A computational model of human granulopoiesis to simulate the hematotoxic effects of multicycle polychemotherapy

Abstract

Moderate intensification of conventional multicycle chemotherapy has recently been shown to improve treatment results in malignant lymphomas and might prove to be beneficial also in other malignancies. However, the feasibility of such regimens is mainly limited by their granulopoietic toxicity. To identify and quantify the basic cell kinetic mechanisms of damage and stimulation caused by cytotoxic drugs and recombinant human granulocyte colony-stimulating factor (rhG-CSF), respectively, we developed a mathematical model of human granulopoiesis that allows simulation of leukocyte concentration profiles under 10 different multicycle polychemotherapy regimens with varying drug composition, dosage, and scheduling, including rhG-CSF assistance. Clinical data on leukocyte profiles were obtained from large numbers of patients treated within several multicenter trials. Simulation studies show that the leukocyte profiles of all regimens can be appropriately fitted using one single set of assumptions and parameters for the cell kinetic effects of cytotoxic drugs and rhG-CSF. Furthermore, the model can be used to explain the interindividual heterogeneity of hematotoxicity by a differential chemosensitivity, which might be useful in drug scheduling for specific risk groups. It is demonstrated that the model can be used to design and to select new drug schedules for subsequent clinical trial testing.

Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization

“…A mathematical description of granulopoiesis has recently been published by our group. 47 Although the granulopoiesis model has been adjusted for the human situation, the plan is to link these 2 model classes to arrive at a comprehensive model of hematopoiesis including the dynamics of stem cells and differentiated cells as well as interaction effects between them.…”

The impact of CD34+ cell dose on engraftment after SCTs: personalized estimates based on mathematical modeling

“…The existing models of healthy hematopoiesis are either mostly phenomenological [20][21][22][23][24] or solely based on regulation in the stem cell pool [24][25][26] and do not describe regulation of the whole system of differentiating cells. The latter is crucial for reconstitution after large perturbations and for quantitative analysis of post transplant dynamics.…”

Mathematical study on kinetics of hematopoietic stem cells – theoretical conditions for successful transplantation

“…Considerable efforts have been devoted to describe the pharmacokinetic dynamics of G-CSF injection for postchemotherapy to cancer [23,26,61,70,71,75] or treatment to SCN and CN [3,9,27,69]. Note that G-CSF can affect the neutrophil maturation period.…”