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Acute Lymphoblastic Leukemia
Fenofibrate reduces osteonecrosis without affecting antileukemic efficacy in dexamethasone-treated mice
Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2095-2101
Emily R. Finch,1 Monique A. Payton,1 David A. Jenkins,1 Xiangjun Cai,1 Lie Li,1 Seth E. Karol,2 Mary V. Relling1 and Laura J. Janke3
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital; 2Department of Oncology, St. Jude Children’s Research Hospital and 3Department of Pathology, Division of Comparative Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
ABSTRACT
Recent clinical trials in children with acute lymphoblastic leukemia (ALL) indicate that severe hypertriglyceridemia (>1000 mg/dL) dur- ing therapy is associated with an increased frequency of sympto- matic osteonecrosis. Interventions to lower triglycerides have been con- sidered, but there have been no preclinical studies investigating the impact of lowering triglycerides on osteonecrosis risk, nor whether such interventions interfere with the antileukemic efficacy of ALL treatment. We utilized our clinically relevant mouse model of dexamethasone- induced osteonecrosis to determine whether fenofibrate decreased osteonecrosis. To test whether fenofibrate affected the antileukemic effi- cacy of dexamethasone, we utilized a BCR-ABL+ model of ALL. Serum triglycerides were reduced by fenofibrate throughout the period of treat- ment, with the most pronounced, 4.5-fold, decrease at week 3 (P<1x10-6). Both frequency (33% vs. 74%, P=0.006) and severity (median necrosis score of 0 vs. 75; P=6x10-5) of osteonecrosis were reduced with fenofi- brate. Fenofibrate had no impact on BCR-ABL+ ALL survival (P=0.65) nor on the antileukemic properties of dexamethasone (P=0.49). These data suggest that lowering triglycerides with fenofibrate reduces dexametha- sone-induced osteonecrosis while maintaining antileukemic efficacy, and thus may be considered for clinical trials.
Introduction
Hypertriglyceridemia occurs in 4-19% of children treated with glucocorticoids and/or asparaginase during therapy for acute lymphoblastic leukemia (ALL).1-7 Although hypertriglyceridemia has been thought to be transient and relatively benign,1,2 recent studies suggest that patients with severe hypertriglyceridemia (>1000 mg/dL) during ALL therapy may be at increased risk of long-term compli- cations, including symptomatic osteonecrosis.3,7,8
Recent recommendations for pharmaceutical management of severe hypertriglyc- eridemia include the use of fibrates, specifically fenofibrate.9 In addition to being associated with fewer drug-drug interactions than statins,10-12 fenofibrate specifically reduces serum triglycerides by as much as 50%, with minimal adverse reactions,13-15 whereas the main effect of statins is the decrease of serum low-density lipoprotein cholesterol.9,16,17 The active metabolite of fenofibrate, fenofibric acid, targets peroxi- some proliferator activated receptor-α, leading to activation of lipoprotein lipase which increases lipolysis and elimination of triglyceride-rich particles,18 resulting in reduction of circulating serum triglycerides.19,20 Therefore, it has been suggested that fenofibrate could be useful in the management of acute hypertriglyceridemia, such as that observed during ALL therapy. However, there is no evidence that lowering triglyceride levels with fenofibrate can reduce risk of osteonecrosis. Moreover, with very effective ALL therapy, caution must be exercised before adding any new agents to treatment regimens, to avoid untoward drug interactions.
In these proof-of-principle experiments, we tested the hypothesis that lowering serum triglyceride levels with fenofibrate in dexamethasone-treated mice would
Correspondence:
LAURA JANKE
laura.janke@stjude.org
Received: March 18, 2020. Accepted: July 6, 2020. Pre-published: July 16, 2020.
https://doi.org/10.3324/haematol.2020.252767
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