L-Carnitine Ameliorates L-Asparaginase-Induced Acute Liver Toxicity in Steatotic Rat Livers

Roesmann, Anne; Afify, Mohamed; Panse, Jens; Eisert, Albrecht; Steitz, Julia; Tolba, René

doi:10.1159/000353402

Cited by 26 publications

(28 citation statements)

References 43 publications

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“…The current association of obesity with liver toxicity is of interest given the histopathologic finding of steatosis in asparaginase‐induced liver disease . In animal models, the toxicity of L‐asparaginase is increased with hepatic steatosis compared to normal livers . Our finding that elevated BMI is associated with grades 3–4 transaminitis and hyperbilirubinemia is consistent with the hypothesis that hepatic steatosis predisposes to increased risk of hepatotoxicity with L‐asparaginase use.…”

Section: Resultssupporting

confidence: 87%

Toxicity profile of repeated doses of PEG‐asparaginase incorporated into a pediatric‐type regimen for adult acute lymphoblastic leukemia

Aldoss

Douer

Behrendt

et al. 2015

European J of Haematology

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Despite having been long regarded as too toxic for adult patients, pediatric-like regimens containing L-asparaginase have resulted in improved outcomes for adults with acute lymphoblastic leukemia (ALL). To characterize the spectrum of toxicity of repeated doses of polyethylene glycolated-asparaginase (PEG-asp) in adults, we reviewed all doses (2000 IU/m(2) ) administered as part of a pediatric-inspired regimen in adult ALL at our center. Subjects aged 18-60 yr with ALL (n = 152, 69.1% male) contributed 522 dose cycles to the study. Hepatotoxicity was the most common adverse event: grades 3-4 transaminitis and hyperbilirubinemia occurred in 53.9% and 23.7% of subjects, respectively. Hepatotoxicity was reversible; no cases of fulminate hepatic failure were observed. Other toxicities affecting at least 5% of subjects were grades 3-4 triglyceridemia in 50.9%, hypofibrinogenemia (<100 mg/dL) in 47.9%, clinical pancreatitis in 12.6%, venous thromboembolism in 11.2%, allergic reaction in 7.2%, and any grade bleeding in 5.3%. PEG-asp was always discontinued after grades 3-4 pancreatitis or allergic reaction. Otherwise, toxicities did not preclude administration of additional cycles of the drug. Our results suggest that repeated PEG-asp dosing is safe in adults aged 18-60 yr, even after occurrence of a drug-related toxicity.

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Section: Resultssupporting

confidence: 87%

Toxicity profile of repeated doses of PEG‐asparaginase incorporated into a pediatric‐type regimen for adult acute lymphoblastic leukemia

Aldoss

Douer

Behrendt

et al. 2015

European J of Haematology

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“…Although L -asparaginase is a very effective drug in the BFM protocol, it has severe side effects which limit its clinical use, especially in elderly patients with preexisting hepatopathies. Besides the well-known hypersensitivity reactions, coagulopathy, gastrointestinal and renal disorders, pancreatitis and hepatotoxicity are reported to be common [14]. In our study, only mild liver enzyme elevations were seen that did not cause any treatment delay.…”

Section: Discussionsupporting

confidence: 39%

Is the BFM Regimen Feasible for the Treatment of Adult Acute Lymphoblastic Leukemia? A Retrospective Analysis of the Outcomes of BFM and Hyper-CVAD Chemotherapy in Two Centers

Alacacıoğlu

Medeni²,

Özsan³

et al. 2014

Chemotherapy

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Multiple induction regimens have been developed for adult patients with acute lymphoblastic leukemia (ALL). However, there have been no prospective randomized trials that directly compare these regimens. In this study, we wanted to evaluate the outcome of 50 adult ALL patients treated with BFM (i.e. Berlin-Frankfurt-Munster, n = 20) and hyper-CVAD (n = 30) protocols between March 2006 and October 2012. The median age was 25 years in the BFM group and 30.5 years in the hyper-CVAD group with a male/female ratio of 15:5 and 17:13, respectively. Forty-five percent of the patients in the BFM group and 30.3% in the hyper-CVAD group were <25 years old. The majority of cases were B cell in origin (80% in the BFM group and 70% in the hyper-CVAD group). Complete remission after induction therapy was achieved in 95 and 96% of the patients, respectively. The median follow-up time was 37 months. The 5-year survival rate was higher in the BFM group than in the hyper-CVAD group (59 vs. 34%). There were also no complications which could cause a delay during the hyper-CVAD regimen. Both chemotherapies were well tolerated. None of the patients died from drug-related toxicity. Only mild liver enzyme elevations were seen as toxicity in the BFM group; these did not cause any delay in therapy. The BFM regimen seems to be feasible for adult patients with ALL in terms of tolerability and efficacy, especially in young adults.

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“…The role of L -carnitine as a dietary supplement for nonalcoholic steatohepatitis was investigated in 3 clinical trials, and it was found to be safe and have favorable outcomes [6,7,8]. In a rat model of asparaginase-induced injury to an already steatotic liver, treatment with L -carnitine was effective in reducing the elevation of liver enzymes to levels comparable to those of normal baseline livers [9].…”

Section: Discussionmentioning

confidence: 99%

<smlcap>L</smlcap>-Carnitine for Treatment of Pegasparaginase-Induced Hepatotoxicity

Nasany

Douer²

2016

Acta Haematol

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Introduction: Similar to pediatric regimens, multiple doses of L-asparaginase (PEG-Asp) are being increasingly used in adults with newly diagnosed acute lymphoblastic leukemia (ALL) with promising results. One of the most common side effects of the drug in adults is high-grade hyperbilirubinemia and transaminitis. Despite being almost always reversible and may not recur, clinicians may still be reluctant to continue with PEG-Asp in patients with liver toxicity, losing the benefit from multiple doses of the drug. Case Report: We describe a case of adult ALL who developed PEG-Asp-related high grade liver toxicity. The rising hyperbilirubinemia and transaminitis rapidly and permanently reversed using the amino-acid derivative L-carnitine. This case goes in line with similar observations in animal models and humans. Conclusion:L-Carnitine may show therapeutic benefit in PEG-Asp-related hepatotoxicity and should be considered in clinical trials of the drug.

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L-Carnitine Ameliorates L-Asparaginase-Induced Acute Liver Toxicity in Steatotic Rat Livers

Cited by 26 publications

References 43 publications

Toxicity profile of repeated doses of PEG‐asparaginase incorporated into a pediatric‐type regimen for adult acute lymphoblastic leukemia

Toxicity profile of repeated doses of PEG‐asparaginase incorporated into a pediatric‐type regimen for adult acute lymphoblastic leukemia

Is the BFM Regimen Feasible for the Treatment of Adult Acute Lymphoblastic Leukemia? A Retrospective Analysis of the Outcomes of BFM and Hyper-CVAD Chemotherapy in Two Centers

<smlcap>L</smlcap>-Carnitine for Treatment of Pegasparaginase-Induced Hepatotoxicity

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