Irinotecan-induced neutropenia: A comprehensive review of pathogenesis, risk factors, and management
image: Irinotecan is metabolized by carboxylesterase (CES) into the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 can enter the liver via organic anion transporting polypeptide (OATP) 1B1 transporters and be transported out of the liver via ABC transporters. Within the liver, it is catalyzed by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A9 into the inactive metabolite SN-38 glucuronide (SN-38G). Irinotecan and SN-38 are also excreted into the intestine via ABC transporter-mediated biliary secretion. In the intestine, irinotecan is metabolized by CES into SN-38, which is then glucuronidated by UGT1A1 and UGT1A7 to form SN-38G. SN-38G can also be converted back to SN-38 by β-glucuronidase.
Credit: Chengliang Zhang, Chengren Shu
Irinotecan is widely used for advanced solid tumours, but neutropenia (NP) remains a major dose‑limiting toxicity. This review summarises the pathogenesis, risk factors, and management of irinotecan‑induced neutropenia (IIN). IIN is primarily driven by SN‑38‑mediated topoisomerase I inhibition and mitochondrial injury in haematopoietic stem cells. Risk factors include irinotecan dosage, UGT1A and transporter gene polymorphisms, patient characteristics, organ function, and concomitant chemotherapy. Management strategies include genotype‑guided dosing, G‑CSF, alkalinising agents, and microbiota modulation. Integrating pharmacogenetics and supportive care may improve treatment safety and continuity.
Introduction
Irinotecan is converted to SN‑38, a potent topoisomerase I inhibitor. NP (ANC <1.5×10⁹/L) is a common adverse effect, leading to dose reduction, treatment delay, and increased infection risk. This review examines the classification, epidemiology, pathogenesis, risk factors, and management of IIN.
Classification and Epidemiology
IIN is acute NP (≤3 months), graded 1–4 by CTCAE (Grade 4: ANC <0.5×10⁹/L). Grades 3–4 are severe, increasing infection and sepsis risk. Incidence varies widely (8–34% for Grade 3–4), depending on dose, regimen, and patient factors. Peak NP occurs around day 8 after administration.
Pathogenesis
IIN is mediated by SN‑38. Irinotecan is converted to SN‑38 by carboxylesterase; SN‑38 is inactivated by UGT1A1 to SN‑38G and excreted in bile. In the gut, bacterial β‑glucuronidase reconverts SN‑38G to SN‑38, which is reabsorbed (enterohepatic circulation). High SN‑38 exposure correlates with NP severity.
SN‑38 inhibits TOPO I in HSCs, causing DNA damage and reduced neutrophil production. It also damages mitochondria—inhibiting electron transport, promoting ROS, and damaging mtDNA—leading to HSC apoptosis and NP.
Risk Factors
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Dosage: Dose‑dependent; higher doses increase risk.
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UGT1A polymorphisms: UGT1A1*28, *6, UGT1A7*3, and UGT1A9*22 reduce SN‑38 clearance.
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Transporter polymorphisms: SLCO1B1 521T>C and ABC transporter variants affect SN‑38 uptake/efflux.
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Patient factors: Age ≥65, female sex, impaired liver/kidney function increase risk. Smoking reduces risk due to enhanced SN‑38 glucuronidation.
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Combinations: Platinum agents and 5‑FU increase NP risk.
Prevention and Management
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Genotype‑guided dosing: UGT1A1 testing; 25% dose reduction for *28/28 patients lowers severe NP from 45% to 18%.
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Dose adjustment: Reducing irinotecan in combination regimens decreases NP.
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Oral alkalinising agents: Sodium bicarbonate or magnesium oxide raise intestinal pH, reducing SN‑38 reabsorption.
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G‑CSF: Promotes granulocyte production; recommended for high‑risk patients.
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Microbiota modulation: Inhibiting bacterial β‑glucuronidase (e.g., with probiotics, flavonoids) may reduce SN‑38 reactivation.
Limitations and Future Directions
Most trials have small sample sizes; mechanistic studies are limited. Future research should focus on large‑scale trials, animal models for mechanism elucidation, and pharmacogenomic risk prediction models.
Conclusions
IIN is a common dose‑limiting toxicity. Its pathogenesis involves SN‑38‑mediated TOPO I inhibition and mitochondrial dysfunction in HSCs. Genotype‑guided dosing, G‑CSF, and microbiota modulation offer promising strategies. This review provides a theoretical basis for clinical IIN management.
Full text
https://www.xiahepublishing.com/2572-5505/JERP-2026-00002
The study was recently published in the Journal of Exploratory Research in Pharmacology.
Journal of Exploratory Research in Pharmacology (JERP) publishes original innovative exploratory research articles, state-of-the-art reviews, editorials, short communications that focus on novel findings and the most recent advances in basic and clinical pharmacology, covering topics from drug research, drug development, clinical trials and application.
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