Occurrence of AHA after mass administration of the antimalaria drug primaquine (PQ) was first documented in some US soldiers in Korea. The so-called PQ sensitivity syndrome was more common among African Americans and clinically identical to “favism” (i.e., AHA after ingestion of fava beans). The underlying biochemical (Fig. 1) and genetic (variants in G6PD) causes of the clinical phenotype (i.e., AHA after PQ and fava beans, as well as for neonatal jaundice) were identified, and the disease was named G6PD deficiency.[1] The severity of AHA in individuals with G6PD deficiency after treatment with drugs that induce oxidative stress is also influenced by host and environmental factors (see Fig. 1).

Fig1. FACTORS INFLUENCING THE PHENOTYPE HEMOLYSIS IN INDIVIDUALS WITH G6PD DEFICIENCY. Damaging variants in the G6PD gene lead to G6PD deficiency in red blood cells, which, under oxidative stress, (1) leads to depletion of glutathione (with low cellular NADPH and GSH pools causing low activity of GPX [the enzyme that detoxifies H₂O₂ ]) and subsequent loss of protection against oxidation of proteins, with precipitation of denaturized hemoglobin leading to AHA, and (2) oxidation of hemoglobin (Hb) iron with formation of methemoglobin (MetHb is converted back to Hb via an NADPH-dependent reaction; as the cellular NADPH pool is low, MetHb accumulates), resulting in methemoglobinemia. The severity of AHA and tissue hypoxia in individuals with G6PD deficiency after treatment with drugs that induce oxidative stress is influenced by (3) host factors such as genetic variants in G6PD and comorbidities such as malaria, methemoglobinemia, and ALL, as well as environmental factors (i.e., drugs, their dose, and schedule of administration). 6PG, 6-Phosphogluconolactone; AHA, acute hemolytic anemia; ALL, acute lymphoblastic leukemia; G6P, glucose 6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; GPX, glutathione peroxidase; GSH, glutathione; GSR, glutathione reductase; GSSG, glutathione disulfide; H₂O₂ , hydrogen peroxide; NADP(H), nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species.

The G6PD gene is localized on Xq28, and currently more than 160 pathogenic variants have been identified. The biochemical characterization of these variants has revealed a range of effects, such as changes in kinetic activity, thermostability, and protein folding.[2] The clinical phenotypes of G6PD variants are largely determined by a trade-off between protein stability and catalytic activity.

G6PD is an “essential gene” (i.e., complete loss of G6PD is lethal). Very rare, more complex variants, for instance, in-frame deletions in exon 10, which affect important regions within the enzyme such as the substrate binding site, can cause severe transfusion-dependent chronic nonspherocytic hemolytic anemia (CNSHA). Variants have been divided into five classes based on enzyme activity in red blood cells (RBCs) and clinical presentation: class I (CNSHA, activity less than 10%), class II (no CNSHA, activity less than 10%), class III (no CNSHA, greater than 10% to 60%), class IV (normal activity; variants G6PD B and G6PD A), and class V (higher activity). It is estimated that approximately 5% of the world’s population has G6PD deficiency, and almost all of these individuals have class II or III variants.[3]

Drugs that have the potential to cause oxidative stress in erythrocytes, which results in AHA in G6PD-deficient patients, have been recently classified into two groups: (1) predictable hemolysis (i.e., AHA can be expected in a G6PD-deficient patient after administration of the drug) and (2) possible hemolysis (i.e., AHA may or may not occur, related to dosage and administration of the drug, comorbidities).[1] Drugs with predictable hemolysis include, for instance, the antimalaria drug PQ and the recombinant urate oxidase rasburicase. A comprehensive list of drugs is provided elsewhere,[1,3] and we focus on rasburicase herein.

Rasburicase is used in the prophylaxis and treatment of hyperuricemia, and the most important indications are tumor lysis (e.g., in patients with hyperleukocytosis leukemia or lymphoma) or after acute renal failure in infants. Rasburicase catalyzes the cleavage of uric acid, thereby producing hydrogen peroxide. Normally, hydrogen peroxide is promptly inactivated via glutathione peroxidase (GPX). However, in individuals with G6PD deficiency, the activity of GPX is markedly reduced due to impaired glutathione metabolism, and rasburicase induces AHA and often significant methemoglobinemia. This can cause severe tissue hypoxia, especially in patients with leukemia who have already reduced RBC counts, and fatalities have been reported after rasburicase administration in ALL patients with G6PD deficiency (see Fig. 1).[3]

The FDA and the European Medicines Agency (EMA) have contraindicated the use of rasburicase in individuals with G6PD deficiency. However, tumor lysis syndrome (TLS) is also a life-threatening condition, and one must carefully balance the risk of reversible severe AHA and methemoglobinemia, which can be treated via RBC trans fusions, and the risk of renal failure and hyperkalemia in TLS. Online enzyme activity testing before the use of rasburicase (i.e., providing results within 1 hour) is an ideal but not commonly achievable scenario. More information on available genetic and activity test options is provided in the updated CPIC guidelines (see Table 1).[3]

Table1. CPIC Recommendations on Medications Whose Adverse Effects Have Been Associated with Variability in Candidate Genes and Manifest Predominantly as Hematologic Abnormalities

Of interest are the results of a recent pharmacoepigenetic investigation in which HDACis selectively reinstated enzyme activity in G6PD-deficient erythroid precursors in vitro by boosting G6PD gene transcription.[4] Whether administration of the epidrug HDACi sodium butyrate can also increase G6PD activity in patients with G6PD deficiency to levels that protect their erythrocytes from oxidative damage by rasburicase or other oxidative stressors and if such an approach is not associated with severe side effects remain to be proven. However, the ability of HDACi to increase the transcription of a subset of active genes, such as G6PD, would offer a novel and appealing therapeutic approach, especially for the subset of patients with severe forms of enzymopathies, such as CNSAH class I or II G6PD deficiency.

A different PGx approach to establish drug therapy for patients with severe G6PD deficiency was recently reported. Using crystal lographic studies and mutagenesis analyses, researchers identified the structural and functional defects of one common variant in G6PD (i.e., “Canton variant [R459L], which is the most common causative variant in patients with G6PD deficiency in China and Southeast Asia). The Canton variant is associated with severe G6PD deficiency (class II, 18% activity). Using high-throughput screening, a small molecule—AG1—was identified, which increases the activity of wild-type G6PD, the Canton variant, and several other common G6PD variants in vitro. Clearly, further studies are necessary to investigate if treatment with AG1 can result in clinical benefit for a subset of patients with severe forms of G6PD deficiency.[2]

References

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[1] Luzzatto L, Seneca E. G6PD deficiency: a classic example of pharmacogenomics with on-going clinical implications. Br J Haematol. 2014;164:469–480.

 [2] Hwang S, Mruk K, Rahighi S, et al. Correcting glucose-6-phosphate dehydrogenase deficiency with a small-molecule activator. Nat Commun. 2018;9(1):4045.

[3] Relling MV, McDonagh EM, Chang T, et al. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype. Clin Pharmacol Ther. 2014;96(2):169–174.

[4] Makarona K, Caputo VS, Costa JR, et al. Transcriptional and epigenetic basis for restoration of G6PD enzymatic activity in human G6PD-deficient cells. Blood. 2014;124(1):134–141.

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