Alkalinization Urinary alkalinization has been a long-standing

zation. In consensus guidelines, Coiffi er et al. 2008 recommend against routine urine alkalini- zation, while Tosi et al. 2008 recommend urine alkalinization in low-risk patients, highlighting the lack of evidence to make fi rm uniform guid- ance. An update of the Tosi et al. 2008 Italian guidelines recommend against alkalinization even in low-risk patients Pession et al. 2011 . Sodium bicarbonate is generally used as the additive to intravenous fl uids with a goal urine pH of 7.0. It is unlikely that patients without risk of HU benefi t from urinary alkalization; those with high tumor burdens and risk for TLS may benefi t from urine alkalinization although data are lacking. Additionally, with the availability of rasburicase to rapidly degrade existing uric acid to a much more soluble byproduct, the risk of hyperuricemia and subsequent urate precipita- tion is almost nonexistent in settings with rasbu- ricase availability thereby negating the need for alkalinization Tosi et al. 2008 ; Howard et al. 2011 . Patients with hyperphosphatemia should not be alkalinized due to the increased risk of calcium phosphate precipitation and availability of rasburicase to treat concomitant hyperurice- mia, if present Howard et al. 2011 . In the patient with elevated uric acid or risk of hyper- uricemia without hyperphosphatemia started on alkalinization, the alkalinization can be discon- tinued as the uric acid normalizes and the tumor burden decreases over the fi rst few days of ther- apy Table 3.3 .

3.4.1.2 Allopurinol Allopurinol inhibits xanthine oxidase, an enzyme

which converts hypoxanthine and xanthine to uric acid. Krakoff and Meyer 1965 and DeConti and Calabresi 1966 fi rst showed that allopuri- nol effectively reduced serum uric acid levels without leading to signifi cant accumulation of xanthine and hypoxanthine due to differential solubility products. Allopurinol has been noted to be quite safe and is extremely inexpensive. Xanthine nephropathy secondary to TLS and leading to AKI with concomitant allopurinol has been rarely reported in the literature Band et al. 1970 ; Hande et al. 1981 ; Andreoli et al. 1986 ; Potter and Silvidi 1987 ; LaRosa et al. 2007 . Andreoli et al. 1986 reported that although xan- thine exceeded its solubility limit in 16 of 19 children with ALL receiving allopurinol, only 8 were noted to have precipitated xanthine in urine sediment and only half of those children devel- oped AKI. They therefore theorized that addi- tional factors are involved in the development of AKI during TLS. Xanthine nephropathy should be considered in the patient with AKI but appro- priate TLS prophylaxis; in such cases allopurinol should be reduced or discontinued, xanthine levels should be drawn and patients should be tested for a defect in the hypoxanthine- guanine phosphoribosyl trans ferase HGPRT enzyme LaRosa et al. 2007 . Drawbacks to allopurinol include a relatively slow onset of action i.e., 24–72 h, the neces- sity of dose reduction in the setting of renal insuffi ciency and its inability to degrade preex- isting uric acid Howard et al. 2011 . Intravenous allopurinol has been shown to be equally effec- tive and safe as compared to oral allopurinol but comes at a much higher cost 2,000-fold Smalley et al. 2000 ; Feusner and Farber 2001 ; Patel et al. 2012 . Prior to the advent of rasburi- case, intravenous allopurinol was a potential option in patients unable to tolerate oral intake but is no longer available in Europe Feusner and Farber 2001 ; Will and Tholouli 2011 . Utilizing a single low dose of rasburicase, Patel et al. 2012 were able to extrapolate a signifi - cant cost savings over intravenous allopurinol. Consensus guidelines recommend allopurinol in low- and intermediate- risk patients i.e., those patients not recommended to receive rasburi- case Coiffi er et al. 2008 ; Pession et al. 2011 . Consensus guidelines recommend that patients who receive rasburicase should only have allo- purinol initiated after rasburicase discontinua- tion in order to inhibit additional uric acid formation until the tumor burden is signifi cantly decreased i.e., usually 3–7 total days Coiffi er et al. 2008 ; Tosi et al. 2008 . Given the slow onset of action for allopurinol it may be more prudent to initiate allopurinol prior to this rec- ommended time point. Similar to urine alkalini- zation, it is unclear if the addition of allopurinol is benefi cial in patients with a low tumor burden and low risk of developing HU Table 3.3 Pession et al. 2011 .

3.4.1.3 Rasburicase Rasburicase, recombinant urate oxidase, converts

uric acid into allantoin, a fi ve to ten times more soluble compound, in an extremely effective manner. Due to this fact, many studies have shown that rasburicase is effi cacious in correct- ing HU in pediatric and adult patients Pui et al. 2001 ; Patte et al. 2002 ; Bosly et al. 2003 ; Coiffi er et al. 2003 ; Jeha et al. 2005 ; Pession et al. 2005 ; Shin et al. 2006 ; Kikuchi et al. 2009 . Follow-up studies comparing effi cacy of rasburicase and allopurinol naturally show that rasburicase is much more effective in rapidly and dramatically reducing the uric acid level although such studies fail to incorporate a clinically relevant endpoint Goldman et al. 2001 ; Cortes et al. 2010 . Many of these studies were supported by the pharma- ceutical maker of rasburicase, including grant support, providing the drug, logistic support, edi- torial support, and data management, and some study authors had a fi nancial stake in the pharma- ceutical company Goldman et al. 2001 ; Pui et al. 2001 ; Patte et al. 2002 ; Bosly et al. 2003 ; Coiffi er et al. 2003 ; Jeha et al. 2005 ; Shin et al. 2006 ; Kikuchi et al. 2009 ; Cortes et al. 2010 . Early studies also utilized higher doses of rasburicase i.e., 0.15–0.2 mgkgday and for a longer dura- tion up to 7 days based on the recommendation of the manufacturer and what was approved by the United States Food and Drug Administration [FDA], rather than what is more rational based on the mechanism of the drug and underlying dis- ease process Pui et al. 2001 ; Patte et al. 2002 ; Bosly et al. 2003 ; Coiffi er et al. 2003 ; Jeha et al. 2005 ; Pession et al. 2005 ; Shin et al. 2006 ; Kikuchi et al. 2009 . Rasburicase doses as low as 0.017 mgkg as a single dose have subsequently been found effec- tive; many studies have shown that abbreviated rasburicase schedules are suffi cient Hummel et al. 2003 ; Lee et al. 2003 ; Liu et al. 2005 ; Ho et al. 2006 ; Hutcherson et al. 2006 ; McDonnell et al. 2006 ; Trifi lio et al. 2006 ; Reeves and Bestul 2008 ; Campara et al. 2009 ; Giraldez and Puto 2010 ; Vadhan-Raj et al. 2012 . Hummel et al. 2007 were able to utilize a low-dosing schedule resulting in an average decrease in uric acid lev- els by 83 while utilizing a median total dose of rasburicase of 0.049 mgkg, resulting in a cost reduction of 96.8 based on manufacturer dos- ing recommendations. Adult patients with initial average hyperuricemia of 13.1 mgdL were able to achieve uric acid 8.0 mgdL with an average single rasburicase dose of 0.032 mgkg Hummel et al. 2007 . Knoebel et al. 2011 similarly showed that most adult patients could be effec- tively treated with a single 0.05 mgkg dose. Yet, recent consensus guidelines still recommend a range of 1–7 days of rasburicase at a dose of 0.1–0.2 mgkgdose Coiffi er et al. 2008 ; Tosi et al. 2008 ; Pession et al. 2011 . Although gener- ally safe, rasburicase must be avoided in patients with glucose-6-phosphate dehydrogenase G6PD defi ciency and methemoglobinemia, and hemolytic anemia has been reported in childhood ALL Bauters et al. 2011 . Even though HU is a factor in LTLS, data are less clear that rasburicase is more effective in the prevention of CTLS than allopurinol. In their analysis of BFM data, Wössmann et al. 2003 compared LTLS and anuria risk in pediatric ALL and stage IIIIV BL patients with LDH ≥500 UL treated with either allopurinol or rasburicase; they found that although ALL patients treated with rasburicase had a trend toward decreased LTLS, it was not clinically signifi cant although there was a signifi cant decrease in the incidence of anuria. LTLS or anuria risk in children with BL was not signifi cantly different between rasbu- ricase and allopurinol Wössmann et al. 2003 . Despite decreasing uric acid levels, Ahn et al. 2011 noted no statistical difference in LTLS, CTLS or need for renal dialysis with rasburicase compared with allopurinol. A Cochrane review of rasburicase for the prevention and treatment of TLS in children with cancer similarly showed signifi cant reduction in uric acid levels, but the relevant analyzed studies failed to show that this equated to a signifi cant reduction in clinically signifi cant endpoints, specifi cally renal failure and mortality Cheuk et al. 2010 . Rasburicase remains an extremely expensive drug 535 per 1.5 mg vial compared to allopu- rinol and therefore it is vital to appropriately select patients that would benefi t from rasburi- case through the prevention of CTLS Goldman