How I Treat Tumor Lysis Syndrome

Introduction

Tumor lysis syndrome results from the spontaneous or therapy-induced destruction of malignant cells, releasing intracellular content into extracellular space. Extracellular histones, other damage-associated molecular patterns (DAMPs), and excessive inflammatory cytokines may induce endothelial alterations causing AKI¹ and sometimes multiple organ failures.

Although guidelines have been published on the classification, grading, and treatment of tumor lysis syndrome,^2–4 these are mainly on the basis of expert opinions and areas of uncertainty persist.

Patient Presentation

A 37-year-old woman diagnosed with Burkitt lymphoma was admitted in the hematology department for urgent chemotherapy. Her computed tomography scan revealed enlarged lymph nodes in the cervical, axillary, mediastinal, and abdominal regions.

Blood tests before chemotherapy showed a sodium level of 140 mmol/L (136–145), potassium 4 mmol/L (3.5–4.5), serum creatinine 1.19 mg/dl, lactate dehydrogenase (LDH) 2500 IU/L (125–245), uric acid 7.06 mg/dl (2.52–6.05), calcium 8.82 mg/dl (8.82–10.22), and phosphate 4.65 mg/dl (2.48–4.49), and bone marrow aspirate smear showed 6% Burkitt-like cells.

Risk Stratification

Evaluating the risk of tumor lysis syndrome before administration of tumor-specific therapy is of utmost importance because preventive strategies are a cornerstone in the management of high-risk patients. The risk of tumor lysis increases with tumor size, spontaneous cell turnover rate, and sensitivity to therapy. More specifically, high-grade lymphomas and hyperleukocytic acute leukemias represent high-risk situations, whereas solid tumors (with the notable exceptions of germ-cell tumors and small-cell lung cancers) are at lower risk.³ Apart from tumor-related risk factors, baseline kidney function, age, and use of nephrotoxic drugs further refine risk stratification.³ The emergence of targeted therapies has modified the spectrum of tumor lysis syndrome that can occur in a delayed fashion or in patients otherwise considered at low risk.⁵

The incidence of tumor lysis syndrome can reach 30% in high-risk patients,⁶ for whom preemptive intensive care unit admission should be considered, as well as debulking strategies to gradually reduce tumor burden, with escalating doses of chemotherapy or oral first-line treatments (e.g., hydroxyurea for acute myeloid leukemia).

Hydration

Enhanced clearance of electrolytes, DNA, and histones released by dying tumor cells through volume repletion is the first step in preventing tumor lysis syndrome. Hydration with large volumes of crystalloid fluids is usually proposed,⁴ with an objective of urine output above 100 ml/h.

Monitoring of urine output, body weight, and echocardiography is required regarding the risk of cardiac overload, especially in patients with known cardiac failure.

Although urine alkalinization increases the solubility of uric acid, it decreases the solubility of calcium phosphate. Because uric acid nephropathy may now be treated by using hypouricemic drugs, urinary alkalinization is no longer recommended and is potentially harmful.²

Forced diuresis using loop diuretics has also been proposed to enhance the urinary flow rate and decrease the risk of crystallization, but this approach has never been properly evaluated.² Concomitant hydration and depletion can be hazardous, and association with cytokine-mediated hemodynamic instability seen in tumor lysis syndrome can jeopardize renal hemodynamics.

Monitoring

Clinical and biological monitoring of patients at risk of tumor lysis syndrome depends on risk stratification, with blood tests and assessments of volume status several times daily.

Twelve hours after chemotherapy, a new blood sample revealed AKI with a serum creatinine level of 3.17 mg/dl, potassium 5.5 mmol/L (3.5–4.5), LDH 8200 IU/L (125–245), uric acid 12.95 mg/dl (2.52–6.05), calcium 8.22 mg/dl (8.82–10.22), and phosphate 5.88 mg/dl (2.48–4.49).

Diagnosis and Pitfalls

A definition of tumor lysis syndrome was published in 2004: Laboratory tumor lysis syndrome includes the presence of ≥2 electrolytic abnormalities among hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia in a patient with cancer within (−3; +7) days of treatment. Clinical tumor lysis syndrome is defined as AKI, cardiac arrhythmia, seizure, or sudden death occurring in this context.⁷

Many laboratory abnormalities observed in tumor lysis syndrome are not specific, and diagnosis may not be straightforward. Kinetics of electrolytic abnormalities, occurring before the onset of AKI, is usually suggestive of tumor lysis. Furthermore, the course of LDH plasma levels, although not included in the definition, can be useful to discriminate between abnormalities directly stemming from tumor lysis and the consequences of decreased electrolyte excretion resulting from AKI.

Fluid Management

After the onset of tumor lysis syndrome, effective fluid management remains a crucial aspect of therapy. As kidney function deteriorates, the risk of fluid overload increases, underscoring the need for diligent monitoring.

Hypouricemic Agents

Allopurinol and febuxostat inhibit the conversion of xanthine to uric acid. Allopurinol is recommended in intermediate and low-risk patients.³ Although more expensive, febuxostat may be used in patients with impaired kidney function. Both of these xanthine oxidase inhibitors are ineffective in dissolving already-formed urate crystals and should be started 48–72 hours before chemotherapy to be effective.⁸ Furthermore, inordinate purine catabolism may exceed their pharmacologic effect, and allopurinol exposes to dermatologic and digestive side effects.

Rasburicase is a recombinant urate oxidase that converts uric acid into soluble allantoin. It is used as first-line hypouricemic therapy in high-risk patients and is effective in reducing uric acid levels below the detection limit within hours,⁸ although its efficacy in achieving meaningful clinical outcomes has never been established, probably because of crystal-independent mechanisms.¹ Although the licensed dose of rasburicase is 0.2 mg/kg per day repeated daily for up to 7 days, several studies have showed that a single fixed dose of 3 mg, repeated only in case of subsequent rise of uric acid levels, is safe and effective.⁹

Caution is warranted in people from the Mediterranean, Africa, or Asia because of the risk of severe and potentially lethal hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Its potential benefit is outweighed by the risk of hemolysis in patients at risk of G6PD deficiency. Therefore, we recommend G6PD testing in these patients before the administration of rasburicase.

Calcium and Phosphate Control

Asymptomatic hypocalcemia should not elicit calcium supplementation that may increase the risk of calcium–phosphate precipitation. Calcium-free phosphate binders function as anion exchange resin or form insoluble phosphate complexes in the gut. Their therapeutic potential in reducing tumor lysis–induced hyperphosphatemia is, therefore, limited and has not been demonstrated.^2–4

KRT

KRT is required in cases of severe tumor lysis syndrome–induced AKI (6%–36%),⁶ when the measures described earlier fail to prevent kidney deterioration. Consensual indications for KRT include threatening hyperkalemia, prolonged oligoanuria, and fluid overload. Whether early initiation of KRT could be beneficial, by removing harmful intracellular compounds before crystal formation or endothelial injury, remains controversial.¹⁰

Hemodialysis is rapidly efficient in patients with severe, threatening hyperkalemia. Furthermore, intermittent hemodialysis allows for the administration of chemotherapy in the interval between two sessions. Contrarily, continuous hemofiltration thwarts the ongoing release of intracellular contents. Prolonged hemodialysis sessions might be a welcome option by combining the benefits of both KRT strategies.

Optimal treatment of tumor lysis syndrome includes risk stratification, followed by hydration, hypouricemic treatments, and close monitoring. Once tumor lysis syndrome diagnosis is established, fluid management, rasburicase, and KRT represent the mainstay of therapy (Figure 1).

Figure 1.

Prevention and treatment of tumor lysis syndrome. Risk stratification relies on a set of arguments, including tumor- and patient-related factors.³ DAMP, damage-associated molecular pattern; LDH, lactate dehydrogenase.

Pending issues and future perspectives regarding treatment include the incorporation of novel urinary and serum biomarkers into tumor lysis syndrome definition, timing of initiation and modalities of KRT, and potential DAMP-targeted therapies.

Disclosures

L. Zafrani reports receiving fees for lectures for MSD and Sanofi. L. Zafrani's institution has received a research grant from Jazz Pharmaceuticals. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

Conceptualization: Adrien Joseph, Lara Zafrani.

Investigation: Adrien Joseph.

Writing – original draft: Adrien Joseph, Lara Zafrani.

Writing – review & editing: Adrien Joseph, Lara Zafrani.