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.

Highlights

  • Acute myeloid leukaemia (AML) is a malignant clonal disorder of myeloid stem and progenitor cells

  • Regarding the root mean squared errors for M1-M5 the results implied that one transition compartment and initial approach I3 were the best choice for the structural model and served as a starting point to analyse different pharmacodynamic effects of anthracyclines and/or cytarabine (Ara-C)

  • Comparing the mean maturation time (MMT) resulting from the population approach for M1-M3 we achieved a slight decrease from 154 h to 144 h to 128 h by using the corrected formula MMT = n/ktr[17] instead of the original formula MMT = (n + 1)/ktr [12]

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Summary

Introduction

Acute myeloid leukaemia (AML) is a malignant clonal disorder of myeloid stem and progenitor cells. In untreated AML, immature neoplastic myeloid blasts rapidly proliferate and suppress the generation and maturation of blood cells in the bone marrow. While being a curable disease using chemotherapy including anthracyclines and/or cytarabine (Ara-C), this approach leads to prolonged myelosuppression with extremely low white blood cell (WBC) counts (leukopenia), i.e. values below 1 G/L, associated with a high risk of infection and treatment-related mortality [1]. Consolidation treatment, repetitive (up to 4) cycles of intermediate-/high-dose Ara-C (1 − 3 g/m2) [2], is given once patients achieve complete remission (CR) and is considered the most important part of chemotherapy in preventing relapses.

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