Page 71 - 2021_06-Haematologica-web

Fenofibrate reduces experimental osteonecrosis
A
BC
D
Figure 4. Fenofibrate does not affect efficacy of dexamethasone in BCR-ABL+ acute lymphoblastic leukemia. (A) Experimental design. DEX water: continuous dex- amethasone in drinking water; base-water: drinking water; base-diet: folic acid-deficient diet. (B) Ventral luminescence was measured weekly. (C) A log-rank test of survival data shows P-values for the comparisons between the various groups: control mice, mice treated with fenofibrate only, dexamethasone (DEX) only and DEX + fenofibrate. P<1x106 between DEX-treated groups (DEX only and DEX + fenofibrate) versus no DEX treatment (control and fenofibrate only). The shaded yellow area indicates time on therapy. (D) Fasting serum triglyceride levels at day 24 (3 weeks after BCR-ABL transplant). N=9-10/group.
Discussion
Although the etiology of osteonecrosis is not completely understood, the involvement of lipid metabolism has been well documented.35-37 However, there have been few studies investigating whether pharmacologically lowering triglyc- erides prevents osteonecrosis.38
We found that fenofibrate supplementation successfully managed dexamethasone-induced hypertriglyceridemia (Figure 2) and was associated with reductions in the fre- quency and severity of osteonecrosis (Figure 3). The corre- lation between week 3, but not week 6 triglyceride levels (Online Supplementary Figure S1), and osteonecrosis suggest that management of triglycerides is especially important early in the progression of the disease. Although there was an increase in triglyceride levels between mice treated with fenofibrate + dexamethasone and those treated with fenofi- brate only by week 6 (Figure 2A), fenofibrate was able to maintain triglyceride levels comparable to those in control mice, even with prolonged continuous exposure to dexam- ethasone.
Any addition to ALL therapy must be thoroughly assessed to ensure that it does not interfere with the highly effective modern drug regimens. For our purposes, we uti- lized a model of BCR-ABL+ ALL known to be sensitive to dexamethasone treatment. Fenofibrate supplementation did not cause observable differences in the efficacy of dex- amethasone in the treatment of experimental BCR-ABL+ ALL (Figure 4).
In our experimental models, the dosage of both dexa- methasone and fenofibrate were well tolerated (Figure 1C) and resulted in plasma levels of the drug/metabolites in the
clinical range.13,39,40 Although the plasma concentration of fenofibric acid was lower in mice treated with dexametha- sone + fenofibrate than in those treated with fenofibrate only (Online Supplementary Figure S2B), it was still effective in reducing dexamethasone-induced hypertriglyceridemia (Figure 2A) and osteonecrosis (Figure 3), while not affecting BCR-ABL+ ALL treatment (Figure 4). Statins have been sug- gested as possible agents to reduce osteonecrosis41-43 but because they have potent interactions with CYP3A and with SLCO1B1 (enzymes involved in the metabolism and disposition of multiple ALL drugs), their likelihood of drug interactions makes them less desirable agents to use in patients with ALL.
Dexamethasone treatment is associated with hyper- triglyceridemia.1,3,44 It has been shown that elevated levels of serum triglyceride-rich lipoproteins contribute to endothe- lial dysfunction and subsequent atherosclerosis.45 We hypothesized that dexamethasone-induced arteriopathy and subsequent osteonecrosis are related to hypertension caused by endothelial dysfunction.27,46 We therefore suspect that the mechanism by which fenofibrate reduced the inci- dence of osteonecrosis and arteriopathy was by lowering the dexamethasone-induced elevation of triglyceride-rich lipoproteins and thereby mitigating the effects of endothe- lial dysfunction.
In children with ALL, there are no specific guidelines for managing triglyceride levels during glucocorticoid and/or asparaginase treatment. However, conservative use of fibrates has been successful in managing triglycerides in specific cases, with no reported adverse events.3,5,47 In gener- al, the use of fibrates in children is limited to cases of extreme hypertriglyceridemia to prevent pancreatitis, pri-
haematologica | 2021; 106(8)
2099