Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

Area of Science:

• Oncology
• Pharmacology
• Genetics

Background:

• Acute lymphoblastic leukemia (ALL) treatments, including glucocorticoids and asparaginase, can lead to hypertriglyceridemia.
• This study compares triglyceride levels and associated toxicities between two ALL trials using different asparaginase formulations.

Purpose of the Study:

• To compare the effects of native Escherichia coli l-asparaginase versus pegylated asparaginase (PEG-asparaginase) on triglyceride levels in ALL patients.
• To investigate risk factors, including genetic predisposition (triglyceride polygenic risk score), and associated toxicities like osteonecrosis, thrombosis, and pancreatitis.

Main Methods:

• Two ALL clinical trials (Total XV and Total XVI) at St. Jude Children's Research Hospital were analyzed.
• Triglyceride levels were measured, and a triglyceride polygenic risk score (triglyceride-PRS) was used to assess genetic contribution.
• Osteonecrosis, thrombosis, and pancreatitis were prospectively graded.

Main Results:

• Pegylated-asparaginase (in TXVI) led to more severe hypertriglyceridemia in standard/high-risk patients compared to native asparaginase (in TXV) (10.5% vs. 5.5%).
• Hypertriglyceridemia was significantly associated with osteonecrosis (P=.0006) and thrombosis (P=.005), but not pancreatitis (P=.4).
• Drug effects, particularly PEG-asparaginase, had a greater impact on triglycerides than dexamethasone or genetic factors.

Conclusions:

• Pegylated-asparaginase causes more significant hypertriglyceridemia than native asparaginase.
• Hypertriglyceridemia is associated with osteonecrosis and thrombosis in ALL patients.
• The role of triglycerides as either a cause or biomarker of these toxicities requires further investigation.