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The Timing of Cyclic Cytotoxic Chemotherapy Can Worsen Neutropenia and Neutrophilia

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The Timing of Cyclic Cytotoxic Chemotherapy Can Worsen Neutropenia and Neutrophilia Received: 11 April 2020 Revised: 17 May 2020 Accepted: 28 May 2020 DOI: 10.1111/bcp.14424 SHORT REPORT The timing of cyclic cytotoxic chemotherapy can worsen neutropenia and neutrophilia Michael C. Mackey1 | Sanja Glisovic2 | Jean-Marie Leclerc2,3 | Yves Pastore2,3 | Maja Krajinovic2,4 | Morgan Craig1,2,5 1Department of Physiology, McGill University, Montreal, Canada Despite recent advances in immunotherapies, cytotoxic chemotherapy continues to 2CHU Sainte-Justine Research Centre, be a first-line treatment option for the majority of cancers. Unfortunately, a common Montreal, Canada side effect in patients undergoing chemotherapy treatment is neutropenia. To miti- 3Department of Pediatrics, University of Montreal, Montreal, Canada gate the risk of neutropenia and febrile neutropenia, prophylactic treatment with 4Department of Pharmacology and Physiology, granulocyte-colony stimulating factor (G-CSF) is administered. Extensive University of Montreal, Montreal, Canada pharmacokinetic/pharmacodynamic modelling of myelosuppression during chemo- 5Department of Mathematics and Statistics, University of Montreal, Montreal, Canada therapy has suggested avenues for therapy optimization to mitigate this neutropenia. However, the issue of resonance, whereby neutrophil oscillations are induced by the Correspondence Morgan Craig, CHU Sainte-Justine, 3175 periodic administration of cytotoxic chemotherapy and the coadministration of G- chemin de la Côte-Sainte-Catherine, H3T 1C5. CSF, potentially aggravating a patient's neutropenic/neutrophilic status, is not well- Montreal, Quebec, Canada. Email: [email protected] characterized in the clinical literature. Here, through analysis of neutrophil data from young acute lymphoblastic leukaemia patients, we find that resonance is occurring during cyclic chemotherapy treatment in 26% of these patients. Motivated by these data and our previous modelling studies on adult lymphoma patients, we examined resonance during treatment with or without G-CSF. Using our quantitative systems pharmacology model of granulopoiesis, we show that the timing of cyclic chemother- apy can worsen neutropenia or neutrophilia, and suggest clinically-actionable sched- ules to reduce the resonant effect. We emphasize that delaying supportive G-CSF therapy to 6–7 days after chemotherapy can mitigate myelosuppressive effects. This study therefore highlights the importance of quantitative systems pharmacology for the clinical practice for developing rational therapeutic strategies. KEYWORDS chemotherapy scheduling, chemotherapy-induced neutropenia, cytotoxic chemotherapy, quantitative systems pharmacology 1 | INTRODUCTION rapidly-renewing precursors of the terminally-differentiated circulat- ing neutrophils.1 Chemotherapy-induced neutropenia is of concern Cytotoxic chemotherapeutic agents specifically target cellular division for both patients and clinicians,2,3 since a reduction in circulating neu- pathways and mechanisms to interrupt cell division and slow or halt trophil counts leaves patients susceptible to infections and is there- cancer progression. Unfortunately, this can have significant deleteri- fore a frequent cause of dose reduction (or complete cessation) ous effects on other replicating cells in the body, including the during chemotherapy. As a result, rescue drugs are regularly adminis- tered concomitantly during anticancer treatments to boost neutrophil Michael C. Mackey and Morgan Craig contributed equally. counts, primarily exogenous forms of granulocyte colony-stimulating Br J Clin Pharmacol. 2020;1–7. wileyonlinelibrary.com/journal/bcp © 2020 The British Pharmacological Society 1 2 MACKEY ET AL. factor (G-CSF), the principal cytokine responsible for the control of neutrophil production. What is already known about this subject Chemotherapy protocols are designed to be delivered periodically throughout the treatment period. Cycle length is dictated by • Owing to their mechanisms of action, cytotoxic chemo- established treatment schedules4 but can be modified according to a therapeutic agents provoke serious haematological toxic patient's response to therapy and disease status. In childhood acute side effects, particularly chemotherapy-induced neutro- lymphoblastic leukaemia (ALL)/lymphoblastic lymphoma, patients are penia. In response, pharmaceutical modelling of stratified into low, standard, high and very high risk groups based myelosuppression during chemotherapy is an increasingly largely on their WBC counts, age, cytogenetics and the patient's initial crucial element of dose-determination for cytotoxic anti- response to therapy.5 Prognoses are also correlated to initial thera- cancer therapy with or without supportive granulocyte peutic response.5 colony-stimulating factor (G-CSF). Mathematical model- Given the incidence of chemotherapy-induced neutropenia ling has also predicted that the timing of cyclic chemo- (e.g. around 11% in breast cancer patients and 40% of lymphoma therapy can aggravate the neutropenic nadir, in a patients were reported with grade 3–4 neutropenia6; over 50% of phenomenon called resonance. We have previously patients with gynaecological cancers7), tailoring chemotherapy regi- developed a quantitative systems pharmacology model of mens and stratifying patients based on neutropenic-risk are current neutrophil production that accurately predicts neutrophil clinical practices.8 Childhood ALL is usually treated in several phases and G-CSF dynamics during chemotherapy with and (including induction, consolidation and maintenance) that aim to bring without exogenous G-CSF. about leukaemic remission. Treatment strategies and schedules vary as a function of risk stratification and integrate a variety of chemo- What this study adds therapeutic and steroidal agents.3,9 Neutropenia is a frequent side effect in childhood ALL; a recent retrospective analysis of 266 patients • Clinical confirmation of neutrophil resonance has yet to identified 74.7% of neutropenic episodes occurring during the induc- be reported. Here, for the first time, we identified reso- tion phase of treatment.10–12 On an individual basis, the optimal nance in neutrophil counts from lymphoma patients timing of periodic chemotherapy administration with or without adju- undergoing cyclic cytotoxic chemotherapy. Leveraging vant G-CSF support is difficult to assess and is variable from person- our quantitative systems pharmacology model, we then to-person. The optimization of cytotoxic chemotherapy treatment predicted that the length of chemotherapy cycles (with with or without prophylactic or supportive G-CSF is therefore a ques- and without G-CSF) has an important influence on the tion of intense research in both mathematical biology and the pharma- severity of the neutrophil nadir. This study therefore ceutical sciences.2,13–16 highlights that the continued assessment of chemother- Cytotoxic agents disrupt cellular division and thus have important apy schedules using quantitative approaches is required implications for neutrophil progenitors, which rapidly divide within to minimize unwanted side effects and improve patient the bone marrow to maintain circulating neutrophils at basal concen- outcomes. trations. Despite their short residence time in the blood,17,18 produc- ing a single neutrophil from a haematopoietic stem cell takes on the order of weeks. Thus, disturbances to proliferating, immature neutro- phils during cytotoxic chemotherapy cause decreases in neutrophil counts within 6–7 days after chemotherapy (the time necessary for neutrophil maturation within the bone marrow19). G-CSF concentra- mathematical model predictive of realistic clinical considerations. The tions then rise and stimulate neutrophil concentrations in circulation. model's predictions were further verified in vitro using murine lym- This strong stimulation provokes an overshoot in neutrophil counts phoma cells and normal dose regimens of cytarabine. Agur et al. beyond basal concentrations as G-CSF and neutrophil concentrations extended their analyses to the toxic effects of cell-cycle-phase- equilibrate because G-CSF and neutrophils are in an inverse relation- specific dosing, and predicted that administering periodic chemother- ship with one another. apy at a time equal to some integer multiple of the mean cell cycle Resonance occurs when the amplitude of neutrophil oscillations length of cancerous cells also reduced haematopoietic toxicity on is amplified by the periodic administration of cytotoxic chemotherapy, bone marrow granulocytes.21 potentially aggravating a patient's neutrophilic status. The presence of The semimechanistic Friberg model of myelosuppression22 has resonance was discussed by Agur et al.20 who used mathematical contributed significantly to predicting the time-course of circulating modelling to predict that short drug pulses administered at integer neutrophil counts after cytotoxic chemotherapy.2 Building upon this multiples of the mean cell cycle length (but not exactly equal to the model, a number of such semi-mechanistic models, including Quartino mean cell cycle time) were preferable to arbitrary chemotherapy cycle et al.23 and Meille et al. 2008 and 2016,24,25 have further integrated length and continuous drug administration. While this may now seem the effects of G-CSF. A phenomenological model of neutrophil pro- intuitive, it is an early demonstration of the ability to develop a duction and the PD effects of both chemotherapy and G-CSF support MACKEY ET AL. 3 was also recently used to optimize the use
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