Tumour lysis syndrome

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Review

Tumour lysis syndrome夽 Jose Manuel Calvo Villas Servicio de Hematología y Hemoterapia, Hospital Universitario Miguel Servet, Zaragoza, Spain

a r t i c l e

i n f o

Article history: Received 23 August 2018 Accepted 25 October 2018 Available online xxx Keywords: Tumour lysis syndrome Acute renal failure Rasburicase

a b s t r a c t Tumour lysis syndrome (TLS) is a life-threatening emergency characterised by a massive cytolysis with the release of intracellular electrolytes, nucleic acids, and metabolites into the circulation. TLS comprises laboratory derangements (hyperuricaemia, hyperkalaemia, hyperphosphataemia, and hypocalcaemia) responsible for acute kidney injury. In patients with haematological malignancies after cytotoxic therapy or spontaneously and also in advanced solid tumours. Assessment of disease specific risk level for TLS in patients receiving anti-tumoural therapy is essential for early diagnosis. Prophylaxis is the mainstay of management of TLS. It is important to routinely initiate a risk-adapted prophylactic strategy to correct metabolic alterations and preserve renal function. High and intermediate risk patients and patients with established TLS should be managed with multidisciplinary medical care in a hospital unit to receive monitoring and medical care. Renal replacement therapy should be considered in patients with refractory TLS. ˜ S.L.U. All rights reserved. © 2018 Elsevier Espana,

Síndrome de lisis tumoral r e s u m e n Palabras clave: Síndrome de lisis tumoral Insuficiencia renal aguda Rasburicasa

El síndrome de lisis tumoral (SLT) es una urgencia potencialmente letal caracterizada por una muerte celular masiva que libera a la circulación sistémica iones, ácidos nucleicos y metabolitos intracelulares. El SLT conlleva unas alteraciones de laboratorio (hiperuricemia, hiperpotasemia, hiperfosfatemia e hipocalcemia) que son responsables de la insuficiencia renal aguda. La valoración del grado de riesgo del SLT en los pacientes en tratamiento citorreductor es primordial para el diagnóstico precoz. La profilaxis es clave en el tratamiento del SLT. Es importante iniciar de forma sistemática una estrategia preventiva adaptada al riesgo para corregir las alteraciones metabólicas y conservar la función renal. Los pacientes con riesgo intermedio o alto de SLT y aquellos con un SLT establecido deberían ser tratados por un equipo médico multidisciplinar en una unidad hospitalaria que favorezca la monitorización clínica y el tratamiento médico. La diálisis se debería utilizar en pacientes con un SLT refractario al tratamiento médico. ˜ S.L.U. Todos los derechos reservados. © 2018 Elsevier Espana,

Introduction Tumour lysis syndrome (TLS) is a set of metabolic disorders and a consequence of the rapid release of intracellular components such as potassium, phosphates, nucleic acids, proteins and their metabolites into the bloodstream as a result of the massive destruction of a tumour population.1,2 It was originally described in 1929 by Bedrna and Polˇcák,3 but it was not until 1980 that Burkitt outlines the clinical and laboratory syndrome in patients with lymphoma.4

夽 Please cite this article as: Calvo Villas JM. Síndrome de lisis tumoral. Med Clin (Barc). 2019. https://doi.org/10.1016/j.medcli.2018.10.029 E-mail address: [email protected]

Although it usually occurs at the beginning of treatment, up to one third of patients develop it in the absence of cytotoxic treatment, distinguishing between induced and spontaneous TLS.5,6 TLS is a oncohaematological emergency with metabolic alterations that present with musculoskeletal, renal, cardiac and neurological complications – potentially lethal if not diagnosed and treated in a timely manner.1,2 A correct therapeutic strategy is based on the previous assessment of TLS risk in oncohaematological patients. Prophylaxis and treatment include the replacement of fluids, the use of hypouricemic agents, the correction of metabolic complications and extrarenal filtering with dialysis.7–9 The purpose of this article is to review the pathophysiology data and the clinical and laboratory criteria that define the diagnosis, and provide its risk stratification criteria prior to a prophylaxis adapted

˜ S.L.U. All rights reserved. 2387-0206/© 2018 Elsevier Espana,

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Spontaneous cytotoxic therapy

Neoplastic cell

Tumour lysis

Nucleic acids

Phosphorus

Calcium

Cytokines

Potassium

Hypoxanthine

Hypotension

Inflammation

Xanthine oxidase Allopurinol Febuxostat

Xanthine Xanthine oxidase

↓calcium

↑ Increase in uric acid Rasburicase

Urate oxidase

Allantoin

↑ phosphorus

↑ potassium

Calcium phosphate crystals

Xanthine crystals

Acute renal Insufficiency

Uric acid crystals

Oliguria

Urinary excretion

Accumulation

tumour lysis syndrome

Fig. 1. Pathophysiology of tumour lysis syndrome. TLS: tumour lysis syndrome.

to it during cytoreductive treatment and a treatment for patients with already established TLS.

in cases of TLS associated with newer oncological treatments, such as tyrosine kinase inhibitors, monoclonal antibodies, immunomodulatory agents and proteasome inhibitors.10,15,19

Incidence Pathophysiology The incidence of TLS in haematologic patients in our series varied from 3 to 26% according to factors such as type of neoplasia, antitumour treatment, early recognition, prophylaxis measures, and patient characteristics.10–13 It is more frequent at the beginning of treatment for acute oncohaematological diseases with high tumour mass and/or with high proliferative index, such as Burkitt-type non-Hodgkin lymphoma and other aggressive lymphomas with bulky masses, acute myeloblastic leukaemia with hyperleucocytosis and acute lymphoblastic leukaemia, especially immunophenotype T.2,6,14 It has also been described in other haematological malignancies15 such as chronic lymphatic leukaemia and chronic myeloid leukaemia, and in several types of solid tumours, usually metastatic.16,17 The different incidence rates between haematological and solid neoplasms can be attributed to the differences in the sensitivity to antitumour drugs, heterogeneity of solid tumours, a lower index of suspicion and a greater difficulty in identifying TLS in solid neoplasms.18 The different types of solid neoplasms, according to the organ and tumour histology, in which an TLS has been described include lung cancer; oesophageal, gastric and colorectal carcinomas; gastrointestinal stromal tumour; hepatocellular carcinoma and hepatoblastoma; breast carcinoma; gynaecological cancer (endometrium and ovary); urological, renal and genitourinary cancer; neurological neoplasms (medulloblastoma and neuroblastoma); skin cancer (melanoma and Merkel cell carcinoma) and a miscellany (extragonadal germ cell tumour, myxoid liposarcoma of the quadriceps, adenocarcinoma of unknown origin, pheochromocytoma, thymoma and others). A notable aspect is the increase

The massive release of intracellular components into the bloodstream leads to hyperuricaemia, hyperphosphatemia, hyperkalaemia, and hypocalcemia (Fig. 1). This massive accumulation of intracellular products exceeds the elimination capacity of the kidney, causing alterations in hydroelectrolytic metabolism and renal failure.2,6,20,21 Hyperuricaemia is key to and the most frequent factor in the pathogenesis of TLS.20,21 The nucleotides of the nucleic acids are metabolised into hypoxanthine by xanthine oxidase, then into xanthine, and finally to uric acid, which is eliminated intact by the kidneys. When uric acid exceeds the excretory capacity of the renal tubule, it accumulates causing hyperuricaemia. The acidic environment of the renal collecting tubules causes uric acid to crystallise and precipitate in the distal nephron, causing tubular obstruction and renal failure due to obstructive nephropathy.2,6,22 Hyperphosphataemia is a consequence of the release of the high intracellular content of phosphates from neoplastic cells and a decrease in their elimination by the kidney. The massive release of phosphates alters the calcium–phosphorus balance and causes calcium phosphate to crystallise and precipitate into microcirculation and renal tubules.1,2,20,21 This precipitation of calcium phosphate crystals alters the glomerular filtration rate, increasing the risk of renal failure due to nephrocalcinosis or tubular obstruction.20,23 The mechanism of secondary hypocalcaemia is calcium phosphate tissue precipitation caused by hyperphosphataemia together with an abnormal activity of the renal enzyme 1-alpha hydroxylase and low levels of 1-25 dihydroxyvitamin D3.6,24

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Table 1 Diagnostic criteria for Cairo and Bishop tumour lysis syndrome.

Diagnosis

Laboratory criteriona ≥8 mg/dl or an increase greater than 25% from baseline ≥6.0 mg/dl or an increase greater than 25% from baseline ≥4.5 mg/dl or an increase greater than 25% from baseline (adults) ≥6.5 mg/dl or an increase greater than 25% from baseline (children) ≤7 mg/dl or an increase greater than 25% from baseline

Uric acid Potassium Phosphorus

Corrected calcium

3

Clinical definitionb Creatinine ≥ 1.5 times the upper limit of normality adjusted for age Arrhythmias/sudden death Seizures Source: Cairo and Bishop.1 a Laboratory tumour lysis syndrome with two or more laboratory criteria within the previous three days and the week after the start of therapy. b Clinical tumour lysis syndrome that presents with at least one accompanying clinical manifestation or death of the patient.

Since the first definition by Hande and Garrow11 in 1993, several TLS classification systems have been designed to identify patients who can access a specific treatment. The classification proposed in 2004 by Cairo and Bishop1 puts forward two definitions for TLS (Table 1): a laboratory TLS, with two or more biochemical criteria between the three previous days and the week following initiation of treatment, and a clinical TLS, with at least one clinical manifestation or death of the patient.1 The diagnosis of TLS requires compliance with this Cairo and Bishop criteria.1 The 2010 recommendations8 and the review by Howard et al.2 modified the diagnostic criterion of a change of 25% from baseline biological parameters because it was not useful as a general criterion. The Cairo and Bishop classification has an undoubted diagnostic utility, but its prognostic interest is limited by the absence of a commonly accepted definition that allows comparison between studies. The medical team’s experience and a regular assessment of laboratory alterations is the most reliable guide to establishing an adapted therapeutic strategy.9,24 The severity of TLS depends on clinical and laboratory alterations, as shown in Table 2. Risk factors

Hyperkalaemia is the earliest alteration. The release of intracellular potassium and renal failure are the mechanisms that most favour hyperkalaemia.20,21,23 The incidence rate of acute renal failure in TLS is 25–38%; multiple pathophysiological mechanisms are implicated in its appearance, such as tubular deposition of uric acid crystals and phosphocalcic products and alterations in renal blood perfusion.14,23 The pathophysiology of acute renal failure can be systematised in two mechanisms:

(a) The precipitation of calcium phosphate, uric acid and xanthine crystals directly causes tubular obstruction, nephrocalcinosis, obstructive uropathy and acute renal failure and, indirectly, hypocalcaemia. Renal insufficiency and tubular acidosis decrease the solubility of uric acid and favour hyperphosphataemia, perpetuating renal failure.5,20,21,24 (b) The proinflammatory, oxidative and activating effect of the renal renin–angiotensin system of hyperuricaemia is responsible for renal vasoconstriction, the production of cytokines and TNF-␣ and the anti-angiogenic effects acting on the autoregulation of the renal microvascular bed, which can lead to vasomotor nephropathy, a systemic inflammatory response syndrome and, finally, multiorgan failure.25

Table 3 shows the risk factors for the development of a TLS, which include laboratory alterations, neoplasm and patient characteristics, renal function and cytotoxic treatment.26–28 The risk category depends on the severity of these risk factors, as shown in Table 2, which should be assessed before the most appropriate therapeutic strategy for each patient is decided.28–31 Renal failure of any cause in patients with haematological malignancies is an independent risk factor for in-hospital mortality.32,33 The greatest severity occurs in elderly patients or those with a history of chronic renal failure, oliguria, dehydration, hypotension and/or heart disease.33,34 The mortality of the TLS has been estimated to range between five and 20% due to the immediate mortality of hyperkalaemia and/or hypocalcaemia or renal failure complications.10,12,14 Clinical symptoms Symptoms derive from electrolyte and metabolic alterations, and from neoplastic disease.27,35 They manifest most clearly between days one and three after initiating antitumour treatment.21,24,29 Hyperuricaemia manifests as anorexia, vomiting, diarrhoea, lethargy, haematuria, oliguria and anuria.6,35

Table 2 Severity criteria of tumour lysis syndromes, according to Cairo and Bishop. Laboratory syndrome

Creatinine

Arrhythmias

Seizures

Grade 0 Grade I Grade II

Absent Present Present

1.5× ULN 1.5× ULN 1.5–3× ULN

– Intervention not indicated Non-urgent intervention

Grade III

Present

3.0–6.0× ULN

Grade IV

Present

>6.0× ULN

Grade V

Present

Death

Symptomatic arrhythmia, incompletely controlled or controlled with defibrillation Arrhythmia with heart failure, hypotension or syncope Death

– – A brief and generalised one, which is controlled with antiepileptic drugs Seizures with altered consciousness

Source: Cairo and Bishop.1 ULN: upper limit of normality.

Epileptic status

Death

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Table 3 Risk factors for tumour lysis syndrome. Laboratory biochemical alterations Prior hyperuricemia >4.5 mg/dl (an increase of 1 mg/dl increases the risk of TLS 1.7 times, and renal impairment, 2.2 times) Hyperkalaemia Hyperphosphataemia Leucocyte count > 100 × 109 l−1 Increase in initial LDH > 400 U/l Initial creatinine level > 1.4 mg/dl Related to the disease Acute lymphoblastic leukaemia Non-Hodgkin’s Lymphoma Burkitt type Lymphoblastic lymphoma Solid tumours with high growth rate and with greater sensitivity to chemotherapy Haematological diseases with hyperleucocytosis, massive involvement of bone marrow and/or bulky tumour masses Related to the patient Advanced age (>65) Presence of hepatosplenomegaly Dehydration Related to kidney function Acute or chronic renal failure Previous nephropathy Low diuresis (<1 ml/h) Presence of obstructive uropathy Ureteral compression by tumour mass Tumour infiltration of the renal parenchyma Diuresis with urine with urine pH at <6 Hyponatraemia Related to the treatment Regimens with cytarabine, platinum compounds, glucocorticoids Lower incidence with methotrexate, radiotherapy and non-chemotherapeutic oncological drugs Exposure to nephrotoxic products

Hyperkalaemia causes alterations of skeletal muscle and cardiac muscle. Cardiac arrhythmias in the form of ventricular tachycardia and fibrillation are a medical emergency detected when potassium levels rise above 5.0 mEquiv./l.22,23,35 Electrocardiographic changes include spiked T waves, expanded QRS complexes, and fusion of the QRS complex with the T wave. Neuromuscular symptoms include fatigue, muscle cramps, anorexia, paresthesias and irritability. Previous renal damage, metabolic acidosis, potassium sparing treatment and the rate of potassium increase favour cardiovascular toxicity.23,24 The clinical profile of mild or moderate hyperphosphataemia is usually not evident and when it is intense it is confused with symptoms of secondary hypocalcaemia, which include nausea, vomiting,

tetany, neurological symptoms (lethargy and seizures) and alterations in cardiac conduction.20,23.35 The severity of hypocalcaemia symptoms depends on ionic calcium values and the speed calcium levels decrease. Hypocalcaemia manifests with anorexia, nausea and vomiting, along with neurological symptoms such as muscle cramps, carpopedal spasms, laryngospasm, tetany, seizures and coma, and cardiac manifestations such as severe arrhythmias (polymorphic ventricular tachycardia and sudden death) and depression of cardiac contractility (heart failure, arterial hypotension and cardiogenic shock).10,20,23 Manifestations of acute renal failure will be mainly those derived from ionic disorders and hypovolaemia.10,20 Risk stratification The multidisciplinary medical team must carry out risk stratification to ensure a personalised prophylaxis strategy according to the patient’s group.9,27–30 Table 4 shows the TLS risk assessment for oncohematological neoplasms.1 The probability of TLS is 1% for low risk, 1–5% for intermediate risk and greater than 5% for high risk.1 The presence of hyperuricaemia or renal alterations prior to treatment move up the risk stratification. The British Committee for Standards in Haematology,9 the Spanish Society of Haematology and Haemotherapy36 and other authors28,37 have proposed other predictive classifications for TLS in oncohematological neoplasms. Fig. 2 outlines a therapeutic strategy for patients with oncohematological diseases according to their risk group. Prevention The key therapeutic approach for TLS is prevention.9,27 All patients diagnosed with oncohematological disease receiving cytoreductive treatment should receive prophylaxis for TLS based on a personalised stratification prior to the risk group (Table 4).2,7,9 The prevention of TLS attempts to preserve renal function, decrease uric acid levels and prevent complications from hyperkalaemia and other metabolic alterations.38 Prophylaxis begins between 24 and 48 h before treatment until at least 72 h after.9,27 In the low risk patient group, prevention comprises an adequate replacement of intravenous fluids by providing isotonic saline of 0.9% at replacement doses of 2500–3000 ml/m2 /day.15,29,39 Replacement should be individualised and monitored daily to ensure diuresis is maintained at over 100 ml/m2 /h. Isotonic saline prevents the crystallisation of uric acid and calcium phosphate in renal tubules.39,40 Exogenous intake of potassium and/or phosphorus should be avoided,6 as should potassium-sparing diuretics,

Table 4 Stratification of tumour lysis syndrome by risk groups. Type of neoplasm

High risk

Moderate risk

Low risk

Hodgkin/non-Hodgkin lymphoma

Burkitt lymphoma Lymphoblastic lymphoma Advanced stage LDH >2 normal value Mass > 10 cm on CT Leucocytosis > 100,000 mm–3 LDH >2 normal value Leucocytosis > 100,000 mm–3

Burkitt lymphoma Lymphoblastic lymphoma Early stage LDH < 2 normal value Mass < 10 cm on CT Leucocytes 50,000–100,000 mm–3 LDH < 2 normal value Leucocytes 25,000–100,000 mm–3 LDH >2 normal value Rapid cell proliferation Good response to chemotherapy High tumour mass High sensitivity to cytotoxic treatment LDH >2 normal value

Indolent lymphoma Follicular lymphoma MALT lymphoma Hodgkin lymphoma

Acute lymphoblastic leukaemia Acute myeloblastic leukaemia Other haematological neoplasms Solid neoplasia

LDH: lactate dehydrogenase; MALT: mucosa-associated lymphoid tissues; CT: computerised tomography scan.

Leucocytes < 50,000 mm–3 Leucocytes < 25,000 mm–3 LDH < 2 normal value Chronic lymphocytic leukaemia Chronic myeloid leukaemia

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ONCO-HAEMATOLOGICAL NEOPLASIA

TUMOUR LYSIS SYNDROME Hyperkalaemia, hyperphosphataemia, hypocalcaemia, hyperuricaemia, acute renal failure

NOT ESTABLISHED

ESTABLISHED

RISK ASSESSMENT

LOW RISK

MEDIUM RISK

– Hyperhydration – Rasburicase 0.2 mg/kg/day

HIGH RISK

– Treatment of hydro electrolyte alterations PROPHYLAXIS – Fluid replacement iv – Diuresis monitoring – Daily biological monitoring – Allopurinol, if necessary – Reassessment of risk

PROPHYLAXIS – Hyperhydration – Allopurinol, 7 days – Rasburicase? – Biological monitoring every 8-12 hours – Reassessment of risk

PROPHYLAXIS – Hyperhydration – Rasburicase 3 mg – Clinical and biological monitoring every six hours – Cardiological monitoring – Reassessment of risk

– Clinical and biological monitoring every six hours

TLS REFRACTORY RENAL INSUFFICIENCY

Dialysis evaluation

At 72 hours with high uric acid Allopurinol

At 72 hours with normal aciduric

Fig. 2. Prophylactic-therapeutic algorithm according to the risk of tumour lysis syndrome. TLS: tumour lysis syndrome. Source: Coiffier et al.,7 Jones et al.,9 National Committee of Haematology24 and Mughal et al.54

any other type of diuretic in the presence of oliguria and/or hypovolemia,29–31 and any nephrotoxic drug.24,39 In the group of patients with intermediate risk, a correct intravenous hydration should be ensured with isotonic saline solution at 0.9%. The alkalinisation of urine has been replaced by new therapies for hyperuricaemia. Treatment options for hyperuricaemia are drugs that inhibit the xanthine oxidase enzyme and the urate oxidase enzyme (Fig. 2). Allopurinol acts through the competitive inhibition of xanthine oxidase, an enzyme that inhibits the production of uric acid, increasing the concentrations of xanthine and hypoxanthine (Fig. 1).41 Early prophylaxis with oral allopurinol prevents the formation of new uric acid, but has no uricolytic effect on previously synthesised uric acid. Because it starts acting after two or three days, its usefulness in established TLS is restricted.27,42 Allopurinol reduces the risk of urate nephropathy, although it does not prevent xanthine nephropathy.5,27,34 The recommended oral dose is 100 mg/m2 /8 h, with a maximum daily dose of 800 mg.24,42 It is administered 48 h before treatment until the normalisation of uric acid.30,41 The dose should be adjusted in severe renal failure and when it is used in combination with methotrexate or 6-mercaptopurine. Side effects include hypersensitivity reactions, severe cutaneous toxicity, hepatotoxicity and hypereosinophilia.29,42 The febuxostat is a new and more selective antagonist of the xanthine oxidase that favours the elimination of uric acid through the hepatic system. It could be an alternative to allopurinol because it does not require dose adjustment in renal failure, due to the absence of hypersensitivity reactions and the minimal risk of xanthine nephropathy.43 More studies are needed to assess its preventive use in patients with oncohematological diseases. Urate-oxidase is a proteolytic enzyme present in mammals, but not in humans; it is currently the drug of reference in the treatment of TLS.44–46 Rasburicase is a recombinant urate oxidase enzyme that promotes the catabolism of uric acid towards allantoin. Allantoin is a

non-toxic substance that is more soluble than uric acid in urine, not crystallisable in organic liquids and easily metabolised and eliminated by the kidneys, regardless of renal function.6,26,27,33 Rasburicase has no hepatic metabolism or renal elimination, does not interfere with drugs that are metabolised by the cytochrome P450 system, and does not require monitoring of drug levels. Unlike allopurinol, it metabolises present uric acid and urate deposits, drastically reducing levels of uric acid in over 98% of patients 4 h after administration.47,48 It also reduces the accumulation of hypoxanthine and xanthine, which prevents both urate nephropathy and xanthine nephropathy.45,47 Acute toxicity is exceptional, although it is contraindicated in patients with asthma, risk of hypersensitivity and/or deficiency of glucose-6-phosphate dehydrogenase.47,48 Some clinical trials have shown the efficacy and safety of rasburicase in the treatment of TLS in adults.49,50 Rasburicase is an alternative to prophylaxis with allopurinol in patients with renal insufficiency or hypersensitivity to the drug.29,30 Rasburicase should not be associated with allopurinol to avoid the potential deleterious effect of xanthine and hypoxanthine. Although it is a high-cost treatment, rasburicase, can preserve and improve renal function by reducing phosphorus levels, and it is associated with a significant decrease in the need for dialysis compared to allopurinol.39,51 Parenteral hydration is recommended for the high risk patient group and the therapy of choice is rasburicase in a single dose of 3 mg; post-treatment should be assessed according to uric acid figures.12,38,47 Patients at increased risk should receive intravenous hydration to improve renal perfusion and glomerular filtration, prevent oliguria and minimise acidosis.7–9,39 Patients whose electrolyte values normalise should be treated as those in the intermediate risk group; patients whose electrolyte values remain elevated should continue with rasburicase until they normalise. Patients in intermediate and high risk groups should be admitted to an intensive care unit (ICU) for 48–72 h in order to ensure the prevention strategy is optimised by a multidisciplinary medical team that includes the Haematology/Oncology, Nephrology and

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Intensive Medicine.9,29,30 During admission to the ICU, the patient’s renal and cardiac function, diuresis rhythm and laboratory parameters should be strictly monitored every 4–6 h, adapting therapy according to the results. If diuresis decreases, furosemide should be administered intravenous 1–2 mg/kg/dose, intravenous mannitol 0.5–1 g/kg/dose and/or dopamine at diuretic dose in continuous infusion at 2.5–5 ␮g/kg/min. If there is no response, treatment with dialysis should be considered.9,33,51 The decision to initiate cytoreductive treatment, its continuation at full dose or reduction, is based on the severity of the TLS alterations and the patient’s clinical status. If renal insufficiency and metabolic alterations are the result of tumour infiltration, initiating cytotoxic treatment is recommended and postponing or suspending it in case of needing dialysis therapy is not necessary.29,30

Treatment Current therapeutic strategy is based on the control of hydroelectrolyte alterations and the treatment of acute renal failure.8,9,52 However, recommendations are based on studies that do not have much clinical evidence.30 Patients who already have TLS require treatments given by multidisciplinary teams that include Haaematology, Nephrology and Intensive Care services and admission to the ICU.7,29 The basic aspects of treatment are maintenance of diuresis, urate oxidase inhibitors, correction of electrolyte disorders and dialysis therapy.9,51,52 Hyperhydration Hyperhydration is the fundamental pillar in the treatment of TLS.7,29–31 Replacement of fluids increases the renal tubular flow, stimulates diuresis and thereby promotes and favours the elimination of urates and phosphates, preventing their precipitation in the tubular lumen.24,39 In general terms, the hydration scheme should be 3 l/m2 /day, although the dose must be individualised according to the patient’s characteristics, metabolic alterations and the underlying disease.29–31 Initially, the contribution of potassium, calcium and/or phosphorus is not recommended due to the risk of hyperkalaemia, hyperphosphataemia and calcium phosphate precipitation.16 Replacement is accompanied by haemodynamic monitoring to maintain a diuresis of >1 ml/kg/h. When diuresis is insufficient despite optimal overhydration, there are no signs of hypovolaemia and obstructive uropathy is excluded, furosemide can be administered at doses of 0.5–1.0 mg/kg.24

The duration of treatment with rasburicase usually varies between three and seven days depending on clinical and biological response.30,50 Rasburicase does not prevent the onset of acute renal failure, so treatment must be maintained for the other hydroelectrolytic abnormalities. After the administration of rasburicase, the need for dialysis is reduced to between 1 and 4% of patients.7,51 Treatment of hyperphosphataemia The need to treat hyperphosphataemia depends on the severity of the clinical manifestations. Treatment relies on the restriction of the exogenous phosphate uptake and hyperhydration, rasburicase and diuretics such as furosemide or mannitol promote renal excretion.9,51 Non-calcium phosphate binders are a therapeutic option.24,30 Oral doses of aluminium hydroxide at 50–150 mg /kg/day every 6–8 h for a maximum of two days and a 400 mg/12 h dose of sevelamer for 10 days have been used as chelates in the paediatric population.53 Dialysis is the most effective treatment for hyperphosphataemia associated with acute renal failure. Treatment of hypocalcaemia Treatment should be based on the presence of clinical manifestations of hypocalcaemia and not on ionic calcium values.2,6,52 The contribution of calcium can favour tissue precipitation of calcium phosphate.54 The control of hyperphosphatemia prevents the appearance of secondary hypocalcaemia.39,53,54 Symptomatic hypocalcaemia is treated with intravenous calcium gluconate at doses of 100–200 mg/kg/6–8 h.6,39 If hypocalcaemia persists with hypomagnesaemia and renal function is normal, intravenous dose of magnesium sulphate at 10% at 12–24 mg/kg/day with a previous bolus of 2.5–5 mg/kg is administered. Treatment of hyperkalaemia The treatment of hyperkalaemia depends on potassium values and changes in heart rhythm. The administration of exogenous potassium should be avoided even in asymptomatic hyperkalaemia prior to cytotoxic treatment.27,52 In asymptomatic patients with potassium levels of <6 mEquiv./l, suspending exogenous potassium, ion exchange resins orally or rectally at a dose of 1 g/kg/4–6 h and furosemide, is recommended. Admit patients with potassium levels of >6 mEquiv./l or heart rhythm disturbances to an ICU. Sequential treatment and combined with bicarbonate, glucose, insulin and calcium gluconate is recommended. Haemodialysis and haemofiltration effectively remove potassium.

Treatment of hyperuricaemia Extrarenal purification with dialysis techniques Treating hyperuricaemia with normal renal function includes hyperhydration and rasburicase, together with diuretics if the renal function is impaired and dialysis if there is refractoriness to the treatment. The alkalinisation of urine is not an accepted therapy for the treatment of TLS.6,7,39,51 Although allopurinol continues to be useful in the prevention of TLS in patients at low and intermediate risk of this syndrome, this drug does not currently play a role in the treatment of established TLS.2 Allopurinol alone is a therapeutic alternative in patients with deficiency of the glucose-6-phosphate dehydrogenase enzyme or who are allergic to rasburicase.30 The dosage of Rasburicase is 0.2 mg/kg/day by 30 min intravenous infusion, although that length can be adapted to patients’ clinical and biological response.47,48,51 The first dose is administered between four and 24 h before starting therapy, and drastically reduces uric acid levels 4 h later.

Dialysis is the treatment choice for critically ill patients with acute renal failure.6,9,30,33 Dialysis increases the purification of potassium, phosphate and uric acid, and corrects metabolic acidosis and calcium changes.55 Dialysis in TLS is currently indicated for oliguria, metabolic alterations refractory to conventional treatment, haemodynamic instability, acute renal failure, hypervolaemia, uncontrollable hypertension and as a supportive treatment for spontaneous TLS.6,24,33,56 Haemodialysis should be established early in haematooncological patients with established TLS, since its deferred use is associated with worse responses of renal failure and higher mortality.6,21,55 The rebound effect of potassium and phosphorus values in intermittent techniques means using continuous high efficiency dialysis is recommended.27 In a severe TLS, filtration techniques ensure a slower purification of potassium and

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phosphorus. The elimination of phosphates is more effective with continuous conventional haemodialysis than with haemofiltration, although its association prevents the rebound effect of conventional haemodialysis. Peritoneal dialysis is less effective than haemodialysis and is not indicated in patients with abdominal masses. Dialysis should be maintained until normalisation of renal function and ionic alterations.56–58 There is not currently enough scientific evidence to include haemodialysis in the preventive treatment strategy for TLS.

Monitoring A clinical history, a physical examination and a laboratory evaluation should be performed in all patients at risk of TLS. In the initial anamnesis, the patient’s history of renal and urinary tract diseases and the date and type of the last cytotoxic treatment should be carefully studied. In the clinical examination, special attention should be paid to the neurological examination, haemodynamic status, hydration status, diuresis rhythm and signs related to hydroelectrolytic alterations and renal failure. Monitoring must be continuous during the TLS risk period.29,30,54 Diuresis is key in monitoring, adjust treatment to maintain a diuresis rate above 100 ml/m2 . The laboratory monitoring plan includes blood count, gasometry, ionogram, ionic and total calcium, phosphorus, potassium, urea, creatinine, uric acid, urine test and uric acid/creatine ratio. In patients at low risk, daily monitoring of renal function, hydroelectrolytic and metabolic balance and haemodynamic status is recommended; in patients at intermediate risk, control of diuresis and laboratory monitoring every 8–12 h.9,29,30 Clinical controls for patients at high risk or with an established TLS must assess a strict water balance with inputs and outputs and a diuresis rhythm every 6 h, weight every 12 h, and blood pressure, assessing signs of volume overload every 6 h.7,29

Prognostic The prognosis of TLS depends on the severity of hydroelectrolyte alterations and the deterioration of renal function. The most serious and increased mortality are spontaneous forms of TLS and patients with acute renal failure.43,55 Acute renal failure is one of the main adverse prognostic markers,33,54,55 although the patient’s admission to an ICU is a favourable prognostic criterion as it increases survival by facilitating cytotoxic therapy and increasing the rate of complete remission of the underlying disease.33 In a recent multicentre study conducted in patients hospitalised in the United States, many of those with TLS developed potentially lethal complications and 21% died during hospitalisation.58 Rasburicase has improved the prognosis of high-risk patients and those with established TLS. Finally, the long-term prognostic impact of TLS treatment depends on the type of neoplasm and its remission. In summary, a universally accepted definition, the improvement of diagnostic criteria and the establishment of an optimal preventive and therapeutic approach based on the previous stratification of the risk of TLS can improve the prognosis of patients with haematological and non-haematological neoplastic diseases who receive any type of antitumour treatment.

Conflict of interest The author declares no conflict of interest.

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References 1. Cairo MS, Bishop M. Tumor lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3–11. 2. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364:1844–54. 3. Bedrna J, Polcák J. Actuary ureter closure after irradiation with X-rays for chronic leukemias. Med Klin. 1929;25:1700–1. 4. Cohen LF, Balow JE, Magrath IT, Poplack DG, Ziegler JL. Acute tumor lysis syndrome. A review of 37 patients with Burkitt’s lymphoma. Am J Med. 1980;68:486–91. 5. Dubbs SB. Rapid fire: tumor lysis syndrome. Emerg Med Clin North Am. 2018;36:517–25. 6. Tiu RV, Mountantonakis SE, Dunbar AJ, Schreiber MJ Jr. Tumor lysis syndrome. Semin Thromb Hemost. 2007;33:397–407. 7. Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:2767–78. 8. Cairo MS, Coiffier B, Reiter A, Younes A. Recommendations for the evaluation of risk and prophylaxis of tumor lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:578–86. 9. Jones GL, Will A, Jackson GH, Webb NJ, Rule S. British Committee for Standards in Haematology. 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. Br J Haematol. 2015;169: 661–71. 10. Locatelli F, Rossi F. Incidence and pathogenesis of tumor lysis syndrome. Contrib Nephrol. 2005;147:61–8. 11. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med. 1993;94:133–9. 12. Annemans L, Moeremans K, Lamotte M, Garcia Conde J, van der Berg H, Myint H, et al. Incidence, medical resource utilisation and costs of hyperuricemia and tumour lysis syndrome in patients with acute leukaemia and non-Hodgkin’s lymphoma in four European countries. Leuk Lymphoma. 2003;44:77–83. 13. Cairo MS, Thompson S, Stern L, Sherman S. Incidence of treatment-related, laboratory and clinical tumor lysis syndrome. Blood. 2012;120:238. 14. Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol. 1993;13:273–80. 15. Howard S, Trifilio S, Gregory T, Baxter N, McBride A. Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review. Ann Hematol. 2016;95:563–73. 16. Caravaca-Fontán F, Martínez-Sáez O, Pampa-Saico S, Olmedo ME, Gomis A, Garrido P. Tumor lysis syndrome in solid tumors: clinical characteristics and prognosis. Med Clin (Barc). 2017;148:121–4. 17. Mirrakhimov AE, Ali AM, Khan M, Barbaryan A. Tumor lysis syndrome in solid tumors: an up to date review of the literature. Rare Tumors. 2014;6: 5389. 18. Gemici C. Tumour lysis syndrome in solid tumours. Clin Oncol (R Coll Radiol). 2006;18:773–80. 19. Bose P, Qubaiah O. A review of tumour lysis syndrome with targeted therapies and the role of rasburicase. J Clin Pharm Ther. 2011;36:299–326. 20. Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ. Pathophysiology, clinical consequences and treatment of tumor lysis syndrome. Am J Med. 2004;116:546–54. 21. Hochberg J, Cairo M. Tumor lysis syndrome: current perspective. Haematologica. 2008;93:9–13. 22. Shimada M, Johnson RJ, May WS Jr, Lingegowda V, Sood P, Nakagawa T, et al. A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome. Nephrol Dial Transplant. 2009;24:2960–4. 23. Flombaum CD. Metabolic emergencies in the cancer patient. Semin Oncol. 2000;27:322–34. 24. Comité Nacional de Hematología. Guideline for management of tumor lysis syndrome [Spanish]. Arch Argent Pediatr. 2011;109:77–82. 25. Soares M, Feres GA, Salluh JIF. Systemic inflammatory response syndrome and multiple organ dysfunction in patients with acute tumor lysis syndrome. Clinics (Sao Paulo). 2009;64:479–81. 26. Michallet AS, Tartas S, Coiffier B. Optimizing management of tumor lysis syndrome in adults with hematologic malignancies. Support Cancer Ther. 2005;2:159–66. 27. Tosi P, Barosi G, Lazzaro C, Liso V, Marchetti M, Morra E, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica. 2008;93:1877–85. 28. Montesinos P, Lorenzo I, Martín G, Sanz J, Pérez-Sirvent ML, Ortí G, et al. Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model. Haematologica. 2008; 93:67–74. 29. Burghi G, Berrutti D, Manzanares W. Síndrome de lisis tumoral en terapia intensiva: encare diagnóstico y terapéutico. Med Intensiva. 2011;35:170–8. 30. Vasseur AS, Moreau AS. Analysis of the British guidelines 2015 for the management of adult tumor lysis syndrome. Reanimation. 2017;26:285–95. 31. Dupré A, Mousseaux C, Bouguerba A, Ayed S, Barchazs J, Boukari M, et al. Analysis of the 2015 British guidelines on the prevention and management of tumor lysis syndrome [French]. Rev Med Interne. 2017;38:36–43. 32. Darmon M, Vincent F, Canet E, Mokart D, Pène F, Kouatchet A, et al. Acute kidney injury in critically ill patients with haematological malignancies: results of a multicentre cohort study from the Groupe de Recherche en Réanima-

G Model 8

33. 34. 35. 36.

37.

38.

39. 40. 41.

42.

43.

44.

45.

ARTICLE IN PRESS J.M. Calvo Villas / Med Clin (Barc). 2019;xxx(xx):xxx–xxx

tion Respiratoire en Onco-Hématologie. Nephrol Dial Transplant. 2015;30: 2006–13. Darmon M, Guichard I, Vincent F, Schlemmer B, Azoulay E. Prognostic of acute renal injury in acute tumor lysis syndrome. Leuk Lymphoma. 2010;51:221–7. Pumo V, Sciacca D, Malaguarnera M. Tumor lysis syndrome in ederly. Crit Rev Oncol Hematol. 2007;64:31–42. Spinazzé S, Schrijvers D. Metabolic emergencies. Crit Rev Oncol Hematol. 2006;58:79–89. Burgaleta A, Alegre A. Manual del Médico Residente en Hematología y Hemoter˜ apia. Madrid: Sociedad Espanola de Hematología y Hemoterapia/Editores Médicos S. A.; 2014. p. 381–6. Mato AR, Riccio BE, Qin L, Heitjan DF, Carroll M, Loren A, et al. A predictive model for the detection of tumor lysis syndrome during AML induction therapy. Leuk Lymphoma. 2006;47:877–83. Alakel N, Middeke JM, Schetelig J, Bornhäuser M. Prevention and treatment of tumor lysis syndrome, and the efficacy and role of rasburicase. OncoTargets Ther. 2017;10:597–605. Wilson FP, Berns JS. Tumor lysis syndrome: new challenges and recent advances. Adv Chronic Kidney Dis. 2014;21:18–26. Conger JD, Falk SA. Intrarenal dynamics in the pathogenesis and prevention of acute urate nephropathy. J Clin Invest. 1977;59:786–93. LaRosa C, McMullen L, Bakdash S, Ellis D, Krishnamurti L, Wu HY, et al. Acute renal failure from xanthine nephropathy during management of acute leukemia. Pediatr Nephrol. 2007;22:132–5. Smalley RV, Guaspari A, Haase-Statz S, Anderson SA, Cederberg D, Hohneker JA. Allopurinol: intravenous use for prevention and treatment of hyperuricemia. J Clin Oncol. 2000;18:1758–63. Tamura K, Kawai Y, Kiguchi T, Okamoto M, Kaneko M, Maemondo M, et al. Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol. Int J Clin Oncol. 2016;21:996–1003. Bosly A, Sonet A, Pinkerton CR, McCowage G, Bron D, Sanz MA, et al. Rasburicase (recombinant urate oxidase) for the management of hyperuricemia in patients with cancer: report of an international compassionate use study. Cancer. 2003;98:1048–54. Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and gout. Int J Med Sci. 2007;4:83–93.

46. Vincent F, Darmon M. Tumor lysis syndrome in the 21st century: to recreate risk factors and prognosis? Oncologist. 2018;23, http://dx.doi.org/10.1634/ theoncologist.2017-0505, pii: theoncologist.2017-0505. 47. Lopez-Olivo MA, Pratt G, Palla SL, Salahudeen A. Rasburicase in tumor lysis syndrome of the adult: a systematic review and meta-analysis. Am J Kidney Dis. 2013;62:481–92. 48. Llinares F, Burgos A, Fernández P, Villarubia B, Ferrandis P, Ordovás JP. Análisis y protocolización de la utilización de rasburicasa en pacientes con neoplasias hematológicas. Farm Hosp. 2006;30:92–8. 49. Cortes J, Moore JO, Maziarz RT, Wetzler M, Craig M, Matous J, et al. Control of plasma uric acid in adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone: results of a multicenter phase iii study. J Clin Oncol. 2010;28:4207–13. 50. Cairo MS, Thompson S, Tangirala K, Eaddy MT. A clinical and economic comparison of rasburicase and allopurinol in the treatment of patients with clinical or laboratory tumor lysis syndrome. Clin Lymphoma Myeloma Leuk. 2017;17:173–8. 51. Will A, Tholouli E. The clinical management of tumour lysis syndrome in haematological malignancies: review. Br J Haematol. 2011;154:3–13. 52. Yarpuzlu AA. A review of clinical and laboratory findings and treatment of tumor lysis syndrome. Clin Chim Acta. 2003;333:13–8. 53. Abdullah S, Diezi M, Sung L, Dupuis LL, Geary D, Abla O. Sevelamer hydrochloride: a novel treatment of hyperphosphatemia associated with tumor lysis syndrome in children. Pediatr Blood Cancer. 2008;51:59–61. 54. Mughal TL, Ejaz A, Foringer JR, Coiffier B. An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treat Rev. 2010;36:164–76. 55. Wilson FP, Berns JS. Onco-nephrology: tumor lysis syndrome. Clin J Am Soc Nephrol. 2012;7:1730–9. 56. Darmon M, Ciroldi M, Thiery G, Schlemmer B, Azoulay E. Clinical review: specific aspects of acute renal failure in cancer patients. Crit Care. 2006;10:211. 57. Garimella PS, Balakrishnan P, Ammakkanavar NR, Patel S, Patel A, Konstantinidis I, et al. Impact of dialysis requirement on outcomes in tumor lysis syndrome. Nephrology (Carlton). 2017;22:85–8. 58. Durani U, Shah ND, Go RS. In-hospital outcomes of tumor lysis syndrome: a population-based study using the national inpatient sample. Oncologist. 2017;22:1506–9.