Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia

Abstract

Background: Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l-asparaginase was front-line therapy versus the pegylated formulation (PEG-asparaginase) in Total XVI (TXVI).

Procedure: Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low-risk (LR) or standard/high-risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride-PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded.

Results: The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG-asparaginase (4.5-fold increase; P <1 × 10-15 ). SHR patients treated with PEG-asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l-asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride-PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4).

Conclusion: Triglycerides were affected more by PEG-asparaginase than native l-asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.

Keywords: acute lymphoblastic leukemia; asparaginase; hypertriglyceridemia.

Conflict of interest statement

Conflict of interest disclosure: Dr. Mary Relling and St. Jude Children’s Research Hospital receive investigator-initiated research funding from Servier Pharmaceuticals.

© 2019 Wiley Periodicals, Inc.

Figures

Figure 1:. The greatest increase in triglycerides was observed in SHR patients after dexamethasone and asparaginase at week 8.

Intrapatient triglyceride (y-axis) changes shown by protocol and treatment risk-arm. A. TXV, LR (n=142). B. TXVI, LR (n=229). C. TXV, SHR (n=123). D. TXVI, SHR (n=279). Solid red arrows indicate dexamethasone treatment time periods; open orange arrows indicate asparaginase treatment time periods. Details of therapy have been described. Grade 4 hypertriglyceridemia (1000 mg/dL) is indicated with a dashed horizontal line. P-values calculated using Wilcoxon tests for paired samples. LR= low risk treatment arm, SHR= standard/high risk treatment arm.

Figure 2:. Maximum hypertriglyceridemia grade was significantly higher in TXVI versus TXV SHR arms; there was no difference between TXV versus TXVI for the LR arms.

TXV, LR (n=189); TXVI, LR (n=255); TXV, SHR (n=173); TXVI, SHR (n=308). Only patients with at least two lipid measurements were included in analyses. LR (low risk treatment arm); SHR (standard/high risk treatment arm); hyperTG (hypertriglyceridemia).

Figure 3:. Longitudinal triglyceride cluster analysis identified three unique groups of patients.

A. K-means for longitudinal data (KML) was used to cluster patients (n=773, TXV+TXVI) with similar triglyceride trends over the observed course of therapy. B. TXV, LR patients (n=142). C. TXVI, LR patients (n=229). D. TXV, SHR patients (n=123). E. TXVI, SHR patients (n=279). NOTE: 84% (61/73) of patients with maximum hypertriglyceridemia grade 4 (>1000 mg/dL dotted line on graph) were in high-risk cluster C; 16% (12/73) were in intermediate-risk cluster B. Only patients with four triglyceride measurements were included (n= 773).

Figure 4:. Percent of variation in triglycerides explained by the triglyceride-PRS at four time-points in white patients on TXV and TXVI.

Triglycerides (TG) were treated as a continuous variable at each time point. P-values were generated using linear regression models with TG measurement as the independent variable with covariates including age, sex, protocol, and risk-arm. Baseline, p=3×10−8; week 7, p= 1×10−6; week 8, p=1×10−6; week 12/17, p=1×10−5. N=642.

Figure 5:. Osteonecrosis and thrombosis, but not pancreatitis, were significantly associated with maximum hypertriglyceridemia grade.

Adverse events were A symptomatic osteonecrosis grade 2–4. B. thrombosis grade 3–4. C. pancreatitis grade 3–4 (TXV) or grade 2–4 (TXVI). Multivariate p-values from proportional odds models included age, gender, race, minimum serum albumin, risk-arm, and protocol as covariates. Ratios at top of each bar indicate the number of patients positive for the specific toxicity in each maximum hypertriglyceridemia (hyperTG) grade.