British Society for Haematology updated guidelines for the diagnosis and management of tumour lysis syndrome in adults and children with haematological malignancies: A focus on patient safety

This guideline update was compiled according to the British Society for Haematology (BSH) process at For Guidelines writers and Taskforce Members (b-s-h.org.uk). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. A literature search was performed using the EMBASE and MEDLINE databases using the following search terms: ‘tumour lysis syndrome’ and ‘tumor lysis syndrome’ from 01/10/2013 to 01/06/2024. Papers published in non-English journals or non-human subjects were excluded from review. Review of the manuscript was performed by the BSH Guidelines Committee Haemato-oncology Task Force, the BSH Guidelines Committee and the Haemato-Oncology sounding board of BSH. It was also reviewed by the representatives from the National Health Service England (NHSE) Patient Safety team and Specialist Pharmacy Services (SPSs). These organisations do not necessarily approve or endorse the contents. In response to a reported incident of delayed administration of rasburicase, the NHSE Patient Safety team undertook an analysis to answer the patient safety question, ‘Are there wider issues relating to delayed or omitted administration of medication to treat/prevent tumour lysis syndrome?’. Between September 2016 and January 2020, the team identified 64 relevant reported incidents, of which 16 were reported as being associated with harm. The analysis identified several themes including a lack of staff knowledge (medical, nursing and pharmacy) around the management of tumour lysis syndrome (TLS), including the critical nature of medications to prevent/treat this complication. It also identified a lack of availability of critical medications to treat TLS at ward and pharmacy level. Our writing group was formed in response to this analysis, to review the published literature and update the guidelines on the diagnosis and management of TLS in adults and children with a haematological malignancy with particular focus on patient safety. Where the guidance differs between adults and children, for example, medication doses or fluid infusion rates, this has been specifically stated in the text. TLS remains a life-threatening complication of haematological cancer and is caused when large-scale destruction of malignant cells releases intracellular contents and electrolytes into the bloodstream that overwhelm the normal physiological mechanisms of clearance. This can occur spontaneously in malignancies with a high proliferative rate (e.g. Burkitt lymphoma) but more commonly occurs following the administration of anti-cancer therapy. Since the publication of the previous BSH guidelines for TLS in 2015,1 there have been significant developments in the management of haematological malignancies with numerous novel targeted anticancer agents and immunotherapies. These represent important advances in therapy, but some are associated with a higher risk of TLS, including in diseases that previously would not have been considered high risk for TLS. We present an updated review of the management of TLS with particular focus on practical considerations to ensure patient safety and prompt drug delivery. The definition and pathophysiology of TLS remain unchanged from the 2015 guideline: Management of TLS in adults and children with haematological malignancies.1 For completeness, we have reproduced the original definition of TLS2 in Table 1 and TLS grading in Table S1. Laboratory TLS The presence of two of more of the following abnormalities in a patient with cancer or undergoing treatment for cancer within 3 days prior and up to 7 days after initiation of treatment. Clinical TLS A patient with laboratory TLS and at least one of: Assessment of TLS risk is required for each patient prior to starting any new line of therapy. It is important that risk assessment considers patient and treatment factors in addition to disease risks. This combined approach will provide a personalised prophylactic strategy to mitigate the risk of TLS. The disease-specific factors described in the international expert consensus panel guidelines9 are still relevant today and the TLS risk stratification flow charts from this paper are summarised with small modifications in Table 2. These highlight specific disease histologies and/or markers of higher disease burden, for example, lactate dehydrogenase (LDH)/disease stage/high white blood cell count (WBC)/cancer mass >500 g in adults or >300 g/m2 in children, that are associated with a higher risk of TLS.10, 11 Patient factors such as renal dysfunction and/or features of pre-existing TLS (e.g. hyperuricaemia/hyperphosphataemia/hyperkalaemia) will also influence the overall TLS risk assessment. For example, an adult patient with acute lymphoblastic leukaemia (ALL), WBC <100 × 109/L and normal LDH would be classified as intermediate risk for TLS on disease criteria alone. However, they would be ‘upgraded’ to high risk for TLS if they had co-existent renal dysfunction or other features of pre-existing TLS. With the plethora of new therapeutic agents, further consideration needs to be given as to whether any of these ‘upgrade’ a patient's risk.6 Venetoclax in the treatment of CLL and acute myeloid leukaemia (AML) is a commonly used example, but it is not possible to provide a comprehensive list of all novel agents within this guideline. It is vital for clinicians to keep up to date with published literature regarding the TLS risk in new therapies. Importantly, trial reported rates of TLS may differ from the incidence of TLS in the ‘real-world’ population.12-14 Cases of TLS have been reported across a range of solid and haematological malignancies, even in those who are receiving radiotherapy or non-systemic therapy such as intrathecal chemotherapy,15 and thus measures to reduce risk and incorporate monitoring strategies should always be considered. This includes those thought to be low risk. Timing of the measures is also important, with the best risk reduction occurring if measures are put in place prior to definitive treatment of the malignancy, especially in those cancers which have a high risk of spontaneous TLS. Furthermore, decisions should be made as to whether a patient is suitable for outpatient strategies or requires hospital admission for either treatment to be given intravenously or for more intensive monitoring strategies. Vigorous hydration and diuresis are a key part in preventing and managing TLS. Patients should be educated about the importance of drinking 2–3 L/day of fluids if possible depending on renal function, equivalent to 2.5–3 L/m2/day in children, starting the day prior to the treatment. If necessary, intravenous hydration should be used to meet these targets, particularly in those at high risk for developing TLS. Loop diuretics could be considered in those liable to fluid overload, as this promotes potassium excretion through urine and has fewer interactions (e.g. with allopurinol) than other diuretics. Potassium and phosphate supplementation should be avoided. Caution is required in patients with high count leukaemia and low haemoglobin, as hyperhydration may cause further haemodilution and exacerbate anaemia. There is no evidence that alkalinisation of urine reduces the risk of TLS as, while it increases the solubility of uric acid, it does not increase the solubility of xanthine and hypoxanthine. Alkalinization decreases the solubility of Ca2+ and PO4−, increasing the development of calcium/phosphate crystals and renal dysfunction (Figure 1). The choice of uricosuric drug depends not only on the TLS risk of the patient, but also on the urgency with which definitive therapy needs to commence, potential toxicities of the agents and pre-existing uric acid and phosphate levels. One should also consider the dose of the uricosuric agent to give (Table 3). 0.2 mg/kg OD licensed dose A single fixed dose (3 mg) may be sufficient for prophylaxis Allopurinol can be considered in those with low or intermediate risk of TLS. The usual dose administered is 300 mg daily orally although higher doses can be given and there is an intravenous formulation (although not often routinely stocked). This should be started at least 12 h prior to definitive therapy. For children, allopurinol should be given at a dose of 100 mg/m2 8-hourly. Caution should be employed in those with pre-existing renal impairment or in those who are taking diuretics or other drugs that may potentially interact with allopurinol. Prescribers should also be aware of the high incidence of skin reactions with allopurinol.16 An alternative xanthine oxidase inhibitor with fewer interactions is febuxostat 120 mg daily for adults. The safety and efficacy of febuxostat in children under the age of 18 years has not been established and not currently recommended in this guideline. A phase III double-blind study randomising patients between febuxostat and allopurinol showed a more effective reduction in uric acid levels in those taking febuxostat although there was no difference in TLS rates between the two arms.17 A lower dose of 60 mg has been trialled successfully in a randomised non-inferiority study with allopurinol in the control arm for 100 patients with an intermediate or high risk of TLS.18 Allopurinol and febuxostat have demonstrated similar efficacy in retrospective studies of 45 paediatric patients19 and 78 adult patients.20 There is real-world evidence for the use of even lower doses, for example, 10 mg, but these studies involve a very small number of patients and, at this point, this approach cannot be recommended outside a clinical trial.21 It should be noted that there have been safety reports regarding hypersensitivity reactions with febuxostat, and the Medicines and Healthcare products Regulatory Agency (MHRA) cautions its use in those with pre-existing major cardiovascular disease.22 There have been cases of xanthine crystal formation leading to xanthine nephrolithiasis and worsening renal function in patients receiving allopurinol and febuxostat.23, 24 This is thought to occur as xanthine is less soluble than uric acid. Xanthine levels are not routinely measured in hospital laboratories but, if this complication is suspected, management would include hydration, discontinuation of the xanthine oxidase inhibitor and switching to rasburicase. We recommend the use of rasburicase for patients at high risk of TLS, or in those who are at intermediate risk and cannot take xanthine oxidase inhibitors, or in whom immediate therapy is required and pre-existing urate levels are high. Patients who may receive rasburicase for either TLS prophylaxis or treatment should be tested for glucose 6-phosphate dehydrogenase (G6PD) deficiency, as rasburicase administration in at-risk patients can result in haemolytic anaemia or methaemoglobinaemia. This should ideally happen at the time of diagnosis, in all patients, but particularly in those whose ethnic origin suggests a significant probability of deficiency, that is, in people of African, Mediterranean or Asian descent.25 However, this may be challenging to achieve in practice, with one study demonstrating only 18% of patients had G6PD historical screening prior to the administration of rasburicase.26 The licensed dose of rasburicase in adults and children is 0.2 mg/kg/day for 5 days as an intravenous infusion over 30 min; although there have been many low-quality studies exploring either single dose27 or single fixed dose strategies. As per previous guidelines, in adults we recommend that a single fixed 3 mg dose of rasburicase may be sufficient as prophylaxis, with appropriate monitoring and a further 3 mg dose given if necessary.28, 29 Lower doses have been trialled in small case series.30 If a patient develops clinical TLS on subsequent monitoring, then they should be treated as having established TLS, which includes increasing the dose of rasburicase to 0.2 mg/kg/day for up to 7 days in adults or switching to rasburicase if patients were previously on either allopurinol/febuxostat. Escalating rasburicase to treatment dose should also be used for patients who develop biochemical signs of TLS on subsequent monitoring. In paediatrics, we continue to recommend using the licensed dose of 0.2 mg/kg for up to 5 days for prophylaxis in patients who are high risk for TLS.31 Rasburicase can affect uric acid levels ex vivo, leading to falsely low urate levels and ideally samples post-rasburicase should be sent to the laboratory on ice to prevent this from happening if uric acid levels are required for clinical decision-making. It should be noted that while there is clear evidence that rasburicase reduces the level of uric acid more quickly than allopurinol, this has not translated into a lower rate of renal impairment, albeit based on limited low quality evidence.32-35 If rasburicase is given initially as a single dose, continuation of prophylaxis with allopurinol can be considered and can be recommenced 24 h after last rasburicase dose.36 There is evidence in those high risk for TLS either due to inherent disease properties such as ALL or in those who are having therapy that increases their risk for TLS for example, venetoclax for CLL, that by treating beforehand either with corticosteroids or alternative therapy such as obinutuzumab or ibrutinib, the rate of TLS reduces substantially.37 Similarly, stepwise dose escalation of those treatments that markedly increase risk has also been employed to reduce severity of TLS. Retrospective evidence for this strategy was demonstrated in paediatric patients with ALL in two tertiary care hospitals in South Korea. By comparing the incidence of TLS in those who had prephase steroid treatment for at least 7 days compared to those that did not, they found an 88% reduction in the risk of TLS in those who had steroids.38 In contrast, debulking strategies for AML have not been shown to be beneficial, but this may perhaps be due to the differing baseline risk of TLS between the two types of leukaemia.39 While there may be a theoretical rationale for leukapheresis reducing the risk of TLS in those with newly diagnosed acute leukaemia with leucocytosis, this has not been borne out by retrospective analyses.39, 40 We do not recommend this strategy for reducing TLS risk due to lack of evidence. Patients should be counselled on the risk of TLS and the relevant signs of symptoms prior to starting therapy. The need for good oral fluid intake and to should they develop urine should be should also include the importance of to the prophylactic and outpatient monitoring This may include a need to to the treating for a of In some this may review at a A review of the patient's medication should be to consider those that may for example, and other those that may affect renal such as or other potentially for example, a key part of TLS prophylaxis and should be to risk. including renal function, levels and uric acid or urate should be and at least daily in patients at high risk of developing TLS, increasing to up to a day in those who are at very high for example, those patients who have disease and factors that also increase risk for TLS. Patients with high risk for TLS who are should have fluid monitoring, a good urine In addition to the some therapeutic agents with a high risk of TLS have their strategies to assess and mitigate the for example, venetoclax in A approach is required to patients with established TLS and should involve adult or paediatric and intensive care to ensure patient It is recommended that patients are in an the wider team nursing care and have in managing patients and the of disease and Vigorous hydration with intravenous fluid is an of TLS treatment. For a rate of 3 should be and the rate to a urine of 100 In children, a rate of up to can be depending on renal function, clinical and fluid In cases of TLS, the management of should In cases of this may include administration of intravenous and glucose or oral potassium such as and Potassium not be to any intravenous fluids Caution should be in the administration of for example, as they also should be treated if a patient is for example, or should be initially with intravenous can be used to their in phosphate reduction will be If and are to therapy should be considered. monitoring may also be considered in some We recommend treatment of associated with TLS with rasburicase at a dose of 0.2 This can be for up to 7 days (although days is and the of treatment is by clinical response and uric acid levels. Allopurinol should be when rasburicase is and can be recommenced 24 h after the last dose of rasburicase. We that there is in using lower doses, often with numerous studies using doses of rasburicase to treat TLS. are retrospective studies that also include patients at high risk of TLS prophylaxis than which of the study One retrospective compared to fixed doses of or 3 There was no significant difference between the in of the of uric acid at 24 but some patients required a further dose of rasburicase at and However, patients fixed doses, for example, 3 mg TLS Clinical TLS compared to those who doses TLS Clinical TLS patients who lower doses of rasburicase had lower uric acid that the treating only used low fixed doses of rasburicase in less cases of clinical TLS. A clinical have reported the of using fixed doses of rasburicase. used a single fixed mg rasburicase dose in patients with laboratory TLS and patients with clinical TLS. cases spontaneously than being and all cases of clinical TLS were to patients in the required and one patient after treatment. mg rasburicase to patients laboratory 11 clinical patients had impairment, of which required patients renal studies have using fixed doses of rasburicase that are by (e.g. 3 or mass 3 mg mg and clinical mg mg albeit in of one reported only to which may to the of their This the importance of a clear to In the paediatric there is a lack of studies whether in the recommended dose of rasburicase can be used to treat established TLS, leading to A retrospective studies from have been as the of rasburicase can be in used a fixed dose of mg of rasburicase to treat children with established TLS clinical 16 laboratory children, with uric acid at 24 while the two children required a further dose of rasburicase and following the However, other studies reported with only and of patients successfully uric acid levels with lower doses of rasburicase. One study reported of 18 children from spontaneous TLS, and this approach cannot be recommended in a clinical are the in using doses of rasburicase that are lower than that recommended by the there is a lack of randomised clinical trial to recommend this In very patients, consideration should be made to give rasburicase for a G6PD This should be made by the with overall patient and following of the and for the It is important to of uric acid, and The of blood is required However, in life-threatening more targeted monitoring (e.g. potassium in life-threatening may clinical decision-making. clinical of the patient's fluid and urine is also required to response to therapy and for in TLS are in line with those for other of acute and include fluid and that is to However, the for should be lower compared to other clinical as tumour cell is and the in electrolytes may be and As a in the of and/or significant reduction in urine and that are to management should prompt with or intensive care for consideration of There is no evidence to choice of in an intensive care should be considered in those patients who are or There have been of patients with haematological malignancies have in receiving medication to prevent TLS. We have with the NHSE Patient Safety team and to the factors and mitigate The time critical use of is on the A of is TLS remains an important cause of and in adults and children with a haematological The 2015 BSH guidelines on the management of TLS remain and overall strategies in prophylaxis and treatment remain Importantly, febuxostat is for TLS prophylaxis in or This may be for patients who are or have skin reactions to allopurinol although it should be noted there have been about its use in patients with major cardiovascular There is an increasing of evidence to endorse the use of a fixed 3 mg dose of rasburicase for prophylaxis in adult However, there is evidence to recommend dose for the treatment of clinical TLS and we continue to recommend rasburicase 0.2 mg/kg/day for up to 7 days for adults and advances in have been of to patients, but effective novel agents cell can increase the risk of TLS, which needs to be and to ensure patient safety. risk stratification is for all patients with haematological malignancy receiving anti-cancer therapy. This requires consideration of patient, disease and therapy factors to a personalised approach in TLS cases of patient from delayed administration of TLS therapy occur and in a when medications are used in This updated guideline has been in with the NHSE Patient Safety team and the to these and provide to mitigate to writing and this guideline. The to for in the literature review. The would also to and Patient Safety and Pharmacy for their in the writing of this guideline. The BSH Haemato-oncology at the time of writing this guideline were and The would to the BSH sounding board and the BSH guidelines for their in this guideline. formed and the writing group on of the BSH Haemato-oncology The BSH the the writing of this have made a of to the BSH and Task which may be reviewed on has for has from from is on the board for and is a of The is a of and and of the Clinical for clinical from and is a study and previous with has an from to The following of the writing and have no of to Members of the writing group will the writing group if any new evidence that would the strength of the made in this or it The will be and from the BSH guidelines if it If new are an will be published on the BSH guidelines While the and in this guidance are to be and at the time of to the the BSH the any for the of this Table S1. grading of tumour lysis The is not for the or of any by the than should be to the for the