Rasburicase and G6PD

Rasburicase (generic for Elitek ®) is used to reduce elevated levels of uric acid in the plasma of children and adults with leukemia, lymphoma, and solid tumor malignancies who have developed tumor lysis syndrome as a result of receiving chemotherapy. This condition is the most common disease-related emergency in patients with hematologic (blood related) cancers and most commonly affects individuals with non-Hodgkin’s lymphoma and acute leukemia. Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, which causes potentially fatal electrolyte and metabolic disturbances, including elevated levels of uric acid, potassium, phosphate, and calcium. Rasburicase is administered to reduce the toxic effects of tumor lysis brought on by chemotherapy. Rasburicase is a recombinant urate-oxidase enzyme that converts uric acid to allantoin, an inactive intermediate of uric acid that is water-soluble and able to be eliminated in the urine. Rasburicase is administered intravenously as a 30-minute infusion. A single course of this treatment is recommended.

The gene of interest is glucose-6-phophate dehydrogenase (G6PD). G6PD is an enzyme that is essential in order for red blood cells to handle oxidative stress. Oxidative stress occurs when highly reactive oxygen-containing molecules are produced in excess of the body’s ability to process them. In individuals with G6PD deficiency, oxidative stress can cause damage to red blood cells. Substances which can cause oxidative stress include fava beans, certain legumes, and several medications (i.e. rasburicase). Although normally the body is able to process these substances without a problem, individuals who have a G6PD deficiency may experience hemolytic anemia with jaundice (a yellowish pigmentation of the skin) due to sudden destruction of red blood cells.

G6PD deficiency is sex-linked, meaning it is hereditary. Since the G6PD gene is carried on the X chromosome, males can only have one copy while females can have either one or two copies. G6PD deficiency is the most prevalent enzyme deficiency in the world. It is estimated that nearly 330 million individuals worldwide have a G6PD deficiency, which represents 5% of the global population. G6PD deficiency has been shown to be most prevalent in geographic areas where inhabitants were exposed to endemic malaria. The highest amount of G6PD deficiencies was reported in sub-Saharan Africa, followed by the Middle East. In the United States, this enzyme deficiency primarily affects populations of African and Mediterranean descent.

Rasburicase is contraindicated in patients with a G6PD deficiency. Patients of African or Mediterranean ancestry who are at higher risk of having a G6PD deficiency should be screened before receiving rasburicase. This medication should only be administered to males with one non-deficient G6PD allele or females with two non-deficient G6PD alleles. If a patient develops hemolysis (rupture of blood cells) while taking rasburicase, treatment should be discontinued immediately and permanently.

Marcus is a 52-year-old Caucasian male who has been recently diagnosed with leukemia and will begin his first round of chemotherapy this month. His oncologist, Dr. John, would like to prescribe Marcus a medication to control his uric acid levels. Dr. John decides to prescribe Marcus the drug rasburicase, which was approved by the FDA to manage plasma uric acid levels in patients receiving chemotherapy. Before starting therapy, Dr. John asks if Marcus is interested in being genotyped to test for G6PD deficiency. This would delay treatment and would be an added cost, but could help him avoid serious side effects. Marcus declined the test and was given 0.2 mg/kg over 30 minutes twelve hours before his first round of chemotherapy. A day later, Marcus was admitted to the ER with signs and symptoms of hemolytic anemia, including severe jaundice, dark urine and pale skin. Dr. John immediately calls for Marcus to be genotyped and it was revealed that Marcus was G6PD deficient. Dr. John discontinues the rasburicase treatment and places Marcus on allopurinol.

Later that year Jeffery, a 58 year old African American male, is being treated by Dr. John for lymphoma. Dr. John wishes to prescribe Jeffery rasburicase to manage uric acid levels during his chemotherapy regimen. Since Jeffery is an African American, Dr. John knows that he has a higher chance of being G6PD deficient and decides to order a genetic test before starting the rasburicase. The test came back, and Jeffery had a class III allele, making him G6PD deficient. Since rasburicase would put Jeffery at a high risk for developing hemolytic anemia, Dr. John decides against it and gives Jeffery a prescription for allopurinol.

G6PD genetic testing does not completely rule out the risks of taking rasburicase, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

The links below provide access to important articles and information relative to rasburicase. The links are to external websites and will be checked regularly for consistency.

• Rasburicase Prescribing Information
• Rasburicase Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Rasburicase

Elitek (rasburicase) [package insert on the Internet]. Bridgewater (NJ): Sanofi-Aventis U.S. LLC; c2005-2012 [cited 2015 Mar 1]. Available from: http://products.sanofi.us/elitek/elitek.html

Facts & Comparisons [Internet]. Clinical Drug Information, LLC. 2015. Rasburicase; [cited 2015 Dec 4]; [about 1 screen]. Available from: http://0-online.factsandcomparisons. com.polar.onu.edu/MonoDisp.aspx?monoID=fandc-hcp13517&quick=-29254%7c5 &search=-29254%7c5&isstemmed=True&NDCmapping=-1&fromTop=true#firstMatch/.

G6PD Deficiency Association [Internet]. Associazione Italiana Favismo – Deficit di G6PD Onlus; c1996-2015. What is G6PD deficiency; [cited 2015 Dec 4]; [about 1 screen]. Available from: http://www.g6pd.org/en/G6PDDeficiency.aspx/.

Howard SC, Jones DP, Pui C-H. The Tumor Lysis Syndrome. The New England Journal of Medicine [Internet]. 2011 May 12 [cited 2015 Dec 4];364(19):1844–1854.

Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells, Molecules, and Diseases [Internet]. 2009 Feb 23 [cited 2015 Dec 4];42(3):267-278.

PharmGKB [Internet]. PharmGKB. c2001-2015. Clinical Pharmacogenetics Implementation Consortium (CPIC) for rasburicase and G6PD; [updated 2015 Sept 18; cited 2015 Dec 4]; [about 2 screens]. Available from: https://www.pharmgkb.org/chemical/PA10176#tabview =tab0 &subtab=31/.

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 Aug;96(2):169-74.