Management of hyperuricemia in adults with or at risk of tumor lysis syndrome

Manuscript received September 9, 2010; accepted April 8, 2011.

* Current affiliation: Incyte Corporation, Wilmington, DE.

Correspondence to: Karen P. Seiter, MD, New York Medical College, Munger Pavilion, Room 250, Valhalla, NY 10595; telephone: 914-493-7514; fax: 914-594-4420; e-mail: [email protected].

Tumor lysis syndrome (TLS) is a relatively common, potentially life-threatening complication of aggressive cytotoxic therapy characterized by metabolite and electrolyte abnormalities (eg, hyperuricemia). To increase the awareness of the risk of hyperuricemia and TLS in adult patients with cancer, who are likely to have age- or lifestyle-related comorbidities, the authors examine the pathophysiology and risk of TLS in adult patients with a broad spectrum of cancer diagnoses. Current recommendations for effective prophylaxis and management of TLS are summarized briefly. Particular emphasis is given to the appropriate role of antihyperuricemic therapy with rasburicase in adults, based on the recent results of a phase III clinical study.

Tumor lysis syndrome (TLS) is a serious, potentially life-threatening condition of metabolic derangement and impaired electrolyte homeostasis. TLS can occur in patients with cancer as a result of spontaneous or, more commonly, treatment-induced tumor cell death and typically is seen in patients with hematologic, rather than solid organ, malignancies who are undergoing chemotherapy. It is particularly an issue for patients with rapidly growing tumors and a high tumor burden (as evidenced by a high white blood cell [WBC] count in leukemia and elevated serum lactate dehydrogenase [LDH] levels and/or advanced clinical stage in lymphoma) at the beginning of chemotherapy. TLS is caused by a sudden, massive release of cell content from lysed tumor cells into the bloodstream, which overwhelms the body’s capacity for homeostatic regulation. Because persistent or progressive metabolic derangement is associated with a high risk of organ failure, TLS is a clinical emergency.

To facilitate the diagnosis, prevention, and treatment of TLS, Cairo and Bishop established precise criteria for the categorization of TLS on the basis of metabolic abnormalities and the associated significant clinical toxicities that require clinical intervention.1 According to Cairo and Bishop, laboratory TLS (LTLS) is defined by the presence of two or more of the following metabolic abnormalities: hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia. Clinical TLS (CTLS) is defined as LTLS accompanied by at least one clinical complication, such as renal impairment (defined as a serum creatinine concentration greater than 1.5 times the upper limit of normal), cardiac arrhythmia, or seizure. The aforementioned clinical manifestations should not be directly or likely attributable to a therapeutic agent (eg, a rise in creatinine levels after administration of a nephrotoxic drug).1

Estimates from clinical studies of the incidence of TLS vary widely.2 In a review of case records of 102 patients with high-grade non-Hodgkin’s lymphoma (NHL), 42% of patients had signs of LTLS and 6% had CTLS.3 In contrast, analysis of data from a sample of 755 European children and adults with newly diagnosed or recurrent acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or NHL indicated a 19% incidence of hyperuricemia and a 5% incidence of LTLS per episode of administration of an induction therapy ¬regimen.4

Pathophysiology of TLS in adults

The pathophysiology and clinical consequences of TLS have been discussed infrequently in the context of adult patient populations. Yet adult ¬patients are more likely than pediatric patients to experience potentially serious metabolic, cardiac, renal, or multisystemic comorbidities. Such comorbidities, whether chronic illnesses present at the initiation of anticancer therapy or acute conditions that develop during administration of aggressive cytoreductive regimens, require special consideration because they may amplify the metabolic and electrolyte imbalances caused by tumor cell lysis and may have secondary pathophysiologic consequences. In adults, these effects may further weaken an already strained homeostatic regulation and thereby significantly increase the risk of serious clinical complications of TLS.5 Elderly patients (age > 65 years) with cancer are particularly likely to have comorbidities, which may worsen their prognosis in the event of TLS, including baseline chronic renal insufficiency and/or heart disease.6

Hyperuricemia is one of the hallmarks of LTLS. If not reversed quickly, severe hyperuricemia may have serious clinical consequences, particularly acute kidney injury (AKI), which is an independent risk factor for mortality (even mild AKI).2 Additionally, hyperuricemia can lead to a variety of distressing symptoms, such as gastrointestinal complaints (nausea, vomiting, diarrhea, and anorexia), lethargy, hematuria, flank or back pain, fluid overload, edema, arthralgias, hypertension, and signs of obstructive uropathy.7

The risk of renal complications is particularly high in elderly patients with baseline renal disease, which may have been caused by diabetes, hypertension, renal artery stenosis, chronic pyelonephritis, amyloidosis, glomerular disease, or treated malignancies.6 Furthermore, congestive heart failure, use of thiazide or loop diuretics, obesity, type II diabetes, renal impairment, hypertriglyceridemia, and peripheral vascular disease are major cardiovascular risk factors associated with hyperuricemia.6

Serious clinical consequences may arise not only from hyperuricemia but also from TLS-related electrolyte abnormalities (ie, hyperphosphatemia, hyperkalemia, or hypocalcemia). AKI, cardiac arrhythmia, and neurologic impairment, such as seizures or higher CNS dysfunction, may result from severe hyperphosphatemia and secondary hypocalcemia caused by calcium phosphate precipitation in renal tubules. These two metabolic disturbances also may present with muscle cramps, tetany, or perioral numbness or tingling; rare symptoms include fatigue, bone and joint pain, pruritus, and rash.7 Hyperphosphatemia can be exacerbated by excessive use of phosphate-containing laxatives or enemas, which is especially common in the elderly. Hyperkalemia also can lead to neuromuscular symptoms, but principally, it may cause potentially life-threatening cardiac dysfunction.2

Because of the decrease in physiologic reserves with age, the aforementioned electrolyte abnormalities are associated with increased morbidity and mortality in the elderly.8 For example, renal function generally declines with age, and age-related reduction in renin and aldosterone levels increases the risk of hyperkalemia.6 Particularly among the elderly, the risk of hyperkalemia is increased in those with renal tubular reabsorption/secretion defects, those with type II diabetes who develop type IV renal tubular acidosis as the result of hyporeninemic hypoaldosteronism, and those who take nonsteroidal anti-inflammatory drugs on a long-term, scheduled basis.9,10 Although antihypertensive medications generally have cardioprotective and renoprotective properties, many antihypertensives actually may increase the risk of hyperkalemia in elderly patients with renal tubular acidosis.11,12 Also in adults, hypocalcemia may result from vitamin D deficiency, impaired vitamin D metabolism, low intestinal Ca2+ absorption, phosphate retention, chronic hypomagnesemia, serum protein abnormalities, and parathyroid hormone resistance; it may also occur as a medication adverse effect (specifically relevant for patients with cancer treated with bisphosphonates, anticonvulsants, cis¬platin, and the combination of 5-fluor¬¬ouracil and ¬leucovorin).6,13

Risk of TLS in adults with cancer

The risk of TLS in adults with cancer depends on multiple components, including disease-related factors, the type and aggressiveness of anticancer treatment, other medications concomitantly administered, and patient (host)-related factors. TLS has been observed primarily in patients with hematologic malignancies, with particularly high incidences reported for those with Burkitt (and Burkitt-like) lymphoma, precursor B-lymphoblastic leukemia/lymphoma, high-stage T-cell anaplastic large cell lymphoma, and ALL.2

Demographic data from compassionate-use studies of the uricolytic agent rasburicase (Elitek) in patients with or at high risk of acute cancer-associated hyperuricemia and TLS seem to suggest that AML with high WBC counts and select types of NHL (mostly high-grade and some intermediate-grade lymphomas) are associated with a high risk of TLS in adults.14,15 Based on the findings of two European studies, between 3% and 17% of adult patients with AML may experience LTLS or CTLS in response to induction therapy.4,16 In one of the two studies, approximately 20% of adults with AML, ALL, or NHL experienced hyperuricemia after induction therapy.4 Data from the second study, which included 772 adults with AML (including some cases of chronic myelogenous leukemia [CML] in blast crisis) who had received induction chemotherapy, were used to develop a risk-prediction model for CTLS in adult patients with AML.16 According to the model, high WBC count, pretreatment hyperuricemia, and high baseline serum creatinine and LDH concentrations were significant independent prognostic factors for the development of LTLS and CTLS.16

An independent international panel of experts in pediatric and adult hematologic malignancies and TLS recently developed guidelines for the management of TLS based on a comprehensive risk-stratification algorithm. These guidelines were published in 2008 by the American Society of Clinical Oncology.17 Patients were considered to be at high, intermediate, or low risk of TLS, depending on the specific type of malignancy, tumor burden, and type of cytoreductive therapy administered.

In addition to these basic risk categories, other risk factors such as renal function and plasma uric acid (PUA) level at baseline were incorporated into the recommendations for TLS prevention and treatment.17 For example, the presence of baseline hyperuricemia (defined as a serum uric acid level > 7.5 mg/dL) is a modifier of the recommendation of antihyperuricemic therapy for patients at intermediate risk of TLS; if there are high baseline PUA levels, the drug of choice should not be allopurinol but rather rasburicase.17 However, these guidelines do not address all malignancies or uniformly assess risk depending on renal involvement by the disease or kidney function.

Consequently, another consensus panel was convened to build upon the 2008 guidelines and produce a medical decision tree for ranking patients with cancer as low, intermediate, or high risk of TLS. For this project, risk factors included biologic evidence of LTLS, tumor proliferation, and bulk and stage of malignant tumor, as well as renal impairment and/or involvement by the disease at the time of TLS diagnosis; subsequently, an algorithmic model of low-, intermediate-, and high-risk TLS classification and associated TLS prophylaxis recommendations were finalized.18 TLS risk factors of particular relevance for elderly patients are age-related alterations in heart anatomy and function, obesity, generalized deconditioning, alterations of the cardiovascular and circulatory systems, use of multiple drugs with potential pharmacodynamic interactions, age-related decrease in glomerular filtration rate, tobacco use, excessive alcohol consumption, and unhealthy dietary ¬habits.6

In addition to hematologic malignancies, solid tumors may result in TLS as a response to chemo(bio)-therapy or radiation/chemoradiation therapy or spontaneously. In adults, solid tumors that have been associated with TLS include, but are not limited to, breast cancer, lung cancer (especially small cell lung cancer), gastrointestinal stromal tumor, germ cell tumor, hepatocellular carcinoma, melanoma, malignant pheochromocytoma, ovarian cancer, colon cancer, and renal cell carcinoma.19–21 Table 1 presents a list of recent reports of TLS in adults with hematologic malignancies or solid tumors.22–41 Although TLS is less common in patients with solid tumors than in those with hematologic malignancies, its onset and progression in patients with solid tumors often are less predictable.19 Consequently, patients with TLS from solid tumors tend to have worse prognoses.19 In patients with solid tumors, TLS may develop days or even weeks after initiation of chemotherapy, providing no or limited opportunity for effective prophylaxis. Thus, for patients with solid tumors, heightened awareness of and vigilance for TLS are necessary to ensure appropriate and timely management of TLS.

The importance of such timely management of TLS is illustrated by several case studies. In one such case, a 55-year-old man with advanced hepatocellular carcinoma developed acute renal failure, hyperkalemia, and hyperuricemia 30 days after the initiation of treatment with the oral tyrosine kinase inhibitor sorafenib (Nexavar). The patient eventually died of multiple organ failure, despite treatment with hyperhydration, administration of the maximal daily dose of allopurinol, and use of emergency hemodialysis.37

Another fatal outcome of TLS was reported for a 62-year-old man with metastatic colon cancer and a 10-year complicated history of treatments. The patient, who had extensive lung metastases, hyperuricemia, and elevated serum LDH and creatinine concentrations at baseline, developed severe TLS within 2 days of receiving bevacizumab (Avastin) with combination chemotherapy and eventually died of acute renal failure.34

Furthermore, a rare case of spontaneous TLS occurred in a patient with Crohn’s disease who developed plasmacytoma while being treated with immunosuppressants. The patient experienced extreme hyperuricemia (a PUA level of 44 mg/dL) and died of the consequences of acute oliguric renal failure, despite hyperhydration, alkalinization, treatment with maximal doses of allopurinol followed by rasburicase, and hemodialysis.39

According to current TLS management guidelines, patients with multiple myeloma or rapidly growing solid tumors and an expected rapid response to therapy are considered to be at intermediate risk of TLS. However, the risk of TLS in patients with solid tumors is increased by the presence of bulky disease (masses or lymph nodes > 10 cm),17 unfavorable host baseline characteristics (such as renal insufficiency and baseline hyperuricemia),17 and the presence of liver metastases.19 According to relatively recent case reports, TLS occurred in two adult patients with hepatocellular carcinoma undergoing transarterial chemoembolization36 and in a 58-year-old man with metastatic melanoma and bulky liver metastases, who developed TLS within 24 hours after receiving intra-arterial infusion of cisplatin and embolization therapy.42 TLS from palliative radiotherapy, although rare, also has been reported; two fatal cases include a 74-year-old man with diffuse large B-cell lymphoma43 and a 52-year-old man with non-small cell lung cancer.38

Chemo(bio)therapy regimens associated with risk of TLS

The availability of new agents (either as monotherapy or in combination regimens) with high tumor response rates is expected to increase the risk and incidence of TLS. Even for hematologic malignancies with a relatively low incidence of TLS, such as chronic lymphocytic leukemia (CLL), the risk of TLS may increase with the growing use of novel agents that are highly effective inducers of apoptosis.44

In CLL associated with WBC counts of 10,000–100,000 cells/µL, fludarabine therapy (as monotherapy or combination therapy) confers intermediate-risk status (for TLS), according to current TLS management guidelines.17 Current US prescribing information for rituximab (Rituxan), which together with fludara¬bine (± cyclophosphamide) constitutes the standard treatment backbone for previously untreated CLL,45 contains a black-box warning for TLS when rituximab is given for the treatment of NHL.46 A warning for TLS also has been issued for the use of bendamustine (Treanda) for CLL.47 Alvocidib (flavopiridol), a cyclin-dependent kinase inhibitor in clinical development (phase II studies) for the treatment of adults with relapsed CLL, has been associated with a high incidence of TLS, particularly in patients with WBC counts > 200,000 cells/µL.48,49 Finally, lenalidomide (Revlimid) was associated with TLS and a tumor flare phenomenon in patients with CLL in phase II clinical studies.50

A number of case reports have associated imatinib (Gleevec), bortezomib (Velcade), and thalidomide (Thalomid) with the development of TLS in adults. Administration of imatinib led to TLS in two patients treated for ALL and in one patient treated for CML.23 Bortezomib and/or thalidomide caused TLS in several patients treated for multiple myeloma.31,51–54 TLS also is common in patients receiving chemotherapy for acute adult human T-cell lymphotrophic virus-1–associated T-cell leukemia/lymphoma (ATLL). Fatal TLS recently occurred in an obese 57-year-old woman with ATLL, in the background of systemic lupus erythematosus, after chemotherapy with high-dose prednisone and adjusted doses of cyclophosphamide and doxorubicin.33

Management of hyperuricemia in adults: the role of rasburicase

Because hyperuricemia can increase both the risk and the severity of CTLS, management of hyperuricemia that focuses on its prevention and, in cases where it has already emerged, its rapid reversal is an important strategy in reducing TLS-associated mortality and morbidity. The current recommendations for the prevention and management of TLS-associated hyperuricemia have been reviewed in great detail recently.2 Monitoring and clinical judgment generally are adequate for low-risk patients, but patients with higher risk require hydration and antihyperuricemic management with appropriate drug therapy.2 For most patients with an intermediate risk of TLS, prophylactic antihyperuricemic therapy with allopurinol is sufficient, because allopurinol can prevent the buildup of uric acid by blocking the enzymatic conversion of hypoxanthine and xanthine to uric acid (via direct inhibition of xanthine oxidase). However, allopurinol does not modify existing uric acid pools and thus is inadequate for the prevention or management of hyperuricemia in high-risk patients.2 Because a TLS-associated rise in uric acid levels can occur suddenly and rapidly in patients at high risk, effective and safe degradation of uric acid is essential for preventing or reversing life-threatening hyperuricemia.

The effectiveness of rasburicase as antihyperuricemic therapy for adult patients with cancer was demonstrated initially in two international multicenter compassionate-use studies. One study, conducted in the United States and Canada, included 387 adults (and 682 children) with mostly hematologic malignancies who received daily 30-minute IV administrations of rasburicase for 1–7 days at a dose of 0.2 mg/kg.15 All patients who received rasburicase for TLS prophylaxis, including 126 adults, maintained low PUA levels during chemotherapy, and all 212 adults with hyperuricemia at baseline responded to treatment with prompt and impressive reduction in PUA levels, which was maintained for several days.15 Rasburicase generally was well tolerated; only two adults experienced a single episode each of grade 3 toxicity, and no adult experienced grade 4 toxicity.15

The second study—a multicenter compassionate-use study in patients with leukemia or lymphoma from Europe and Australia—included 112 adults (and 166 children) with generally large tumor burdens, as assessed by WBC counts for leukemia and clinical stage and also by serum LDH levels for lymphoma.14 Reduction in PUA levels with rasburicase was statistically and clinically highly significant, resulting in PUA response rates of 100% in both adults and children. Only one adult patient, a 41-year-old man with AML and hyperuricemia at baseline, required hemodialysis because of acute renal failure, although PUA levels returned to normal after treatment with rasburicase. The patient subsequently died of respiratory failure attributable to disease ¬progression.14

The multicenter US registrational trial for the adult indication of rasburicase included 280 patients with hematologic malignancies who were at risk of TLS.55 Patients were randomly assigned to one of three treatments: rasburicase (0.2 mg/kg/d given as a 30-minute IV infusion) for 5 days, rasburicase for 3 days followed by oral allopurinol (300 mg/d) for 2 days, or allopurinol for 5 days. Rasburicase alone achieved significantly greater response rates than allopurinol monotherapy both in patients with a high risk of TLS and in those with baseline hyperuricemia (Table 2). In this clinical trial, control of PUA concentrations was achieved within 4 hours with rasburicase (compared with a median time interval of 27 hours with allopurinol) and was maintained during the 7-day monitoring period after initiation of antihyperuricemic therapy. Although reduction in the incidence of TLS was not an efficacy endpoint of the study, safety data analysis revealed that the occurrence of LTLS or CTLS was less common in the rasburicase than in the allopurinol treatment arm.55

In this large, randomized clinical study, rasburicase was safe and generally well tolerated during the 5-day treatment period. Patients who received rasburicase and those who received allopurinol had a similar incidence of adverse events.55,56 The only drug-related adverse events observed among the 184 patients who received rasburicase (alone or in combination with allopurinol) were potential hypersensitivity reactions in five patients, including irritation at the injection site (one patient); arthralgia, myalgia, and rash (one patient); peripheral edema (one patient); and grade 3 hypersensitivity (two patients). One patient with grade 3 hypersensitivity related to rasburicase discontinued study participation on day 1. No grade 4 hypersensitivity reaction, anaphylaxis, hemolytic reaction, or methemoglobinemia occurred with rasburicase.55

In summary, the results of this phase III randomized controlled study show that rasburicase may be superior to allopurinol in preventing hyperuricemia in adult leukemia/lymphoma patients at high risk of TLS and in achieving rapid and effective control of PUA levels in patients with hyperuricemia. The results support the recommendation within the current TLS management guidelines of using rasburicase for prophylaxis in high-risk patients and for treatment of hyperuricemia of malignancy, as well as in those patients with fully developed LTLS or CTLS (irrespective of PUA levels).17

Conclusion

In adult patients with cancer, the risk of serious clinical consequences of TLS often is increased by the presence of renal impairment, heart disease, baseline metabolic imbalances, and multiorgan derangements. Even in adult patients without serious comorbidities, an age-related decrease in physiologic resistance (reduced pathobiologic reserve), lifestyle factors (eg, adverse chronic exposure to tobacco, alcohol, or other toxins; sedentary existence; obesity; and vitamin and macro/micronutrient deficiencies), and dependence on multiple medications (polypharmacy and an associated increased risk for drug-drug interactions) should be considered for both TLS risk assessment and therapeutic choices in TLS prophylaxis and treatment. Although TLS is most common in patients with hematologic malignancies, serious cases of TLS have been reported in patients with a large variety of solid tumors, with sometimes fatal outcomes.

Assessment of TLS risk in patients with solid tumors, who generally tend to belong to a more aged population, is more difficult than in those with hematologic malignancies. Tumor burden and the type of chemotherapy are the most important risk factors for development of TLS in association with solid tumors; however, an unexpected occurrence of acute spontaneous TLS with hyperuricemia has been observed, even in the absence of these two factors.

Hyperuricemia is a key manifestation of TLS and is associated with risks of AKI, fluid overload, heart failure, and death. Prevention of hyperuricemia in high-risk patients and its rapid reversal in those with hyperuricemia at presentation or in those with fully developed TLS are of utmost importance in the successful management of TLS in adults with cancer. Results of the recent phase III study of rasburicase in adult patients with cancer demonstrated that rasburicase is superior to allopurinol in providing rapid and effective control of PUA levels.

Acknowledgments: Editorial assistance provided by Roland Tacke, PhD, and Candace Lundin, DVM, MS, was funded by sanofi-aventis US. The authors were fully responsible for all content and editorial decisions and did not receive financial support or compensation related to the development of this article.

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ABOUT THE AUTHORS

Affiliations: Dr. Seiter is Professor of Medicine and Director of the Leukemia Service at New York Medical College, Valhalla, NY. Dr. Sarlis is currently Vice President and Head of the Medical Affairs Department at Incyte Corporation, Wilmington, DE. Dr. Kim is Associate Professor and Chief, Section of Head and Neck Medical Oncology, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: Dr. Sarlis was an employee of sanofi-aventis U.S. at the time this article was written and holds stock options and stock in this company. Drs. Seiter and Kim have no pertinent conflicts of interest to disclose.

Karen P. Seiter, MD,¹ Nicholas J. Sarlis, MD, PhD, FACP,^2* and Edward S. Kim, MD³

1. New York Medical College, Valhalla, NY;
2. Medical Affairs–Oncology, sanofi-aventis U.S., Bridgewater, NJ; and
3. The University of Texas MD Anderson Cancer Center, Houston, TX

Manuscript received September 9, 2010; accepted April 8, 2011.

* Current affiliation: Incyte Corporation, Wilmington, DE.

Correspondence to: Karen P. Seiter, MD, New York Medical College, Munger Pavilion, Room 250, Valhalla, NY 10595; telephone: 914-493-7514; fax: 914-594-4420; e-mail: [email protected].

Tumor lysis syndrome (TLS) is a relatively common, potentially life-threatening complication of aggressive cytotoxic therapy characterized by metabolite and electrolyte abnormalities (eg, hyperuricemia). To increase the awareness of the risk of hyperuricemia and TLS in adult patients with cancer, who are likely to have age- or lifestyle-related comorbidities, the authors examine the pathophysiology and risk of TLS in adult patients with a broad spectrum of cancer diagnoses. Current recommendations for effective prophylaxis and management of TLS are summarized briefly. Particular emphasis is given to the appropriate role of antihyperuricemic therapy with rasburicase in adults, based on the recent results of a phase III clinical study.

Tumor lysis syndrome (TLS) is a serious, potentially life-threatening condition of metabolic derangement and impaired electrolyte homeostasis. TLS can occur in patients with cancer as a result of spontaneous or, more commonly, treatment-induced tumor cell death and typically is seen in patients with hematologic, rather than solid organ, malignancies who are undergoing chemotherapy. It is particularly an issue for patients with rapidly growing tumors and a high tumor burden (as evidenced by a high white blood cell [WBC] count in leukemia and elevated serum lactate dehydrogenase [LDH] levels and/or advanced clinical stage in lymphoma) at the beginning of chemotherapy. TLS is caused by a sudden, massive release of cell content from lysed tumor cells into the bloodstream, which overwhelms the body’s capacity for homeostatic regulation. Because persistent or progressive metabolic derangement is associated with a high risk of organ failure, TLS is a clinical emergency.

To facilitate the diagnosis, prevention, and treatment of TLS, Cairo and Bishop established precise criteria for the categorization of TLS on the basis of metabolic abnormalities and the associated significant clinical toxicities that require clinical intervention.1 According to Cairo and Bishop, laboratory TLS (LTLS) is defined by the presence of two or more of the following metabolic abnormalities: hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia. Clinical TLS (CTLS) is defined as LTLS accompanied by at least one clinical complication, such as renal impairment (defined as a serum creatinine concentration greater than 1.5 times the upper limit of normal), cardiac arrhythmia, or seizure. The aforementioned clinical manifestations should not be directly or likely attributable to a therapeutic agent (eg, a rise in creatinine levels after administration of a nephrotoxic drug).1

Estimates from clinical studies of the incidence of TLS vary widely.2 In a review of case records of 102 patients with high-grade non-Hodgkin’s lymphoma (NHL), 42% of patients had signs of LTLS and 6% had CTLS.3 In contrast, analysis of data from a sample of 755 European children and adults with newly diagnosed or recurrent acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or NHL indicated a 19% incidence of hyperuricemia and a 5% incidence of LTLS per episode of administration of an induction therapy ¬regimen.4

Pathophysiology of TLS in adults

The pathophysiology and clinical consequences of TLS have been discussed infrequently in the context of adult patient populations. Yet adult ¬patients are more likely than pediatric patients to experience potentially serious metabolic, cardiac, renal, or multisystemic comorbidities. Such comorbidities, whether chronic illnesses present at the initiation of anticancer therapy or acute conditions that develop during administration of aggressive cytoreductive regimens, require special consideration because they may amplify the metabolic and electrolyte imbalances caused by tumor cell lysis and may have secondary pathophysiologic consequences. In adults, these effects may further weaken an already strained homeostatic regulation and thereby significantly increase the risk of serious clinical complications of TLS.5 Elderly patients (age > 65 years) with cancer are particularly likely to have comorbidities, which may worsen their prognosis in the event of TLS, including baseline chronic renal insufficiency and/or heart disease.6

Hyperuricemia is one of the hallmarks of LTLS. If not reversed quickly, severe hyperuricemia may have serious clinical consequences, particularly acute kidney injury (AKI), which is an independent risk factor for mortality (even mild AKI).2 Additionally, hyperuricemia can lead to a variety of distressing symptoms, such as gastrointestinal complaints (nausea, vomiting, diarrhea, and anorexia), lethargy, hematuria, flank or back pain, fluid overload, edema, arthralgias, hypertension, and signs of obstructive uropathy.7

The risk of renal complications is particularly high in elderly patients with baseline renal disease, which may have been caused by diabetes, hypertension, renal artery stenosis, chronic pyelonephritis, amyloidosis, glomerular disease, or treated malignancies.6 Furthermore, congestive heart failure, use of thiazide or loop diuretics, obesity, type II diabetes, renal impairment, hypertriglyceridemia, and peripheral vascular disease are major cardiovascular risk factors associated with hyperuricemia.6

Serious clinical consequences may arise not only from hyperuricemia but also from TLS-related electrolyte abnormalities (ie, hyperphosphatemia, hyperkalemia, or hypocalcemia). AKI, cardiac arrhythmia, and neurologic impairment, such as seizures or higher CNS dysfunction, may result from severe hyperphosphatemia and secondary hypocalcemia caused by calcium phosphate precipitation in renal tubules. These two metabolic disturbances also may present with muscle cramps, tetany, or perioral numbness or tingling; rare symptoms include fatigue, bone and joint pain, pruritus, and rash.7 Hyperphosphatemia can be exacerbated by excessive use of phosphate-containing laxatives or enemas, which is especially common in the elderly. Hyperkalemia also can lead to neuromuscular symptoms, but principally, it may cause potentially life-threatening cardiac dysfunction.2

Because of the decrease in physiologic reserves with age, the aforementioned electrolyte abnormalities are associated with increased morbidity and mortality in the elderly.8 For example, renal function generally declines with age, and age-related reduction in renin and aldosterone levels increases the risk of hyperkalemia.6 Particularly among the elderly, the risk of hyperkalemia is increased in those with renal tubular reabsorption/secretion defects, those with type II diabetes who develop type IV renal tubular acidosis as the result of hyporeninemic hypoaldosteronism, and those who take nonsteroidal anti-inflammatory drugs on a long-term, scheduled basis.9,10 Although antihypertensive medications generally have cardioprotective and renoprotective properties, many antihypertensives actually may increase the risk of hyperkalemia in elderly patients with renal tubular acidosis.11,12 Also in adults, hypocalcemia may result from vitamin D deficiency, impaired vitamin D metabolism, low intestinal Ca2+ absorption, phosphate retention, chronic hypomagnesemia, serum protein abnormalities, and parathyroid hormone resistance; it may also occur as a medication adverse effect (specifically relevant for patients with cancer treated with bisphosphonates, anticonvulsants, cis¬platin, and the combination of 5-fluor¬¬ouracil and ¬leucovorin).6,13

Risk of TLS in adults with cancer

The risk of TLS in adults with cancer depends on multiple components, including disease-related factors, the type and aggressiveness of anticancer treatment, other medications concomitantly administered, and patient (host)-related factors. TLS has been observed primarily in patients with hematologic malignancies, with particularly high incidences reported for those with Burkitt (and Burkitt-like) lymphoma, precursor B-lymphoblastic leukemia/lymphoma, high-stage T-cell anaplastic large cell lymphoma, and ALL.2

Demographic data from compassionate-use studies of the uricolytic agent rasburicase (Elitek) in patients with or at high risk of acute cancer-associated hyperuricemia and TLS seem to suggest that AML with high WBC counts and select types of NHL (mostly high-grade and some intermediate-grade lymphomas) are associated with a high risk of TLS in adults.14,15 Based on the findings of two European studies, between 3% and 17% of adult patients with AML may experience LTLS or CTLS in response to induction therapy.4,16 In one of the two studies, approximately 20% of adults with AML, ALL, or NHL experienced hyperuricemia after induction therapy.4 Data from the second study, which included 772 adults with AML (including some cases of chronic myelogenous leukemia [CML] in blast crisis) who had received induction chemotherapy, were used to develop a risk-prediction model for CTLS in adult patients with AML.16 According to the model, high WBC count, pretreatment hyperuricemia, and high baseline serum creatinine and LDH concentrations were significant independent prognostic factors for the development of LTLS and CTLS.16

An independent international panel of experts in pediatric and adult hematologic malignancies and TLS recently developed guidelines for the management of TLS based on a comprehensive risk-stratification algorithm. These guidelines were published in 2008 by the American Society of Clinical Oncology.17 Patients were considered to be at high, intermediate, or low risk of TLS, depending on the specific type of malignancy, tumor burden, and type of cytoreductive therapy administered.

In addition to these basic risk categories, other risk factors such as renal function and plasma uric acid (PUA) level at baseline were incorporated into the recommendations for TLS prevention and treatment.17 For example, the presence of baseline hyperuricemia (defined as a serum uric acid level > 7.5 mg/dL) is a modifier of the recommendation of antihyperuricemic therapy for patients at intermediate risk of TLS; if there are high baseline PUA levels, the drug of choice should not be allopurinol but rather rasburicase.17 However, these guidelines do not address all malignancies or uniformly assess risk depending on renal involvement by the disease or kidney function.

Consequently, another consensus panel was convened to build upon the 2008 guidelines and produce a medical decision tree for ranking patients with cancer as low, intermediate, or high risk of TLS. For this project, risk factors included biologic evidence of LTLS, tumor proliferation, and bulk and stage of malignant tumor, as well as renal impairment and/or involvement by the disease at the time of TLS diagnosis; subsequently, an algorithmic model of low-, intermediate-, and high-risk TLS classification and associated TLS prophylaxis recommendations were finalized.18 TLS risk factors of particular relevance for elderly patients are age-related alterations in heart anatomy and function, obesity, generalized deconditioning, alterations of the cardiovascular and circulatory systems, use of multiple drugs with potential pharmacodynamic interactions, age-related decrease in glomerular filtration rate, tobacco use, excessive alcohol consumption, and unhealthy dietary ¬habits.6

In addition to hematologic malignancies, solid tumors may result in TLS as a response to chemo(bio)-therapy or radiation/chemoradiation therapy or spontaneously. In adults, solid tumors that have been associated with TLS include, but are not limited to, breast cancer, lung cancer (especially small cell lung cancer), gastrointestinal stromal tumor, germ cell tumor, hepatocellular carcinoma, melanoma, malignant pheochromocytoma, ovarian cancer, colon cancer, and renal cell carcinoma.19–21 Table 1 presents a list of recent reports of TLS in adults with hematologic malignancies or solid tumors.22–41 Although TLS is less common in patients with solid tumors than in those with hematologic malignancies, its onset and progression in patients with solid tumors often are less predictable.19 Consequently, patients with TLS from solid tumors tend to have worse prognoses.19 In patients with solid tumors, TLS may develop days or even weeks after initiation of chemotherapy, providing no or limited opportunity for effective prophylaxis. Thus, for patients with solid tumors, heightened awareness of and vigilance for TLS are necessary to ensure appropriate and timely management of TLS.

The importance of such timely management of TLS is illustrated by several case studies. In one such case, a 55-year-old man with advanced hepatocellular carcinoma developed acute renal failure, hyperkalemia, and hyperuricemia 30 days after the initiation of treatment with the oral tyrosine kinase inhibitor sorafenib (Nexavar). The patient eventually died of multiple organ failure, despite treatment with hyperhydration, administration of the maximal daily dose of allopurinol, and use of emergency hemodialysis.37

Another fatal outcome of TLS was reported for a 62-year-old man with metastatic colon cancer and a 10-year complicated history of treatments. The patient, who had extensive lung metastases, hyperuricemia, and elevated serum LDH and creatinine concentrations at baseline, developed severe TLS within 2 days of receiving bevacizumab (Avastin) with combination chemotherapy and eventually died of acute renal failure.34

Furthermore, a rare case of spontaneous TLS occurred in a patient with Crohn’s disease who developed plasmacytoma while being treated with immunosuppressants. The patient experienced extreme hyperuricemia (a PUA level of 44 mg/dL) and died of the consequences of acute oliguric renal failure, despite hyperhydration, alkalinization, treatment with maximal doses of allopurinol followed by rasburicase, and hemodialysis.39

According to current TLS management guidelines, patients with multiple myeloma or rapidly growing solid tumors and an expected rapid response to therapy are considered to be at intermediate risk of TLS. However, the risk of TLS in patients with solid tumors is increased by the presence of bulky disease (masses or lymph nodes > 10 cm),17 unfavorable host baseline characteristics (such as renal insufficiency and baseline hyperuricemia),17 and the presence of liver metastases.19 According to relatively recent case reports, TLS occurred in two adult patients with hepatocellular carcinoma undergoing transarterial chemoembolization36 and in a 58-year-old man with metastatic melanoma and bulky liver metastases, who developed TLS within 24 hours after receiving intra-arterial infusion of cisplatin and embolization therapy.42 TLS from palliative radiotherapy, although rare, also has been reported; two fatal cases include a 74-year-old man with diffuse large B-cell lymphoma43 and a 52-year-old man with non-small cell lung cancer.38

Chemo(bio)therapy regimens associated with risk of TLS

The availability of new agents (either as monotherapy or in combination regimens) with high tumor response rates is expected to increase the risk and incidence of TLS. Even for hematologic malignancies with a relatively low incidence of TLS, such as chronic lymphocytic leukemia (CLL), the risk of TLS may increase with the growing use of novel agents that are highly effective inducers of apoptosis.44

In CLL associated with WBC counts of 10,000–100,000 cells/µL, fludarabine therapy (as monotherapy or combination therapy) confers intermediate-risk status (for TLS), according to current TLS management guidelines.17 Current US prescribing information for rituximab (Rituxan), which together with fludara¬bine (± cyclophosphamide) constitutes the standard treatment backbone for previously untreated CLL,45 contains a black-box warning for TLS when rituximab is given for the treatment of NHL.46 A warning for TLS also has been issued for the use of bendamustine (Treanda) for CLL.47 Alvocidib (flavopiridol), a cyclin-dependent kinase inhibitor in clinical development (phase II studies) for the treatment of adults with relapsed CLL, has been associated with a high incidence of TLS, particularly in patients with WBC counts > 200,000 cells/µL.48,49 Finally, lenalidomide (Revlimid) was associated with TLS and a tumor flare phenomenon in patients with CLL in phase II clinical studies.50

A number of case reports have associated imatinib (Gleevec), bortezomib (Velcade), and thalidomide (Thalomid) with the development of TLS in adults. Administration of imatinib led to TLS in two patients treated for ALL and in one patient treated for CML.23 Bortezomib and/or thalidomide caused TLS in several patients treated for multiple myeloma.31,51–54 TLS also is common in patients receiving chemotherapy for acute adult human T-cell lymphotrophic virus-1–associated T-cell leukemia/lymphoma (ATLL). Fatal TLS recently occurred in an obese 57-year-old woman with ATLL, in the background of systemic lupus erythematosus, after chemotherapy with high-dose prednisone and adjusted doses of cyclophosphamide and doxorubicin.33

Management of hyperuricemia in adults: the role of rasburicase

Because hyperuricemia can increase both the risk and the severity of CTLS, management of hyperuricemia that focuses on its prevention and, in cases where it has already emerged, its rapid reversal is an important strategy in reducing TLS-associated mortality and morbidity. The current recommendations for the prevention and management of TLS-associated hyperuricemia have been reviewed in great detail recently.2 Monitoring and clinical judgment generally are adequate for low-risk patients, but patients with higher risk require hydration and antihyperuricemic management with appropriate drug therapy.2 For most patients with an intermediate risk of TLS, prophylactic antihyperuricemic therapy with allopurinol is sufficient, because allopurinol can prevent the buildup of uric acid by blocking the enzymatic conversion of hypoxanthine and xanthine to uric acid (via direct inhibition of xanthine oxidase). However, allopurinol does not modify existing uric acid pools and thus is inadequate for the prevention or management of hyperuricemia in high-risk patients.2 Because a TLS-associated rise in uric acid levels can occur suddenly and rapidly in patients at high risk, effective and safe degradation of uric acid is essential for preventing or reversing life-threatening hyperuricemia.

The effectiveness of rasburicase as antihyperuricemic therapy for adult patients with cancer was demonstrated initially in two international multicenter compassionate-use studies. One study, conducted in the United States and Canada, included 387 adults (and 682 children) with mostly hematologic malignancies who received daily 30-minute IV administrations of rasburicase for 1–7 days at a dose of 0.2 mg/kg.15 All patients who received rasburicase for TLS prophylaxis, including 126 adults, maintained low PUA levels during chemotherapy, and all 212 adults with hyperuricemia at baseline responded to treatment with prompt and impressive reduction in PUA levels, which was maintained for several days.15 Rasburicase generally was well tolerated; only two adults experienced a single episode each of grade 3 toxicity, and no adult experienced grade 4 toxicity.15

The second study—a multicenter compassionate-use study in patients with leukemia or lymphoma from Europe and Australia—included 112 adults (and 166 children) with generally large tumor burdens, as assessed by WBC counts for leukemia and clinical stage and also by serum LDH levels for lymphoma.14 Reduction in PUA levels with rasburicase was statistically and clinically highly significant, resulting in PUA response rates of 100% in both adults and children. Only one adult patient, a 41-year-old man with AML and hyperuricemia at baseline, required hemodialysis because of acute renal failure, although PUA levels returned to normal after treatment with rasburicase. The patient subsequently died of respiratory failure attributable to disease ¬progression.14

The multicenter US registrational trial for the adult indication of rasburicase included 280 patients with hematologic malignancies who were at risk of TLS.55 Patients were randomly assigned to one of three treatments: rasburicase (0.2 mg/kg/d given as a 30-minute IV infusion) for 5 days, rasburicase for 3 days followed by oral allopurinol (300 mg/d) for 2 days, or allopurinol for 5 days. Rasburicase alone achieved significantly greater response rates than allopurinol monotherapy both in patients with a high risk of TLS and in those with baseline hyperuricemia (Table 2). In this clinical trial, control of PUA concentrations was achieved within 4 hours with rasburicase (compared with a median time interval of 27 hours with allopurinol) and was maintained during the 7-day monitoring period after initiation of antihyperuricemic therapy. Although reduction in the incidence of TLS was not an efficacy endpoint of the study, safety data analysis revealed that the occurrence of LTLS or CTLS was less common in the rasburicase than in the allopurinol treatment arm.55

In this large, randomized clinical study, rasburicase was safe and generally well tolerated during the 5-day treatment period. Patients who received rasburicase and those who received allopurinol had a similar incidence of adverse events.55,56 The only drug-related adverse events observed among the 184 patients who received rasburicase (alone or in combination with allopurinol) were potential hypersensitivity reactions in five patients, including irritation at the injection site (one patient); arthralgia, myalgia, and rash (one patient); peripheral edema (one patient); and grade 3 hypersensitivity (two patients). One patient with grade 3 hypersensitivity related to rasburicase discontinued study participation on day 1. No grade 4 hypersensitivity reaction, anaphylaxis, hemolytic reaction, or methemoglobinemia occurred with rasburicase.55

In summary, the results of this phase III randomized controlled study show that rasburicase may be superior to allopurinol in preventing hyperuricemia in adult leukemia/lymphoma patients at high risk of TLS and in achieving rapid and effective control of PUA levels in patients with hyperuricemia. The results support the recommendation within the current TLS management guidelines of using rasburicase for prophylaxis in high-risk patients and for treatment of hyperuricemia of malignancy, as well as in those patients with fully developed LTLS or CTLS (irrespective of PUA levels).17

Conclusion

In adult patients with cancer, the risk of serious clinical consequences of TLS often is increased by the presence of renal impairment, heart disease, baseline metabolic imbalances, and multiorgan derangements. Even in adult patients without serious comorbidities, an age-related decrease in physiologic resistance (reduced pathobiologic reserve), lifestyle factors (eg, adverse chronic exposure to tobacco, alcohol, or other toxins; sedentary existence; obesity; and vitamin and macro/micronutrient deficiencies), and dependence on multiple medications (polypharmacy and an associated increased risk for drug-drug interactions) should be considered for both TLS risk assessment and therapeutic choices in TLS prophylaxis and treatment. Although TLS is most common in patients with hematologic malignancies, serious cases of TLS have been reported in patients with a large variety of solid tumors, with sometimes fatal outcomes.

Assessment of TLS risk in patients with solid tumors, who generally tend to belong to a more aged population, is more difficult than in those with hematologic malignancies. Tumor burden and the type of chemotherapy are the most important risk factors for development of TLS in association with solid tumors; however, an unexpected occurrence of acute spontaneous TLS with hyperuricemia has been observed, even in the absence of these two factors.

Hyperuricemia is a key manifestation of TLS and is associated with risks of AKI, fluid overload, heart failure, and death. Prevention of hyperuricemia in high-risk patients and its rapid reversal in those with hyperuricemia at presentation or in those with fully developed TLS are of utmost importance in the successful management of TLS in adults with cancer. Results of the recent phase III study of rasburicase in adult patients with cancer demonstrated that rasburicase is superior to allopurinol in providing rapid and effective control of PUA levels.

Acknowledgments: Editorial assistance provided by Roland Tacke, PhD, and Candace Lundin, DVM, MS, was funded by sanofi-aventis US. The authors were fully responsible for all content and editorial decisions and did not receive financial support or compensation related to the development of this article.

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ABOUT THE AUTHORS

Affiliations: Dr. Seiter is Professor of Medicine and Director of the Leukemia Service at New York Medical College, Valhalla, NY. Dr. Sarlis is currently Vice President and Head of the Medical Affairs Department at Incyte Corporation, Wilmington, DE. Dr. Kim is Associate Professor and Chief, Section of Head and Neck Medical Oncology, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: Dr. Sarlis was an employee of sanofi-aventis U.S. at the time this article was written and holds stock options and stock in this company. Drs. Seiter and Kim have no pertinent conflicts of interest to disclose.

Karen P. Seiter, MD,¹ Nicholas J. Sarlis, MD, PhD, FACP,^2* and Edward S. Kim, MD³

1. New York Medical College, Valhalla, NY;
2. Medical Affairs–Oncology, sanofi-aventis U.S., Bridgewater, NJ; and
3. The University of Texas MD Anderson Cancer Center, Houston, TX

Manuscript received September 9, 2010; accepted April 8, 2011.

* Current affiliation: Incyte Corporation, Wilmington, DE.

Correspondence to: Karen P. Seiter, MD, New York Medical College, Munger Pavilion, Room 250, Valhalla, NY 10595; telephone: 914-493-7514; fax: 914-594-4420; e-mail: [email protected].

Tumor lysis syndrome (TLS) is a relatively common, potentially life-threatening complication of aggressive cytotoxic therapy characterized by metabolite and electrolyte abnormalities (eg, hyperuricemia). To increase the awareness of the risk of hyperuricemia and TLS in adult patients with cancer, who are likely to have age- or lifestyle-related comorbidities, the authors examine the pathophysiology and risk of TLS in adult patients with a broad spectrum of cancer diagnoses. Current recommendations for effective prophylaxis and management of TLS are summarized briefly. Particular emphasis is given to the appropriate role of antihyperuricemic therapy with rasburicase in adults, based on the recent results of a phase III clinical study.

Tumor lysis syndrome (TLS) is a serious, potentially life-threatening condition of metabolic derangement and impaired electrolyte homeostasis. TLS can occur in patients with cancer as a result of spontaneous or, more commonly, treatment-induced tumor cell death and typically is seen in patients with hematologic, rather than solid organ, malignancies who are undergoing chemotherapy. It is particularly an issue for patients with rapidly growing tumors and a high tumor burden (as evidenced by a high white blood cell [WBC] count in leukemia and elevated serum lactate dehydrogenase [LDH] levels and/or advanced clinical stage in lymphoma) at the beginning of chemotherapy. TLS is caused by a sudden, massive release of cell content from lysed tumor cells into the bloodstream, which overwhelms the body’s capacity for homeostatic regulation. Because persistent or progressive metabolic derangement is associated with a high risk of organ failure, TLS is a clinical emergency.

To facilitate the diagnosis, prevention, and treatment of TLS, Cairo and Bishop established precise criteria for the categorization of TLS on the basis of metabolic abnormalities and the associated significant clinical toxicities that require clinical intervention.1 According to Cairo and Bishop, laboratory TLS (LTLS) is defined by the presence of two or more of the following metabolic abnormalities: hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary hypocalcemia. Clinical TLS (CTLS) is defined as LTLS accompanied by at least one clinical complication, such as renal impairment (defined as a serum creatinine concentration greater than 1.5 times the upper limit of normal), cardiac arrhythmia, or seizure. The aforementioned clinical manifestations should not be directly or likely attributable to a therapeutic agent (eg, a rise in creatinine levels after administration of a nephrotoxic drug).1

Estimates from clinical studies of the incidence of TLS vary widely.2 In a review of case records of 102 patients with high-grade non-Hodgkin’s lymphoma (NHL), 42% of patients had signs of LTLS and 6% had CTLS.3 In contrast, analysis of data from a sample of 755 European children and adults with newly diagnosed or recurrent acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or NHL indicated a 19% incidence of hyperuricemia and a 5% incidence of LTLS per episode of administration of an induction therapy ¬regimen.4

Pathophysiology of TLS in adults

The pathophysiology and clinical consequences of TLS have been discussed infrequently in the context of adult patient populations. Yet adult ¬patients are more likely than pediatric patients to experience potentially serious metabolic, cardiac, renal, or multisystemic comorbidities. Such comorbidities, whether chronic illnesses present at the initiation of anticancer therapy or acute conditions that develop during administration of aggressive cytoreductive regimens, require special consideration because they may amplify the metabolic and electrolyte imbalances caused by tumor cell lysis and may have secondary pathophysiologic consequences. In adults, these effects may further weaken an already strained homeostatic regulation and thereby significantly increase the risk of serious clinical complications of TLS.5 Elderly patients (age > 65 years) with cancer are particularly likely to have comorbidities, which may worsen their prognosis in the event of TLS, including baseline chronic renal insufficiency and/or heart disease.6

Hyperuricemia is one of the hallmarks of LTLS. If not reversed quickly, severe hyperuricemia may have serious clinical consequences, particularly acute kidney injury (AKI), which is an independent risk factor for mortality (even mild AKI).2 Additionally, hyperuricemia can lead to a variety of distressing symptoms, such as gastrointestinal complaints (nausea, vomiting, diarrhea, and anorexia), lethargy, hematuria, flank or back pain, fluid overload, edema, arthralgias, hypertension, and signs of obstructive uropathy.7

The risk of renal complications is particularly high in elderly patients with baseline renal disease, which may have been caused by diabetes, hypertension, renal artery stenosis, chronic pyelonephritis, amyloidosis, glomerular disease, or treated malignancies.6 Furthermore, congestive heart failure, use of thiazide or loop diuretics, obesity, type II diabetes, renal impairment, hypertriglyceridemia, and peripheral vascular disease are major cardiovascular risk factors associated with hyperuricemia.6

Serious clinical consequences may arise not only from hyperuricemia but also from TLS-related electrolyte abnormalities (ie, hyperphosphatemia, hyperkalemia, or hypocalcemia). AKI, cardiac arrhythmia, and neurologic impairment, such as seizures or higher CNS dysfunction, may result from severe hyperphosphatemia and secondary hypocalcemia caused by calcium phosphate precipitation in renal tubules. These two metabolic disturbances also may present with muscle cramps, tetany, or perioral numbness or tingling; rare symptoms include fatigue, bone and joint pain, pruritus, and rash.7 Hyperphosphatemia can be exacerbated by excessive use of phosphate-containing laxatives or enemas, which is especially common in the elderly. Hyperkalemia also can lead to neuromuscular symptoms, but principally, it may cause potentially life-threatening cardiac dysfunction.2

Because of the decrease in physiologic reserves with age, the aforementioned electrolyte abnormalities are associated with increased morbidity and mortality in the elderly.8 For example, renal function generally declines with age, and age-related reduction in renin and aldosterone levels increases the risk of hyperkalemia.6 Particularly among the elderly, the risk of hyperkalemia is increased in those with renal tubular reabsorption/secretion defects, those with type II diabetes who develop type IV renal tubular acidosis as the result of hyporeninemic hypoaldosteronism, and those who take nonsteroidal anti-inflammatory drugs on a long-term, scheduled basis.9,10 Although antihypertensive medications generally have cardioprotective and renoprotective properties, many antihypertensives actually may increase the risk of hyperkalemia in elderly patients with renal tubular acidosis.11,12 Also in adults, hypocalcemia may result from vitamin D deficiency, impaired vitamin D metabolism, low intestinal Ca2+ absorption, phosphate retention, chronic hypomagnesemia, serum protein abnormalities, and parathyroid hormone resistance; it may also occur as a medication adverse effect (specifically relevant for patients with cancer treated with bisphosphonates, anticonvulsants, cis¬platin, and the combination of 5-fluor¬¬ouracil and ¬leucovorin).6,13

Risk of TLS in adults with cancer

The risk of TLS in adults with cancer depends on multiple components, including disease-related factors, the type and aggressiveness of anticancer treatment, other medications concomitantly administered, and patient (host)-related factors. TLS has been observed primarily in patients with hematologic malignancies, with particularly high incidences reported for those with Burkitt (and Burkitt-like) lymphoma, precursor B-lymphoblastic leukemia/lymphoma, high-stage T-cell anaplastic large cell lymphoma, and ALL.2

Demographic data from compassionate-use studies of the uricolytic agent rasburicase (Elitek) in patients with or at high risk of acute cancer-associated hyperuricemia and TLS seem to suggest that AML with high WBC counts and select types of NHL (mostly high-grade and some intermediate-grade lymphomas) are associated with a high risk of TLS in adults.14,15 Based on the findings of two European studies, between 3% and 17% of adult patients with AML may experience LTLS or CTLS in response to induction therapy.4,16 In one of the two studies, approximately 20% of adults with AML, ALL, or NHL experienced hyperuricemia after induction therapy.4 Data from the second study, which included 772 adults with AML (including some cases of chronic myelogenous leukemia [CML] in blast crisis) who had received induction chemotherapy, were used to develop a risk-prediction model for CTLS in adult patients with AML.16 According to the model, high WBC count, pretreatment hyperuricemia, and high baseline serum creatinine and LDH concentrations were significant independent prognostic factors for the development of LTLS and CTLS.16

An independent international panel of experts in pediatric and adult hematologic malignancies and TLS recently developed guidelines for the management of TLS based on a comprehensive risk-stratification algorithm. These guidelines were published in 2008 by the American Society of Clinical Oncology.17 Patients were considered to be at high, intermediate, or low risk of TLS, depending on the specific type of malignancy, tumor burden, and type of cytoreductive therapy administered.

In addition to these basic risk categories, other risk factors such as renal function and plasma uric acid (PUA) level at baseline were incorporated into the recommendations for TLS prevention and treatment.17 For example, the presence of baseline hyperuricemia (defined as a serum uric acid level > 7.5 mg/dL) is a modifier of the recommendation of antihyperuricemic therapy for patients at intermediate risk of TLS; if there are high baseline PUA levels, the drug of choice should not be allopurinol but rather rasburicase.17 However, these guidelines do not address all malignancies or uniformly assess risk depending on renal involvement by the disease or kidney function.

Consequently, another consensus panel was convened to build upon the 2008 guidelines and produce a medical decision tree for ranking patients with cancer as low, intermediate, or high risk of TLS. For this project, risk factors included biologic evidence of LTLS, tumor proliferation, and bulk and stage of malignant tumor, as well as renal impairment and/or involvement by the disease at the time of TLS diagnosis; subsequently, an algorithmic model of low-, intermediate-, and high-risk TLS classification and associated TLS prophylaxis recommendations were finalized.18 TLS risk factors of particular relevance for elderly patients are age-related alterations in heart anatomy and function, obesity, generalized deconditioning, alterations of the cardiovascular and circulatory systems, use of multiple drugs with potential pharmacodynamic interactions, age-related decrease in glomerular filtration rate, tobacco use, excessive alcohol consumption, and unhealthy dietary ¬habits.6

In addition to hematologic malignancies, solid tumors may result in TLS as a response to chemo(bio)-therapy or radiation/chemoradiation therapy or spontaneously. In adults, solid tumors that have been associated with TLS include, but are not limited to, breast cancer, lung cancer (especially small cell lung cancer), gastrointestinal stromal tumor, germ cell tumor, hepatocellular carcinoma, melanoma, malignant pheochromocytoma, ovarian cancer, colon cancer, and renal cell carcinoma.19–21 Table 1 presents a list of recent reports of TLS in adults with hematologic malignancies or solid tumors.22–41 Although TLS is less common in patients with solid tumors than in those with hematologic malignancies, its onset and progression in patients with solid tumors often are less predictable.19 Consequently, patients with TLS from solid tumors tend to have worse prognoses.19 In patients with solid tumors, TLS may develop days or even weeks after initiation of chemotherapy, providing no or limited opportunity for effective prophylaxis. Thus, for patients with solid tumors, heightened awareness of and vigilance for TLS are necessary to ensure appropriate and timely management of TLS.

The importance of such timely management of TLS is illustrated by several case studies. In one such case, a 55-year-old man with advanced hepatocellular carcinoma developed acute renal failure, hyperkalemia, and hyperuricemia 30 days after the initiation of treatment with the oral tyrosine kinase inhibitor sorafenib (Nexavar). The patient eventually died of multiple organ failure, despite treatment with hyperhydration, administration of the maximal daily dose of allopurinol, and use of emergency hemodialysis.37

Another fatal outcome of TLS was reported for a 62-year-old man with metastatic colon cancer and a 10-year complicated history of treatments. The patient, who had extensive lung metastases, hyperuricemia, and elevated serum LDH and creatinine concentrations at baseline, developed severe TLS within 2 days of receiving bevacizumab (Avastin) with combination chemotherapy and eventually died of acute renal failure.34

Furthermore, a rare case of spontaneous TLS occurred in a patient with Crohn’s disease who developed plasmacytoma while being treated with immunosuppressants. The patient experienced extreme hyperuricemia (a PUA level of 44 mg/dL) and died of the consequences of acute oliguric renal failure, despite hyperhydration, alkalinization, treatment with maximal doses of allopurinol followed by rasburicase, and hemodialysis.39

According to current TLS management guidelines, patients with multiple myeloma or rapidly growing solid tumors and an expected rapid response to therapy are considered to be at intermediate risk of TLS. However, the risk of TLS in patients with solid tumors is increased by the presence of bulky disease (masses or lymph nodes > 10 cm),17 unfavorable host baseline characteristics (such as renal insufficiency and baseline hyperuricemia),17 and the presence of liver metastases.19 According to relatively recent case reports, TLS occurred in two adult patients with hepatocellular carcinoma undergoing transarterial chemoembolization36 and in a 58-year-old man with metastatic melanoma and bulky liver metastases, who developed TLS within 24 hours after receiving intra-arterial infusion of cisplatin and embolization therapy.42 TLS from palliative radiotherapy, although rare, also has been reported; two fatal cases include a 74-year-old man with diffuse large B-cell lymphoma43 and a 52-year-old man with non-small cell lung cancer.38

Chemo(bio)therapy regimens associated with risk of TLS

The availability of new agents (either as monotherapy or in combination regimens) with high tumor response rates is expected to increase the risk and incidence of TLS. Even for hematologic malignancies with a relatively low incidence of TLS, such as chronic lymphocytic leukemia (CLL), the risk of TLS may increase with the growing use of novel agents that are highly effective inducers of apoptosis.44

In CLL associated with WBC counts of 10,000–100,000 cells/µL, fludarabine therapy (as monotherapy or combination therapy) confers intermediate-risk status (for TLS), according to current TLS management guidelines.17 Current US prescribing information for rituximab (Rituxan), which together with fludara¬bine (± cyclophosphamide) constitutes the standard treatment backbone for previously untreated CLL,45 contains a black-box warning for TLS when rituximab is given for the treatment of NHL.46 A warning for TLS also has been issued for the use of bendamustine (Treanda) for CLL.47 Alvocidib (flavopiridol), a cyclin-dependent kinase inhibitor in clinical development (phase II studies) for the treatment of adults with relapsed CLL, has been associated with a high incidence of TLS, particularly in patients with WBC counts > 200,000 cells/µL.48,49 Finally, lenalidomide (Revlimid) was associated with TLS and a tumor flare phenomenon in patients with CLL in phase II clinical studies.50

A number of case reports have associated imatinib (Gleevec), bortezomib (Velcade), and thalidomide (Thalomid) with the development of TLS in adults. Administration of imatinib led to TLS in two patients treated for ALL and in one patient treated for CML.23 Bortezomib and/or thalidomide caused TLS in several patients treated for multiple myeloma.31,51–54 TLS also is common in patients receiving chemotherapy for acute adult human T-cell lymphotrophic virus-1–associated T-cell leukemia/lymphoma (ATLL). Fatal TLS recently occurred in an obese 57-year-old woman with ATLL, in the background of systemic lupus erythematosus, after chemotherapy with high-dose prednisone and adjusted doses of cyclophosphamide and doxorubicin.33

Management of hyperuricemia in adults: the role of rasburicase

Because hyperuricemia can increase both the risk and the severity of CTLS, management of hyperuricemia that focuses on its prevention and, in cases where it has already emerged, its rapid reversal is an important strategy in reducing TLS-associated mortality and morbidity. The current recommendations for the prevention and management of TLS-associated hyperuricemia have been reviewed in great detail recently.2 Monitoring and clinical judgment generally are adequate for low-risk patients, but patients with higher risk require hydration and antihyperuricemic management with appropriate drug therapy.2 For most patients with an intermediate risk of TLS, prophylactic antihyperuricemic therapy with allopurinol is sufficient, because allopurinol can prevent the buildup of uric acid by blocking the enzymatic conversion of hypoxanthine and xanthine to uric acid (via direct inhibition of xanthine oxidase). However, allopurinol does not modify existing uric acid pools and thus is inadequate for the prevention or management of hyperuricemia in high-risk patients.2 Because a TLS-associated rise in uric acid levels can occur suddenly and rapidly in patients at high risk, effective and safe degradation of uric acid is essential for preventing or reversing life-threatening hyperuricemia.

The effectiveness of rasburicase as antihyperuricemic therapy for adult patients with cancer was demonstrated initially in two international multicenter compassionate-use studies. One study, conducted in the United States and Canada, included 387 adults (and 682 children) with mostly hematologic malignancies who received daily 30-minute IV administrations of rasburicase for 1–7 days at a dose of 0.2 mg/kg.15 All patients who received rasburicase for TLS prophylaxis, including 126 adults, maintained low PUA levels during chemotherapy, and all 212 adults with hyperuricemia at baseline responded to treatment with prompt and impressive reduction in PUA levels, which was maintained for several days.15 Rasburicase generally was well tolerated; only two adults experienced a single episode each of grade 3 toxicity, and no adult experienced grade 4 toxicity.15

The second study—a multicenter compassionate-use study in patients with leukemia or lymphoma from Europe and Australia—included 112 adults (and 166 children) with generally large tumor burdens, as assessed by WBC counts for leukemia and clinical stage and also by serum LDH levels for lymphoma.14 Reduction in PUA levels with rasburicase was statistically and clinically highly significant, resulting in PUA response rates of 100% in both adults and children. Only one adult patient, a 41-year-old man with AML and hyperuricemia at baseline, required hemodialysis because of acute renal failure, although PUA levels returned to normal after treatment with rasburicase. The patient subsequently died of respiratory failure attributable to disease ¬progression.14

The multicenter US registrational trial for the adult indication of rasburicase included 280 patients with hematologic malignancies who were at risk of TLS.55 Patients were randomly assigned to one of three treatments: rasburicase (0.2 mg/kg/d given as a 30-minute IV infusion) for 5 days, rasburicase for 3 days followed by oral allopurinol (300 mg/d) for 2 days, or allopurinol for 5 days. Rasburicase alone achieved significantly greater response rates than allopurinol monotherapy both in patients with a high risk of TLS and in those with baseline hyperuricemia (Table 2). In this clinical trial, control of PUA concentrations was achieved within 4 hours with rasburicase (compared with a median time interval of 27 hours with allopurinol) and was maintained during the 7-day monitoring period after initiation of antihyperuricemic therapy. Although reduction in the incidence of TLS was not an efficacy endpoint of the study, safety data analysis revealed that the occurrence of LTLS or CTLS was less common in the rasburicase than in the allopurinol treatment arm.55

In this large, randomized clinical study, rasburicase was safe and generally well tolerated during the 5-day treatment period. Patients who received rasburicase and those who received allopurinol had a similar incidence of adverse events.55,56 The only drug-related adverse events observed among the 184 patients who received rasburicase (alone or in combination with allopurinol) were potential hypersensitivity reactions in five patients, including irritation at the injection site (one patient); arthralgia, myalgia, and rash (one patient); peripheral edema (one patient); and grade 3 hypersensitivity (two patients). One patient with grade 3 hypersensitivity related to rasburicase discontinued study participation on day 1. No grade 4 hypersensitivity reaction, anaphylaxis, hemolytic reaction, or methemoglobinemia occurred with rasburicase.55

In summary, the results of this phase III randomized controlled study show that rasburicase may be superior to allopurinol in preventing hyperuricemia in adult leukemia/lymphoma patients at high risk of TLS and in achieving rapid and effective control of PUA levels in patients with hyperuricemia. The results support the recommendation within the current TLS management guidelines of using rasburicase for prophylaxis in high-risk patients and for treatment of hyperuricemia of malignancy, as well as in those patients with fully developed LTLS or CTLS (irrespective of PUA levels).17

Conclusion

In adult patients with cancer, the risk of serious clinical consequences of TLS often is increased by the presence of renal impairment, heart disease, baseline metabolic imbalances, and multiorgan derangements. Even in adult patients without serious comorbidities, an age-related decrease in physiologic resistance (reduced pathobiologic reserve), lifestyle factors (eg, adverse chronic exposure to tobacco, alcohol, or other toxins; sedentary existence; obesity; and vitamin and macro/micronutrient deficiencies), and dependence on multiple medications (polypharmacy and an associated increased risk for drug-drug interactions) should be considered for both TLS risk assessment and therapeutic choices in TLS prophylaxis and treatment. Although TLS is most common in patients with hematologic malignancies, serious cases of TLS have been reported in patients with a large variety of solid tumors, with sometimes fatal outcomes.

Assessment of TLS risk in patients with solid tumors, who generally tend to belong to a more aged population, is more difficult than in those with hematologic malignancies. Tumor burden and the type of chemotherapy are the most important risk factors for development of TLS in association with solid tumors; however, an unexpected occurrence of acute spontaneous TLS with hyperuricemia has been observed, even in the absence of these two factors.

Hyperuricemia is a key manifestation of TLS and is associated with risks of AKI, fluid overload, heart failure, and death. Prevention of hyperuricemia in high-risk patients and its rapid reversal in those with hyperuricemia at presentation or in those with fully developed TLS are of utmost importance in the successful management of TLS in adults with cancer. Results of the recent phase III study of rasburicase in adult patients with cancer demonstrated that rasburicase is superior to allopurinol in providing rapid and effective control of PUA levels.

Acknowledgments: Editorial assistance provided by Roland Tacke, PhD, and Candace Lundin, DVM, MS, was funded by sanofi-aventis US. The authors were fully responsible for all content and editorial decisions and did not receive financial support or compensation related to the development of this article.

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ABOUT THE AUTHORS

Affiliations: Dr. Seiter is Professor of Medicine and Director of the Leukemia Service at New York Medical College, Valhalla, NY. Dr. Sarlis is currently Vice President and Head of the Medical Affairs Department at Incyte Corporation, Wilmington, DE. Dr. Kim is Associate Professor and Chief, Section of Head and Neck Medical Oncology, Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston, TX.

Conflicts of interest: Dr. Sarlis was an employee of sanofi-aventis U.S. at the time this article was written and holds stock options and stock in this company. Drs. Seiter and Kim have no pertinent conflicts of interest to disclose.

Karen P. Seiter, MD,¹ Nicholas J. Sarlis, MD, PhD, FACP,^2* and Edward S. Kim, MD³

1. New York Medical College, Valhalla, NY;
2. Medical Affairs–Oncology, sanofi-aventis U.S., Bridgewater, NJ; and
3. The University of Texas MD Anderson Cancer Center, Houston, TX