(200d) A Biologically-Motivated Model of Chemotherapy-Induced Thrombocytopenia

A Biologically-Motivated Model of Chemotherapy-Induced Thrombocytopenia

Christine M. Carcillo¹, Robert S Parker^1,2,3,4

1. Department of Chemical and Petroleum Engineering, Swanson School of Engineering 2. University of Pittsburgh Cancer Institute University of Pittsburgh 3. McGowan Institute of Regenerative Medicine 4. Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Laboratories, Department of Critical Care Medicine

Chemotherapy-induced thrombocytopenia is a hematological toxicity characterized by a thrombocyte, or platelet, count below average (<150,000 platelets/microliter). ¹ Commonly employed drugs used against a variety of cancers (breast, small- and non-small-cell lung, ovarian, lymphoma, leukemia, and sarcoma) that lead to thrombocytopenia include doxorubicin, cyclophosphamide, ifosfamide, paclitaxel, carboplatin, cisplatin and etoposide.  These chemotherapeutics kill stem and progenitor cells in the bone marrow, thereby decreasing the number of platelets released into circulation.  With platelets having a lifespan of 7-10 days¹, the dynamic response to thrombocytopenic chemotherapy limits treatment. If toxicity is too severe, dose reductions must occur, thereby decreasing efficacy.  By characterizing this toxic response to chemotherapy using a mathematical model, we can contribute to the design of patient-tailored treatment schedules for thrombocytopenic chemotherapeutics.

Mapping the biology onto mathematics, thrombopoiesis consists of a maturation chain that represents differentiation from a stem cell along its progression to progenitor cell, promegakaryocyte, and finally megakaryocyte, which bud off platelets into the blood stream.  Once in circulation, about one-third of platelets sequester in the spleen, while the kidney, liver, and other organs and tissues also serve to sequester platelets at smaller fractions.  Platelets are degraded by macrophages.  Thrombopoietin (TPO), produced mainly in the liver and kidneys, is the primary regulator of thrombopoiesis, and it is inversely related to platelet production due to uptake of TPO by platelet and megakaryocyte TPO receptors.  When platelet counts are low, the excess TPO stimulates the maturation chain.  However, in TPO-deficient mice growth factors SDF-1 and FGF-4 were sufficient to increase platelet production post thrombocytopenia.² Hence, a more complex interactive network of positive and negative feedback is needed to maintain homeostasis.  Once chemotherapy perturbs this homeostasis, a lag period of decreased platelet production will occur. An understanding of the life cycle of the platelet and the major regulatory players will lend insight into the recovery time after a specific chemotherapy challenge, as well as the potential interaction between different chemotherapy agents.  At the systems scale, we use ordinary differential equations to describe the chemotherapeutic agent pharmacokinetic (PK) distribution and elimination.  This, in turn, drives the biologically-motivated pharmacodynamic (PD) model of thrombocytopenia.  As a result, the model is drug-specific, using the sigmoid Emax model parameters (Emax, EC50) to characterize the thrombocytopenic effect of a given agent, as well as interactions between agents.

Existing models of chemotherapy-induced thrombocytopenia have a phenomenological point of view, neglecting drug pharmacokinetics (PK) [Scholz et al. (2010)] or incorporating biological response and regulation via a nonlinear mathematical feedback effect [Bender et al. (2012)]. ^3,4 Our aim is to provide a more biologically relevant toxicity model that explicitly incorporates the effect of particular drugs – and their interactions – on the thrombocytopenia response.

As a case study, we examine the FDA-approved agent carboplatin.  The PK model of Joerger et al. (2007) is used to drive the thrombocytopenia model, starting from a high dose of 800 mg/m² over 30 minutes.⁵ Fitting parameters, including Emax and EC50 for carboplatin on thrombopoiesis, were adjusted to match model-derived platelet counts after carboplatin exposure to patient data from literature.^{5, 6} Looking forward, combination therapy of paclitaxel and carboplatin has been shown to synergistically reduce thrombocytopenia when paclitaxel is administered first.⁷  Modeling specific drugs and drug combinations can provide insight into dose scheduling, magnitude and duration.  Additionally, cytokine treatments such as interleukin-1α can be administered to mitigate thrombocytopenia.⁶ When employed in combination with a model-based treatment design algorithm, the thrombocytopenia model may contribute to patient-tailored dosing regimens that can reduce the number of severe toxicities encountered by cancer patients.

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2. Avecilla, Scott T., et al. "Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis." Nature medicine 10.1 (2004): 64-71.

3. Scholz, Markus, Arnd Gross, and Markus Loeffler. "A biomathematical model of human thrombopoiesis under chemotherapy." Journal of theoretical biology 264.2 (2010): 287-300.

4. Bender, Brendan C., et al. "A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer." Cancer chemotherapy and pharmacology 70.4 (2012): 591-601.

5. Joerger, Markus, et al. "Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group." Clinical Cancer Research 13.21 (2007): 6410-6418.

6. Smith, John W., et al. "The effects of treatment with interleukin-1α on platelet recovery after high-dose carboplatin." New England Journal of Medicine 328.11 (1993): 756-761.

7. Xiong, Xiaoxiong, et al. "Cell cycle dependent antagonistic interactions between paclitaxel and carboplatin in combination therapy." CANCER BIOLOGY AND THERAPY 6.7 (2007): 1067.