Introduction

Rasburicase (brand name Elitek) is a uric oxidase used to treat the high levels of uric acid that are associated with tumor lysis syndrome (TLS).

Tumor lysis syndrome is a potentially life-threatening condition caused by rapid break down of tumor cells during chemotherapy. Tumor lysis syndrome is associated with the treatment of aggressive lymphoma and leukemia, but it may also occur with other tumors including solid tumors. Massive cell breakdown results in the release of potassium, phosphate, and uric acid into the circulation. Urate crystals can precipitate in the kidneys, causing acute kidney damage.

Prophylaxis and treatment of TLS involve aggressive intravenous (IV) hydration and the use of drugs to lower uric acid levels. Rasburicase breaks down uric acid to a more soluble metabolite (allantoin), which is then eliminated by the kidneys. A by-product of this reaction is hydrogen peroxide, an oxidizing agent.

Red blood cells that lack the enzyme glucose-6-phosphate dehydrogenase (G6PD) are sensitive to oxidative damage caused by agents like hydrogen peroxide due to a deficiency in nicotinamide adenine dinucleotide phosphate (NADPH). Once exposed, the red blood cells become rigid, trapped, and are rapidly broken down (hemolysis). This can lead to a deficiency of mature red blood cells (hemolytic anemia) and the production of red blood cells with abnormally high levels of methemoglobin (methemoglobinemia).

Approximately 400 million people worldwide have G6PD deficiency. Most of these individuals are asymptomatic. However, they are at risk of life-threating hemolytic reactions and methemoglobinemia if given oxidizing drugs such as rasburicase.

Rasburicase is contraindicated in individuals with G6PD deficiency. The FDA-approved drug label states that individuals at higher risk for G6PD deficiency should be screened before starting rasburicase therapy, for example, individuals of African or Mediterranean ancestry (Table 1) (1). Approximately 12% of African-Americans have G6PD deficiency.

A rare cause of methemoglobinemia is a deficiency of antioxidant enzymes such as cytochrome b5 reductase 3 (CYB5R3). The drug label states it is not known whether individuals who have a deficiency of this enzyme, or another enzyme with antioxidant activity, are at increased risk of methemoglobinemia or hemolytic anemia during rasburicase therapy.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published dosing recommendations for rasburicase based on G6PD phenotype (Table 2). The CPIC states for individuals with normal G6PD phenotype, there is no reason to withhold rasburicase based on G6PD status. For individuals who are G6PD deficient, with or without hemolytic anemia, rasburicase is contraindicated. For individuals who have a variable G6PD phenotype, G6PD enzyme activity must be measured to ascertain that G6PD status is normal. For cases where rasburicase is contraindicated, alternative drugs include allopurinol (2).

Drug: Rasburicase

Rasburicase is a urate-lowering drug used to prevent and manage TLS. In individuals with cancers such as acute leukemia and lymphoma, chemotherapy can lead to massive break down of cells, which releases large amounts of potassium, phosphate, and nucleic acids into the circulation. The purines found in nucleic acids are broken down to uric acid, which leads to hyperuricemia (uric acid levels above 6.8 mg/dL).

Tumor lysis syndrome is potentially life threatening – hemorrhage may occur, and acute kidney damage can be caused by the precipitation of urate crystals within the kidney tubules. The management of TLS is centered on prevention, with aggressive IV hydration and the use of hypouricemic agents such as allopurinol and rasburicase.

The tumors that have the highest risk of TLS are acute lymphoblastic leukemia and aggressive lymphomas, especially Burkitt’s lymphoma. But TLS can also occur in other tumors including solid tumors –– risk factors include a high tumor burden, a high proliferative rate, and a high sensitivity to chemotherapy (3).

Rasburicase is a uric acid oxidase (uricase). It converts uric acid to allantoin – a metabolite that is 5–10 times more soluble than uric acid, which can be excreted by the kidneys. The uricase enzyme is present in many mammals, but absent in humans. Rasburicase is a recombinant protein derived from a genetically modified strain of yeast (Saccharomyces cerevisiae). Pegloticase is another uricase that is used to manage gout, and is derived from the uricase found in pigs.

Rasburicase is given by an IV infusion, daily, for up to 5 days. Dosing beyond 5 days, or giving more than one course, is not recommended. Recent studies have found that conservative treatment with rasburicase is as beneficial, with a single dose of rasburicase being sufficient to normalize the uric acid levels in most individuals with TLS (4-6).

Rasburicase may cause fetal harm and should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus. There are no adequate studies in pregnant women, but in animal studies, rasburicase was shown to be teratogenic (caused abnormal development in rabbit embryos). (1)

The use of rasburicase is contraindicated in individuals known to have G6PD deficiency, and individuals at risk of G6PD deficiency should be screened before starting rasburicase therapy. This is because an oxidizing agent, hydrogen peroxide, is produced during the conversion of uric acid to allantoin.

Individuals who have G6PD deficiency have red blood cells that are susceptible to oxidative damage. If exposed to agents such as hydrogen peroxide, the red blood cells become rigid, get trapped, and are subsequently destroyed by macrophages in the spleen, bone marrow, and liver. The rapid destruction of red blood cells is called hemolysis, and it may result in hemolytic anemia (a deficiency of red blood cells or hemoglobin, caused by hemolysis).

In addition, rasburicase can result in methemoglobinemia –– the production of red blood cells with abnormally high levels of oxidised hemoglobin, namely, methemoglobin. Individuals who may be at increased risk of methemoglobinemia include individuals with a rare hereditary form of methemoglobinemia. This condition may be asymptomatic, and only become apparent after an adverse reaction to an oxidizing drug such as rasburicase (1).

Gene: G6PD

The G6PD enzyme is encoded by the G6PD gene, which is located on chromosome Xq28. As such, males are hemizygous for one G6PD allele, making them more susceptible to this X-linked disorder. Females randomly inactivate one X chromosome during development, resulting in a mosaic expression of either one X chromosome or the other in their somatic cells. This mosaicism can occur in the hematopoietic progenitor cells that give rise to red blood cells, resulting in mixed expression of G6PD alleles. Females with Turner syndrome (45, X) have only one X chromosome and thus are also hemizygous for the G6PD gene.

Glucose-6-phosphate dehydrogenase deficiency affects 400 million people worldwide (7), with a worldwide prevalence of approximately 5%. This deficiency appears to be protective against malaria infection leading to a higher prevalence (more than 25%) in countries where malaria is, or once was, endemic, for example, tropical Africa, tropical and subtropical Asia, the Middle East, and some parts of the Mediterranean (8-10). In the US, G6PD deficiency is more common among African-Americans, affecting approximately 12% (11).

The G6PD enzyme catalyzes the first step in the hexose monophosphate shunt (HMP) pathway, which converts glucose to pentose sugars for nucleic acid synthesis. In this step nicotinamide adenine dinucleotide phosphate (NADP+) is reduced to NADPH, which protects cells from oxidative stress. In mature red blood cells, the HMP pathway is the only source of NADPH. This promotes the generation of reduced glutathione that protects the sulphydryl groups of hemoglobin, which are susceptible to oxidation by hydrogen peroxide and oxygen radicals. Red blood cells that lack G6PD also have a deficiency of NADPH(12).

Red blood cells that are G6PD and NADPH deficient are more susceptible to oxidative stress (for example, by oxygen free radicals and hydrogen peroxide). Oxidative stress occurs naturally, but is increased during illnesses, such as infections and diabetic ketoacidosis. Oxidative stress can also follow the ingestion of fresh fava beans (favism), and is an adverse effect of several drugs, for example, the uric acid lowering drugs pegloticase and rasburicase, the antimalarial drug primaquine, the antibiotic sulfamethoxazole, and the skin cancer drug dabrafenib.

Most individuals with G6PD deficiency are asymptomatic –– they have a normal lifespan and may not know they have G6PD deficiency. But at birth, they are predisposed to neonatal jaundice, and throughout life, they will be sensitive to oxidizing agents. All individuals with G6PD deficiency should avoid oxidizing agents when possible, including drugs such as rasburicase.

Symptomatic individuals with G6PD deficiency may suffer from episodes of acute hemolytic anemia or chronic non-spherocytic hemolytic anemia. The management of hemolytic episodes depends on the severity of hemolysis, with more severe cases requiring blood transfusions. Folic acid may be given to prevent the worsening of anemia in individuals with folate deficiency and to induce formation of new red blood cells.

More than 180 genetic variants of the G6PD gene have been identified so far, with approximately 400 biochemical and enzyme variants (13). Most genetic variations are missense point variants (14). Large deletions are rare, and a complete lack of G6PD activity is thought to be fatal in utero.

The normal (wild-type) copy of the G6PD gene is known as G6PD B, and is found in most Caucasians, Asians, and Blacks. Common G6PD variants include:

• G6PD A+ (p.Asn126Asp) has normal enzyme activity and is not associated with hemolysis, and is found in up to 30% of Blacks from Africa (15)
• G6PD A- (p.Asn126Asp and p.Val68Met) is associated with mild to moderate hemolysis, and is found in up to 15% of African-Americans (16). Additional A-haplotypes have also been identified, both with the A+ variant with a second SNP (p.Asn126Asp with p.Arg227Leu; and p.Asn126Asp with p.Leu323Pro. See Nomenclature table below for additional information) (17)
• G6PD Mediterranean (p.Ser218Phe) can cause severe hemolysis, and is the most common abnormal variant in Caucasians (18)
• G6PD Canton (p.Arg489Leu) can cause severe hemolysis, and is found in Asians (19)

The World Health Organization categorized G6PD variants into 5 classes according to the level of enzyme activity and severity of hemolysis. Class 1 variants are the most severe, but rare. These variants have less than 10% of normal GP6D enzyme activity and are associated with chronic hemolytic anemia.

Most individuals with G6PD deficiency have variants that belong to class II (enzyme activity less than 10% but no chronic hemolytic anemia) and class III (enzyme activity between 10% and 60%). Class II and III variants are associated with intermittent hemolysis, usually triggered by infection or drugs, but for most of the time, affected individuals have no symptoms. Class IV and V variants are not considered to be clinically significant, class IV variants are associated with normal enzyme activity, and class V variants with increased enzyme activity (2).

The Clinical Pharmacogenetics Implementation Consortium (CPIC) assign G6PD phenotype based on G6PD genotype (Table 3) (2).

Gene: CYB5R3

The cytochrome b5 reductases (CYB5R family, formerly known as methemoglobin reductases) are a family of flavoproteins that catalyze reduction reactions by using NADH. In humans, there are 4 members of this family (CYB5R1-4), and they are involved in several metabolic reactions, including the formation and breakdown of fatty acids, cholesterol synthesis, and the metabolism of drugs (20).

One important reaction primarily catalyzed by CYB5R3 is the reduction of methemoglobin to hemoglobin. Hemoglobin binds and delivers oxygen to the body’s tissues, while methemoglobin does not.

Methemoglobin is produced when heme ferrous iron molecules (Fe2+) are oxidized to ferric iron (Fe3+), which are unable to bind oxygen. In addition, the remaining ferrous iron molecules have increased affinity for oxygen, and are less likely to release oxygen to the peripheral tissues (21).

Normally, the oxidation of hemoglobin occurs at a slow rate –– approximately 1% of red blood cells contain methemoglobin (3). An increase in methemoglobin (methemoglobinemia) is caused either by an increased production (for example, triggered by the ingestion of poison, street drugs, and certain medications) or be decreased removal (for example, kidney failure). Symptoms include a bluish skin color (cyanosis), headache, fatigue, and shortness of breath. When levels of methemoglobin approach 10%, cyanosis occurs. Higher levels may cause seizures, and levels above 30% are life threatening.

Most cases of methemoglobinemia are acquired. The antibiotics dapsone and chloroquine, anesthetics such as benzocaine, and rasburicase, have all been associated with methemoglobinemia.

Much less commonly, methemoglobinemia is inherited. There are 2 main causes of hereditary methemglobinemia –– Hemoglobin M disease and CYB5R3 deficiency. The former is an autosomal dominant disorder in which a variant occurs in one of the globin chains and results in defective hemoglobin. The latter, CYB5R3 deficiency, is a rare autosomal recessive disorder that is more common in specific populations, for example, Athabascan Alaskans, and Navajo Indians. A variant in the CYB5R3 gene results in 2 forms of CYB5R deficiency: in type 1, the mutated enzyme is unstable with reduced activity; type 2 is lethal in early pregnancy because the mutated enzyme has no activity (3, 22, 23).

In type 1 CYB5R3 deficiency, the mutated enzyme is expressed in all tissues – but the enzyme is only deficient in red blood cells. This is because unlike other cell types, mature red blood cells lack the ability to synthesize new proteins. Therefore the mutated enzyme, which is easily degraded, is not replaced (22).

Individuals who have 2 copies of the CYB5R3 variant (homozygous) have high levels of methemoglobin (up to 40%) and may appear cyanotic. However, their symptoms are typically mild (“blue but well”) and lifespan is normal – this is because they are adapted to accommodate cyanosis, for example, they have an increased red blood cell mass (24).

In contrast, individuals who have one copy of the CYB5R3 variant (heterozygous) have lower levels of methemoglobin (approximately 10%) and do not have cyanosis. However, because these individuals are not adapted, they are at high risk of developing life-threatening methemogolobinemia if they are treated with medications that can increase methemoglobin levels (3).

The drug label for rasburicase warns that rasburicase can result in methemoglobinemia in some individuals, and warms to immediately and permanently discontinue rasburicase in individuals developing methemoglobinemia (1).

Linking Gene Variation with Treatment Response

Genetic Testing

The NIH Genetic Testing Registry, GTR, displays genetic tests that are available for rasburicase response, and the genes G6PD and CYB5R3. Molecular genetic testing can be used to confirm the diagnosis of G6PD or CYB5R3 deficiency. Testing may also be used to screen females with a family history of G6PD deficiency to see if they are carriers.

G6PD deficiency is inherited in an X-linked recessive pattern and most individuals are asymptomatic throughout life.

X-linked disorders affect males at a much higher rate than females because males only have one copy of the X chromosome (hemizygous, XY). Since females have 2 copies of the X chromosome (XX) they tend to be less affected. However, female carriers can present with a range of phenotypes from no symptoms through a severe deficiency due to the high frequency of G6PD variants. Females randomly inactivate one X chromosome in somatic cells during development, resulting in a mixed population of somatic cells expressing one G6PD allele or the other.

Glucose-6-phosphate dehydrogenase deficiency occurs in homozygous and compound heterozygous females (who have inherited 2 copies of G6PD deficiency alleles) and in heterozygous females (one normal G6PD allele and one deficiency G6PD allele) with skewed X-chromosome inactivation of the functional allele (9). Genetic testing alone is insufficient for heterozygous females with one normal function G6PD allele, as the expression of the 2 alleles will vary between blood cells and over time (2).

A heterozygous mother has a 50% chance of passing G6PD deficiency to a son and a 50% chance of passing the carrier trait to a daughter. Affected fathers pass the variant G6PD gene to their daughters, but not to their sons (12, 34).

The FDA recommends that individuals at risk of G6PD deficiency be screened for G6PD deficiency before starting rasburicase therapy. However, individuals of all ancestries may be G6PD deficient (worldwide prevalence of 5%). Therefore, caution must be taken in all individuals when initiating rasburicase therapy.

In routine clinical practice, G6PD deficiency is diagnosed by measuring G6PD activity in red blood cells. Two different types of enzyme activity tests are used: qualitative and quantitative. Often, qualitative tests do not accurately detect individuals with intermediate G6PD activity. False results may be obtained immediately after a blood transfusion, because transfused cells are likely to have normal G6PD levels, and immediately after an episode of hemolysis, because young red blood cells have higher levels of G6PD. Therefore, screening for G6PD levels should be performed 23 months after a blood transfusion or hemolytic episode. Note, false negatives have been reported (2, 12, 35).

In men, if genetic testing was used to determine that an individual was positive for G6PD deficiency, the use of rasburicase would be contraindicated. However, a negative result cannot be entirely relied upon because only a small subset of G6PD variants are routinely tested for via targeted assays (2, 4, 12, 34, 36). In addition, G6PD phenotype may be unpredictable in heterozygous females because of X-chromosome inactivation, which can happen in a variable percentage of somatic cells.

Universal neonatal screening programs for G6PD deficiency are employed in some countries with a high incidence of G6PD deficiency (more than 3–5% of males) (37). These populations are primarily in Asia, Africa, along the Mediterranean and in the Middle East. Screening either uses quantitative enzyme activity assays, or the fluorescent spot test that visually identifies NADPH, which is produced by G6PD (if the blood spot does not fluoresce, the test is positive for G6PD deficiency) (2).

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

Nomenclature for Selected G6PD Variants

Acknowledgments

The authors would like to thank Stuart A. Scott, Professor, Department of Pathology, Stanford University, Palo Alto, CA, Laboratory Director, Stanford Medicine Clinical Genomics Program, Stanford, CA, USA, Bernard Esquivel, MD, MHA, PhD, Latin American Association for Personalized Medicine, Vancouver, BC, Canada and Munir Pirmohamed, MB ChB (Hons), PhD, FRCP, FRCP(E), FFPM, FRSB, FBPhS, FMedSci, David Weatherall Chair of Medicine and NHS Chair of Pharmacogenetics, Director, MRC Centre for Drug Safety Science and Wolfson Centre for Personalized Medicine, Director, HDR UK North, President, British Pharmacological Society, Institute of Systems, Molecular and Integrative Biology (ISMIB), University of Liverpool, Liverpool, UK for reviewing this summary.

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