Key Clinical Questions
Introduction
Tumor Lysis Syndrome
A 30-year-old Caucasian man developed lethargy and nausea. He recently started chemotherapy for Burkitt lymphoma. He was mildly tachycardic, afebrile, and had a large, easily palpable abdominal mass. In addition to anemia and thrombocytopenia, the blood work was notable for potassium of 5.8 mmol/L and creatinine of 3.9 mg/dL (350 umol/L). The nurse reported that he had produced only 200 mL of urine in the previous 8 hours. What other blood tests should be ordered? What measures can be taken to prevent permanent renal failure? The serum uric acid was 15.6 mg/dL (925 mmol/L), the phosphate is 7.9 mg/dL (2.57 mmol/L), and the calcium was 7.88 mg/dL (1.97 mmol/L). Urinalysis showed marked uric acid crystals. The electrocardiogram was essentially normal. Glucose, insulin and Kayexalate for the hyperkalemia, normal saline 200 mL/h, aluminum hydroxide 60 mL four time a day, and rasburicase 0.2 mg/kg intravenously was administered. A Foley catheter was inserted and the patient was monitored closely for signs of fluid overload. Serum electrolytes and renal function were checked every four hours overnight, and the covering physician alerted the nephrologist and the patient’s treating hematologist to the situation. |
A 56-year-old woman presented to the emergency room for five days of progressive shortness of breath and headache, for which she took aspirin. Her oxygen saturation was 87% on room air, and she was tachycardic, mildly hypotensive, and febrile. Her examiners noted a palpable spleen 4 cm below the costal margin, lower extremities covered in petechia, and engored retinal veins. They did not identify focal neurologic deficits. Her white count was 135 × 109/L with large, monocytic-appearing blasts on the peripheral blood film, hematocrit 22%, and platelet count 18 × 109/L. Her chemistry profile revealed hyperkalemia, a creatinine double her baseline, a uric acid level of 17 mg/dL, and an INR of 1.5. Her chest X-ray showed diffuse bilateral infiltrates. Physician orders includec hydroxyurea 3 g orally stat, then 2 g every 8 hours, a platelet transfusion, normal saline at 125 mL/hour (2 L/m2/day), continuously monitoring O2 saturation, treatment of the hyperkalemia, and ceftazidime and rasburicase. Unfortunately, while her physicians were arranging transfer to a tertiary care hospital, the patient’s level of consciousness deteriorated. A stat brain CT showed a large parietal hemorrhage with midline shift and herniation. The patient was immediately intubated, but the neurosurgeon concluded that surgical intervention would be futile. Two days later, her family elected to withdraw ventilator support and she passed away in the intensive care unit. |
Tumor lysis syndrome (TLS) may occur spontaneously or upon initiation of treatment for hematologic malignancies with high proliferation rates or large tumor burden (as reflected in high lactate dehydrogenase [LDH]), or exquisite sensitivity to chemotherapy, radiation, glucocorticoids, or cytotoxic antibodies. TLS usually occurs within 12 to 72 hours of initiating cytotoxic treatment. Burkitt lymphoma and acute lymphoblastic leukemia (ALL) account for the majority of cases, but TLS is observed frequently with acute myeloid leukemia (AML), aggressive lymphomas like diffuse large B-cell lymphoma (DLBCL) or extensive mantle cell lymphoma, and some newer regimens for chronic lymphocytic leukemia (CLL). Massive tumor lysis releases potassium, phosphate, and nucleic acids in the circulation. Purines are catabolized to uric acid, which may precipitate in renal tubules and lead to acute renal failure.
It is better to institute preventive measures rather than wait for overt TLS to develop. In patients with spontaneous TLS, it is preferable to defer cytotoxic therapy for a couple days, if possible, until the patient is prehydrated and metabolic derangements are controlled.
Either allopurinol or rasburicase may prevent hyperuricemia. Allopurinol inhibits urate production by blocking xanthine oxidase. Uric acid and, to a lesser degree, xanthine solubility is higher in alkaline urine, so urine alkalinization was traditionally attempted when employing allopurinol to reduce precipitation of uric acid and xanthine crystals in the renal tubules, but is no longer recommended (discussed in more detail later in this chapter). Allopurinol does not decrease already-formed uric acid and takes several days to meaningfully decrease hyperuricemia. Rasburicase is a recombinant urate oxidase enzyme that catalyses the conversion of uric acid to allantoin, an inactive metabolite of purine metabolism; allantoin is 5 to 10 times more soluble than uric acid, so its renal excretion is more effective. Rasburicase is effective within four hours of administration and is the treatment of choice in patients with marked hyperuricemia (> 450 umol/L or > 7.5 mg/dL) or in patients deemed at high risk for TLS. Note that rasburicase continues to degrade uric acid while the blood sample is sitting at room temperature, so it is important to keep the sample on ice to avoid spuriously low values in patients who have received this drug. Rare instances of hemolytic anemia, methemoglobinemia, and hypersensitivity are reported. The drug is contraindicated in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
The best choice of intravenous (IV) fluids is controversial. Urinary alkalinization to a minimum pH of 6.5–7.0 using IV sodium bicarbonate (eg, 3 ampules = 150 mEq NaHCO3 added to each liter of 5% dextrose in water solution [D5W]) or acetazolamide was previously recommended in patients treated with allopurinol. However, an animal study suggests that high tubular flow, whether induced by water or solute diuresis, is critically important to preventing urate nephropathy while urinary alkalinization plays at most a minor protective role. Current guidelines advise against routine alkalinization because of the lack of evidence of efficacy and the risk of promoting precipitation of calcium-phosphate crystals, but the advisability of alkalinization in patients receiving allopurinol is unclear. Alkalinization is not required in patients receiving rasburicase. In adults, the total fluid intake should be approximately one to two times greater than a standard maintenance IV rate (2–3L/m2/day) with a goal urine output of 80–100 ml/hr. Diuretics may be used to enhance tubular flow but caution must be exercised to avoid intravascular volume depletion.
Electrolytes, uric acid, and renal function should be monitored at least one to two times daily until evidence of TLS has resolved. Hyperkalemia should be treated by the usual algorithms. In patients with hyperleukocytosis, blood potassium levels should be measured in the plasma, since serum results may be factitiously high due to potassium release from leukemic blasts during clotting. Alkalinization may be useful in patients with metabolic acidosis; consultation with a nephrologist is advised. Dialysis may be required for any of these metabolic complications.
Patients with asymptomatic hypocalcemia should be closely monitored with serial electrocardiographs (ECGs) and telemetry. Intravenous calcium gluconate or calcium carbonate can worsen nephrocalcinosis, but symptomatic hypocalcemia should be treated. Hypocalcemia can also cause cardiac arrhythmias and tetany. A phosphate binder such as aluminum hydroxide (30–60 mL three to four times a day with meals) prevents and treats hyperphosphatemia. Phosphate precipitates with calcium, resulting in nephrocalcinosis, currently the leading cause of TLS-induced renal failure.
Hyperleukocytosis with Leukostasis
Hyperleukocytosis (white blood cell count > 100 × 109/L) may present with symptomatic leukostasis. Leukostasis refers to impaired microcirculation by leukemic cells resulting in tissue hypoxia. The elaboration of cytokines and toxic metabolic products also contributes to endothelial damage and resulting hemorrhage. Leukostasis is most often seen in myelomonocytic or monocytic AML (FAB M4 or M5) because tissue infiltration by blasts contributes to the pathology. Usually, the circulating AML blast count is above 50–100 × 109/L. Patients with chronic myeloid leukemia (CML), even in chronic phase, may develop symptomatic leukostasis at white counts above 250 × 109/L. Leukostasis is rare in patients with ALL, even at extremely high blast counts, because lymphoid blasts are less adherent to the endothelium compared with myeloid cells. Hyperleukocytosis related to differentiation therapy of acute promyelocytic leukemia (APL) was discussed in the section on acute myeloid leukemias in Chapter 179.
Clinically, neurologic and pulmonary symptoms usually predominate. The patient may complain of headache, blurred vision, or be confused. Ischemic stroke, often with some hemorrhagic conversion, or primary hemorrhagic stroke may occur. Hypoxia due to impaired pulmonary capillary blood flow, subendocardial ischemia, and congestive heart failure may supervene. Damage to the renal medulla may cause acute renal failure. Priapism may occur. Coagulopathy and frank disseminated intravascular coagulation (DIC) are common. Acute mortality is between 20% and 40%.
While awaiting diagnosis, hydroxyurea (4–8 g/day orally in divided doses) for suspected myeloid leukemias or glucocorticoids for suspected lymphoid leukemias should be started. Both may be started if the differentiation between lymphoid and myeloid phenotype is not immediately clear. If oral therapy is not feasible, cytarabine or cyclophosphamide may be given intravenously. Treatment relies on prompt cytoreduction. If the diagnosis is known, the appropriate chemotherapy protocol should be started.
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The role of leukapheresis is controversial. Limited evidence from two retrospective case series suggests a beneficial impact on early mortality but no difference in medium or long-term survival. Leukapheresis should not supplant chemotherapy but may be a valuable temporizing measure. If leukapheresis is chosen, chemotherapy should be given as soon as feasible.
Patients with hyperleukocytosis, and especially those with leukostasis, are at high risk of central nervous system (CNS) leukemia. A diagnostic lumbar puncture should be performed once peripheral blood blasts have cleared. There is a lack of evidence for or against incorporating prophylactic intrathecal chemotherapy in treatment cycles in patients with AML. High-dose IV cytarabine used for consolidation does penetrate the CNS. ALL regimens already incorporate CNS prophylaxis.
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