Contents Page No. 1. Outline of Procedure 2. Area of Application 3. Objective 4. Stages of the Process 5. Responsibilities

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2 Contents Page No. 1. Outline of Procedure 3 2. Area of Application 3 3. Objective 3 4. Stages of the Process 3 5. Responsibilities 8 6. Other useful information 8 7. References 8 Page 2 of 10

3 Clinical Policy for Tumour Lysis Syndrome Management 1. Outline of Procedure To provide information to Haematology and Oncology staff on the Prevention and management of tumour lysis syndrome. 2. Area of Application This SOP applies to all adult SACT services across the NOSCAN region, excepting for the administrative areas of Argyll and Bute in NHS Highland which are linked to the WOSCAN CEL (2012) 30 governance framework. 3. Objective This document covers the prevention and treatment of tumour lysis syndrome (TLS) in adults. Please refer to the appropriate guidelines for metabolic derangement or renal failure related to other causes. 4. Stages of the Process Tumour lysis syndrome (TLS) is an emergency that is caused by massive tumour cell lysis, with the release of large amounts of potassium, phosphate and nucleic acids in to the systemic circulation. Catabolism of nucleic acids to uric acid leads to hyperuricaemia, resulting in the precipitation of uric acid in the renal tubules. Hyperphosphataemia can lead to the deposition of calcium phosphate deposition in the renal tubules and can also cause acute kidney injury. Symptoms and signs of tumour lysis syndrome include nausea, vomiting, diarrhoea, anorexia, lethargy, oedema, fluid overload, haematuria, congestive heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope and possible sudden death. Tumour lysis can occur spontaneously but generally occurs 12 to 72 hours after initiation of cytoreductive therapy. Care should be taken to avoid potentially nephrotoxic substances, including intravenous contrast and NSAIDs in patients at risk of tumour lysis syndrome. The cornerstones of management are recognition of the high risk patient and appropriate pre-emptive treatment. Diagnosis of tumour lysis syndrome There is no universally accepted system for grading TLS. It may be classified according to clinical or laboratory features. A laboratory screen for TLS is given below: Table 1: laboratory screen for tumour lysis syndrome Uric acid* 476 µmol/l or 25% increase Potassium* 6.0 mmol/l or 25% increase Phosphate* 1.45 mmol/l or 25% increase Corrected calcium* 1.75 mmol/l or 25% decrease LDH >2 x upper limit of normal Serum creatinine 1.5 x upper limit of normal Page 3 of 10

4 * 2 of these features between 3 days pre- and 7 days post-administration of chemotherapy meets the Cairo-Bishop laboratory definition of tumour lysis syndrome. A clinical diagnosis of tumour lysis syndrome can be made if acute renal failure, cardiac arrhythmia or seizures occur in conjunction with the Cairo-Bishop laboratory features listed above. Risk assessment and stratification pre-chemotherapy Prior to starting the first cycle of chemotherapy (including steroid monotherapy), a risk assessment for TLS must be carried out in all patients with malignancies being treated in Haematology and Oncology. This assessment must take into account disease type, white cell count and additional risk factors (Table 2). The individual should be assessed for the presence of renal dysfunction or renal involvement by the malignancy (e.g. oliguria, preexisting renal failure or hyperuricaemia) and for signs of TLS. Where possible, the risk group should be recorded at the MDT. Individuals with evidence of TLS at presentation should be treated as for high risk disease. An individual s risk of tumour lysis should be upgraded (low to intermediate risk or intermediate to high risk) if any one of the following is present (with the exception of individuals with solid tumours or myeloma): Pre-existing nephropathy/renal impairment Dehydration Acidosis Hypotension Prior exposure to a nephrotoxic agent Renal involvement by underlying disease process Page 4 of 10

5 Table 2 Low risk disease (<1%) Most solid tumours Intermediate risk disease (1-5%) High risk disease (>5%) Rarely highly chemotherapy-sensitive tumours e.g. germ cell tumour, small cell lung cancer with bulky or advanced stage disease Bulky metastatic germ cell tumours prior to chemotherapy Myeloma Plasma cell leukaemia N/A CML N/A N/A Indolent NHL N/A FL treated with PI3K inhibitors Hodgkin lymphoma N/A N/A CLL and white cell count (WCC) <50 x 10 9 /L, treated only with alkylating agents AML and WCC <50 x 10 9 /L and LDH <2 x ULN Adult intermediate grade NHL and LDH within normal limits Adult Anaplastic Large Cell Lymphoma (ALCL) N/A N/A CLL treated with fludarabine, rituximab or lenalidomide, and/or those with high WCC 50 x 10 9 /L AML with WCC x 10 9 /L; AML and WCC <25 x 10 9 /L and LDH 2 x ULN Adult T-cell leukaemia/lymphoma, diffuse large B-cell lymphoma, transformed high grade lymphoma, and mantle cell lymphomas with LDH >ULN but <2 x ULN, non bulky Childhood ALCL stage III or IV Childhood intermediate grade NHL stage III/IV with LDH <2 x ULN ALL and WCC <100 x 10 9 /L and LDH <2 x ULN CLL treated with PI3K inhibitors AML and WCC 100 x 10 9 /L Adult T-cell leukaemia/lymphoma, diffuse large B-cell lymphoma, transformed high grade lymphoma, and mantle cell lymphomas with bulky disease and LDH 2 x ULN prior to radiotherapy or chemotherapy N/A Stage III/IV childhood diffuse large B- cell lymphoma with LDH 2 x ULN Burkitt s leukaemia; Other ALL and WCC 100 x 10 9 /L and/or LDH 2 x ULN N/A Burkitt lymphoma and LDH <2 x ULN Burkitt lymphoma stage III/IV and/or LDH 2 x ULN N/A Lymphoblastic lymphoma stage I/II and LDH <2 x ULN Lymphoblastic lymphoma stage III/IV and/or LDH 2 x ULN N/A N/A Intermediate risk disease (IRD) with renal dysfunction and/or renal involvement; IRD with uric acid, potassium and/or phosphate >ULN Prophylaxis recommendations Monitoring Monitoring Monitoring Hydration Hydration Hydration ± allopurinol Allopurinol Rasburicase* *Rasburicase is contraindicated in patients with a history consistent with glucose-6 phosphate dehydrogenase deficiency. In these patients, rasburicase should be substituted with allopurinol. Page 5 of 10

6 Pre-emptive treatment of tumour lysis syndrome Hydration: High or intermediate risk of TLS: aggressive fluid hydration (2 3 L/m 2 daily) should be started at least 24 hours prior to chemotherapy, aiming for a urine output of at least ml/m 2 /hr (no added potassium unless specifically advised by consultant). If there is no evidence of acute obstructive uropathy and/or hypovolaemia, a loop diuretic may be used to maintain the urine output, although evidence for the benefits of this approach in humans with TLS is limited. Urinary alkalinisation is not recommended. Hypouricaemic agents Risk of TLS High risk Intermediate risk Low risk Treatment Rasburicase (0 2 mg/kg) for one dose and start allopurinol treatment. Monitor uric acid levels closely* and give additional doses of rasburicase given when and if hyperuricaemia recurs If uric acid levels are <476 µmol/l, give allopurinol mg orally 8 hourly***. Monitor for TLS and its complications. If the uric acid level is 476 µmol/l, give a single dose of rasburicase (0.2 mg/kg, 3 or 6 mg depending on body weight) and monitor uric acid levels closely. Watch and wait approach hydration and close monitoring, rather than prophylactic allopurinol or rasburicase. * Blood samples for uric acid should be collected in a pre-chilled tube, immediately placed on ice, and the assay completed within 4 hours, if possible. In patients with a history of glucose- 6-phosphate dehydrogenase (G6PD) deficiency, rasburicase is contraindicated and allopurinol should be utilized instead of rasburicase. Where possible, consider testing patients at risk (including those from African, Mediterranean, or Southeast Asian descent) of G6PD deficiency before administering rasburicase. **In the absence of established clinical or laboratory TLS, an alternative approach would be to use a single fixed dose of 3 mg rasburicase, with repeat dosing to be guided by careful monitoring of clinical and biochemical parameters. ***allopurinol and renal impairment: GFR ml/min: allopurinol dose mg daily GFR ml/min: allopurinol dose mg daily GFR <10 ml/min: allopurinol dose 100 mg daily or 100 mg on alternate days For patients receiving dialysis, see renal handbook. DOSE IN PATIENTS UNDERGOIN Post treatment monitoring Patients at high risk for TLS require intensive supportive care, continuous cardiac monitoring, close monitoring of urine output and fluid balance and frequent serial measurement of electrolytes, creatinine and uric acid. Page 6 of 10

7 For patients at intermediate or high risk of developing TLS, monitor the serum uric acid, phosphate, potassium, creatinine, corrected calcium and LDH 4 6 hours after the initial administration of chemotherapy, and every 6 12 hours thereafter. Delays in specimen transport and/or processing should be avoided especially in patients with high white counts to prevent spurious elevations in potassium. Immediate therapeutic intervention is required if evidence of TLS or rising level of uric acid. Adult patients at intermediate risk not receiving rasburicase should have electrolytes checked 8 hours after chemotherapy and should be monitored for at least 24 hours after completion of the first cycle of chemotherapy. Management of established tumour lysis syndrome Electrolyte abnormalities: monitor electrolytes, creatinine and uric acid every 4 6 hours and treat as shown in table 3. Table 3. Electrolyte abnormality Hyperphosphataemia (>2.1 mmol/l) Moderate Severe Hypocalcaemia (albumin corrected calcium 1.75 mmol/l) Asymptomatic Symptomatic Hyperkalaemia (see local guidelines*) Moderate ( 6.0 mmol/l) Severe ( 7.0 mmol/l) Renal failure (uraemia) Hyperuricaemia ( 476 µmol/l) Management Aluminum hydroxide (oral) mg/kg day in 4 divided doses (1 2 days) as phosphate binder if the patient is unsuitable for dialysis. Haemodialysis if unresponsive to conservative measures No therapy Calcium gluconate 10% ml iv as slow infusion over 10 minutes** Avoid potassium supplements ECG: if cardiotoxicity present give iv calcium gluconate, insulin and dextrose iv infusion and undertake haemodialysis if conservative management fails Haemodialysis Fluid, electrolyte and blood pressure management. Dose-adjust nephrotoxic drugs. Haemodialysis if conservative management fails Rasburicase for established hyperuricaemia and TLS *see acute medicine resource centre/electrolytes/hyperkalaemia on NHSG clinical guidance intranet ** Calcium gluconate will reverse the clinical effects of hypocalcaemia in the short term, but will further increase the deposition of calcium phosphate in the renal tubules, potentially worsening acute kidney injury Indications for renal replacement therapy: Severe oliguria or anuria Persistent hyperkalaemia Hyperphosphataemia-induced symptomatic hypocalcaemia Page 7 of 10

8 5. Responsibilities Clinical Haematology and Oncology staff. 6. Other useful information Overview of medications Detailed information relating to dosages, administration, toxicities and drug interactions can be found in the SPC on Allopurinol: this suppresses the formation of uric acid by inhibiting xanthine oxidase in the purine metabolic pathway. Skin rashes are common ( 1% and <10%) and, if they occur, allopurinol should be stopped and rasburicase started in its place. Hypersensitivity reactions are uncommon ( 0.1% and <1%). There are potential interactions with mercaptopurine, azathioprine, ciclosporin and thiazide diuretics. There may be no benefits to combining allopurinol with rasburicase in the prophylaxis or management of TLS. Rasburicase: this is a recombinant urate oxidase and converts uric acid into allantoin, which is readily soluble and easily excreted. The most significant drug-related adverse events are common allergic reactions, mainly rashes and urticaria. Cases of hypotension (<1%), bronchospasm (<1%), rhinitis (<0.1%) and severe hypersensitivity reactions (<1%), including anaphylaxis (<0.1%) have also been attributed to rasburicase. Rasburicase is contraindicated in glucose-6-phosphate (G6PD) deficiency. Oral phosphate binders: e.g. aluminium hydroxide. These are slow to act and poorly tolerated by ill patients. They should seldom be used, except if the patient is unfit for dialysis or as a temporary measure where immediate access to renal dialysis is not available. Diuretic therapy: this should only be given on the advice of a Nephrologist. It is important to be certain that the patient is not volume-depleted before considering diuretic therapy. Diuretics may encourage the precipitation of urate in renal tubules if administered to a patient who is not fluid replete 7. References Bose P, Qubaiah O. (2011) A review of tumour lysis syndrome with targeted therapies and role of rasburicase. J Clin Pharm Ther 2011; 36(3): Cairo MS, Coiffier B, Reiter A, Younes A; TLS Expert Panel (2010) Recommendation 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 2010; 149(4): Coiffier B, Altman A, Pui CH, Younes A, Cairo MS (2008) Guidelines for the management of paediatric and adult tumour lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26: Letter: ibid Author reply: ibid: Coutsouvelis J, Wiseman M, Hui L, Poole, S, Dooley M, Patil S, Avery S, Wei A, Spencer A. (2012) Effectiveness of a single fixed dose of rasburicase 3mg in the management of tumour lysis syndrome. Br J Clin Pharmacol 2012; 75(2): Page 8 of 10

9 Darmon M, Guichard I, Vincent F (2011) Rasburicase and tumour lysis syndrome: lower dosage, consideration of indications, and hyperhydrations. J Clin Oncol 2011; 29(3): e67-e68 Reply: Cortes J ibid e69 Darmon M, Vincent F, Camous L et al. (2013) Tumour lysis syndrome and acute kidney injury in highrisk haematology patients in the rasburicase era. A prospective multicentre study. Br J Haematol 2013; 162(4): Eaddy M et al (2009) The economic implications of rasburicase treatment in adult tumour lysis syndrome patients. J Clin Oncol Suppl abstr e17503 (Abstract only) Feng X, Dong K, Pham D, Pence S, Inciardi J, Bhutada NS. (2013) Efficacy and cost of single-dose rasburicase in prevention and treatment of adult tumour lysis syndrome: a meta-analysis. J Clin Pharm Ther 2013; 38(4): McBride A, Westervelt P. (2012) Recognising and managing the expanded risk of tumour lysis syndrome in haematologic and solid malignancies. J Hematol Oncol 2012; 5: 75 Sanofi (2012) FASTURTEC [Rasburicase] Summary of product characteristics. [acessed via medicines.org.uk, last updated on emc 23/11/12] Vadhan-Raj S, Fayad LE, Fanale MA et al. (2012) A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumour lysis syndrome. Ann Oncol 2012; 23(6): Will A, Tholouli E. (2011) The clinical management of tumour lysis syndrome in haematological malignancies. Br J Haematol 2011; 154(1): 3-13 Wilson FP, Berns JS. (2012) Onco-nephrology: Tumour lysis syndrome. Clin J Am Soc Nephrol 2012; 7(10): UK Renal Association (Apr 2013) Clinical Practice Guidelines: Treatment of Acute Hyperkalaemia in Adults. Page 9 of 10

10 Replaces: Lead Author/Co-ordinator: Responsibilities of the Lead Author/Co-ordinator Key word(s): Document application: Purpose/description: (detail previous unique identifier if applicable) (as per front cover) Ensuring registration of this document on Document and Information Silo Disseminating document as per distribution list Retaining the master copy of this document Reviewing document in advance of review date (to help with the document search on intranet home page) NOSCAN (purpose of document) Policy statement: It is the responsibility of all staff to ensure that they are working to the most up to date and relevant clinical process documents. Responsibilities for implementation: Organisational: Operational Management Team and Chief Executive Sector General Managers, Medical Leads and Nursing Leads Departmental: Clinical Leads Area: Line Manager Review frequency and date of next review: (Include a statement that indicates that in the absence of any obvious changes review should occur every 2 years) Revision History: Revision Date Previous Revision Date Summary of Changes (Descriptive summary of the changes made) Changes Marked (Identify page numbers and section heading )