Abstract
Recent mathematical models have been developed to study the dynamics of chronic myelogenous leukemia (CML) under imatinib treatment. None of these models incorporates the anti-leukemia immune response. Recent experimental data show that imatinib treatment may promote the development of anti-leukemia immune responses as patients enter remission. Using these experimental data we develop a mathematical model to gain insights into the dynamics and potential impact of the resulting anti-leukemia immune response on CML. We model the immune response using a system of delay differential equations, where the delay term accounts for the duration of cell division. The mathematical model suggests that anti-leukemia T cell responses may play a critical role in maintaining CML patients in remission under imatinib therapy. Furthermore, it proposes a novel concept of an “optimal load zone” for leukemic cells in which the anti-leukemia immune response is most effective. Imatinib therapy may drive leukemic cell populations to enter and fall below this optimal load zone too rapidly to sustain the anti-leukemia T cell response. As a potential therapeutic strategy, the model shows that vaccination approaches in combination with imatinib therapy may optimally sustain the anti-leukemia T cell response to potentially eradicate residual leukemic cells for a durable cure of CML. The approach presented in this paper accounts for the role of the anti-leukemia specific immune response in the dynamics of CML. By combining experimental data and mathematical models, we demonstrate that persistence of anti-leukemia T cells even at low levels seems to prevent the leukemia from relapsing (for at least 50 months). As a consequence, we hypothesize that anti-leukemia T cell responses may help maintain remission under imatinib therapy. The mathematical model together with the new experimental data imply that there may be a feasible, low-risk, clinical approach to enhancing the effects of imatinib treatment.
Highlights
Chronic myelogenous leukemia (CML) results from the uncontrolled growth of white blood cells due to up-regulation of the abl tyrosine kinase [1]
We hypothesize that anti-leukemia T cells responses may help maintain remission under imatinib therapy
The approach presented in this paper accounts for the role of the anti-leukemia specific immune response in the dynamics of chronic myelogenous leukemia (CML)
Summary
Chronic myelogenous leukemia (CML) results from the uncontrolled growth of white blood cells due to up-regulation of the abl tyrosine kinase [1]. The standard first-line therapy against CML is imatinib, a molecular-targeted drug that inhibits the abl tyrosine kinase [2]. Most patients attain hematologic remission (HR) [3] and 75% achieve cytogenetic remission (CR) [4]. Imatinib does not completely eliminate residual leukemia cells and patients inevitably relapse after stopping treatment [4]. We note that for a hematologic remission ( known as complete hematologic response) the following must be present: Platelet count 450,000/mL, WBC count ,10,000/mL, WBC differential: no immature granulocytes and ,5% basophils, Spleen nonpalpable. Cytogenetic remission (or response) is defined with the following sub-categories. None: Ph+ cells .95%; Minimal: Ph+ cells 66–95%; Minor: Ph+ cells 36– 65%; Partial: Ph+ cells 1–35%; Complete: Ph+ cells 0%
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