Rasburicase Therapy and G6PD and CYB5R Genotype

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).