine of the patients (1 only in the first cycle and 7 CCs each for d123 and D123) did not receive lenograstim. For the analysis in the subsequent section called Modeling exogenous G-CSF, the patientwise cycles of the current dataset were treated independently (although several cycles belong to the same patient) and combined with the publicly available dataset (denoted by MD in Figure 2(a)) from the supporting information of [34]. This dataset was retrospectively collected from records of clinical routine and provided by the Department of Hematology and Oncology, Magdeburg University Hospital, Magdeburg, Germany.…”

“…The two-compartment PK model (x 1 , x 2 ) for Ara-C was taken from [34] as our clinical data did not contain Ara-C measurements. The PK model describes the PKs and biphasic elimination of Ara-C after high-dose infusions [35].…”

“…Matured cells x wbc die by apoptosis with a death rate constant k wbc . Ara-C is incorporated into the DNA leading to cell death, such that a loglinear PD term as a first order kinetics negatively influences the proliferation of stem cells, equivalent to [34]. We assumed that the plasma concentration is an adequate surrogate for the PD effect of Ara-C in the BM, as no PK model for high-dose Ara-C is available which considering the BM as an additional compartment.…”

“…The upper limit of hourly Ara-C infusions was chosen to be 2 g per hour, being the recommended maximum amount of a high-dose treatment schedule for a patient under 60 years with a BSA of 2 m 2 which should not be exceeded [1]. As mentioned in the introduction, intermediate Ara-C dosage is administered to elderly patients but in our previous study [34] a 64 year old patient was treated with D12 such that we decided to define the upper limit of 2 g per hour as a further degree of freedom during optimization. The upper limit of lenograstim administrations was chosen to be 263 µg equivalently to the actual daily administered dose amount.…”