Acute Leukemias - Republican Scientific Medical Library

282 Chapter 23 · Emergencies in Acute Lymphoblastic Leukemia
acid. Second, administration of allopurinol increases
the serum levels of the purine precursors, xanthine
and hypoxanthine, which may lead to xanthine nephropathy
and obstructive uropathy [4, 6]. Third, allopurinol
reduces the degradation of other purines, including
6-mercaptopurine (6-MP) and azathioprine, requiring
50–70% of their dose reduction [6].
An alternative to preventing uric acid formation by
inhibiting xanthine oxidase with allopurinol is to promote
the catabolism of uric acid to much more soluble
allantoin by urate oxidase [7]. Urate oxidase (UO) is an
endogenous enzyme commonly found in many mammalian
species, but not in humans, due to a nonsense
mutation in the coding region of the urate oxidase-encoding
gene [8]. A nonrecombinant UO, extracted from
Aspergillus flavus species, has been demonstrated to reduce
uric acid levels in patients at risk for ATLS and has
been available in France since 1975 and in Italy since
1984 [9–11]. Subsequently, the gene coding for the UO
was isolated from the A. flavus species and expressed
in the yeast Saccharomyces cerevisiae strain to yield large
quantities of the pure recombinant form of UO [12].
Recombinant UO (rasburicase) [12], which recently
became available in the USA, was demonstrated to be
a safe and effective alternative to allopurinol in several
multicenter clinical trials [5, 13, 14]. In a randomized
clinical trial rasburicase was shown to significantly reduce
the exposure to uric acid in patients with hyperuricemia
compared to allopurinol [5]. Although the recommended
dose of rasburicase is 0.15–0.2 mg/kg/day
for 5 days, at our institution, an excellent control of hyperuricemia
was achieved with a lower dose of 3 mg/
day. Administration of 3 mg of rasburicase to 18 patients
with hyperuricemia secondary to leukemia/lymphoma
resulted in the normalization of the uric acid
in 11 patients with just a single dose of rasburicase, in
six patients with two doses, and in one patient with
three doses [15].
Patients with ALL, who either present with or are at
high risk of developing ATLS (high tumor burden with
WBC > 50´10 9 /L, high LDH, or mediastinal mass; elevated
uric acid level; renal infiltration with leukemic
cells, or renal insufficiency) are good candidates for rasburicase
therapy [6].
Hypocalcemia, one of the most dangerous sequelae
of ATLS, may result in potentially lethal cardiac (ventricular
arrhythmias, heart block) and neurological
(hallucination, seizures, coma) manifestations [16]. In
an asymptomatic patient with laboratory evidence of
hypocalcemia and hyperphosphatemia, calcium replacement
is not recommended, since it may precipitate
metastatic calcifications [16]. However, in a patient with
symptomatic hypocalcemia, calcium gluconate may be
carefully administered to correct the clinical symptoms.
Hyperkalemia, defined by a potassium level of
> 6 mmol/l, caused by massive cellular degradation,
may precipitate significant neuromuscular (muscle
weakness, cramps, paresthesias) and potentially lifethreatening
cardiac (asystole, ventricular tachycardia,
and ventricular fibrillation) abnormalities [16]. Patients
should be treated with oral sodium-potassium exchange
resin, such as kayexalate 15–30 g every 6 h and/or combined
glucose/insulin therapy [17].
Serum electrolytes, uric acid, phosphorus, calcium,
and creatinine should be monitored several times a
day, depending on the severity of the clinical condition
and degree of metabolic abnormality. Early hemodialysis
may be required in patients who develop oliguric renal
failure or recalcitrant electrolyte disturbances. The
electrocardiogram should be obtained and cardiac
rhythm monitored while these abnormalities are corrected.
23.3 Lactic Acidosis
Primary leukemia-induced lactic acidosis (LA) is a rare
yet potentially fatal event, characterized by low arterial
pH due to the accumulation of blood lactate. It has been
suggested that LA occurring in the setting of hematological
malignancy is associated with an extremely poor
prognosis [18]. Lactate, the end product of anaerobic
glycolysis, is metabolized to glucose by the liver and
kidneys. Because leukemic cells have a high rate of glycolysis
even in the presence of oxygen and produce a
large quantity of lactate, LA may result from an imbalance
between lactate production and hepatic lactate utilization
[18]. Several factors may contribute to the high
rate of glycolysis. Overexpression or aberrant expression
of glycolytic enzymes, such as hexokinase, the first
rate-limiting enzyme in the glycolytic pathway [19], allows
tumor cells to proliferate rapidly and survive for
prolonged periods [20]. Although insulin normally regulates
the expression of this enzyme, insulin-like growth
factors (IGFs), which are overexpressed by malignant
leukemic cells, can mimic insulin activity [21–23]. Lactate
production may also be increased by the paracrine
and systemic action of TNF-a [24].