Tumor Lysis Syndrome

36 

Tumor Lysis Syndrome Scott C. Howard

S UMMARY

OF

K EY

P OI N T S

• Tumor lysis syndrome can occur in any patient with newly diagnosed or relapsed cancer, so all patients should undergo risk stratification and management according to their risk for clinical tumor lysis syndrome. • Laboratory tumor lysis syndrome is defined as the presence of two or more of the following abnormalities present on the same day: hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia because of hyperphosphatemia. • Clinical tumor lysis syndrome is defined as laboratory tumor lysis syndrome plus acute kidney injury, symptomatic hyperkalemia, or symptomatic hypocalcemia. It should be prevented whenever possible. • Risk factors for clinical tumor lysis syndrome include a large cancer cell mass, high cell lysis potential (chemosensitivity), unmodifiable

patient factors (e.g., preexisting nephropathy, gout), modifiable presenting features (e.g., dehydration, acidosis, hypotension, recent nephrotoxin exposure, hyperuricemia), and supportive care (risk-stratified management that includes hydration, removal of uric acid, and reduction of phosphorus and potassium). Appropriate risk-adapted supportive care prevents acute kidney injury, renal failure, and death, even for patients at high a priori risk. • Management depends on the risk of clinical tumor lysis syndrome: ○ Negligible risk—no prophylaxis, no monitoring ○ Low risk (1% risk for clinical tumor lysis syndrome)—hyperhydration, avoid dietary or intravenous potassium and phosphorus, daily laboratory evaluation ○ Intermediate risk (2%–5% risk for clinical tumor lysis

DEFINITION AND EPIDEMIOLOGY Tumor lysis syndrome is a potentially fatal metabolic condition that occurs most frequently in patients with rapidly proliferating, bulky, chemosensitive tumors (Table 36.1).1 In the past, it was most commonly reported in patients with high-grade non-Hodgkin lymphoma (NHL) and acute leukemias, but it can occur in persons with virtually any type of cancer when a large cancer cell mass is present and the cancer is sensitive to initial therapy. Indeed, as extremely effective new therapies have become available for a variety of cancers, tumor lysis syndrome has become more common. For example, 70% of drugs approved in the past 5 years for management of hematologic malignancies now include warnings about tumor lysis syndrome in their package inserts, and in some cases the dose-limiting toxicity in phase I studies was tumor lysis syndrome, which demonstrates the high cell lysis potential that results from use of extremely effective anticancer therapies.2–10 The 2017 National Comprehensive Cancer Network (NCCN) guidelines highlight the increasing incidence and importance of tumor lysis syndrome by including recommendations for tumor lysis syndrome prevention and management in the NCCN guidelines for acute lymphoblastic leukemia (ALL), NHL, and chronic lymphocytic leukemia (CLL).11 Indeed, there is even a special section devoted to tumor lysis syndrome prophylaxis and monitoring for CLL patients 572

syndrome)—hyperhydration, avoid dietary or intravenous potassium and phosphorus, rasburicase, laboratory evaluation every 8 to 12 hours ○ High risk (>5% risk for clinical tumor lysis syndrome)— hyperhydration, avoid dietary or intravenous potassium and phosphorus, rasburicase, cardiac monitoring on the inpatient ward, laboratory evaluation every 6 to 8 hours, and rapid access to hemodialysis ○ Established clinical tumor lysis syndrome at presentation— hyperhydration, avoid dietary or intravenous potassium and phosphorus, rasburicase, cardiac monitoring in the intensive care unit, laboratory evaluation every 4 to 6 hours, and rapid access to hemodialysis

treated with venetoclax, which illustrates the increasing importance of early supportive care for patients treated with highly effective new therapies, and represents the first time a tumor lysis syndrome guideline has been developed for a specific drug and disease pair. Ibrutinib has also been associated with tumor lysis syndrome in patients with CLL.9 In many hematologic cancers, such as multiple myeloma and diffuse large B-cell lymphoma, the evolution of tumor lysis syndrome risk parallels that of CLL: as new highly active therapies are developed, patients experience improved event-free survival, but also face increased tumor lysis syndrome risk during the first week of therapy.2,10,12

ETIOLOGY AND PATHOGENESIS Tumor lysis syndrome occurs most commonly after treatment with cytotoxic therapy but can occur spontaneously in patients with highly proliferative tumors. By releasing tumor cellular components into the bloodstream, tumor lysis syndrome results in metabolic abnormalities including hyperphosphatemia, hyperkalemia, hypocalcemia, hyperuricemia, and azotemia (Fig. 36.1). Acute kidney injury, seizures, cardiac arrhythmias, nausea, and vomiting may occur because of these metabolic abnormalities. To reduce morbidity and mortality, early diagnosis and identification of patients at risk for tumor lysis syndrome are of the utmost importance.1,13 As cancer cells lyse, their DNA is

Tumor Lysis Syndrome  •  CHAPTER 36 573

Table 36.1  Classification of Tumor Lysis Syndrome1 Laboratory tumor lysis syndrome

Two or more of the metabolic abnormalities in the next column present on the same day Occurring within 3 days before initiation of therapy or 7 days after initiation of therapy Assumes the patient receives adequate hydration and a hypouricemic agent

Clinical tumor lysis syndrome

Laboratory tumor lysis syndrome plus any of the criteria in the next column (not attributable to other causes)

Uric acid ≥476 µmol/L (8 mg/dL) in adults or the upper limits of normal in children Potassium ≥6.0 mmol/L Phosphorus ≥1.5 mmol/L (4.5 mg/dL) in adults or ≥2.1 mmol/L (6.5 mg/dL) in children Calcium ≤1.75 mmol/L (7 mg/dL) or ionized calcium <1.2 mmol/L (4.5 mg/dL) Acute kidney injury, defined as an increase in creatinine of 26.5 µmol /L (0.3 mg/dL) or when no baseline creatinine is documented, a single value ≥1.5 times the upper limits of normal for the patient’s age and sex Symptomatic hypocalcemia (e.g., tetany or paresthesias), seizure, cardiac dysrhythmia, or sudden death attributed to hypocalcemia or hyperkalemia

Lysis of cancer cells with release of intracellular contents

DNA

Phosphate

Potassium

Cytokines

DNAase breaks down DNA, releasing purines

Adenosine

Guanosine

Inosine

Guanine

Hypotension

Inflammation

Acute kidney injury

Hypoxanthine Xanthine oxidase

Allopurinol

Xanthine Xanthine oxidase

Allantoin

No tumor lysis syndrome

Rasburicase

Uric acid

Phosphate

Urinary excretion

Potassium

Accumulation

Tumor lysis syndrome

Figure 36.1  •  Pathophysiology of tumor lysis syndrome. Lysis of cancer cells releases DNA, phosphate, potassium, and cytokines. DNA released from the lysed cells is metabolized into adenosine and guanosine, both of which are converted into xanthine. Xanthine is then oxidized by xanthine oxidase, leading to the production of uric acid, which is excreted by the kidneys. When the accumulation of phosphate, potassium, xanthine, or uric acid is more rapid than excretion, tumor lysis syndrome develops. Cytokines cause hypotension, inflammation, and acute kidney injury, which increase the risk for tumor lysis syndrome. The bidirectional dashed line between acute kidney injury and tumor lysis syndrome indicates that acute kidney injury increases the risk of tumor lysis syndrome by reducing the ability of the kidneys to excrete uric acid, xanthine, phosphate, and potassium. By the same token, development of tumor lysis syndrome can cause acute kidney injury by renal precipitation of uric acid, xanthine, and calcium phosphate crystals and by crystal-independent mechanisms. Allopurinol inhibits xanthine oxidase and prevents the conversion of hypoxanthine and xanthine into uric acid but does not remove existing uric acid. In contrast, rasburicase removes uric acid by enzymatically degrading it into allantoin, a highly soluble product that has no known adverse effects on health.1

broken down into pyrimidines and purines, which are metabolized into uric acid. Purines are first degraded into hypoxanthine, then xanthine, and finally into uric acid through the action of xanthine oxidase (see Fig. 36.1).1 Hyperuricemia leads to the deposition of uric acid crystals in the renal tubules because of the poor solubility of uric acid and can result in acute kidney injury (Fig. 36.2). Hyperphosphatemia can also cause acute kidney injury. Phosphate combines with calcium, generating calcium phosphate salts that deposit in the renal tubules and other soft tissues, including the conducting system of the heart. The binding of calcium by phosphate leads to hypocalcemia, which in turn can cause vomiting, muscle cramps, tetany, paresthesias, seizures, and cardiac dysrhythmias. Hyperkalemia from cellular lysis can lead to cardiac dysrhythmias, ventricular tachycardia,

fibrillations, or cardiac arrest.1 In most cases, appropriate prophylaxis and management prevents these complications.

RISK STRATIFICATION FOR CLINICAL TUMOR LYSIS SYNDROME Prophylaxis and management of patients at risk for tumor lysis syndrome depend heavily on the risk group assignment. Numerous risk factors for tumor lysis syndrome can be classified into cancer factors (cancer bulk and cell lysis potential), unmodifiable patient factors (e.g., nephropathy, hypertension, diabetes, gout), and modifiable presenting features (e.g., recent nephrotoxin exposure, dehydration, hypotension, acidosis, hyperuricemia).7 Certain tumor types have historically been

574 Part II: Problems Common to Cancer and Therapy

associated with an increased risk for the development of tumor lysis syndrome, including ALL, acute myeloid leukemia (AML), and NHL (particularly Burkitt lymphoma); patients with these tumor types were the most frequently enrolled in trials of uricases.14 However, tumor lysis syndrome can develop in any patient with chemosensitive disease. Acute leukemias and high-grade lymphomas often have a high proliferative rate and a large tumor burden and are particularly sensitive to chemotherapy; the combination of large cancer bulk and high sensitivity to therapy (cell lysis potential) makes tumor lysis syndrome more

Solubility (mg/dL)

1000

100

10

1 4.5

5

5.5

Allantoin Hypoxanthine

6 6.5 Urine pH Uric acid Calcium phosphate

7

7.5

Xanthine

Figure 36.2  •  Solubility of purine metabolites by urine pH. Uric acid

solubility depends on pH. As urine pH rises from 5 to 7, the solubility increases 25-fold, from 8 mg/dL to 200 mg/dL. This increased uric acid solubility and consequent decreased risk of crystal formation and acute kidney injury is the reason urine alkalinization was standard for patients at risk for tumor lysis syndrome before the advent of rasburicase. In contrast to uric acid, calcium phosphate becomes less soluble and more likely to crystallize as urine pH increases. Xanthine has low solubility and hypoxanthine relatively high solubility, regardless of urine pH. Note that the scale is logarithmic.1

likely (Figs. 36.3, 36.4, and 36.5). Furthermore, the proportion of cancer cells exposed to initial chemotherapy is very high in these cancers, compared with a large solid tumor mass with areas of hypoxia and poor perfusion that may not be accessible at the onset of therapy. In the current risk stratification system, all cancer-related risk factors are reduced to two: cancer bulk and cell lysis potential.

Risk Stratification—Cancer Factors Cell lysis potential includes the biology of the cancer and the efficacy of the treatment and therefore is expected to increase as more effective treatments and therapeutic combinations are developed. Rather than attempt to provide specific guidance for each combination of disease and therapy, as the NCCN has done for venetoclax for CLL, the clinician is expected to assess the likely efficacy of the therapy in the specific patient, considering the response of similar patients in published trials, the number of prior regimens that have failed in the patient, and other factors that could affect the rapidity of tumor lysis. Lactate dehydrogenase (LDH) has been included in many tumor lysis syndrome risk stratification schemes and indicates higher cell lysis potential, because cancers undergoing spontaneous cell turnover are more likely to lyse briskly when therapy is initiated. Any new agents or combinations for which published experience is limited should be assumed to have high lysis potential. Estimating cancer bulk causes confusion for clinicians, and inaccurate bulk assessment can lead to undertreatment or overtreatment for tumor lysis syndrome. Many previous risk stratification schemes have included risk factors related to cancer bulk, such as the white blood cell count for patients with acute leukemia, the greatest diameter of masses or lymph nodes, organomegaly, bone marrow involvement, and LDH. Fig. 36.3 shows the typical ellipsoid shape of a mediastinal mass in a patient with NHL and provides the formula for calculating the volume of ellipsoid masses. However, such calculations are timeconsuming and unlikely to be used by busy clinicians whose patient needs prompt initiation of therapy, so Fig. 36.4 provides a table for rapid estimation of the bulk of tumor masses or lymph nodes. Each mass or node contributes “bulk points” according to its volume, and these bulk points are added to those from other sites of disease, including bone marrow, spleen, liver, and kidneys. Because the specific gravity

Figure 36.3  •  Volume of tumors with ellipsoid shapes. The volume of tumors and lymph nodes with ellipsoid shapes can be approximated by this formula: Volume = π (Length × Width × Height)/6. Note that for spheres this formula reduces to Volume = 4 3 π (radius)3. (Used with permission of Scott C. Howard, MD.)

Tumor Lysis Syndrome  •  CHAPTER 36 575

Site

Low bulk (0 bulk points)

Tumor masses or lymph nodes

No tumors or nodes >4 cm in largest diameter

Intermediate bulk

High bulk

Use the Tumor Bulk Score Table to calculate the mass of each lesion with longest diameter >4 cm. Add the bulk points for all sites of disease. 1 bulk point for every 10% marrow infiltration (e.g., 60% infiltration = 6 bulk points)

Bone marrow

Uninvolved

Spleen

Normal

Moderate splenomegaly — palpable but <5 cm below the costal margin (2 bulk points)

Massive splenomegaly — palpable ≥5 cm below the costal margin (4 bulk points)

Normal

Moderate hepatomegaly — palpable but <5 cm below the costal margin (3 bulk points)

Massive hepatomegaly — palpable but <5 cm below the costal margin (5 bulk points)

Mild to moderate nephromegaly visible by imaging (1 bulk point)

Significant nephromegaly visible by imaging (3 bulk points)

Liver

Kidneys

Normal kidneys

Short axis

Long axis

5 6 7 8 9 10 11 12 13

4 1 1 1 1 1 1 2 2 3

5 1 1 1 1 2 2 2 3 4

6

7

8

9

10

1 1 2 2 3 3 4 4

2 2 3 3 4 4 5

3 3 4 4 5 5

4 4 5 5 5

5 5 5 5

Figure 36.4  •  Rapid assessment of cancer bulk using the bulk score of each site of involvement. When estimating cancer bulk for tumor lysis syndrome management, time-consuming exact measurements of each tumor and lymph node are not necessary. Instead, a rapid estimation of bulk is possible with use of a cancer bulk score, in which each “bulk point” represents approximately 100 g of cancer mass. For tumor masses and lymph nodes with ellipsoid shapes, the bulk points can be obtained from the table through use of the shortest and longest axes of the mass. Note that the bone marrow is a very large organ, with a mass of about 1400 g in an average adult. However, the bone marrow rarely contains 100% cancer cells, even in acute leukemias. The bone marrow’s contribution to cancer bulk can be estimated by assigning 1 bulk point for every 10% of marrow infiltration. (Used with permission of Scott C. Howard, MD.)

of most tissues is 1 to 1.1, the volume is a very good surrogate for mass (1 mL of tumor has a mass of 1 g), and the two are used interchangeably here. The volume of leukemia in the blood contributes modestly to cancer bulk, especially in AML, where a white blood cell count of 200,000 cells/mm3 represents 400 g of cancer (assuming that 100% of white cells are circulating blasts); the clinical observation that patients with hyperleukocytosis have a high tumor lysis syndrome risk stems from the fact that such patients have a very high percentage of the bone marrow replaced with leukemia and often have organomegaly from leukemic infiltration of spleen, liver, and kidney. The bone marrow is a large organ (1400 g in adults), so replacement of even 10% of the marrow represents at least 100 g of cancer cells (one bulk point); the percentage of marrow replacement is now included in the bulk scoring system (see Fig. 36.4). The spleen represents a site of bulky disease and can increase from a mean mass of 254 g to more than a kilogram in patients with hematologic cancers. When it is palpable 5 cm or more below the costal margin, it likely contains at least 400 g of tumor, so it gets a bulk score of 4 (see Fig. 36.4).15 Finally, specific cytotoxic agents have been associated with tumor lysis syndrome in particular diseases, such as fludarabine, bendamustine, lenalidomide, ibrutinib, and venetoclax in patients treated for CLL.8,9,16–19 Because the risk of clinical tumor lysis syndrome is

proportional to the rapidity of response to therapy, patients whose tumors respond quickly to a new therapeutic agent have an increased risk for the development of tumor lysis syndrome. Patients with diagnoses not typically associated with tumor lysis syndrome (e.g., metastatic colon cancer) can also be affected by tumor lysis syndrome when the treatment includes highly active agents, such as cetuximab or regorafenib.20,21 Successful management of tumor lysis syndrome requires identification of patients at risk and prevention tailored to the risk group, as described in the next section.1

Risk Stratification—Patient and Presenting Factors Cancer factors are essential when assessing tumor lysis syndrome risk, but patient and presenting factors are equally important. They include generally unmodifiable patient factors such as preexisting nephropathy, hypertension, diabetes, and gout and potentially modifiable presenting features such as hyperuricemia, dehydration, decreased urine output, hypotension, and recent nephrotoxin exposure.22 Modifiable presenting features should be addressed to the extent possible as soon as the patient is seen, and hypovolemic patients should receive consecutive normal saline boluses of 20 mL/kg of body weight until euvolemic and with good urine output, followed by hyperhydration thereafter.1

576 Part II: Problems Common to Cancer and Therapy

Cancer cell lysis potential Cancer bulk

Low

Intermediate

High

Very small (<100 g)

Negligible risk

Negligible risk

Low risk

Small (100–249 g)

Negligible risk

Low risk

Intermediate risk

Medium (250–499 g)

Low risk

Intermediate risk

High risk

Large (500–999 g)

Low risk

High risk

High risk

Very large (≥1000 g)

Intermediate risk

High risk

High risk

Figure 36.5  •  Risk of clinical tumor lysis syndrome based on cancer bulk and cancer cell lysis potential. After the bulk points from all sites of cancer are

added up, the total cancer bulk can be combined with the cancer cell lysis potential in order to assign a tumor lysis syndrome risk category. Estimating cancer bulk is an objective process based on the volume of cancer at each site of disease (see Fig. 36.4). By contrast, the cancer cell lysis potential depends on the chemosensitivity of the cancer, the dose and schedule of initial therapy, agents used in combination, and possibly other factors, including the accessibility of the cancer cells to initial therapy, which is greater for leukemias and perhaps less for heterogeneous large solid tumors with areas of poor vascularity. Clinicians must use their best judgment and, when in doubt, err on the side of the higher risk category. (Used with permission of Scott C. Howard, MD.)

PREVENTION AND MANAGEMENT OF TUMOR LYSIS SYNDROME Published guidelines for the diagnosis, prevention, and management of tumor lysis syndrome differ in their details, but all agree that patients at risk for tumor lysis syndrome should undergo risk stratification and management on the basis of their risk. Clinical tumor lysis syndrome is the outcome that should be prevented, because by definition it is associated with morbidity. Standard prophylaxis includes close monitoring; hyperhydration to increase urine output and facilitate renal excretion of uric acid and phosphorus; administration of a hypouricemic agent, such as allopurinol or rasburicase, to prevent the formation of uric acid crystals in the kidney; and administration of phosphate binders to reduce calcium phosphate precipitation in the kidneys.1,13 All patients at intermediate or high risk for clinical tumor lysis syndrome should receive hyperhydration with intravenous fluids at 2500 mL/m2/day (or higher) to achieve very high urine output (at minimum 100 mL/h) and reduce the risk of uric acid and calciumphosphate precipitation in renal tubules. If urine output is inadequate even after hyperhydration of if fluid overload develops, a diuretic may be added to increase urine output, but only after the patient is very well hydrated.1 Patients at intermediate risk should be monitored with serum electrolytes and uric acid measurement every 8 to 12 hours, and those at high risk should be monitored in the hospital with serum electrolytes and uric acid measurement every 4 to 6 hours. Patients with tumor lysis syndrome should be connected to a cardiac monitor and observed in an intensive care or step-down unit. Frequent reassessment allows prompt intervention if new risk factors or complications develop. Indeed, the most important determinant of outcome is not the risk group, but the supportive care provided, and without it even patients with colon cancer can die from tumor lysis syndrome.21

Prephase Prevention of tumor lysis syndrome by hydration, avoidance of dietary potassium and phosphorus, and reduction of uric acid

remains the mainstay of early supportive care, but adjustments in initial chemotherapy can also reduce the risk by decreasing the cell lysis potential and slowing the rate of tumor destruction. Patients with ALL often receive a week of prednisone monotherapy, which allows gradual cytoreduction with reduced tumor lysis syndrome risk, similar to the COP (cyclophosphamide, vincristine, prednisone) prophase used for up-front therapy of high-grade B-cell lymphomas, and hydroxyurea for AML patients with hyperleukocytosis or other sites of bulky disease. After tumor lysis syndrome–associated mortality in the phase I study of venetoclax for CLL, the regimen for the initial doses was adjusted to reduce tumor lysis syndrome risk by starting with a weekly dose of 20 mg and increasing gradually to 400 mg over a period of 5 weeks.8

Urine Alkalinization Is Not Warranted in Countries With Access to Rasburicase Historically, urine has been alkalinized by the administration of bicarbonate to improve the solubility of uric acid (see Fig. 36.2); however, this step is not currently recommended, because the solubility of calcium phosphate decreases at higher pH values (see Fig. 36.2), and therefore precipitation in the renal tubules may be exacerbated.1 In countries in which rasburicase is available for prophylactic administration, rapid uric acid level reduction makes alkalinization unnecessary; if the urine is left acidic, calcium phosphate solubility can be preserved, with a corresponding decreased risk of calcium phosphate crystallization (see Fig. 36.2).

Reducing Uric Acid Improves Outcomes Despite optimal hydration, control of phosphorus and potassium, and use of a prophase, uric acid can still cause considerable kidney damage and lead to dialysis and death. Allopurinol, febuxostat, and rasburicase have all been used to reduce uric acid in patients at risk for tumor lysis syndrome.

Tumor Lysis Syndrome  •  CHAPTER 36 577

Allopurinol and Xanthine Production Allopurinol inhibits xanthine oxidase and prevents metabolism of hypoxanthine and xanthine into uric acid, thus reducing the formation of uric acid before the initiation of chemotherapy (see Fig. 36.3).23–26 Allopurinol’s limitations include delayed onset of action (2–3 days), which may delay initiation of cytotoxic therapy; failure to remove existing uric acid, which can continue to cause kidney injury in patients with significant hyperuricemia; and increased xanthine concentrations in the urine, which can cause xanthine crystal formation and nephropathy.27 Hande and colleagues28 examined purine excretion in 11 patients with bulky lymphomas who received allopurinol 2 to 5 days before chemotherapy. Although urinary concentrations of uric acid and hypoxanthine remained below the limits of solubility in all patients, concentrations of xanthine exceeded solubility in six patients (55%), which indicates that xanthine crystallization was occurring. In 19 children with ALL who received allopurinol for the prevention of tumor lysis syndrome before starting chemotherapy, xanthine concentrations exceeded urine solubility in 16 (84%).29 Because xanthine is rarely measured, its contribution to acute kidney injury in tumor lysis syndrome remains unknown. However, its low solubility at any urine pH and high concentrations in the urine of patients treated with allopurinol suggest that xanthine nephropathy may occur commonly in patients with a high cancer cell mass, who produce large amounts of purines after initiation of chemotherapy.

Febuxostat For years, allopurinol and rasburicase have been used to reduce the incidence of tumor lysis syndrome in pediatric and adult patients. In patients with intermediate to high tumor lysis syndrome risk, febuxostat, a potent xanthine oxidase inhibitor, proved noninferior at a dose of 60 mg/day to allopurinol (at a dose of 200–300 mg/day), and febuxostat 120 mg/day lowered uric acid more effectively than allopurinol at clinician-selected doses of 200, 300, or 600 mg/day.1,24,30 Unfortunately, febuxostat has the same disadvantage that allopurinol has when used for tumor lysis syndrome management: it blocks metabolism of xanthine to uric acid and leads to accumulation of xanthine, which can crystallize and cause acute kidney injury.31,32

Rasburicase Rasburicase converts uric acid into allantoin, a highly soluble metabolite that is excreted by the kidneys (see the green line in Fig. 36.2). Unlike most other mammals, humans lack a functional urate oxidase enzyme because of a nonsense mutation in the genetic sequence. Rasburicase lowers serum uric acid levels quickly and has few adverse effects (see Fig. 36.1).1,25,33 However, rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency because of the high risk of the development of methemoglobinemia and hemolytic anemia after administration of these agents, because of the breakdown of uric acid into hydrogen peroxide.1 In adults with high-risk for tumor lysis syndrome, even rasburicase cannot fully prevent morbidity. For example, in 755 patients with NHL or acute leukemia at high risk for tumor lysis syndrome who received rasburicase for prevention or treatment of tumor lysis syndrome, a 5.3% incidence of tumor lysis syndrome (including both laboratory and clinical tumor lysis syndrome) was documented.34 Seven patients in this study died from tumor lysis syndrome (0.9% of all patients and 17.5% of patients with tumor lysis syndrome). In a multinational study of 235 pediatric patients with advanced-stage B-cell NHL treated with the same chemotherapy protocol, all US patients received allopurinol (because rasburicase was not yet available in the country); 27% experienced tumor lysis syndrome and 15% required dialysis. By contrast, all French patients received rasburicase; 11% experienced tumor lysis syndrome, and only 3% required dialysis.35 Hence, the risk for tumor lysis syndrome depends not only on tumor-related risk

factors but also on the supportive care used (Figs. 36.1, 36.6, and 36.7). A randomized trial of tumor lysis syndrome prevention in 280 adults documented a 49% reduction in laboratory tumor lysis syndrome (P < .05) but no change in clinical tumor lysis syndrome, which occurred in 3% to 4% of each group.25 Finally, a Cochrane review pooled results from six clinical trials in pediatrics and found that rasburicase reduced death from tumor lysis syndrome by 95% (P = .04) and the need for renal replacement therapy by 74% (P = .03).36 Not only do patients at high risk for clinical tumor lysis syndrome who receive rasburicase have a rapid decrease in uric acid, but their glomerular filtration rate improves, and they rarely (only 1.3% of the time) require renal replacement therapy.37,38 In patients with tumor lysis syndrome, rasburicase reduces length of hospital stay, length of intensive care unit stay, and costs.23 Although initially approved for 5 days of consecutive use, one randomized trial compared a single dose with subsequent administration as needed versus five daily doses and found that a single dose was adequate to control uric acid in 99% of patients, and that 85% (34 of 40) did not require a second dose.33 Similarly, in children with bulky NHL or neuroblastoma, 15 of 19 (79%) required only a single dose of rasburicase (0.2 mg/kg) to control uric acid levels and prevent acute kidney injury.38 To reduce costs, some clinicians administer lower doses of rasburicase than the 0.15 to 0.2 mg/kg approved by the US Food and Drug Administration (FDA), in the hope that the lower dose will effectively prevent or manage tumor lysis syndrome. The single-dose and repeatas-needed strategy differs from a reduced-dose strategy, in which small doses of rasburicase are given and uric acid and patient status are monitored carefully to determine which individuals require repeat doses of rasburicase. A systematic review concluded that a 6-mg fixed dose and a 0.15 mg/kg weight-based dose were sufficient to control uric acid initially, but that patients must be monitored and doses repeated as needed.39 Furthermore, clinicians must carefully evaluate nonrandomized studies espousing the benefits of reduced-dose rasburicase to contextualize the findings. For example, Lee and colleagues40 used a 4.5-mg fixed dose to treat three children with ALL. All three patients had a rapid reduction in uric acid, but when the weight-adjusted dose was determined for the 4.5-mg dose, it was found that one patient received a higher quantity than the FDA-approved dose (0.26 mg/kg), one patient received the approved dose (0.17 mg/kg), and one patient received 50% of the approved dose (0.08 mg/kg). This series was in fact a report of two patients treated with a standard dose of rasburicase and one with a reduced dose. Another case series examined 11 adults with hematologic malignancies who were at risk for tumor lysis syndrome.41 Eight patients had renal impairment from tumor lysis syndrome at the time of presentation, and all were treated with a 6-mg single dose of rasburicase (corresponding to a median weight-based dose of 0.08 mg/kg). In 10 of the 11 patients, single-dose rasburicase lowered and maintained normal uric acid levels. One morbidly obese patient required a second dose of rasburicase (12 mg; 0.046 mg/kg, based on actual body weight) to control his uric acid levels. Among the eight patients with renal impairment, three had a return to baseline renal function after receiving rasburicase, one required hemodialysis, and four had no subsequent renal function data reported. The authors concluded that use of a fixed 6-mg dose of rasburicase appeared to be safe and effective, but the fact that one patient required a large second dose and one required dialysis implies inadequate uric acid control, especially when compared with the 98% to 100% efficacy reported in large studies using the FDA-approved dose.11 In resource-limited settings, rasburicase at a lower dose could allow more widespread use. A cohort of patients in India was treated with a mean rasburicase dose of 0.085 mg/kg and hyperuricemia resolved without the need for hemodialysis in 16 of 18 children (89%).42 A fixed rasburicase dose of 3 mg, with repeated doses as needed based on subsequent uric acid levels, was administered to 43 adult patients undergoing stem cell transplantation (51%) or receiving chemotherapy (49%).43 The total doses of rasburicase administered were 3 mg (n =

578 Part II: Problems Common to Cancer and Therapy

Make a histologic diagnosis Select front-line therapy

Cancer factors Tumor bulk (Fig. 36.4) Cell lysis potential*

Stratify clinical TLS risk

Low risk

Negligible risk

Intermediate risk

Patient factors Nephropathy Hypertension Diabetes Gout

High risk

Presenting features Nephrotoxins Dehydration Hypotension Acidosis

Established TLS

Consider reduced intensity initial therapy (prednisone prephase for ALL, COP for Burkitt lymphoma)

Initiate therapy as originally planned Manage TLS prophylaxis according to risk group

*Cell lysis potential is based on expected response to the planned front-line regimen

Monitor for changes that indicate increased TLS risk

Figure 36.6  •  Tumor lysis syndrome (TLS) risk stratification and initial management. Like risk assessment for deep vein thrombosis in hospitalized patients, the process of tumor lysis syndrome risk stratification is dynamic and can change as the patient’s condition changes. This algorithm begins with a histologic diagnosis and risk stratification based on cancer factors (cancer bulk, cell lysis potential), patient factors that are not modifiable (nephropathy, hypertension, diabetes, gout), and presenting features that are potentially modifiable (recent nephrotoxin exposure, dehydration, hypotension, acidosis). Even while the diagnostic evaluation is underway and tumor lysis syndrome risk is being assessed, the modifiable presenting features can be addressed with boluses of intravenous fluid, correction of hypotension and acidosis, and routine supportive care. Patients at high risk or who already have tumor lysis syndrome at presentation may benefit from a modified initial therapy to facilitate gradual cytoreduction with a slower rate of release of cellular contents. ALL, Acute lymphoblastic leukemia; COP, cyclophosphamide, vincristine, prednisone. (Used with permission of Scott C. Howard, MD.)

8 Allopurinol AUC0-96hr = 329 ± 129 mg/dL/h Rasburicase AUC0-96hr = 128 ± 70 mg/dL/h

Uric acid (mg/dL)

7 6 5 4 3

P < .0001

2 1 0 0

4

Allopurinol 25 Rasburicase 27

12

24

36

48 60 Time (h)

72

25 25 24 27 27 26 Number of samples at each time point

84

96 22 25

Figure 36.7  •  Uric acid levels during the first 4 days of treatment in patients at risk for tumor lysis syndrome who were randomly assigned to receive rasburicase versus allopurinol. Rasburicase was associated with a rapid decrease in uric acid and a corresponding lower area under the concentrationtime curve for uric acid, as measured during the first 4 days of therapy (128 ± 70 versus 329 ± 129 mg/dL/h, P < .0001).45

37), 4.5 mg (n = 2), or 6 mg (n = 4), and uric acid levels were all within normal limits 48 hours after the first dose. Although three patients were already receiving dialysis at the time of the study, no additional patients required dialysis. What is not clear from this study is whether the patients were at risk for tumor lysis syndrome. Many patients undergoing stem cell transplantation already have a low bulk

of disease and would not be expected to have tumor lysis syndrome, and the disease status of the patients in the study cohort was not described. Another cohort in which use of a reduced dose of rasburicase was evaluated included 46 adults with hematologic cancers and four with solid tumors.44 Patients were eligible to receive rasburicase if they had bulky disease, an elevated white blood cell count, elevated LDH in addition to elevated uric acid, or a history of tumor lysis syndrome after a prior course of chemotherapy. Rasburicase dosing was at the discretion of the treating clinician, and the initial dose ranged from 1.5 to 16.5 mg. Nine patients had uric acid levels above the normal range after the initial rasburicase dose, despite a mean decrease of 41% from their baseline levels. Because of the heterogeneous cohort of patients (diagnoses included ALL, AML, CLL, myeloma, solid tumors, and both high- and low-grade lymphomas) and the wide range of rasburicase doses used, it is difficult to derive specific treatment recommendations from the data presented. However, the results do suggest that use of doses of rasburicase that are lower than recommended may be effective for some patients, which is concordant with a retrospective study of 247 adults with hematologic cancers who were treated with rasburicase 3 mg. Of those with initial uric acid higher than 12 mg/dL, the failure rate was 84%, compared with a failure rate of 18% in patients with lower initial uric acid.43 The use of reduced doses of rasburicase should be studied in defined cohorts of patients at an intermediate risk for the development of clinical tumor lysis syndrome to determine the optimal dose (i.e., the dose at which no patient experiences acute kidney injury or clinical tumor lysis syndrome and at which the least amount of rasburicase is used). In patients receiving low-dose rasburicase to prevent tumor lysis syndrome, serum uric acid levels must be measured precisely. Blood samples must be collected into chilled tubes, placed on ice immediately, and assayed promptly to avoid ex vivo breakdown of uric acid by rasburicase, which produces artificially low levels of uric acid.

Tumor Lysis Syndrome  •  CHAPTER 36 579

Although the optimal treatment for patients at intermediate risk for clinical tumor lysis syndrome has not been determined by randomized clinical trials, a prudent approach at present is the administration of one standard dose of rasburicase (0.15–0.2 mg/kg), especially if hyperuricemia or laboratory tumor lysis syndrome develops. Patients at high risk for the development of tumor lysis syndrome should receive at least one standard dose of rasburicase. Repeat doses of rasburicase should be given only to patients whose uric acid levels increase after the first dose, and all patients with laboratory tumor lysis syndrome should receive at least one standard dose of rasburicase (0.15–0.2 mg/ kg) to prevent progression to clinical tumor lysis syndrome.

CONCLUSIONS Appropriate management of tumor lysis syndrome includes risk stratification of all patients, hydration, careful monitoring of serum metabolite levels, administration of rasburicase for patients at intermediate or high risk, and administration of allopurinol for patients at low risk of clinical tumor lysis syndrome. Hyperuricemia and hyperphosphatemia should be prevented and treated promptly when they do occur, because their deposition in the renal tubules can cause acute kidney injury. Risk-stratified management prevents seizures, cardiac dysrhythmia, acute kidney injury, the need for dialysis, and death.

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