Case Report: Acute Liver Failure During Deferasirox Therapy and the Potential Role of Pharmacogenetics

Overview

Journal Front Pharmacol

Date 2024 Nov 7

PMID 39508042

Authors

Belen Garcia-Farina

Lydia Rink

Virginia Santarini

Marco Westkemper

Christian Dohna-Schwake

Birte Mohlendick

Affiliations

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Abstract

Background And Aims: A number of case reports have documented the occurrence of acute hepatic and renal toxicity during treatment with deferasirox (DFX). The precise mechanisms underlying these adverse events remain unclear, with the time to toxicity varying considerably between patients-some experiencing it within weeks of treatment initiation, while others after several years. Recent studies have underscored the association of pharmacogenetic variants in genes responsible for the metabolism and clearance of DFX (, , and ) in the development of toxicity. We present the case of an 8-year-old patient with beta thalassemia major who developed acute hepatic failure years after the initiation of DFX therapy. After ruling out the most likely causes, we performed a pharmacogenetic analysis, which suggested a possible link between the patient's genotype and the development of toxicity.

Methods: Sanger sequencing was performed for the most extensively studied single nucleotide polymorphisms (SNPs) studied associated with changes in transporter/enzyme function: rs717620 (c.-24C>T), rs2273697 (c.1249G>A), rs8187710 (c.4544G>A), rs369192412 (g.99781071delG); rs2231142 (c.421C>A); rs4148323 (c.211G>A), rs3064744 (g.233760235TA[8]), rs3064744 (g.233760235TA[6]) and rs3064744 (g.233760235TA[9]).

Results: The patient is heterozygous for two variants, namely rs717620 (c.-24C>T) and rs2273697 (c.1249G>A). These variants have the potential to cause a reduction in transporter function, which could in turn result in decreased drug clearance and increased toxicity.

Discussion: The precise mechanism by which toxicity developed in this case remains unclear and is likely multifactorial. However, it is probable that the presence of SNPs in the gene played a substantial role. Our findings align with those of previously published reports of remarkably similar cases, where patients also exhibited genetic variants in the gene .

References

Wen X, Joy M, Aleksunes L . In Vitro Transport Activity and Trafficking of MRP2/ABCC2 Polymorphic Variants. Pharm Res. 2017; 34(8):1637-1647. PMC: 5500460. DOI: 10.1007/s11095-017-2160-0. View

Allegra S, Cusato J, De Francia S, Longo F, Pirro E, Massano D . Effect of pharmacogenetic markers of vitamin D pathway on deferasirox pharmacokinetics in children. Pharmacogenet Genomics. 2017; 28(1):17-22. DOI: 10.1097/FPC.0000000000000315. View

Mobarra N, Shanaki M, Ehteram H, Nasiri H, Sahmani M, Saeidi M . A Review on Iron Chelators in Treatment of Iron Overload Syndromes. Int J Hematol Oncol Stem Cell Res. 2016; 10(4):239-247. PMC: 5139945. View

Allegra S, De Francia S, Cusato J, Arduino A, Massano D, Longo F . Deferasirox pharmacogenetic influence on pharmacokinetic, efficacy and toxicity in a cohort of pediatric patients. Pharmacogenomics. 2017; 18(6):539-554. DOI: 10.2217/pgs-2016-0176. View

Braga C, Benites B, de Albuquerque D, Alvarez M, Seva-Pereira T, Duarte B . Deferasirox associated with liver failure and death in a sickle cell anemia patient homozygous for the -1774delG polymorphism in the gene. Clin Case Rep. 2017; 5(8):1218-1221. PMC: 5538070. DOI: 10.1002/ccr3.1040. View

Marano M, Bottaro G, Goffredo B, Stoppa F, Pisani M, Marinaro A . Deferasirox-induced serious adverse reaction in a pediatric patient: pharmacokinetic and pharmacogenetic analysis. Eur J Clin Pharmacol. 2015; 72(2):247-8. DOI: 10.1007/s00228-015-1956-2. View

Martinelli D, Goffredo B, Falvella F, Marano M . Acute hyperammonemia in children under deferasirox treatment: cutting the Gordian knot. Clin Toxicol (Phila). 2018; 57(5):375-377. DOI: 10.1080/15563650.2018.1523425. View

Rheault M, Bechtel H, Neglia J, Kashtan C . Reversible Fanconi syndrome in a pediatric patient on deferasirox. Pediatr Blood Cancer. 2011; 56(4):674-6. DOI: 10.1002/pbc.22711. View

Ramaswami A, Rosen D, Chu J, Wistinghausen B, Arnon R . Fulminant Liver Failure in a Child With β-Thalassemia on Deferasirox: A Case Report. J Pediatr Hematol Oncol. 2016; 39(3):235-237. DOI: 10.1097/MPH.0000000000000654. View

10.

Yacobovich J, Stark P, Barzilai-Birenbaum S, Krause I, Pazgal I, Yaniv I . Acquired proximal renal tubular dysfunction in β-thalassemia patients treated with deferasirox. J Pediatr Hematol Oncol. 2010; 32(7):564-7. DOI: 10.1097/MPH.0b013e3181ec0c38. View

11.

Papadopoulos N, Vasiliki A, Aloizos G, Tapinis P, Kikilas A . Hyperchloremic metabolic acidosis due to deferasirox in a patient with beta thalassemia major. Ann Pharmacother. 2009; 44(1):219-21. DOI: 10.1345/aph.1M440. View

12.

Poggiali E, Cassinerio E, Zanaboni L, Cappellini M . An update on iron chelation therapy. Blood Transfus. 2012; 10(4):411-22. PMC: 3496216. DOI: 10.2450/2012.0008-12. View

13.

Waldmeier F, Bruin G, Glaenzel U, Hazell K, Sechaud R, Warrington S . Pharmacokinetics, metabolism, and disposition of deferasirox in beta-thalassemic patients with transfusion-dependent iron overload who are at pharmacokinetic steady state. Drug Metab Dispos. 2010; 38(5):808-16. DOI: 10.1124/dmd.109.030833. View

14.

Ling G, Pinsk V, Golan-Tripto I, Ling E . Acute Liver Failure in a Pediatric Patient with Congenital Dysery-Thropoietic Anemia Type I Treated with Deferasirox. Hematol Rep. 2015; 7(3):5987. PMC: 4591501. DOI: 10.4081/hr.2015.5987. View

15.

Allegra S, Cusato J, De Francia S, Massano D, Piga A, DAvolio A . Deferasirox AUC efficacy cutoff and role of pharmacogenetics. Eur J Clin Pharmacol. 2016; 72(9):1155-7. DOI: 10.1007/s00228-016-2070-9. View

16.

Menaker N, Halligan K, Shur N, Paige J, Hickling M, Nepo A . Acute Liver Failure During Deferasirox Chelation: A Toxicity Worth Considering. J Pediatr Hematol Oncol. 2017; 39(3):217-222. DOI: 10.1097/MPH.0000000000000786. View

17.

Diaz-Garcia J, Gallegos-Villalobos A, Gonzalez-Espinoza L, Sanchez-Nino M, Villarrubia J, Ortiz A . Deferasirox nephrotoxicity-the knowns and unknowns. Nat Rev Nephrol. 2014; 10(10):574-86. DOI: 10.1038/nrneph.2014.121. View

18.

Entezari S, Haghi S, Norouzkhani N, Sahebnazar B, Vosoughian F, Akbarzadeh D . Iron Chelators in Treatment of Iron Overload. J Toxicol. 2022; 2022:4911205. PMC: 9098311. DOI: 10.1155/2022/4911205. View

19.

Gottwald E, Schuh C, Drucker P, Haenni D, Pearson A, Ghazi S . The iron chelator Deferasirox causes severe mitochondrial swelling without depolarization due to a specific effect on inner membrane permeability. Sci Rep. 2020; 10(1):1577. PMC: 6994599. DOI: 10.1038/s41598-020-58386-9. View

20.

Bruin G, Faller T, Wiegand H, Schweitzer A, Nick H, Schneider J . Pharmacokinetics, distribution, metabolism, and excretion of deferasirox and its iron complex in rats. Drug Metab Dispos. 2008; 36(12):2523-38. DOI: 10.1124/dmd.108.022962. View