Introduction
Tumor lysis syndrome (TLS) describes the series of metabolic events that result from the death of rapidly dividing cancer cells. When cancer cells die, either spontaneously or in response to chemotherapy, they lyse and release intracellular contents of electrolytes, nucleic acids, and proteins. These substances accumulate in the systemic circulation and cause multiorgan pathology either directly or via toxic metabolites.
Clinically, patients may experience electrolyte disturbances, such as hyperkalemia, hyperphosphatemia, and hypocalcemia, and end-organ injury, such as acute kidney injury (AKI), seizures, and cardiac arrhythmias. TLS is an oncologic emergency and results in high morbidity and mortality, especially if diagnosis is delayed or prevention and treatment are not quickly instituted. In this chapter, we will focus on the defining characteristics and pathophysiology of TLS, with particular attention to patient- and cancer-specific risk factors that increase susceptibility to TLS. We will also review prevention and treatment strategies that have demonstrated efficacy in reducing the incidence and severity of TLS.
Definition and classification
Hande and Garrow first systematically defined TLS when, based on a retrospective review of 102 patients with non-Hodgkin lymphoma, they classified TLS as laboratory TLS (LTLS) or clinical TLS (CTLS). LTLS included changes in several electrolytes, whereas CTLS reflected the clinical effect of these changes, including arrhythmia or sudden death. Cairo and Bishop expanded upon these criteria to establish a commonly used classification system for TLS ( Table 30.1 ). With their modifications, Cairo and Bishop define LTLS if two or more of the following biochemical abnormalities are noted in patients who are not volume depleted and who have received prophylactic therapy against hyperuricemia: (1) 25% increase from baseline of serum potassium, phosphorous, or uric acid; (2) 25% decrease from baseline of serum calcium. These criteria must be met within 3 days before or 7 days after starting chemotherapy. If LTLS criteria are accompanied by seizure, arrhythmias, AKI with serum creatinine at or above 1.5 times upper limit of normal, or sudden death, Cairo and Bishop classification designates it as CTLS, if no other causative role (including therapeutic agents) can be found for the clinical manifestations. The severity of TLS is also determined by the Cairo-Bishop criteria by a separate grading scale (see Table 30.1 ). In addition, a designation of no LTLS or CTLS is given when there are no metabolic or clinical abnormalities.
| LABORATORY TUMOR LYSIS SYNDROME: TWO OR MORE ABNORMALITIES WITHIN 3 DAYS PRIOR OR 7 DAYS AFTER INITIATION OF CHEMOTHERAPY | ||||||
| Metabolic Parameter | Absolute Value | % Change Compared with Baseline | ||||
| Potassium | > 6 mEq/L | Increase of 25% | ||||
| Phosphorous | > 4.5 mg/dL (adults), > 6.5 mg/dL (children) | Increase of 25% | ||||
| Uric Acid | > 8.0 mg/dL | Increase of 25% | ||||
| Calcium | < 7.0 mg/dL | Decrease of 25% | ||||
| CLINICAL TUMOR LYSIS SYNDROME: LABORATORY TUMOR LYSIS SYNDROME AND ONE OR MORE OF THE FOLLOWING | ||||||
| Grade | 0 (no LTLS) | 1 | 2 | 3 | 4 | 5 |
| Creatinine | < 1.5 × ULN | < 1.5 × ULN | > 1.5–3 × ULN | > 3–6 × ULN | > 6 × ULN | Death |
| Cardiac arrhythmia/sudden death | None | No intervention | Medical intervention (nonurgent) | Uncontrolled medically but controlled with AICD | Life-threatening (shock, syncope) | Death |
| Seizure | None | — | One brief generalized seizure controlled with AEDs or infrequent focal motor seizures | Seizures with altered consciousness. Poorly controlled with breakthrough despite AEDs | Prolonged, repetitive, or difficult to control | Death |
The Cairo and Bishop classification is used in clinical practice but has been subject to criticism. For example, although it is common for multiple metabolic abnormalities to occur simultaneously in LTLS, some patients may only have one derangement followed by another, which may not be directly related to TLS, for example, hypocalcemia from sepsis. In addition, baseline changes in serum electrolyte levels may not result in values that are outside the range of normal, raising the question whether these patients are truly at risk for concerning clinical sequelae of TLS. Based on this, Howard et al. suggested a modified version of the Cairo-Bishop classification system that proposes simultaneous development of two or more metabolic abnormalities and symptomatic hypocalcemia as a criterion irrespective of the absolute percent change from baseline. Lastly, the AKI criteria used by Cairo and Bishop are not standardized definitions, such as in the Acute Kidney Injury Network (AKIN) or the Risk, Failure, Loss, End-stage (RIFLE) kidney disease classification systems. As such, chronic kidney disease (CKD) patients may be erroneously classified as having AKI, as a result of TLS. Some have proposed that the criteria for AKI should match AKIN Stage I and include an absolute increase in serum creatinine of 0.3 mg/dL within 48 hours or relative increase in creatinine of 150% over 7 days.
Pathogenesis/pathophysiology
The clinical and biochemical sequelae of TLS occur with the release of intracellular contents when cancer cells lyse. Electrolytes (particularly potassium and phosphate), cytokines, nucleic acids, and their breakdown products enter the extracellular space in excess amounts. This metabolic load can overwhelm the body’s homeostatic mechanisms when kidney function is inadequate to allow for urinary excretion. As such, AKI (mediated by acute uric acid nephropathy) plays a central role in the development of TLS.
Acute uric acid nephropathy
Released intracellular purines (adenine and guanine) are metabolized to xanthine, and subsequently broken down to uric acid by xanthine oxidase. In humans, uric acid is the final product of purine metabolism ( Fig. 30.1 ). This differs from other mammals that possess the enzyme urate oxidase, which further breaks down uric acid to allantoin (a more soluble substance). , Uric acid has classically been thought to cause kidney injury via precipitation of crystals in the renal tubules leading to microobstruction. A high concentration of solute, cocrystallizing substances, and slow urine flow predispose to crystal-mediated injury.
More recently, crystal-independent mechanisms for uric acid induced kidney injury have been described. In animal models, uric acid increases proximal and distal tubular pressures and peritubular capillary vascular resistance. Uric acid may also reduce bioavailable nitric oxide, leading to renal ischemia via vasoconstriction. Soluble uric acid also increases proinflammatory cytokines, such as tumor necrosis factor-α and monocyte chemotactic protein-1, resulting in inflammatory injury. , These multimodal causes of AKI caused by uric acid in turn impair the kidney’s ability to excrete excess electrolytes and nitrogenous waste products.
Hyperkalemia, hyperphosphatemia, and secondary hypocalcemia
Lysis of tumor cells can lead to a substantially increased extracellular potassium load. Intracellular concentrations of potassium can be as high as 120 mEq/L. This is of particular concern in hematologic malignancies with a large tumor burden. Rapid potassium release may exceed compensatory liver and muscle cell uptake, increasing the risk of hyperkalemia particularly in patients with severe AKI or underlying CKD.
Similar to hyperkalemia, hyperphosphatemia occurs with release of intracellular contents with concomitant impaired renal excretion. Hyperphosphatemia may be more common in therapy-associated versus spontaneous TLS. In the latter, rapidly proliferating tumor cells may consume extracellular phosphate, resulting in a falsely low serum phosphate level (pseudohypophosphatemia). , Excess phosphorous may chelate with calcium, resulting in calcium-phosphate crystal deposition and hypocalcemia. Intrarenal calcium-phosphate crystal deposition likely also contributes to AKI in this setting. , These crystals have also been reported to cause dysrhythmia as a result of deposition in the cardiac conducting system. Hypocalcemia secondary to hyperphosphatemia also has potentially severe sequelae, including arrhythmia, seizures, and tetany. Hypocalcemia in TLS may be protracted (even after normalization of phosphate) because of associated acute deficiencies in 1,25-Vitamin-D.
Epidemiology and risk factors
Incidence of tumor lysis syndrome across hematologic and nonhematologic malignancies
The reported incidence of TLS varies widely among cancers. Hematologic malignancies are at higher risk than solid tumors, with the highest reported incidence in B-cell acute lymphoblastic leukemia (26%), acute myeloid leukemia (AML), particularly with white blood cell (WBC) greater than 75,000 cells/mm 3 (18%), and Burkitt lymphoma (15%). , Intermediate risk hematologic cancers include diffuse large B-cell lymphoma (6%) and AML with WBC 25,000 to 75,000 cells/mm 3 (6%). , More indolent hematologic malignancies are considered to be at lower risk, with incidence of 1% or less, including chronic lymphocytic leukemia and chronic myeloid leukemia and multiple myeloma.
TLS has been reported in solid tumors, including breast, colorectal, nonsmall cell lung, and prostate cancers. Although the exact incidence of TLS in solid malignancies is unknown, it is a rare complication, with most cases occurring in patients with a large burden of chemosensitive tumor.
TLS most commonly occurs following cytotoxic therapy; however, it has also been described in response to targeted agents and monoclonal antibodies (e.g., rituximab, bortezomib, imatinib, and other novel agents), , steroid monotherapy, and radiation treatment.
Spontaneous TLS has been well-documented in high-grade hematologic cancers, including non-Hodgkin lymphoma and acute leukemia, and less so in breast cancer. The incidence and specific precipitants of spontaneous TLS remain unclear.
Risk assessment and stratification
Both cancer- and patient-specific risk factors for TLS have been identified. Tumor characteristics, such as a high cellular proliferation rate, high sensitivity to therapy, and large tumor burden, have been associated with increased risk. High tumor burden has been described as bulky disease with diameter greater than 10 cm, WBC greater than 50,000 per μL, lactate dehydrogenase (LDH) more than two times the upper limit of normal, organ infiltration, or bone marrow involvement.
Patient-level risk factors for TLS include pretreatment renal dysfunction (specifically serum creatinine > 1.4 mg/dL), which is associated with a 10-fold increased odds ratio of TLS. , Similarly, volume depletion, oliguria, and/or acidic urine may predispose patients to TLS as well. Biochemical parameters, such as elevated LDH and pretreatment uric acid levels, have also been observed to predict the development of TLS. In particular, hyperuricemia with serum uric acid in excess of 7.5 mg/dL has been shown to associate with development of TLS. These parameters are incorporated into a number of prediction models for TLS (most often in the setting of acute leukemia). , ,
Guidelines have sought to combine malignancy type and clinical characteristics to categorize patients into low-, intermediate-, and high-risk strata, with corresponding recommendations as to appropriate prophylaxis ( Table 30.2 ).
| Low Risk | Intermediate Risk | High Risk |
|---|---|---|
| LEUKEMIAS | ||
| AML and WBC < 25 × 10 9 /L and LDH < 2 × ULN | AML with WBC 25 to 100 × 10 9 /LAML and WBC < 25 × 109/L and LDH ≥ 2 × ULN | AML and WBC ≥ 100 × 10 9 /L |
| CLL and WBC < 50 × 10 9 /L treated only with alkylating agents | CLL treated with fludarabine, rituximab, or lenalidomide, or venetoclax and lymph node ≥ 5 cm or absolute lymphocyte count ≥ 25 × 10 9 /L, and/or those with high WBC ≥ 50 × 10 9 /L | CLL treated with venetoclax and lymph node ≥ 10 cm, or lymph node ≥ 5 cm and absolute lymphocyte count ≥ 25 × 10 9 /L and elevated baseline uric acid |
| ALL and WBC < 100 × 10 9 /L and LDH < 2 × ULN | Burkitt leukemiaOther ALL and WBC ≥ 100 × 109/L and/or LDH ≥ 2 × ULN | |
| CML | ||
| PLASMA CELL DISORDERS | ||
| MM | Plasma cell leukemia | |
| LYMPHOMAS | ||
| Indolent NHL | ||
| Adult intermediate grade NHL and LDH within normal limits | Adult T-cell leukemia/lymphoma, diffuse large B-cell, transformed, and mantle cell lymphomas with LDH > ULN, nonbulky | Adult T-cell leukemia/lymphoma, diffuse large B-cell, transformed, and mantle cell lymphomas with bulky disease and LDH ≥ 2 × ULN |
| HL | Childhood intermediate grade NHL stage III/IV with LDH < 2 × ULN | Stage III/IV childhood diffuse large B-cell lymphoma with LDH ≥ 2 × ULN |
| Adult ALCL | Childhood ALCL stage III/IV | |
| Burkitt lymphoma and LDH < 2 × ULN | Burkitt lymphoma stage III/IV and/or LDH ≥ 2 × ULN | |
| Lymphoblastic lymphoma stage I/II and LDH < 2 × ULN | Lymphoblastic lymphoma stage III/IV and/or LDH ≥ 2 × ULN | |
| SOLID CANCERS | ||
| Most solid cancers | Highly chemosensitive solid cancers with bulky disease (e.g., neuroblastoma, germ cell tumor, small cell lung cancer) | |
| OTHER | ||
| Intermediate risk disease with renal dysfunction and/or renal involvement, or uric acid, potassium, and/or phosphate > ULN | ||
| SUGGESTED PROPHYLAXIS | ||
| Monitoring Hydration Consider allopurinol | Monitoring Hydration Allopurinol | Monitoring Hydration Rasburicase |
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