Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

Glisovic, Sanja; Pastore, Yves D.; Gagné, Vincent; Plesa, Maria; Laverdière, Caroline; Leclerc, Jean‐Marie; Sinnett, Daniel; Krajinović, Maja

doi:10.1038/tpj.2017.16

Cited by 11 publications

(15 citation statements)

References 98 publications

(83 reference statements)

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“…To assess whether resonance was indeed clinically significant, we leveraged a study of 286 Caucasian children diagnosed with ALL at the Sainte‐Justine University Health Center (Montreal, Canada). In these patients, variants in the DARC , GSDM and CXCL2 loci were previously identified as predictive for neutropenic complications during treatment with the Dana‐Farber Cancer Institute (DFCI) ALL Consortium protocols DFCI 87–01, 91–01, 95–01, or 00–01 10,11,32 . Detailed descriptions of these DFCI protocols are provided elsewhere 33–36 .…”

Section: Methodsmentioning

confidence: 99%

“…Treatment strategies and schedules vary as a function of risk stratification and integrate a variety of chemotherapeutic and steroidal agents 3,9 . Neutropenia is a frequent side effect in childhood ALL; a recent retrospective analysis of 266 patients identified 74.7% of neutropenic episodes occurring during the induction phase of treatment 10–12 . On an individual basis, the optimal timing of periodic chemotherapy administration with or without adjuvant G‐CSF support is difficult to assess and is variable from person‐to‐person.…”

Section: Introductionmentioning

confidence: 99%

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The timing of cyclic cytotoxic chemotherapy can worsen neutropenia and neutrophilia

Mackey

Glisovic

Leclerc

et al. 2020

Brit J Clinical Pharma

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Despite recent advances in immunotherapies, cytotoxic chemotherapy continues to be a first‐line treatment option for the majority of cancers. Unfortunately, a common side effect in patients undergoing chemotherapy treatment is neutropenia. To mitigate the risk of neutropenia and febrile neutropenia, prophylactic treatment with granulocyte‐colony stimulating factor (G‐CSF) is administered. Extensive pharmacokinetic/pharmacodynamic modelling of myelosuppression during chemotherapy has suggested avenues for therapy optimization to mitigate this neutropenia. However, the issue of resonance, whereby neutrophil oscillations are induced by the periodic administration of cytotoxic chemotherapy and the coadministration of G‐CSF, potentially aggravating a patient's neutropenic/neutrophilic status, is not well‐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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The timing of cyclic cytotoxic chemotherapy can worsen neutropenia and neutrophilia

Mackey

Glisovic

Leclerc

et al. 2020

Brit J Clinical Pharma

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“…Variations in ACKR1 , GSDMA and CXCL2 genes were found to play a role in the onset of chemotherapy complications, as was recently demonstrated in children with acute lymphoblastic leukaemia. ACKR1 polymorphism rs3027012 at the 5′‐UTR was associated with higher risk of low absolute phagocyte count and hospitalization due to febrile neutropenia, while protective effect was instead seen for ACKR1 rs12075 A to G substitution (Glisovic et al , ).…”

Section: Possible Implications Of Benign Neutropenia In Cancermentioning

confidence: 99%

The Duffy antigen receptor for chemokines, ACKR1,– ‘Jeanne DARC’ of benign neutropenia

et al. 2018

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Summary Benign neutropenia, observed in different ethnic groups, is the most common form of neutropenia worldwide. A specific single nucleotide polymorphism, rs2814778, located at the promoter of the ACKR1 (previously termed DARC) gene, which disrupts a binding site for the GATA1 erythroid transcription factor, resulting in a ACKR1‐null phenotype, was found to serve as a predictor of low white blood cell and neutrophil counts in African‐Americans and Yemenite Jews. Individuals with benign neutropenia due to the ACKR1‐null allele have been found to have an increased susceptibility to human immunodeficiency virus infection and, on the other hand, a protective effect against malaria. The associated protective effect may explain the spread of the ACKR1‐null allele by natural selection. The reviewed relationships between ACKR1 polymorphism and various pathological states may have important clinical implications to individuals with and without benign neutropenia. Potential mechanisms for ACKR1 (previously termed DARC) modulation during neutrophil recruitment to inflammation, and chemokine bioavailability in the circulation and in local tissue are reviewed and discussed.

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“…Unfortunately, this cytotoxicity can have significant deleterious effects on other dividing cells in the body, including the rapidly-renewing terminally-differentiated neutrophils (Dale and Mackey, 2015). Chemotherapyinduced neutropenia and ensuing infections are a common side effect of cytotoxic chemotherapy (Brooks et al, 2012;Craig et al, 2015;Friberg et al, 2002;Glisovic et al, 2018), necessitating dose size reductions or complete therapy cessation. These therapy modifications leave the patient particularly vulnerable to infection, a major cause of treatment-related mortality even in malignancies with high survival rates (Gatineau-Sailliant et al, 2019;Glisovic et al, 2018).…”

mentioning

confidence: 99%

“…Chemotherapyinduced neutropenia and ensuing infections are a common side effect of cytotoxic chemotherapy (Brooks et al, 2012;Craig et al, 2015;Friberg et al, 2002;Glisovic et al, 2018), necessitating dose size reductions or complete therapy cessation. These therapy modifications leave the patient particularly vulnerable to infection, a major cause of treatment-related mortality even in malignancies with high survival rates (Gatineau-Sailliant et al, 2019;Glisovic et al, 2018). Thus, there is intense interest in dampening the adverse hematological events associated with cytotoxic chemotherapy, through the design of less toxic chemotherapy combinations or the introduction of prophylactic agents.…”

mentioning

confidence: 99%

Characterizing chemotherapy-induced neutropenia and monocytopenia through mathematical modelling

Cassidy

Humphries

Craig

et al. 2020

Preprint

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Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

Cited by 11 publications

References 98 publications

The timing of cyclic cytotoxic chemotherapy can worsen neutropenia and neutrophilia

The timing of cyclic cytotoxic chemotherapy can worsen neutropenia and neutrophilia

The Duffy antigen receptor for chemokines, ACKR1,– ‘Jeanne DARC’ of benign neutropenia

Characterizing chemotherapy-induced neutropenia and monocytopenia through mathematical modelling

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