Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in Haematology

Abstract

The guideline group was selected to be representative of UK-based medical experts. Recommendations are based on review of the literature using MEDLINE and PUBMED up to December 2013 under the heading: ‘tumour lysis syndrome’. The writing group produced the draft guideline. Review of the manuscript was performed by the British Committee for Standards in Haematology, BCSH Haemato-oncology Task Force, BCSH Executive Committee and by the haemato-oncology sounding board of the British Society for Haematology (BSH). This comprises over 50 members of the BSH who have reviewed the guidance and commented on its content and applicability in the UK setting. It has also been reviewed by representatives from Leukaemia and Lymphoma Research but they do not necessarily approve or endorse the contents. The ‘GRADE’ system was used to quote levels and grades of evidence (www.bcshguidelines.com). The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with tumour lysis syndrome (TLS). The guidance may not be appropriate to every patient and in all cases individual patient circumstances may dictate an alternative approach. First described by Bedrna and Polcák (1929) in patients with chronic leukaemia treated with radiotherapy, tumour lysis syndrome (TLS) is a metabolic syndrome caused by the breakdown of malignant cells. It is characterized by hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. The consequences are potentially severe and include acute kidney injury, cardiac arrhythmias, seizures and even death (Will & Tholouli, 2011). TLS can affect patients of all ages, typically in the first few days after the start of chemotherapy. TLS has also been observed in patients with haematological malignancies given radiotherapy (Yamazaki et al, 2004), steroids (Sparano et al, 1990; Coutinho et al, 1997), immunotherapy (Yang et al, 1999) and as spontaneous TLS secondary to the high turnover of the tumour itself (Jasek & Day, 1994). TLS is caused by the excessive release of nucleic acids, proteins and intracellular metabolites from tumour cells, which overwhelms the normal homeostatic control mechanisms and leads directly to increases in plasma uric acid, phosphate, potassium and a reduction in plasma calcium (Locatelli & Rossi, 2005). TLS is particularly likely to occur during induction chemotherapy when there is high tumour burden and tumour cells have a particularly high rate of cell turnover and an increased sensitivity to antimitotic agents. Other factors may also increase the risk of developing TLS, including an elevated serum lactate dehydrogenase (LDH) level, extensive bone marrow involvement, pre-existing renal disease or reduced urinary output (Ribiero & Pui, 2003; Davidson et al, 2004). There is some evidence that elderly patients may be at increased risk (Locatelli & Rossi, 2005). In a minority of patients the metabolic derangements are already present before the start of treatment, most often in patients with B-cell non-Hodgkin lymphoma (B-cell NHL), particularly Burkitt leukaemia and lymphoma and acute lymphoblastic leukaemia (ALL) (Jasek & Day, 1994; Alkhuja & Ulrick, 2002; Hsu et al, 2004). In some cases TLS develops unexpectedly in patients presenting with apparently low TLS-risk malignancies. Definitions of TLS have evolved for both adults and children over the last two decades. Patients may have metabolic abnormalities alone (laboratory TLS) or both laboratory and clinical problems (clinical TLS). In many cases laboratory TLS will herald clinical TLS, though clinical TLS can be prevented in many patients with appropriate therapy. The Cairo-Bishop definition of TLS (Cairo & Bishop, 2004) is shown in Table 1. It can be seen from the table that the laboratory syndrome is defined by specific electrolyte abnormalities immediately before, during or just after treatment for malignancy. The clinical syndrome is manifest by the development of organ failure or other symptoms caused by the electrolyte imbalance. There has been some debate with regard to the importance or otherwise of the criteria for definition based on 25% changes from baseline. It is, in our opinion, fair to say that these individual calculations are not usually performed by clinicians. Nonetheless, the importance of monitoring and responding to the trajectory of any change in electrolyte balance is absolutely fundamental to good management and dictates the frequency of monitoring as well as therapeutic interventions. The metabolic effects of TLS are caused by the release of intracellular potassium, phosphate and nucleic acids, the catabolism of which produces large amounts of excess uric acid. In patients with a high tumour burden, the normal homeostatic mechanisms for dealing with the release of cellular contents from dying cells are often overwhelmed, causing laboratory and then clinical TLS. The first observed effect of TLS is often hyperkalaemia. This can occur as quickly as 6 h after the start of chemotherapy and may be severe enough to be immediately life threatening (Flombaum, 2000; Locatelli & Rossi, 2005). Simultaneously, as a direct consequence of hyperuricaemia, uric acid crystals precipitate out in the renal tubules, particularly in the acid environment of the distal renal tubules, causing a reduction in the ability of the kidneys to excrete the products of cellular disruption (Will & Tholouli, 2011). Renal function becomes further compromised when the released phosphates increase the plasma phosphate concentration and calcium phosphate begins to crystallize out in the soft tissues, including in the renal tract. The development of acute kidney injury causes further increases in plasma potassium levels and the consequent acidosis accelerates the crystallization of uric acid in the renal tubules (Jones et al, 1995); at this point the situation spirals out of control, causing a cascade to clinical TLS. Whilst clinical TLS is a relatively rare event, affecting around 3-6% of patients with high-grade tumours, the consequences are significant, with one-third of affected patients requiring dialysis and an overall mortality rate in excess of 15% being reported (Annemans et al, 2003; Candrilli et al, 2008). The key to the management of TLS is recognizing those patients at risk of developing the syndrome and using prophylactic measures to prevent its occurrence. It will be difficult, however, to completely eradicate TLS, as a small proportion of patients with very aggressive tumours develop spontaneous TLS prior to receiving any therapy (Galardy et al, 2013). In the UK, two drugs are licensed for the prevention and management of clinical TLS: the oral xanthine oxidase inhibitor, allopurinol; and the exogenous recombinant urate oxidase, rasburicase. Allopurinol is a xanthine oxidase inhibitor. It reduces the production of uric acid by decreasing the rate of the conversion of hypoxanthine to xanthine and xanthine to uric acid (Fig 1). Because both hypoxanthine and xanthine are relatively more soluble than uric acid, this reduces the formation of uric acid crystals in the renal tubules, particularly in the distal tubules where the more acid environment encourages uric acid to precipitate as insoluble urate salts (Hande et al, 1981; Pui et al, 2001). Importantly, it does not increase the rate of breakdown of any uric acid that has already been formed and so its therapeutic effect is delayed by 24–72 h (de Bont & Pieters, 2004; Rampello et al, 2006). Rasburicase is a recombinant form of the enzyme urate oxidase (UO). Urate oxidase is an endogenous enzyme commonly found in most mammalian species, but not humans as a consequence of the acquisition of a nonsense mutation in the coding region during hominoid evolution (Yelandi et al, 1991). Rasburicase metabolizes urate to allantoin (Fig 1), a substance that is approximately five to ten times more soluble than uric acid (Brogard et al, 1972; Pui, 2002). Rasburicase acts immediately, even on already formed urate. It is extremely effective and will reduce the plasma levels of uric acid within 4 h of its intravenous administration, allowing chemotherapy to be started earlier than might be safe with allopurinol (Pui et al, 2001). Given these respective mechanisms of action, where rasburicase is being used in the treatment or prophylaxis of TLS, the addition of allopurinol is unnecessary and has the potential to reduce the effectiveness of rasburicase. The international expert consensus panel (Cairo et al, 2010) have produced an excellent model to allow stratification of patients into 3 main categories: those at low, intermediate or high risk of TLS development. Cairo et al (2010) recommended that those at low risk of TLS development be actively monitored and offered hydration +/- allopurinol prophylaxis. Those at intermediate risk of TLS development were recommended to be offered active monitoring, hydration and allopurinol prophylaxis. Those at high risk of TLS development were recommended to be offered active monitoring, hydration and rasburicase prophylaxis. To our knowledge, there have been no additional publications that fundamentally impact the model proposed by Cairo et al (2010). The issue that seems, to our group, most important to address in these current guidelines is which patients are at high enough risk of TLS to warrant administration of rasburicase. We would therefore propose that high-risk patients are identified early as distinct from those requiring hydration +/- allopurinol only. Patients fulfilling the criteria for high-risk disease should generally be offered a schedule of monitoring and prophylaxis that includes the use of rasburicase. Patients who do not fulfil these criteria should be offered a schedule of monitoring, hydration and possibly allopurinol. There is little evidence available to inform decisions regarding omission of allopurinol and whether specific patient groups can be determined. What is clear though, is that any form of prophylaxis is only likely to be useful during the first course of treatment and at future time points where re-induction or salvage chemotherapy is used. There is no rationale for using prophylaxis in the setting of consolidation therapy including bone marrow transplant if the patient is in or near to a remission. Special attention should be paid when patients, even those with low-grade disease, are being treated with potent novel agents. TLS may be seen in the context of lower risk disease in this instance. The exact fluid volume required is not known but it seems reasonable to aim for 3 l/24 h in adults. In patients at high risk of TLS, the use of allopurinol in association with a forced alkaline diuresis was the traditional method to manage these patients. Uric acid has an increased solubility in an alkaline pH, so giving sodium bicarbonate intravenously might theoretically aid its excretion. However both xanthine and hypoxanthine, that precede uric acid in the biochemical pathway, become less soluble in alkaline conditions and so precipitate before any uric acid can be formed thus negating any potential advantage of the increased solubility of uric acid at high urinary pH. Alkaline diuresis is therefore not recommended (Ten Harkel et al, 1998; Coiffier et al, 2008). The standard recommended dosing schedule for allopurinol in prevention of TLS is 200–400 mg/m2/day in 1–3 divided doses for adults, up to a maximum of 800 mg daily. In children, the recommended dose is 300–450 mg/m2/day in three divided doses up to 400 mg daily. In infants weighing <10 kg the dose is 3·3 mg/kg every 8 h. In practice, most adult haematologists simply use 300 mg/day and, for the most part, this is effective but it may be prudent to increase the dose of allopurinol or, preferably, switch to rasburicase in the presence of deteriorating biochemical or clinical markers., Allopurinol doses may need to be adjusted in renal failure. Allopurinol should be given for up to 7 days after chemotherapy is started. In patients with an allergy to allopurinol it is generally safe to use prophylactic hydration only along with careful monitoring as patients at very high risk of TLS would be given rasburicase. Rasburicase prophylaxis along with appropriate hydration and monitoring is recommended for patients with the very high-risk characteristics detailed in the criteria above. The drug is licensed for the treatment and prophylaxis of TLS but is contra-indicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Rasburicase is highly effective in the treatment of TLS and has been used in prophylaxis but, with the exception of one small underpowered study (Goldman et al, 2001), no other formal randomized trial against allopurinol has been performed. The licensed dose is 0·2 mg/kg and the licensed duration of therapy for prophylaxis is 5–7 days. Rasburicase is undoubtedly a highly effective agent in TLS prophylaxis in both adults and children (Coiffier et al, 2003; Pieters & Uyttebroeck, 2003; Yim et al, 2003; Jeha et al, 2005). Although the licensed dose of rasburicase is 0·2 mg/kg/day, a number of publications have explored lower doses and shorter courses of therapy. Previous guidelines have reflected these observations; Cairo et al (2010) recommended a dose of 0·1–0·2 mg/kg on the first day, repeated daily for up to 7 days. Almost all of these dosing studies have been retrospective analyses of There has been one randomized trial a dose of rasburicase five daily doses in patients at risk of TLS et al, In the dose patients rasburicase which be repeated on a daily if required at the of the patients were in the of which were in the dose and only of those required more than one The that a dose of rasburicase was as effective as therapy for the of patients. Other groups have dosing of patient et al a dose of 3 mg a in a used this dose in a of patients with uric acid levels receiving a cell transplant or chemotherapy for a haematological malignancy. patients required a dose and there were no renal in any this group have in a of adult patients et al, 2011). patients were treated with a dose of rasburicase. failure was defined as failure to uric acid levels h after In patients with a uric acid of the failure rate was as to in those with uric acid The of this lower dose has been in a study of patients at high risk of TLS et al, dose was in patients from a of haematological including patients with and ten patients with but 8 of the patients required a including patients with a cell over There were no no for and no seen in this et al, has at the effectiveness of a dose of rasburicase studies in adult patients at high risk of developing TLS. was with from patients treated with rasburicase given at the licensed dose for days or patients treated with allopurinol. The dose from mg/kg to The for the dose of rasburicase that a dose was as effective as the rasburicase treatment with to the control of uric acid levels but to allopurinol. In a standard dose of defined clinical with the licensed In the first trial the use of rasburicase for the prevention of TLS has been (Galardy et al, 2013). patients, with aggressive B-cell malignancies were treated with rasburicase at the licensed dose with a treatment, which was repeated if prior to or to chemotherapy The number of doses was with patients being given a In this high-risk only of patients renal after rasburicase administration and of those patients patients in required in five of these it was prior to chemotherapy and the other patient required dialysis for It is to the use of rasburicase. these into and available in the of clinical or laboratory TLS, TLS can be prevented in the of adult patients using a dose of 3 mg rasburicase. It is to for biochemical and clinical of TLS and if there is evidence of any then the dose should be repeated daily of TLS have to to TLS will management as described Whilst there is evidence to the use of a dose for prophylaxis in an adult this is in It would very reasonable to this into children based on the that for a dose they will a dose kg than adults for this is In the of however, this a We however, further in this for adult patients, if a rasburicase dose is it is to for biochemical and clinical of TLS. there is evidence of any then the dose should be repeated daily of TLS have to clinical TLS develops prophylaxis then patients should be with a standard 0·2 dose of rasburicase as It be that the presence of rasburicase in the will lower urate levels in are to the laboratory on be that low urate levels are not used to therapy. of this a including and The clinical of the patient can change very quickly and monitoring is are not available for management then should be given to the patient to an or to a a of as defined by BCSH criteria et al, It is to have a high of for TLS. The first in TLS is to a high output with hydration and careful monitoring of fluid The aim is to prevent uric acid crystallization and calcium phosphate in the renal The of these products in the renal tubules a of deteriorating renal function to hyperuricaemia, and hypocalcaemia. biochemical abnormalities in further of uric acid and calcium There are no that a rate of fluid to be than but 3 every h would be reasonable in adults et al, Cairo et al, & Tholouli, with the aim of a output of for infants and for patients. or are and it is that no potassium is to the hydration output should be at and a formal of fluid balance should be at 6 should be to all fluid as or the elderly and those with pre-existing cardiac and renal disease are at risk of fluid can be useful in fluid balance and infants may need to be daily to fluid reduction in output should of fluid balance and laboratory the disease, it may be appropriate to whether there is a to by which may a reduction in output may herald renal failure and fluid may should be in using in this Whilst mg/kg intravenously can be a useful treatment, the drug may uric acid (Jones et al, and is likely to be less in the presence of renal The presence of fluid of the is not recommended to only evidence of and increased risk of calcium phosphate along with reduced xanthine solubility at increased (Coiffier et al, Harkel et al, 1998; & 2004; et al, Allopurinol is a xanthine oxidase that acts by the development of uric acid crystals in the renal tubules but it does not the breakdown of uric acid that has already been this useful in the prophylactic is not the drug of in TLS. In to a recombinant urate oxidase, metabolizes urate directly to the more soluble Rasburicase of uric acid and reduce urate levels more quickly than allopurinol (Goldman et al, Pui et al, et al, 2003; Jeha et al, 2005). patient who has been on allopurinol as a prophylactic should be to rasburicase if they develop clinical TLS, the being patients who have to rasburicase and those in it is to deficiency. In those patients allopurinol should be but renal dialysis is more likely to be The standard recommended dose of rasburicase is 0·2 given as a The duration of treatment should be by the clinical The current and and include daily dosing for up to days. Whilst there are some to duration of rasburicase or reduced dose therapy in the context of prophylaxis there are no those of the to dosing in the setting of TLS. It seems reasonable to rasburicase 0·2 be given for days with careful monitoring of hydration and administration of rasburicase do not prevent hyperphosphataemia, it can be to control phosphate levels other than by The use of has been described Coiffier et al, but is to and thus is not recommended in this setting. should not be treated as treatment can precipitate further calcium phosphate in the calcium levels or there has been a 25% from (Cairo & Bishop, 2004) then cardiac monitoring is cardiac or should be treated with calcium in the standard doses for adults and The aim is to the symptoms but not to the biochemical The effects of including are well It is recommended that patients with potassium levels or a 25% increase in potassium from should be offered cardiac potassium a medical and dialysis is likely to be required measures can be to reduce potassium levels but the effects are and dialysis is often should be treated with a of calcium with cardiac or intravenous can be as can intravenous of and increase of potassium from the to the intracellular The use of urate oxidase therapy to have reduced the need for dialysis in patients at risk of TLS. The group patients with Burkitt and monitored and over an et al, the first time of the study no patients urate In the some were given the drug and in the it was recommended that all patients were treated with a urate the course of the study the of TLS was in one and The of were a study reported a of TLS when a of adults at high risk of TLS was of patients TLS and TLS was an risk for acute kidney injury and increased even in the rasburicase et al, 2013). Nonetheless, when the measures described have to prevent renal and fluid hyperuricaemia, or have renal dialysis is dialysis is not recommended for this clinical is than with other of dialysis & In patients may have which would this approach. There are no with or other and all to be Given the release of metabolites into the in the setting of TLS, some groups have that daily dialysis may be the et al, 2008). In patients who are renal therapy can be should there is of renal function and the and in these guidelines is to be and at the time of to the the British Society for Haematology the any for the content of these The British Committee for Standards in Haematology will review this guideline on an to it the at to if the guideline has been or The will also the the guideline was last reviewed the the draft of the manuscript and the the group, reviewed the literature and the and reviewed the literature and the The to for in the literature and for as a medical The would to the BCSH haemato-oncology BSH sounding BCSH and Leukaemia Lymphoma Research for in these The BCSH paid the during the writing of this medical for was by the have of to the BCSH and Task has for and of the other to of the writing group will inform the writing group if any evidence becomes available that would the of the in this or it The will be and from the BCSH current guidelines if it becomes are an will be on the BCSH guidelines (www.bcshguidelines.com). changes are required to changes in of evidence or additional evidence becomes available to current a of the guidance will be on the BCSH