Optimization of Interferon–Alpha and Imatinib Combination Therapy for Chronic Myeloid Leukemia: A Modeling Approach

Abstract

Chronic myeloid leukemia (CML) in its chronic phase is treated with imatinib, with an attempt at discontinuation after at least three years of therapy in patients with deep molecular responses. Following the attempted discontinuation, approximately half of the patients regress and need to return to the imatinib treatment. Interferon-alpha monotherapy results in a cure in only a small percentage of patients. The combination of both drugs is simulated to optimize the treatment with respect to duration and schedule. This is achieved through a mathematical model in which three cell types are described: leukemic stem cells, mature leukemic cells, and CML-cytotoxic-lymphocyte (CML-CTL) cells. The model is simulated in silico, under different combination treatment regimens of imatinib and interferon-alpha. It is observed that a low level of CML-CTL cells causes failure of the combination treatment; an intermediate level of CML-CTL produces mixed results for the success of the combination treatment; a high level of CML-CTL cells promotes the successof the combination treatment. According to the model, treatment can lead to low-level persistence of CML stem cells after treatment discontinuation, even in the absence of acquired drug resistance. The model defines conditions under which imatinib-interferon-alpha treatment leads to CML eradication.

Nonlinear Dynamics of a Piecewise Modified ABC Fractional-Order Leukemia Model with Symmetric Numerical Simulations

“…Since they are based on assumptions and simplifications, the quality of the input data greatly affects their accuracy. In addition, the findings of simulations are not always easy to comprehend and can be computationally expensive [4][5][6].…”

Differential Response to Cytotoxic Drugs Explains the Dynamics of Leukemic Cell Death: Insights from Experiments and Mathematical Modeling

“…We suggest that numerical simulations of cancer chemotherapies can provide a means for researchers and clinicians to explore the possibility of predicting efficient, personalized treatment protocols based on mathematical parameters of cancer development in an individual. Ordinary differential equation (ODE)-based models have been used to define the modifications of continuous variables in mathematical models and have already been applied to several types of leukemia and lymphoma, including chronic myeloid leukemia [7], acute myeloid leukemia [8], T-cell lymphoma and periodic hematological diseases [9,10]. However, there are still no validated models for CLL.…”

Stability Analysis of a Mathematical Model of Hepatitis B Virus with Unbounded Memory Control on the Immune System in the Neighborhood of the Equilibrium Free Point

“…The combined method with IL-2 therapy was based on the proposed mathematical model described by the system of integro-differential equations. This approach was proven to be efficient in [6][7][8][9][10][11][12][13]. Previous models predicted the success rate of an antiviral cure but without any relation to the immune respond impact [14][15][16].…”