Asparaginase-associated lipid abnormalities in children with acute
lymphoblastic leukemia
SK Parsons, SX Skapek, EJ Neufeld, C Kuhlman, ML Young, M Donnelly, JD Brunzell, JD Otvos, SE Sallan and N Rifai
Department of Laboratory Medicine, Children's Hospital, Boston, MA 02115,
USA.
To further elucidate the incidence and potential mechanism of
asparaginase-associated lipid abnormalities in children with acute
lymphoblastic leukemia (ALL), we serially obtained fasting lipid and
lipoprotein studies on 38 of the 43 consecutively diagnosed children with
ALL before, during, and after asparaginase therapy. We also evaluated a
second population of 30 long-term survivors of childhood ALL; a fasting
lipid and lipoprotein profile was obtained once at study entry. The mean
peak triglyceride level during asparaginase of 465 mg/dL (standard
deviation [SD] 492) was significantly higher (P = .003) than the level of
108 mg/dL (SD 46) before the initiation of asparaginase therapy.
Sixty-seven percent of the newly diagnosed patients had fasting
triglyceride levels greater than 200 mg/dL during asparaginase therapy; 15
patients (42%) had levels greater than 400 mg/ dL, 7 with levels greater
than 1,000 mg/dL. The incidence of hypertriglyceridemia did not vary by
type of asparaginase or risk status of ALL (defined by white blood cell
count and age). None of the 7 patients with triglyceride levels greater
than 1,000 mg/dL developed pancreatitis. In contrast, 4 of the 13 patients
without triglyceride elevation developed pancreatitis; 3 of the 4 patients
had fasting studies at the height of their abdominal pain. Nuclear magnetic
resonance analysis of lipid subclasses showed a significant increase in the
smaller, denser forms of very low density lipoprotein (VLDL) and negligible
chylomicron fraction in a subset of patients with marked triglyceride
elevation. Lipoprotein lipase activity was consistently above normative
values for all levels of triglyceride and could not be explained by obesity
or hyperglycemia. Apolipoprotein B(100) levels increased during
asparaginase therapy, although the mechanism of this remains unclear. LDL
reciprocally decreased with increased VLDL during asparaginase therapy.
After asparaginase therapy, triglyceride levels (mean, 73 mg/dL [SD 33])
were significantly lower than levels obtained during asparaginase therapy.
Triglyceride levels for survivors did not differ from the normal range or
postasparaginase levels in the newly diagnosed patients. These data show a
striking temporal association between asparaginase therapy and
hypertriglyceridemia. Changes in cholesterol, in contrast, were not
temporally related to asparaginase treatment. Cholesterol levels were
elevated (>200 mg/dL) in 20% of the patients after asparaginase, which
may be due to continued treatment with corticosteroids. The mean
cholesterol level of long-term survivors of 177 mg/dL was significantly
higher than the norm (P = .045). High- density lipoprotein (HDL) levels
were significantly lower than normal at all time periods and for both
populations; 25% of survivors had HDL levels less than 35 mg/dL. We
conclude that modifications in asparaginase therapy are not necessary. In
cases of triglyceride elevation greater than 2,000 mg/dL when the risk of
pancreatitis is increased, close clinical monitoring is imperative. Larger
studies are needed to determine the incidence of dyslipidemia in long-term
survivors of ALL as well as the relationship between lipid abnormalities
and other late effects of treatment, notably obesity and cardiomyopathies.
Volume 89,
Issue 6,
pp. 1886-1895,
03/15/1997
Copyright © 1997 by The American Society of Hematology
