Severe Hypertriglyceridemia Associated with Pegylated Asparaginase Successfully Treated with Plasma Exchange

Abstract

Asparaginase (ASP), a chemotherapy treatment used for acute lymphoblastic leukemia (ALL), is known to provoke severe hypertriglyceridemia (HTG). We report the case of a woman with a history of obesity and diabetes mellitus who developed severe HTG (up to 7305 mg/dL) after receiving a pegylated form of ASP for ALL. The patient was treated with one plasma exchange without incident via peripheral veins using 5% albumin as a replacement solution. Her triglycerides were reduced to 485 mg/dL. A single plasma exchange was an efficient, fast, and safe way to decrease triglycerides concentration in plasma.

Introduction

Severe hypertriglyceridemia (HTG) is defined as levels ≥ 1000 mg/dL. There are primary causes such as familial HTG, and secondary causes including obesity, uncontrolled diabetes mellitus, alcohol, pregnancy, and certain medications. ¹ One drug known to cause HTG is asparaginase (ASP), a chemotherapy treatment used for acute lymphoblastic leukemia (ALL). ²

Although the majority of cases of severe HTG induced by ASP are usually asymptomatic and transient, patients may present with complications such as acute pancreatitis (several cases have been described). ³ Therapeutic measures that have been reported in the literature include insulin infusion, heparin, fasting and dietary restriction, plasma exchange, and fibrates. ⁴ Current data suggest that plasma exchange is the most effective option to reduce triglyceride (TG) levels and prevent or treat complications over a short period of time. ⁵ Here we report the case of a patient with severe HTG secondary to the use of pegylated-ASP (PEG-ASP) as a treatment for ALL. The patient was successfully treated with plasma exchange using peripheral vein access and 5% albumin as a replacement fluid.

Case

The patient is a 51-year-old woman with a history of obesity, diabetes mellitus (type 2) treated with glipizide and metformin, and dyslipidemia treated with simvastatin. She came to the hospital reporting asthenia and general malaise of evolving over one week, petechiae on the abdomen and extremities in the last 3 days, and, more recently, gingivorrhagia.

Blood analyses were performed with the following results: white blood cell count 54.7 × 10⁹/L (92% lymphoid-like blasts), Hb 12.9 g/L, platelet count 12 × 10⁹/L, Quick index 73%, aPTT 100% and fibrinogen 4 g/L, lactate dehydrogenase 2406 U/L. A bone marrow aspirate confirmed the diagnosis of proB common ALL. The patient had received induction treatment with daunorubicin, vincristine, and PEG-ASP nuanced at 500 IU/m² due to hepatic steatosis. Six weeks after receiving the first dose of three scheduled doses of PEG-ASP, the patient was asymptomatic and routine tests were performed which showed TG levels of 7305 mg/dL. The patient was admitted for treatment, starting with the administration of gemfibrozil. Her body mass index was 31.2 and glucose was 207 mg/dL. Pancreatic enzymes (lipase and amylase) were normal, and no signs or symptoms of thrombosis were present. The next day a plasma exchange (120% of plasma volume) was performed using a Spectra Optia (TerumoBCT, Lakewook, Co, USA) with 5% albumin (Alburex 5, CSL Behring GmbH, Marburg, Germany) as the replacement solution. Peripheral vein access was used for the plasma exchange which was performed without incident. The procedure lowered TG to 485 mg/dl, a 94.5% reduction. The following day, TG levels were 426 mg/dL, so plasma exchange was not repeated. At discharge TG levels were 166 mg/dL and remained between 150 and 200 mg/dL during follow up (Figure 1).

Discussion

The incidence of HTG during ASP-containing regimens for ALL has been estimated to be 67%, with 19% having levels greater than 1000 mg/dL (severe HTG). ⁶ HTG in ALL therapies using ASP is likely to be underdiagnosed if lipid testing is not performed routinely. ⁷ ASP induces HTG by increasing endogenous very low-density lipoprotein production and decreasing lipoprotein lipase activity, which decreases plasma TG clearance and increases exogenous chylomicrons.^3,6

There are two types of formulations of ASP produced from E.Coli: the native form, L-ASP, and the pegylated form, PEG-ASP. The latter requiring less frequent administration due to its longer half-life. After ASP administration, levels normalize 2-3 weeks after PEG-ASP and 2-3 days after L-ASP. ⁸ This longer half-life is the reason why comparative studies have shown a greater alteration of TG with the pegylated formulation. ⁹

HTG is rarely a significant clinical problem. However, when the TG levels is greater than 1000 mg/dL (severe HTG), the risk of acute pancreatitis is high. ⁷ Acute pancreatitis results when the excess TG is hydrolyzed by pancreatic lipase leading to an accumulation of free fatty acids and lysolecithin which escapes from the acinar cells into the vascular bed of the pancreas. Free fatty acids are toxic and can damage acinar cells and the capillary endothelium. In addition, high concentrations of chylomicrons increase venous blood viscosity and impaired pancreatic blood flow leads to ischemia. Kandemir et al reported in their study of acute pancreatitis induced by HTG a mortality rate of 3% in patients with edematous interstitial pancreatitis and 17% in patients with pancreatic necrosis. ¹⁰

ASP-induced HTG is reversible after drug discontinuation, but concomitant treatment is recommended until TG levels return to normal. Conservative treatments include the combined use of fasting, omega-3 fatty acids, and fenofibrate. Fenofibrates have shown a 31% reduction in TG in these cases. Insulin infusion and heparin infusion have been used in severe HTG due to their activation of lipoprotein lipase. A reduction in triglycerides of 40% in 24 h with insulin infusion has been described.^3,4

Plasma exchange was first reported as a treatment for severe HTG by Betteridge et al in 1978. ¹¹ Since then, several similar reports have been published. With the knowledge that severe HTG increases the risk of acute pancreatitis, and given that PEG-ASP has a long half-life, plasma exchange is an option that allows rapid primary prophylaxis and treatment of acute pancreatitis caused by HTG. Plasma exchange has produced very good results, reducing patient morbidity and mortality. ¹²

The single session of plasma exchange usually lasts about 2 h for exchanging 1.2 to 1.4 plasma volumes and can reduce serum TG by 49-80%. However, those with severe HTG (over 1000 mg/dL) may need 2 sessions. As a replacement solution, 5% human albumin or fresh frozen plasma can be used.^5,10 Nakagawa et al recommend replacing the volume with fresh frozen plasma which, in addition to eliminating TG, also supplied the patient with exogenous lipoprotein lipase. ¹³ However, in other studies, as in our case, excellent results have been obtained using 5% albumin. ¹⁰ This approach avoids the adverse reactions that sometimes occur with the use of fresh frozen plasma. Our patient received a single session of plasma exchange (120% of plasma volume) using a Spectra Optia with 5% albumin as a replacement solution. Plasma exchange was performed via peripheral vein access and a 93.3% reduction in triglyceride concentration was observed.

Conclusion

In summary, a plasma exchange of 120% plasma volume using 5% albumin as replacement solution was a safe and efficient way of lowering TG levels in a case of HTG associated with a long-lasting formulation of ASP.

Figure 1.

Evolution of the plasma tryglyceride concentration of the patient (in mg/dL). Asparaginase was administered on August 15^th and the plasma exchange was performed on October 1^st.