Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia

Abstract

Asparaginase (ASNase) is an integral part of pediatric induction chemotherapy that has also been shown to improve adult survival rates; however, pegylated (PEG)-ASNase induces severe hepatotoxicity in this population. Recent case reports describe the incorporation of levocarnitine (LC) supplementation into PEG-ASNase-containing induction regimens to prevent or treat hepatotoxicity. Because LC facilitates the metabolism of free fatty acids (FFA), a primary fuel source for ALL cells, LC could potentially interfere with ALL chemotherapy efficacy. To test this, we employed in vitro and in vivo models of ALL. We show in vitro that LC supplementation does not impact cytotoxicity from vincristine, daunorubicin, dexamethasone, or ASNase on human ALL cells nor lead to an increase in ALL cell metabolic rate. In vivo, we demonstrate LC does not impair PEG-ASNase monotherapy in mice with syngeneic ALL. Together, our findings show that LC supplementation is a safe strategy to prevent/reverse ASNase-induced toxicities in preclinical models.

Effects of asparaginases and L-carnitine on Western-diet-induced hepatosteatosis in mice

“…Bodyweight changes, blood parameters and clinical chemistry as well as histopathological changes in the livers of mice were analyzed and efficacy of the chemotherapeutic drug was verified by counting the WBCs. Asparaginases were reported to cause reduction in bodyweight 17 due to increased catabolism, 18 which could be also verified in our models in all treatment groups. As expected, the WBCs count showed a marked reduction after administration of Oncaspar or L-asparaginase in all treatment groups.…”

“…Our results were in line with previously published data showing no signs of hepatotoxicity after treating mice with Oncaspar. 17 Amylase, as a marker of pancreatic toxicity, showed a significant increase in FL animals treated with Oncaspar especially in the highest dosage group. However, the model using L-asparaginase showed only amylase elevation due to the Western-diet suggesting that feeding animals with high fat diet stimulate the secretion of amylase as previously described.…”

“…Our results were in line with previously published data showing no signs of hepatotoxicity after treating mice with Oncaspar. 17 …”

Levocarnitine for pegaspargase‐induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia

“…Finally, while raw laboratory data was collected, it is important to note that serial laboratory screening was not performed as it would be in the context of a prospective trial. Despite these limitations, given that levocarnitine was well‐tolerated, with no evidence for chemotherapy interactions in vitro 39 or influence on disease response in this study, our findings do not controvert current levocarnitine usage or recommendations as an intervention with limited risk and potential hepatic protection. Patients who are older or obese constitute an at‐risk population warranting hepatoprotection.…”

SOHO State of the Art Updates and Next Questions: Management of Asparaginase Toxicity in Adolescents and Young Adults with Acute Lymphoblastic Leukemia

“…Response rates are fairly rapid and improvements in liver function test have been seen within 1-6 days 32,40 . Importantly, L-carnitine does not appear to affect Asp cytotoxicity 53,62 . In case of grade 3-4 hepatotoxicity or high risk of hepatotoxicity 40 , a loading dose of 50-100 mg/kg/intravenously (due to low bioavailability) followed by a shift to 50 mg/kg/day orally divided in 3-4 doses after improvement in liver function tests.…”