Asparaginase-Associated Lipid Abnormalities in Children With Acute Lymphoblastic Leukemia

Abstract

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 B100 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.

Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy

“…Dyslipidemia had a different pattern during therapy than the other MS components, as it was surprisingly common at the start of maintenance therapy but largely resolved during the maintenance courses that followed. This observation was most common in patients with high-risk disease and is likely related to PEGasparaginase received during the preceding course of delayed intensification [22]. However, more follow-up for dyslipidemia is required in the long-term survivorship period; after 1 year of maintenance therapy, the prevalence of low HDL was still significantly elevated at 29.4%.…”

Complete blood count using VCS (volume, conductivity, light scatter) technology is affected by hyperlipidemia in a child with acute leukemia

“…Several reports confirm that the administration of asparaginase, as monotherapy or in combination with prednisone, is associated with lipid abnormalities in children receiving treatment for ALL. Parsons et al (1997) reported 67% of incidence of hypertriglyceridemia and 19% with levels greater than 1000 mg/dl. It has been suggested that it may be related to an increase in endogeneous hepatic synthesis of very-lowdensity lipoprotein or decreased enzymatic activity of lipoprotein lipase that is a key enzyme in the removal of triglycerides from plasma (Hoogerbrugge, Jansen & Hoogerbrugge, 1997).…”

Asparaginase‐associated pancreatitis is not predicted by hypertriglyceridemia or pancreatic enzyme levels in children with acute lymphoblastic leukemia

“…Hypertriglyceridemia (HTG) during L-asparaginase treatment is a known adverse event. 10 It has been suggested that it is related to an increase in the endogenous hepatic synthesis of very low-density lipoprotein. Another reason may be decreased activity in lipoprotein lipase, an enzyme involved in the removal of triglyceride-rich lipoproteins from the plasma.…”