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. 2012 May 22;106(11):1742-52.
doi: 10.1038/bjc.2012.142. Epub 2012 Apr 26.

Therapy of Chronic Myeloid Leukaemia Can Benefit From the Activation of Stem Cells: Simulation Studies of Different Treatment Combinations

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Free PMC article

Therapy of Chronic Myeloid Leukaemia Can Benefit From the Activation of Stem Cells: Simulation Studies of Different Treatment Combinations

I Glauche et al. Br J Cancer. .
Free PMC article

Abstract

Background: Newly diagnosed patients with chronic myeloid leukaemia (CML) are currently treated with tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib or dasatinib. However, incomplete eradication of residual disease is a general problem of long-term TKI therapy. Activation of mouse haematopoietic stem cells by interferon-α (IFNα) stimulated the discussion of whether a combination treatment leads to accelerated eradication of the CML clone.

Methods: We base our simulation approach on a mathematical model describing human CML as a competition phenomenon between normal and malignant cells. We amend this model to incorporate the description of IFNα activity and simulate different scenarios for potential treatment combinations.

Results: We demonstrate that the overall sensitivity of CML stem cells to IFNα activation is a crucial determinant for the benefit of a potential combination therapy. We furthermore show that pulsed IFNα together with continuous TKI administration is the most promising strategy for a combination treatment in which the therapeutic benefit prevails adverse side effects.

Conclusion: Our modelling approach is a highly beneficial tool to quantitatively address the competition between normal and leukaemic haematopoiesis in treated CML patients. We derive testable predictions for different experimental settings that are suggested before the clinical implementation of the combination treatment.

Figures

Figure 1
Figure 1
Stem cell model. The model setup is characterised by two different signal contexts, A and Ω between which the cells can reversibly change depending on the cell number within the target context and the cell-specific affinity a (encoded in the transition functions fα/ω). Whereas activated cells in Ω undergo divisions and exponentially degrade their cell-specific affinity a, cells in A are quiescent and regain their affinity value. Cells with a>amin are referred to as stem cells, whereas cells with a<amin are referred to as differentiating cells. The differentiating cells undergo a proliferative phase before they mature without further division. Leukaemic cells (Ph+) have slightly altered transition kinetics between A and Ω. Model parameters are further adapted depending on the particular treatment scenario. BCR–ABL/ABL ratios are calculated based on the fraction of leukaemic cells in the pool of maturing cells.
Figure 2
Figure 2
CML pathogenesis and treatment. (A) Normal (blue) and leukaemic (grey) stem cells are regularly activated from their bone marrow niches (bottom, signalling context A) and subsequently divide (signalling context Ω). For the maintenance of a balance between quiescent and activated cells, some cells return to the niches and self-renew while others undergo further proliferation and differentiation, and contribute to peripheral blood. Owing to an increased activation of the leukaemic cells compared with normal cells the leukaemic pool slowly outcompetes normal haematopoiesis. (B) TKIs preferentially target activated leukaemic cells, thus leading to a significant reduction of tumour load. However, we also assume that leukaemic stem cells are even less likely to be activated under TKI treatment (indicated by the thinner arrows). Therefore, a residual pool of leukaemic cells persists over long time scales. (C) IFNα-mediated activation of both normal and leukaemic stem cells leads to a fast and sustained reduction of the residual leukaemic cells as these activated leukaemic (stem) cells are target for the primary TKI-mediated cell kill.
Figure 3
Figure 3
Continuous TKI plus continuous IFNα. (A) Shown are different response scenarios on the level of BCR–ABL/ABL ratios in peripheral blood: strong activation of leukaemic stem cells similar to normal HSCs (red), weak activation (green) and no activation of leukaemic cells (blue, only normal cells are activated by IFNα). Patient data (black) from the German cohort of the IRIS study (Hochhaus et al, 2009; Roeder et al, 2006) and simulation results for monotherapy with TKI imatinib (grey) are provided for reference. Subfigures (BG) show corresponding stem cell number in A (quiescent) and Ω (activated), compared with TKI monotherapy (grey) for strong (B, C), weak (D, E), and no activation scenarios (F, G).
Figure 4
Figure 4
Continuous TKI plus continuous IFNα with SRD. (A) BCR–ABL/ABL ratios in peripheral blood are shown for strong activation of leukaemic stem cells similar to normal HSCs (red), weak activation (green) and no activation of leukaemic cells (blue). However, in contrast to Figure 3, we assume that IFNα induces an additional SRD among normal and leukaemic cells. Subfigures (BG) show corresponding stem cell numbers in A (quiescent) and Ω (activated), compared with monotherapy with TKI imatinib (grey) for strong (B, C), weak (D, E), and no activation scenarios (F, G).
Figure 5
Figure 5
Continuous TKI plus pulsed IFNα. (A) BCR–ABL/ABL ratios in peripheral blood are shown for pulsed application of IFNα (1 day within 14 days) for different activation scenarios: strong activation of leukaemic stem cells similar to normal HSCs (red), weak activation (green) and no activation of leukaemic cells (blue, only normal cells are activated by IFNα). For the corresponding simulations we do not include the additional, IFNα-induced SRD. However, the simulation results only change marginally if the effect is taken into account (Supplementary Figure 4). Subfigures (BG) show corresponding stem cell numbers in A (quiescent) and Ω (activated), compared with monotherapy with TKI imatinib (grey) for strong (B, C), weak (D, E), and no activation scenarios (F, G).
Figure 6
Figure 6
Pulsed TKI plus pulsed IFNα. We show predicted BCR–ABL/ABL ratios in peripheral blood for the following representative treatment cycles: pulsed application of the TKI (day 1 to 14, no IFNα), pulsed application of only IFNα (day 15, no TKI), treatment interruption of x subsequent days past day 15 for different durations of the treatment interruption x: x=6 days (A, D, G, shown in red), x=2 days (B,E, H, shown in green) and x=0 days (C, F, I, shown in blue). Subfigures A–C correspond to the scenarios with strong activation of leukaemic stem cells by IFNα, subfigures D–F to the weak activation and subfigures G–I to the scenario in which leukaemic stem cells are not activated by IFNα. Thick curves correspond to smoothed values of the maximal BCR–ABL/ABL ratios, whereas the thin lines indicate the expected oscillations due to the cyclic treatment regimen.

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