TUMOUR LYSIS SYNDROME When the giant collapses……… Ali M Shendi Mohamed Lecturer of Nephrology, Zagazig University ISN/UK RA Fellow

Agenda Definition. Pathophysiology. Risk factors Diagnosis Management

Quiz 1- TLS occurs only in the context of tumor chemotherapy. 2- Hyperphosphatemia is the major metabolic abnormality in cases of Spontaneous TLS. 3- Hyperuricemia is diagnostic for laboratory TLS, while elevated creatinine can diagnose clinical TLS in the presence of laboratory criteria. 4- Urinary alkalinization is essential for both prophylaxis and management of TLS. 5- Allopurinol is the hypourecemic of choice in intermediate risk patients with hematologic malignancies and normal uric acid level. 6- Febuxostat has proven to be of superior kidney protection than allopurinol. 7- In the context of TLS, Hypocalcemia should be treated regardless of symptom development and the aim should be normal serum levels.

Agenda Definition. Pathophysiology. Risk factors Diagnosis Management

Definition An oncometabolic emergency that is caused by massive tumor cell lysis with the release of large amounts of cellular contents into the systemic circulation. Patients may have metabolic abnormalities alone (laboratory TLS) or both laboratory and clinical problems (clinical TLS)..

Cytokines K Ph Nucleic acids

SPONTANEOUS TUMOR LYSIS SYNDROME Case A 75 yr old male – Hx: prostate cancer (in remission), DM, hypertension and CKD (creat 1.4 mg/dL) presented with abdominal pain + decreased urine output. Medications: lasix, metoprolol, atorvastatin, amlodipine, and benazepril. Cl.: dry mm with abdominal distension and generalized abdominal tenderness. Lab.: Hb 10 g/dL, K 6.1 mmol/L, creat 7.52 mg/dL, Ca 10 mg/dL, PO4 6.4 mg/dL, LDH 447 U/L, uric acid 14.9 mg/dL. Urinalysis: + blood,1+ proteinuria. ACR: 0.7. Renal US: normal sized kidneys - increased bilateral echogenicity - no hydronephrosis.. Ascites. CT chest and abdomen: bulky LN in the chest and retroperitoneal lymphadenopathy. A retroperitoneal lymph node biopsy: B-cell NHL of germinal center cell origin….. High K + PO4 + uric acid  Laboratory TLS + High Creat  Clinical TLS SPONTANEOUS TUMOR LYSIS SYNDROME Mavani et al., Spontaneous tumor lysis syndrome in a case of B-cell non-Hodgkin's lymphoma. Clin Kidney J. 2014 Aug; 7(4): 422–423.

Agenda Definition. Pathophysiology. Risk factors Diagnosis Management

Massive Tumour cell death Acute urate nephropathy 1- Spontaneous 2- Secondary to cancer targeted treatment (chemotherapy or another pharmacological antitumor intervention, embolization of tumor or radiation therapy) Release of: 4- Cytokines 2- Nucleic acids  Uric acid 3- Phosphorus 1- Potassium 1- skeletal muscle 2- myocardium binds to calcium  calcium phosphorus product or calcium phosphate  deposition in: decrease in free calcium Acute urate nephropathy 1- intrarenal crystallization (uric acid & Xanthine) 2- endothelial dysfunction 3- renal vasoconstriction  ischemia 4- proinflammatory and proxidative states 5- impairment of local renal repair mechanisms 1- CNS  Seizures, Psychiatric 2- Cardiac  prolonged QT 3- Muscle  tetany 1- kidney  Crystal-induced AKI 2- Cardiac tissue  Arrhythmia AKI

Agenda Definition. Pathophysiology. Risk factors Diagnosis Management

A- Patient related factors 1- Older age (reduced renal reserve) 2- A preexisting nephropathy or exposure to nephrotoxins 3- Pretreatment hyperuricemia (serum uric acid >7.5 mg/dL) or hyperphosphatemia 4- Dehydration, volume depletion, or inadequate hydration during treatment 5- Oliguria and/or acidic urine

B- Tumor related factors 1- High tumor cell proliferation rate 2- Large tumor burden: 1- Bulky disease >10 cm in diameter and/or a white blood cell count >50,000 per microL 2- Pretreatment serum lactate dehydrogenase (LDH) more than two times the upper limit of normal 3- Organ infiltration 4- Bone marrow involvement 3- Chemosensitivity of the malignancy 4- Intensity of initial anticancer therapy

Spontaneous TLS   Spontaneous AKI associated with marked hyperuricemia prior to the initiation of therapy. Frequently without hyperphosphatemia !! Described in NHL and acute leukemia.

Agenda Definition. Pathophysiology. Risk factors Diagnosis Management

Tumor Lysis Syndrome Laboratory TLS Clinical TLS 1- Uric acid 2- K 3- Ph 4- Ca 1- Kidney 2- Heart 3- CNS Clinical TLS Hande and Garrow (1993)

Criteria for diagnosis Grading system for severity

Laboratory tumour lysis syndrome (LTLS) = 25% change or level above or below normal for any two or more serum values of uric acid, potassium, phosphate, and calcium within 3 d before or 7 d after the initiation of chemotherapy. 2 of 4 8 mg/dl 6.5 mg/dl 4.5 mg/dl 7 mg/dl

Clinical tumour lysis syndrome (CTLS) = LTLS + any one or more of the following criteria. *Not directly or probably attributable to a therapeutic agent (e.g. rise in creatinine after amphotericin administration).

Clinical presentation Clinical constellation of symptoms of the biochemical disorders 1- Hypocalcemia: Nausea, vomiting Muscular hyperactivation (spasms and tetany), seizures Prolongation of QT interval  cardiac dysrhythmias Alterations of mental status 3- Hyperkalemia: if symptomatic  Generalized fatigue ECG abnormalities, serious cardiac arrhythmias including cardiac arrest 2- Hyperphosphatemia: cardiac rhythm disturbances 4- Hyperphosphatemia + hyperuricemia: AKI (↑ creatinine and ↓ UOP)

Agenda Definition. Pathophysiology. Risk factors Diagnosis Management

Assessment and risk stratification Cairo and Bishop, 2004

TLS risk stratification model 1- Assessment for evidence of laboratory or clinical TLS at diagnosis 2- Risk assessment based on malignant disease type 3- Adjustment of TLS risk based on renal function and/or involvement Cairo et al., 2010. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol;149(4):578-86.

One abnormal test result (No TLS) Laboratory tests serum potassium, phosphorus, calcium, creatinine, uric acid Clinical TLS Laboratory TLS plus one or more: 1- S Creat ≥ 1.5 ULN 2- Seizure 3- Arrhythmia One abnormal test result (No TLS) Laboratory TLS 2 or more abnormal test results Estimate tumor burden and lysis risk High risk Clinical TLS Small tumor burden Medium tumor burden large tumor burden Minimal risk Low risk for lysis Medium or uncertain risk for lysis High risk for lysis High risk Low risk for lysis uncertain risk for lysis High risk for lysis Intermediate risk Patient condition Low risk High risk Abnormalities: 1 Renal dysfunction 2 Dehydration 3 Low blood pressure 4 acidosis Intermediate risk No abnormalities Low risk Howard et al., The Tumor Lysis Syndrome. N Engl J Med 2011;364:1844-54.

` Cairo et al., 2010. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol;149(4):578-86.

Prophylaxis of tumour lysis syndrome 1- Prophylaxis with hydration: Reasonable to aim for 3 l/24 h in adults. Alkaline diuresis is not recommended ?? 2- Hypourecemic drugs: The choice depend on risk stratification 1- Oral xanthine oxidase inhibitor, allopurinol / Febuxostat 2- Recombinant urate oxidase, rasburicase.

Urine output: key factor to monitor Low risk 1- Hydration 2- ± allopurinol 3- Daily monitoring Intermediate risk 1- Hydration 2- Allopurinol (7 days) or rasburicase (no consensus, allopurinol rather than rasburicase for prophylaxis in most of these patients in the absence of pretreatment hyperuricemia) 3- Lab tests every 8-12 hours Urine output: key factor to monitor High risk 1- Hydration 2- Rasburicase (single, 3 mg) 3- Cardiac monitoring 4- Lab tests every 6-8 hours

A- Xanthine oxidase inhibitors: 1- Therapeutic effect is delayed by 24–72 h  allows urate nephropathy. 2- Xanthine may accumulate  Xanthine nephropathy. *Dose: 200–400 mg/m2/day (max 800 mg/d) for 7 days after chemotherapy. B- Rasburicase: * More effective than allopurinol for prevention and treatment of TLS ??? 1- Reduce uric acid within 4 h  chemotherapy to be started earlier. 2- Prevent xanthine accumulation. * Contraindicated in G6PD deficiency. Dose: *Prophylaxis: single fixed dose 3 mg. If progressive  repeated daily. *Therapeutic: 0.2 mg/kg/day for 3–7 days.

Hypouricemic of choice for high risk or established TLS v Rasburicase: Hypouricemic of choice for high risk or established TLS Mean ( ± SE) plasma uric acid concentrations over time for all patients. Squares denote patients who received rasburicase (n = 27) and stars allopurinol (n = 25). Adjusted creatinine levels for patients who were hyperuricemic at presentation. Goldman et al., A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. BLOOD, 2001 97(10)

Treatment of established tumour lysis syndrome 1- Fluid balance: vigorous hydration high urine output. Aim: prevent uric acid and calcium phosphate deposition. Dose: 3 l/m2 every 24 h  UOP > 100 ml/m2/h. Balanced or isotonic solutions……. no potassium is added to the hydration fluid. Urine output should be measured at least hourly. Diuretics: If UOP remains low after achieving optimal state of hydration Alkalinization of the urine is not recommended ? 1- Only equivocal evidence of efficacy and 2- Increased risk of calcium phosphate precipitation - reduced xanthine solubility at increased PH

2- Management of hyperuricaemia: Rasburicase: the drug of choice Allopurinol: only with G6PD deficiency or allergy to rasburicase. 3- Management of hyperphosphataemia and hypocalcaemia. Phosphate binders: given despite lack of studies that show the efficacy. Asymptomatic hypocalcaemia should not be treated ?? Symptomatic hypocalcaemia (arrhythmia, seizure or tetany)  calcium gluconate  treat symptoms but don’t normalize the biochemical parameters!? 4- Hyperkalaemia: Standard measures to reduce potassium levels. Potassium ≥7 mmol/l  dialysis is likely to be required urgently.

Management of severe acute kidney injury Indications for RRT: similar to those with other causes of AKI * Significant fluid overload, hyperkalaemia, hyperuricaemia, hyperphosphataemia or hypocalcaemia (calcium-phosphate product ≥70 mg2/dL2). * Lower thresholds? rapid potassium release and accumulation, particularly with oliguria. * Modality: HD: Daily dialysis may be the best strategy? continuous release of metabolites. CRRT: In patients who are haemodynamically compromised.

Quiz Answers 1- TLS occurs only in the context of tumor chemotherapy. 2- Hyperphosphatemia is the major metabolic abnormality in cases of Spontaneous TLS. 3- Hyperuricemia is diagnostic for laboratory TLS, while elevated creatinine can diagnose clinical TLS in the presence of laboratory criteria. 4- Urinary alkalinization is essential for both prophylaxis and management of TLS. 5- Allopurinol is the hypourecemic of choice in intermediate risk patients with hematologic malignancies and normal uric acid level. 6- Febuxostat has proven to be of superior kidney protection than allopurinol. 7- In the context of TLS, Hypocalcemia should be treated regardless of symptom development and the aim should be normal serum levels.

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