1 Division of Hematology, 3 Division of Clinical Oncology, Department of Internal Medicine I, 2 Division of Nephrology, Department of Internal Medicine III, University Hospital, Vienna, Austria
*E-mail: Gabriela.kornek@akh-wien.ac.at
L-Asparaginase has been used in the treatment of lymphoblastic leukemia and malignant lymphoma for more than 30 years [1]. However, its use is often limited by side-effects, including dysfunction of the liver and pancreas, central nervous system (CNS) toxicity, hypersensitivity reactions and fever, requiring temporary interruption or early discontinuation of treatment in up to 40% of patients.
Early reports on L-asparaginase showed a decrease in serum cholesterol and triglyceride levels in 80% of patients (reviewed in [2]). In contrast to this, two cases with severe hyperlipidemia occurring after an initial episode of hypolipidemia were described in the toxicity report of Oettgen et al. [2]. The mechanism of L-asparaginase-associated hypertriglyceridemia is related to an increase in endogenous synthesis of VLDL (very low density lipoprotein), a decreased lipoprotein lipase activity and/or exogenous chylomicrons [3]. Several reports confirm that the administration of L-asparaginase can be associated with hypertriglyceridemia in children [4], but there are no data available concerning this toxicity in adults, except for the two cases mentioned above [2].
We report a case of severe transient hypertriglyceridemia and hypercholesterolemia associated with neurological symptoms in an adult patient undergoing an L-asparaginase-containing therapy for a T-cell lymphoblastic lymphoma.
A 42-year-old female patient presented with 6 months history of abdominal pain and cough. Computed tomography (CT) and positron emission tomography (FDG-PET) scans showed a large mediastinal tumor, pleural effusion, thoracic and abdominal lymphadenopathy and hepatospenomegaly. Biopsy of the mediastinal tumor revealed a T-cell lymphoblastic lymphoma. The results of bone marrow biopsy and lumbar puncture were normal. On hospital admission, routine laboratory examinations showed a mild hyperlipidemia with serum triglyceride levels of 211 mg/dl and cholesterol of 197 mg/dl. No other abnormalities were found; in particular, there were no signs of hepatic or pancreatic dysfunction.
Remission induction therapy according to the protocol of Hoelzer et al. [5] was initiated. L-Asparaginase was administered at a dose of 5000 IU/m2 for days 1528 on every other day. Mild transient hyperglycemia (up to 170 mg/dl) was observed on days following administration of L-asparaginase. On day 21, pancytopenia and hypofibrinogenemia occurred necessitating substitution therapy. The patient reported dysesthesia and weakness in both lower extremities on day 24. A chemotherapy (vincristine)-induced polyneuropathy was suspected, but neurological assessment revealed normal nerve conduction velocity; similarly, a cranial magnetic resonance imaging (MRI) scan and lumbar puncture showed no evidence of lymphoma infiltration into the CNS.
Symptoms progressed rapidly and led to paraparesis with inability to stand. In addition, spatial and chronological disorientation occurred. Laboratory examinations showed only an elevation of the triglyceride level (696 mg/dl). Despite initiation of a low-fat diet, triglyceride values continued to raise, reaching 4970 mg/dl on day 35. In addition, an increased level of cholesterol of 1100 mg/dl and elevated liver function parameters (bilirubin 2.4 mg/dl, alkaline phosphatase 670 mg/dl, aspartate aminotransferase 55 U/l, alanine aminotransferase 66 U/l, -glutamyltransferase 1140 U/l and lactate dehydrogenase 750 U/l) were detected. The serum values of pancreatic enzymes (amylase and lipase) were within the normal ranges. A lipolytic therapy with insulin (continuous infusion for 8 days) and atorvastatin 20 mg was initiated and resulted in a prompt and continuous decrease in the liver function test results and serum lipid levels. In addition, an immediate neurological improvement was observed. Although plasma viscosity was not determined, this observation makes it very probable that the neurological symptoms were related to a hyperlipidemia-associated hyperviscosity syndrome. The patient was discharged from hospital on day 47 in good general condition, with only a mild residual weakness in both legs.
In conclusion, our case report suggests that L-asparaginase-associated hypertriglyceridemia can occur in adult patients [1] and CNS symptoms may be caused by a hyperviscosity syndrome [2]. Routine laboratory monitoring should therefore include triglyceride and cholesterol levels in all patients (children and adults) receiving L-asparaginase.
B. Meyer1, W. Hagen2, W. Scheithauer3, L. Öhler1 & G. V. Kornek3*
1Division of Hematology, 3Division of Clinical Oncology, Department of Internal Medicine I, 2Division of Nephrology, Department of Internal Medicine III, University Hospital, Vienna, Austria (*E-mail: Gabriela.kornek{at}akh-wien.ac.at)
References
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2. Oettgen HF, Stephenson PA, Schwartz MK et al. Toxicity of E. coli L-asparaginase in man. Cancer 1970; 25: 253278.[Medline]
3. Steinherz PG. Transient, severe hyperlipidemia in patients with acute lymphoblastic leukemia treated with prednisone and asparaginase. Cancer 1994; 74: 32343239.[ISI][Medline]
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5. Hoelzer D, Gokbuget N, Digel W et al. Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 2002; 99: 43794385.