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

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 chemotherapy can worsen neutropenia or neutrophilia, and suggest clinically-actionable schedules 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 circulating 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 administered 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 neutrophils 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 of docetaxel plus epirubicin chemotherapy and our previously developed QSP model of for the treatment of breast cancer guided by patients' haematological chemotherapy-induced chemotherapy. Our results suggest not only statuses.26 In lymphoma, more recent analyses14,19,27 of the CHOP14 that there is resonance occurring during cytotoxic chemotherapy, and CHOP21 protocols on both young and elderly patients4,28 have but that scheduling decisions have an impact on the severity of the also demonstrated the resonance effects of periodic chemotherapy neutropenic nadir. administered with G-CSF support. In particular, our model predicted neutropenia and neutrophilia at regular intervals during treatment. In both Craig et al. 2015 and 2016,19,29 we used a quantitative systems pharmacology (QSP) model of granulopoiesis to predict that delaying 2 | METHODS G-CSF administrations postchemotherapy by 5 or 6 days vs the CHOP14 protocol would reduce the myelosuppressive effects of 2.1 | Childhood ALL data analysis chemotherapy. Even though the idea that chemotherapy periods can influence To assess whether resonance was indeed clinically significant, we the severity of neutropenia (and potentially neutrophilia, during leveraged a study of 286 Caucasian children diagnosed with ALL at exogenous G-CSF treatment) has significant implications for clinical the Sainte-Justine University Health Center (Montreal, Canada). In decision-making, few authors outside of the mathematical biology these patients, variants in the DARC, GSDM and CXCL2 loci were community have studied the issue. Other diseases can provide previously identified as predictive for neutropenic complications insight into chemotherapy-induced resonance, including the rare during treatment with the Dana-Farber Cancer Institute (DFCI) ALL blood disorder cyclic neutropenia (regular oscillations in circulating Consortium protocols DFCI 87–01, 91–01, 95–01, or 00–01.10,11,32 neutrophil counts in antiphase with G-CSF concentrations) caused Detailed descriptions of these DFCI protocols are provided by mutations to the ELAstase Neutrophil Expressed (ELANE, for- elsewhere.33–36 Neutrophil counts were measured at 3-week intervals merly ELA-2) gene in neutrophil progenitors.30 Cyclic neutropenia prior to the next administration of chemotherapy, as previously has also previously been reported prior to ALL diagnosis.31 None- described.10,11,32 Using visual predictive check and Lomb–Scargle theless, observations of neutrophilic resonance have not previously periodogram analysis,37,38 we analysed these neutrophil data to check been reported in the clinical literature. Here we address this using for significant oscillations in neutrophil counts over the treatment data collected over 10 years from children undergoing cyclic period of each patient. Data sharing is not applicable to this article as

FIGURE 1 Schematic representation of quantitative systems pharmacology model of granulopoiesis. As with all blood cells, neutrophils begin as haematopoietic stem cells (HSCs). HSCs self-renew to maintain their population size, die or differentiate to become 1 of the many terminal blood cells. After differentiation into the neutrophil lineages, cells undergo a period of exponential expansion (proliferation), after which they cease to divide. Cells then mature and enter the bone marrow reservoir, from which they die or transit into circulation. The entire process is regulated by granulocyte-colony stimulating factor (G-CSF), which is in negative feedback with circulating neutrophils. G-CSF mobilizes egress from the bone marrow reservoir, subsequently speeding up maturation and proliferation to restock the marrow reserve. G-CSF can also increase the rate of differentiation from the HSCs into the neutrophil lineage. Cytotoxic chemotherapy can only kill cells that divide. Its PD actions are to increase the HSC death rate and decrease the speed of neutrophil proliferation. Figure adapted from Craig 20172 4 MACKEY ET AL. no new data were created or analysed in this study. No direct care 3 | RESULTS of patients was involved in the completion of the present study. 3.1 | Neutrophil resonance occurs during cyclic chemotherapy 2.2.1 | Mathematical modelling of chemotherapy- induced neutropenia Neutrophil counts from 2 representative individuals are presented in Figure 2A. Using visual predictive check, we analysed neutrophil We have previously described a QSP model of granulopoiesis19,39 that counts from the childhood ALL cohort to determine whether reso- tracks the dynamics of haematopoietic stem cells, mature neutrophils nance was occurring in this population. We identified a discernible in the bone marrow reservoir, neutrophils in circulation, and concen- neutrophil resonance pattern in 26% of patients. We have also previ- trations of both freely circulating G-CSF and G-CSF bound to neutro- ously found similar resonance in neutrophil counts in adult lymphoma phil receptors. Self-renewal, differentiation, proliferation and patients being treated with supportive G-CSF during chemotherapy maturation processes are described functionally by delay-differential (Figure 2B). Since there are no prior reports of the incidence of reso- equations.19 Full details of all models are provided in the Supplemen- nance in patient populations in the literature, we cannot wholeheart- tary Information. edly assess whether 26% is high. Nonetheless, the presence of Based on our previous results,19,29 and together with the pharma- resonance has a negative impact on treatment and outcomes, given cokinetic (PK) and pharmacodynamic (PD) models described below, the regularity of the neutropenia patients experienced. we hypothesized that the dynamics of neutropenic resonance during 3.1.1.The timing of cyclic chemotherapy with or without G-CSF chemotherapy could be better understood through the application of can aggravate resonance our QSP model of granulopoiesis to cyclic chemotherapy protocols Leveraging our mathematical model, we explored the impact of with or without G-CSF. changes to chemotherapy cycle length without G-CSF support on the severity and duration of neutropenia, and the predicted neutrophilic behaviour when combining cyclic cytotoxic chemotherapy with G-CSF 2.2 | Chemotherapy and G-CSF PK/PD models (Figure 3A). We predicted that longer chemotherapy cycles without G-CSF support will have less pronounced neutrophil nadirs (generally The PK of chemotherapy was modelled as in Craig et al. 2015 and mild vs severe neutropenia), and that the introduction of G-CSF into 201619,39 using a 4-compartment model.40 Chemotherapy PD was the regimen has an important influence on the predicted neutrophil modelled to affect the HSC death rate and the neutrophil progeni- peak concentration. tors.19 The PK of G-CSF was modelled by 2 ordinary differential equa- A more complete picture of the role inflammation and neutrophils tions tracking the kinetics of G-CSF binding and unbinding on play in promoting tumour progression and metastasis is emerging. In maturing bone marrow neutrophils, mature neutrophils in the reser- lung cancer and colon cancer, for example, the inhibition of neutrophil voir, and circulating neutrophils. G-CSF PDs were described by mech- extracellular traps in mice was suggested to potentially limit metasta- anistic relationships between G-CSF and HSC and neutrophil-lineage sis by decreasing cancer cell adhesion.41 Clinical decisions must there- cells.19 A schematic of the complete model is provided in Figure 1. fore balance managing the toxic haematological side effects of

FIGURE 2 Chemotherapy-induced resonance in lymphoma. A, Neutrophil counts from 2 representative patients undergoing Dana-Farber Cancer Institute acute lymphoblastic leukaemia consortium protocols at Sainte-Justine Hospital. Absolute neutrophil counts (ANCs) were assessed every 3 weeks prior to treatment. B, Model predictions at clinical sampling points (black) compared to quartile results (blue: 75% quartile, pink: Median, green: 25% quartile) from the CHOP14 trial of the German high-grade non-Hodgkin's lymphoma study Group.4,28 From18 MACKEY ET AL. 5

FIGURE 3 Neutrophil resonance from cytotoxic chemotherapy with and without granulocyte-colony stimulating factor (G-CSF) support. A, No G-CSF (top 3 rows): model predictions of the amplitude, nadir, and the % of time spent below the 0.5 × 109 threshold during cytotoxic chemotherapy administered in 14-days cycles without G-CSF support for cycle lengths between 7 and 28 days. Chemo + G-CSF (bottom 3 rows): Model predictions of the amplitude, nadir and the % of time spent above the 7 × 109 threshold during cytotoxic chemotherapy administered in 14-days cycles without G-CSF support for cycle lengths between 7 and 28 days with G-CSF administered 4 days postchemotherapy until the day before the next chemotherapy cycle begins. B, Model predictions for neutrophil counts during 14-day cycles of chemotherapy plus G-CSF starting 4 days postchemotherapy for 10 administrations (blue) and starting 7 days postchemotherapy for 4 days (pink dashed) cytotoxic chemotherapy with potential over-stimulation by concomi- chemotherapeutic treatments, and further demonstrates the benefit tant G-CSF support (either prophylactic or as a rescue drug). of incorporating quantitative predictions into clinical practice to pro- To delineate the effects of G-CSF timing postchemotherapy on vide the best possible care. Given the consequences of resonance with respect to neutrophilia, we simulated the administra- chemotherapy-induced neutrophilia and neutropenia, primarily the tion of G-CSF postchemotherapy based on our previous regimen opti- necessity of regimen adaptations and worse patient outcomes, there mization.39 In this protocol, subcutaneous G-CSF was administered is an inherent interest to quantifying resonance phenomena in the starting 6 days postchemotherapy for chemotherapy cycle lengths context of cytotoxic chemotherapy (with and without G-CSF). To do ranging from 7 to 28 days. We found that the timing of G-CSF so, here we leveraged clinical data and a quantitative systems pharma- postchemotherapy coinciding with the initial drop in neutrophil counts cology model of neutrophil production, combined with PK/PD models (about 6–7 days after chemotherapy) better controlled both the neu- of chemotherapy and G-CSF, to understand the influence of drug tropenic nadir and the neutrophilic rebound (Figure 3B). This result is timing on neutrophilic resonance. Our results suggest that not only is in line with modelling studies from other groups,15,16 and suggests a resonance occurring in the clinic, but that some commonly-used cyto- clinically-actionable strategy for anticipating, and ultimately mitigating toxic chemotherapy schedules may be aggravating patients' neutrope- a patient's neutropenic nadir during cyclic chemotherapy. nic (or neutrophilic, for chemotherapy plus G-CSF) status, and highlight that there is an important influence of chemotherapy cycle length to consider when planning therapy. As we move more towards 4 | DISCUSSION biologics in cancer care, there is an increased recognition of the risk posed by certain immunotherapies towards immune-related adverse The promise of personalized medicine is that each patient receives events, particularly inflammatory toxicities associated with immune their most effective, least toxic therapy. Understanding that the peri- checkpoint inhibitors.42 These toxicities underline the importance of odic administration of cytotoxic and stimulatory drugs can aggravate understanding and predicting the undesired effects on the or improve neutropenic/neutrophilic status allows us to better tailor haematological and immune systems of proposed anticancer 6 MACKEY ET AL. treatment. Based on our results, we emphasize that the increased 9. American Cancer Society. Treatment of Children With Acute Lympho- integration of QSP into the clinic is critical for rationalizing care, and cytic Leukemia (ALL). 10. Glisovic SJ, Pastore YD, Gagne V, et al. Impact of genetic polymor- will ultimately contribute to better patient care and outcomes. phisms determining leukocyte/neutrophil count on chemotherapy toxicity. Pharmacogenomics J. 2018;18(2):270-274. https://doi.org/ ACKNOWLEDGEMENTS 10.1038/tpj.2017.16 M.C.M. would like to acknowledge the encouragement of Prof. Robert 11. 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