Real World Risk of Splenic Rupture with G-CSF/GM-CSF Therapy: A Pharmacovigilance Assessment Using FDA Adverse Event Reporting System (FAERS) Database
Authors: Kaur Anahat , Wang Shuai , Jayarangaiah Apoorva , Malone Mariuxi , Yu Arlene , Kumar Abhishek 
Published: November 2020

Introduction
Splenic rupture is a rare but serious adverse event associated with the use of Granulocyte-Colony Stimulating Factor (G-CSF) and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). Instances of spontaneous splenic rupture following administration of these hematopoietic growth factors have been sporadically documented in case reports. We aimed to conduct a more comprehensive study to generate signal for splenic rupture with G-CSF/GM-CSF therapy using disproportionality analysis.
Methods
The United States Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database, a pharmacovigilance database, was used to extract data. All reported splenic rupture cases between January 1, 1991 and December 31,2019 for G-CSF or GM-CSF were collected by using the search terms "Pegfilgrastim", "Filgrastim", "Lenograstim", "Filgrastim-sndz", "Sargramostim" and "Pegfilgrastim-jmdb". We used reporting odds ratio (ROR) for proportionality analysis. ROR was calculated by SPSS 26 and considered significant with p value &lt;0.05 when lower limit of 95% Confidence Interval (CI) of a ROR signal exceeded 1.0.
Results
Total of 58,725 reports of adverse reactions linked to G-CSF and GM-CSF were extracted from FAERS database. Out of these, splenic rupture was included as adverse event in 100 cases (Table 1). The median age of diagnosis was 54 years (interquartile range 46-62). Gender was reported in 92 cases, out of which 47 were male and 45 females. Final outcomes of 100 patients with growth factor associated splenic rupture showed that 31 were hospitalized, 30 had life-threatening illness and 18 died. ROR was calculated separately for Pegfilgrastim 16.03 (95% CI 11.90-21.59), Filgrastim (49.79; 36.32-68.26), Lenograstim (133.82; 55.39-323.32), Filgrastim-sndz (87.87; 28.21-273.71), Filgrastim+Pegfilgrastim (35.01; 11.26-108.85), Filgrastim+Sargramostim (895.20; 214.83-3730.27) and for all G-CSF/GM-CSF drugs taken together (28.13; 22.92-34.52). All calculated RORs were significant (Table 2).
Conclusion
This study demonstrates disproportionately elevated signals of developing splenic rupture in patient receiving G-CSF/GM-CSF therapy as compared to those receiving other drugs based on the FAERS database. Physicians should be aware of this rare adverse event as it could potentially lead to life-threatening outcomes.

Disclosures
Kumar: Amgen:Current equity holder in publicly-traded company;Bristol-Myers Squibb:Current equity holder in publicly-traded company;AstraZeneca:Current equity holder in publicly-traded company;Aveo Pharma:Current equity holder in publicly-traded company;Viking Therapeutics:Current equity holder in publicly-traded company;Acadia Pharma:Current equity holder in publicly-traded company;Iovance Biosciences:Current equity holder in publicly-traded company;AIKIDO:Current equity holder in publicly-traded company;CRISPR Therapeutics:Current equity holder in publicly-traded company;PTC Therapeutics:Current equity holder in publicly-traded company;ELiLilly:Current equity holder in publicly-traded company;Bio Path Holdings:Current equity holder in publicly-traded company;Northwest Bio:Current equity holder in publicly-traded company;Vertex Pharmaceuticals:Current equity holder in publicly-traded company;Precision Biosciences:Current equity holder in publicly-traded company;Cara Therapeutics:Current equity holder in publicly-traded company;IDEXX Laboratories:Current equity holder in publicly-traded company;Editas Medicine:Current equity holder in publicly-traded company;ChemBio Diagnostics:Current equity holder in publicly-traded company;Beyond Spring:Current equity holder in publicly-traded company;Poseida Therapeutics:Current equity holder in publicly-traded company;Spectrum Pharmaceuticals Inc.:Current equity holder in publicly-traded company;Cardiff Oncology:Current equity holder in publicly-traded company;Contrafect Corp:Current equity holder in publicly-traded company;Globus Medicine Inc.:Current equity holder in publicly-traded company;Johnson and Johnson:Current equity holder in publicly-traded company;AbbVie:Current equity holder in publicly-traded company;Five Prime Therapeutics:Current equity holder in publicly-traded company;ADMA Biologics:Current equity holder in publicly-traded company;CVS Health:Current equity holder in publicly-traded company;AGNEUS:Current equity holder in publicly-traded company;Biotelemetry Inc.:Current equity holder in publicly-traded company;Pfizer:Current equity holder in publicly-traded company.