Fixed-Dose Recombinant Urate Oxidase in the Treatment of Paediatric Tumour Lysis Syndrome: A Regional Cancer Centre Experience.

BACKGROUND: Tumor lysis syndrome (TLS) is an oncologic emergency commonly seen in children with hemato-lymphoid malignancies. Recombinant urate oxidase (RUO) is used in both the prophylaxis and treatment of TLS. However, in resource-constrained countries, its role is mostly limited to the treatment of established TLS and data regarding the use of RUO and its outcome is sparse. OBJECTIVE: To describe the outcome of Pediatric TLS following the use of a fixed - dose of RUO. METHODS: A retrospective chart review of all children <15 years of age admitted in the Department of Paediatric Oncology, Kidwai Cancer Institute from April 2017 to July 2018 with TLS and treated with a single, fixed - dose (1.5 mg) RUO was undertaken. RESULTS: During the study period, 255 children with hemato-lymphoid malignancies were diagnosed to be at risk of developing TLS. Of these, only 22 (8.6%) children developed TLS and received RUO. Among those with TLS, 15 (68.2%) had Acute Lymphoblastic Leukemia (ALL) while 7 (31.8%) had Non - Hodgkin lymphoma (NHL). 91% (20/22) children had spontaneous TLS and the remainder developed therapy-related TLS. Median age at presentation was 8 years (IQR 5.25,1.75) with 4.5:1 male: female ratio. The mean urate level at admission was 19.12 mg/dl (+/- 8mg/dl) (Range: 10.7-34.5). 91% (20/22) children received RUO at less than 0.15 mg/kg and the median dose of RUO was 0.05 mg/kg (IQR 0.038-0.08). Of the 22 children with TLS, 2 children failed to achieve normal serum urate levels at 24 hours in response to a single fixed-dose of RUO and hence received an extra dose of RUO. Serum urate levels remarkably declined following RUO administration from 19.12 mg/dl (+/-8) to 8.2 mg/dl (+/-3.9), 3.99 mg/dl (+/-1.6) and 2.84 mg/dl (+/-1.3) at 12h, 24h and 48h respectively. AKI was present in 15 (68.2%) children. The median eGFR of the group at diagnosis was 49 ml/min/1.73m2 (IQR 26.3, 70). None of the children required hemodialysis. No significant adverse events occurred. CONCLUSION: Fixed-dose RUO can achieve rapid, adequate and sustained drop in serum urate levels in Paediatric TLS. It is a useful strategy for managing TLS in resource-constrained settings.

Emergencies in haematology: tumour lysis syndrome.

Tumour lysis syndrome (TLS) is a significant complication of haematologic malignancies and their management. The syndrome consists of laboratory abnormalities either alone (laboratory TLS) or with clinical sequelae including renal failure, seizures, and arrhythmias (clinical TLS). Clinical TLS is a predictor for worse overall morbidity and mortality in cancer patients, but can be prevented. Thus, accurate prognostication is critical to appropriate management of patients at risk for TLS, and incorporates both disease factors (tumour type and burden) and patient factors (baseline renal insufficiency or hyperuricaemia). Strategies to prevent TLS include hydration and allopurinol in low- and intermediate-risk patients and rasburicase in high-risk patients.

Sorafenib-induced tumor lysis syndrome in a patient with metastatic hepatocellular carcinoma.

Tumor lysis syndrome is a potentially lethal complication of chemotherapy, usually associated with aggressive hematologic malignancies. We describe the case of a young patient with metastatic hepatocellular cancer who developed rapid and fatal tumor lysis syndrome following initiation of sorafenib therapy. Although rare with sorafenib therapy for hepatocellular carcinoma, tumor lysis syndrome is serious complication. Patients with a high burden of disease at therapy initiation should have their metabolic parameters measured prior to starting therapy and closely followed for the first 1-2 weeks while being treated.

An upsurge of the serum free light chains as a possible missing link in tumour lysis syndrome in multiple myeloma.

Multiple myeloma (MM) is a slow-growing malignancy characterized by a low proliferation rate of plasma cells and a relatively rare incidence of tumour lysis syndrome (TLS). Three myeloma patients developed TLS following cytotoxic therapy (two after radiation treatment) that was associated with an abrupt increase of serum free light chains (FLC). All three patients demonstrated extramedullary plasmacytomas that exhibited aggressive features compared to the original myeloma. The findings suggested that an abrupt liberation (rather than slow secretion) of FLC from myeloma cells may trigger a fulminant cast nephropathy and present an unrecognized risk factor and potentially aggravating component of TLS.

Myocardial calcification in a patient with B-lymphoblastic leukemia accompanied by tumor lysis syndrome.

Myocardial calcification, a rare disease that leads to chronic or acute heart failure and with a poor prognosis, occurs in patients with abnormal calcium-phosphorus metabolism. The association between myocardial calcification and tumor lysis syndrome has not been reported to date. A 50-year-old man with hyperthermia and general malaise presented to our hospital and was clinically diagnosed with B-lymphoblastic leukemia (B-ALL) and febrile neutropenia accompanied by septic shock. Prednisolone was administered for tumor reduction. Two to three hours later, electrocardiography demonstrated ST elevation in V4-6, and blood tests showed elevated levels of cardiac enzymes. Transthoracic echocardiogram revealed diffuse severe hypokinesis with decreased left ventricular ejection fraction. Additionally, blood tests showed that serum phosphorus level increased to 8.0 mg/dl, which was likely due to tumor lysis syndrome. Circulatory and respiratory failure due to left heart failure progressed, and he died 3 days after administration of prednisolone. Pathological autopsy revealed diffuse proliferation of atypical B-lymphoblasts in the bone marrow, which led to the pathological diagnosis of B-ALL, accompanied by necrosis. On the cut surface of the heart, the left ventricle was dilated, and patchy yellowish-brown areas were present in the epicardial-side of the myocardium and spread through the circumferential wall of the left ventricle and interventricular septum. Microscopically, myocardial fibers were granularly basophilic in that area and were revealed as calcium deposits by Von Kossa staining. He was diagnosed with myocardial calcification. The drastic increase in the serum phosphorus level caused by tumor lysis syndrome seemed to be associated with myocardial calcification.

Impact of early rasburicase on incidence of clinical tumor lysis syndrome in lymphoma.

Early administration of rasburicase to enhance uric acid (UA) elimination has been adopted without robust evidence in support of its impact on clinical outcomes in tumor lysis syndrome (TLS), specifically, the prevention of acute kidney injury (AKI). This was a retrospective cohort study of adult lymphoma patients at intermediate or high risk for TLS. Excluded patients had AKI or were on dialysis at hospital admission. The incidence of new AKI in the setting of TLS was described along with predictors of its development, including early rasburicase use. In 383 included patients, the incidence of new-onset AKI during hospitalization was 6%. Predictors included age, history of renal or cardiovascular disease, and UA >8 mg/dL. Rasburicase use did not significantly impact the risk of developing AKI (HR 2.3; p = .11). The UA level at the time of administration did not modify the effect of rasburicase on prevention of AKI (p = .36 for the interaction term).

Febuxostat administration for the prevention of tumour lysis syndrome: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Tumour lysis syndrome is an oncological emergency, characterized by rapid cytolysis leading to an abrupt rise of serum uric acid levels. The aim of the present meta-analysis is to evaluate the efficacy and safety of febuxostat as a preventive measure in patients at risk of tumour lysis syndrome development, by comparing it with allopurinol administration. METHODS: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov and Google Scholar databases were searched from inception to 15 December 2018. All studies evaluating the effectiveness of febuxostat in preventing tumour lysis syndrome were held eligible. RESULTS AND DISCUSSION: Six studies were included with a total of 658 patients. Compared to allopurinol, febuxostat achieved a similar response rate (OR: 1.39, 95% CI: [0.55, 3.51]) and tumour lysis syndrome incidence (OR: 1.01, 95% CI: [0.56, 1.81]). Serum uric acid levels did not differ between the investigated groups at the second (MD: -0.21 mg/dL, 95% CI: [-1.30, 0.88]) and seventh (MD: -0.43 mg/dL, 95% CI: [-1.38, 0.51]) day of treatment. Elevation of liver function tests was the most common adverse effect, although its incidence was similar among patients treated with allopurinol and febuxostat. WHAT IS NEW AND CONCLUSIONS: The present meta-analysis suggests that febuxostat may serve as an effective alternative to allopurinol in the prevention of tumour lysis syndrome. Future large-scale studies should define the optimal febuxostat dosage, explore the most appropriate population for its administration and better define its safety profile.

Rational use of rasburicase for the treatment and management of tumor lysis syndrome.

Purpose There is a lack of high-level evidence identifying meaningful outcomes and the optimal place in therapy of rasburicase in patients with, or at high risk for tumor lysis syndrome. The primary objective of this study was to evaluate and characterize outcomes resulting from an institution-specific guideline emphasizing supportive care, xanthine oxidase inhibitors, and lower doses of rasburicase. Methods In this retrospective chart review, we compared conservative rasburicase dosing, in accordance with newly developed UMHS tumor lysis syndrome guidelines, with aggressive rasburicase in adult patients (≥ 18 years of age) with hematological or solid tumor malignancies, and a uric acid level between 8 and 15 mg/dL. The primary efficacy outcome assessed the difference in the proportion of patients achieving a uric acid level <8 mg/dL within 48 h using a one-sided noninferiority test. The principle safety outcomes analyzed included incidence of acute kidney injury and hemodialysis requirement. Results One hundred sixty-one patients met inclusion criteria and were included in the study. Within 48 h of an elevated uric acid level, treatment was successful in 97.03% of patients in the conservative group, as compared with 98.33% in the aggressive group (difference, 1.3 percentage points; 95% confidence interval [CI], -3.33 to 5.93). Furthermore, there was no difference in the proportion of patients requiring hemodialysis (2.97% vs. 10.0%, p-value 0.079), or incidence of acute kidney injury (4.0% vs. 12.5%, p-value 1.00) between the treatment group and control group, respectively. Conclusions Conservative rasburicase use was noninferior to aggressive rasburicase use in patients with or at high risk for tumor lysis syndrome.

Febuxostat as a Prophylaxis for Tumor Lysis Syndrome in Children with Hematological Malignancies.

AIM: The aim of the present study was to determine if febuxostat could prevent tumor lysis syndrome (TLS) in children who received induction chemotherapy for hematologic malignancies. PATIENTS AND METHODS: A retrospective analysis was performed in 45 pediatric patients with hematological malignancies who received febuxostat (10 mg daily, n=20) or allopurinol (300 mg/m2 daily, n=25) as a prophylaxis for TLS. RESULTS: A significant decrease of serum uric acid (UA) level was observed in patients with febuxostat over the first 2 days (6.6±3.8 mg/dl vs. 4.5±2.8 mg/dl, p<0.001). The febuxostat group also showed significant reduction of urinary UA/creatinine ratios during the first two days of treatment (0.98±0.85 vs. 0.51±0.26, p=0.010). No significant differences were observed between febuxostat-treated and allopurinol-treated patients regarding the percent change in serum UA level. CONCLUSION: Febuxostat had a notable effect in reducing serum UA level in children with hematological malignancies.

Serum Uric Acid Exhibits Inverse Relationship with Estimated Glomerular Filtration Rate.

BACKGROUND: In this study, we investigated the relationship between serum uric acid (SUA) and renal function in a unique patient cohort wherein SUA levels fluctuate during the course of standard care. METHODS: Correlation coefficients between SUA and serum creatinine (SCr) and kinetic estimated GFR (KeGFR) were retrospectively investigated in acute myeloid leukemia (AML) patients, and statistically significant and clinically relevant determinants were studied in multiple regression models. RESULTS: One hundred and twenty-six patients were included in the analysis. Baseline SUA was associated with an increased risk for acute kidney injury (AKI; OR 1.27, 95% CI 1.1-1.5, p = 0.003) and laboratory tumor lysis syndrome (OR 1.26, 95% CI 1.1-1.5, p = 0.005). Prophylactic uric acid-lowering therapy and hydration resulted in lower SUA values from baseline in 88.1% of the patients, the lowest values were observed on post-induction day 1 (20.4% reduction). Significant linear correlations were observed between SUA and SCr (r = 0.35, p < 0.001) values with a significant inverse correlation between SUA and KeGFR on day 1 (r = -0.33, p < 0.001) that persisted through day 4. By subgroup analysis, patients with primary AML (r = -0.49, p < 0.001), baseline SUA >5.5 mg/dl (r = -0.41, p = 0.002) and baseline eGFR >60 ml/min/1.73 m2 (r = -0.51, p < 0.001) demonstrated robust relationships between SUA and KeGFR. The relationship was more robust when the groups were combined (primary AML plus baseline SUA >5.5 mg/dl plus baseline eGFR >60 ml/min/1.73 m2, r = -0.52, p < 0.001). CONCLUSION: The demonstration of linear relationship between SUA and SCr and inverse relationship between SUA and KeGFR reinforces the emerging translational physiological evidence regarding the role of uric acid in AKI.

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.

BACKGROUND: Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. METHODS: An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. RESULTS: Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. CONCLUSION: Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. TRIAL REGISTRY: http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.