Single dose Rasburicase is a clinically effective pharmacoeconomic approach for preventing tumour lysis syndrome in children with high tumour burden

Tumour lysis syndrome (TLS) is an oncological metabolic emergency caused by the rapid lysis of tumour cells and subsequent release of large amounts of potassium, phosphate and nucleic acids into the systemic circulation. Catabolism of nucleic acids can lead to a rapid increase of uric acid excretion and a precipitation of uric acid in the renal tubules. Both high levels of uric acid and phosphate can result in kidney impairment and significant morbidity and mortality (Davidson et al, 2004). The main prophylactic strategies are intravenous hydration and the use of anti-hyperuricaemic agents, such as Allopurinol and Rasburicase. Prophylaxis is selected according to individual risk stratification, assessed by the disease burden and the treatment chosen. Rasburicase is a recommended strategy for prevention of TLS in adults and children with high tumour burden. It is a recombinant form of the enzyme urate oxidase, which is present in most mammals except humans (Wu et al, 1989). Rasburicase converts uric acid to thewater-soluble compound, allantoin, promoting its renal excretion. It reduces the uric acid levels much lower than the normal range (Coiffier et al, 2003). In adults, a single dose of Rasburicase has been shown to adequately control the toxic effects of TLS (Feng et al, 2013; Vadhan-Raj et al, 2012). However, there is lack of evidence regarding the effectiveness of single dose Rasburicase in paediatrics. Rasburicase effectively reduces the uric acid levels in children with high tumour burden, but it is not known whether a single dose of 0 2 mg/kg is effective. The British Committee for Standards in Haematology suggests that single dose Rasburicase is adequate in presenting children at risk for TLS (Jones et al, 2015). However, the most up-to-date evidence recommends five doses of Rasburicase and therefore paediatric haematology-oncology physicians use single or multiple doses of Rasburicase at their discretion (Goldman et al, 2001). We recently conducted an email survey of tertiary paediatric centres in England, and found that seven out of eight centres use multiple doses of Rasburicase for highrisk patients. Rasburicase is expensive; hence multiple doses also result in significant financial toxicity. A pharmacoeconomic approach is required to identify potential ways of reducing the cost of cancer care by appropriate usage of high cost drugs. It is therefore important to determine whether a single dose of Rasburicase is clinically effective in children with high tumour burden. We retrospectively evaluated the use of Rasburicase in children presenting with haematological malignancy or neuroblastoma to determine the effectiveness of single dose Rasburicase in normalising uric acid and renal function. Schwartz formula was used to assess the renal function by calculating the Glomerular filtration rate (GFR). All patients with haematological malignancies that received Rasburicase between October 2012 and October 2015 at Birmingham Children’s Hospital were included. These patients were identified through the pharmacy database. Laboratory results and clinical information were retrieved using the hospital’s electronic system. Fifty-three children with a median age of 7 3 years (range: 4 months to 16 years; ≤ 5 years: n = 24; 6–12 years: n = 17; 13–16 years: n = 12) received Rasburicase for the following indications: acute myeloid leukaemia (n = 7), acute lymphoblastic leukaemia (n = 33), Hodgkin lymphoma (n = 2), non-Hodgkin lymphoma (n = 9) and neuroblastoma (n = 2). The tumour burden of white blood cell (WBC) count > 100 9 10/l, Stage 3 or 4 lymphoma or high tumour burden neuroblastoma at presentation were classified as appropriate indications for using Rasburicase. Rasburicase was indicated in 44 out of 53 (83%) children. Twenty-six met the criteria of WBC >100 9 10/l and 18 met the criteria of stage 3 or 4 lymphoma or high burden disease (neuroblastoma). In the remaining 11 children, the tumour burden was low and hence, Rasburicase was not indicated. Laboratory tumour lysis, as per the criteria of Cairo and Bishop (2004), was observed in three patients’ prior receiving single dose and in two patients receiving multiple doses. Nineteen (43%) of 44 children received single dose Rasburicase. The remaining 25 children received between two to five daily doses of Rasburicase. Twenty-four hours after receiving single dose of Rasburicase, normalisation of uric acid was observed in all patients. A sustained normalisation of uric acid was observed in 15 of 19 children receiving a single dose of Rasburicase (Fig 1). In the remaining four children, a rebound of uric acid >400 lmol/l between 48 and 96 h after first dose of Rasburicase was observed. These children were appropriately given second dose of Rasburicase. Thus, moderately elevated uric acid levels were normalised in majority of children after single dose of Rasburicase. A higher uric acid level of >600 lmol/l at presentation was Correspondence