Chemotherapy Drug Scheduling for the Induction Treatment of Patients With Acute Myeloid Leukemia

Abstract

Leukemia is an immediately life-threatening cancer wherein immature blood cells are overproduced, accumulate in the bone marrow (BM) and blood and causes immune and blood system failure. Treatment with chemotherapy can be intensive or nonintensive and can also be life-threatening since only relatively few patient-specific and leukemia-specific factors are considered in current protocols. We have already presented a mathematical model for one intensive chemotherapy cycle with intravenous (i.v.) daunorubicin (DNR), and cytarabine (Ara-C). This model is now extended to nonintensive subcutaneous (SC) Ara-C and for a standard intensive chemotherapy course (four cycles), consistent with clinical practice. Model parameters mainly consist of physiological patient data, indicators of tumor burden and characteristics of cell cycle kinetics. A sensitivity analysis problem is solved and cell cycle parameters are identified to control treatment outcome. Simulation results using published cell cycle data from two acute myeloid leukemia patients are presented for a course of standard treatment using intensive and nonintensive protocols. The aim of remission-induction therapy is to debulk the tumor and achieve normal BM function; by treatment completion, the total leukemic population should be reduced to at most 10(9) cells, at which point BM hypoplasia is achieved. The normal cell number should be higher than that of the leukemic, and a 3-log reduction is the maximum permissible level of population reduction. This optimization problem is formulated and solved for the two patient case studies. The results clearly present the benefits from the use of optimization as an advisory tool for treatment design.

A mathematical model of subpopulation kinetics for the deconvolution of leukaemia heterogeneity

“…This tool also has the potential to evaluate clonal models of leukaemogenesis [4,6,39] in order to better understand the pathogenesis of disease. In the context of CCS drug dosage and scheduling, the PBM could give a narrower window of action than what is currently used in treatment regimens, thereby limiting drug toxicity yet improving efficacy [8,7]. Drugs, such as small molecule inhibitors, currently being tested that specifically target leukaemia subclones (e.g.…”

“…We have previously shown that assessment of proliferation kinetics and cellcycle times in AML may provide optimized chemotherapy protocols in order to improve tumour cell kill yet minimize toxicity for the patient [7,8]. Defining the changes that occur in the cell cycle is central to these optimized treatment protocols since many chemotherapeutic drugs are cell-cycle phase-specific and heterogeneity of patient responses may be broadly defined in terms of cell-cycle phase distributions and timings [9].…”

Mathematical Models for the Influence of Cytarabine on White Blood Cell Dynamics in Acute Myeloid Leukemia

“…The model showed a good trade-off between capturing the important aspects of the dynamics, containing a moderate number of identifiable model parameters, and being applicable for different cytostatic drugs. It has become the gold-standard model in this field with different PK and population-based modifications to topotecan [21], to daunorubicin [22], to a combination therapy of Ara-C (low-dose), etoposide and daunorubicin in the induction treatment for AML [8], to a physiologically based PK model for the induction therapy of AML patients with daunorubicin and Ara-C (low-dose) [23], to a combination therapy of carboplatin, etoposide and thiotepa [24], to paclitaxel [10], to an individual-based approach [25], and to drug specific optimisations [9]. The model assumes a clustering of cells in compartments with identical properties.…”

Selecting a Differential Equation Cell Cycle Model for Simulating Leukemia Treatment

“…8 In this section, each model will be embedded into a PK/PD model of chemotherapy delivery in leukemia 20 and tested for its sensitivity to chemotherapy (as captured by the chemotherapy drug effect parameters k D, S and k D, G for S and G1 phases respectively in CCP-ODE-PD,…”