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DRUG RECORD

 

ASPARAGINASE

OVERVIEW
Asparaginase

 

Introduction

Asparaginase is bacterial enzyme that is used as an antineoplastic agent, largely in the therapy of acute lymphocytic leukemia.  L-asparaginase has many side effects, one of which is hepatic injury that is characterized by inhibition of hepatic protein synthesis and steatosis, which can be severe and lead to death from hepatic failure.

 

Background

Asparaginase (as par' a jin ase), often referred to as L-asparaginase, is a bacterial enzyme that acts to decrease tissue stores of asparagine, a secondary amino acid that is important in the growth of many cancers.  Asparaginase, prepared from E. coli, was introduced into cancer chemotherapy over 50 years ago and remains an important agent in the therapy of acute lymphocytic leukemia.  Asparaginase has activity against other cancer types, but is rarely used for other indications.  Asparaginase was first approved for use in the United States in 1972 as an anticancer agent, with initial preparations being prepared from E. coli.  Pegylated formulations of asparaginase (pegaspargase) became available and were approved for use in 1994.  These preparations can be given every other week and have largely replaced standard asparaginase.  Asparaginase made from other bacteria (Erwinia carotovora) was approved for use in the United States in 2011 and is available under the brand name Erwinaze.  Standard asparaginase is given either by intramuscular injection or, more typically, intravenous injection in doses of 25,000 IU/m2 three times weekly in 14 day cycles.  Pegaspargase can also be given intramuscularly or intravenously, typically in a dose of 2500 IU/m2 every other week.  Both standard and pegylated asparaginase are usually given in combination with other antineoplastic agents such as vincristine, mercaptopurine, methotrexate, daunorubicin, and prednisone.  Asparaginase has many dose related toxicities including nausea, fever, hypersensitivity reactions (urticaria, wheezing), clotting abnormalities, bone marrow suppression, pancreatitis and central nervous system toxicities.

 

Hepatotoxicity

Some abnormalities of liver test results occur in almost all patients treated with asparaginase.  Most typical is a decrease in serum albumin and clotting factors (including II, V, VII, VIII, IX, prothrombin and fibrinogen) due to inhibition of hepatic protein synthesis.  Most patients also have a rise in alkaline phosphatase levels and a lower proportion have increases in serum aminotransferase levels and bilirubin.  Symptoms of fatigue and anorexia may be present.  The inhibition of clotting factor and thrombolytic activity rarely results in excess bleeding, but paradoxically can also cause excessive clotting and a hypercoagulable state.  Serum aminotransferase elevations during asparaginase therapy are mild-to-moderate in severity (2 to 10 times the upper limit of normal) and self-limiting.  The abnormalities typically arise after 2 to 3 weeks of therapy and resolve within 2 to 4 weeks of stopping. 

 

Asparagenase and pegasparase can also result in a more severe and protracted form of liver injury marked by fatigue, dark urine and jaundice arising 2 to 3 weeks after starting the enzyme infusions and often between courses of therapy.  The hepatic dysfunction is accompanied by hepatic steatosis which can be severe and accompanied by jaundice, hepatomegaly and evidence of hepatic failure (somnolence, coma, ascites).  Imaging of the liver shows hepatomegaly and marked fat accumulation.  Autoimmune and immunoallergic features are uncommon. The course of illness varies.  Recovery tends to be slow, jaundice resolving in 2 to 8 weeks and serum enzymes thereafter.  Deaths due to asparaginase hepatotoxicity have been reported, but the rate of injury has been less frequent in recent years, probably because use of safer dosage regimens, more purified preparations of the bacterial enzyme, better monitoring, and dose adjustments based upon better understanding of pharmacokinetics.  Although of unproven benefit, therapy with L-carnitine and vitamin B is often recommended.  Interestingly, in many instances asparaginase therapy at reduced doses is tolerated after recovery from the acute episode.

 

The clinical features of hepatic injury due to asparaginase can be overshadowed by its other systemic toxicities, including severe nausea and vomiting, weakness, edema, pancreatitis and encephalopathy.  Although hypersensitivity reactions to asparaginase are common (it is a bacterial not a human enzyme), these usually occur early before the appearance of liver injury and the hepatic injury is rarely accompanied by fever or eosinophilia or autoantibody formation. 

 

Likelihood score: A (well known cause of clinically apparent liver injury).

 

Mechanism of Liver Injury

Asparaginase is directly toxic to hepatocytes resulting in inhibition of protein synthesis and export of lipoproteins and lipids, with resultant steatosis and hepatic dysfunction.  The mechanism of this injury is not clear but may be due to depletion of arginine as a consequence of the asparaginase activity.  In animal models, asparaginase causes similar hepatic injury.

 

Outcome and Management

Asparaginase is typically given in 14 or 28 day cycles while pegasparase is given at two-weekly intervals, and consequently the hepatic injury may first become clinically apparent after the drug is stopped.  Further use of asparaginase (with dose reduction) should be delayed until hepatic function has been restored.  Patients receiving asparaginase should be monitored for hepatic function and the drug stopped or dose adjusted if liver test abnormalities arise.  Once clinically apparent liver injury arises, supportive clinical care and treatment of complications are essential.  Anedotal reports suggest that intravenous infusions of L-carnitine (50 mg/k daily in divided doses for 5 to 8 days or until the injury resolves) and vitamin B preparations may be helpful.  In animal models, L-carnitine ameliorates the hepatic injury induced by asparaginase. 


Drug Class:  Antineoplastic Agents

 

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CASE REPORTS
Asparaginase

 

Case 1.  Severe hepatic injury and death due to asparaginase.

[Modified from:  Bodmer M, Sulz M, Stadlmann S, Droll A, Terracciano L, Krähenbühl S.  Fatal liver failure in an adult patient with acute lymphoblastic leukemia following treatment with L-asparaginase. Digestion 2006; 74: 28-32. PubMed Citation]

A 68 year old man with acute lymphocytic leukemia was treated with induction chemotherapy using daunorubicin, vincristine, methotrexate, asparaginase, cyclophosphamide and prednisone.  Mild liver test abnormalities were present even before therapy, but rose precipitously between day 19 and 26 of therapy.  Chemotherapy was stopped.  Serum bilirubin was 10.9 mg/dL, ALT 122 U/L and alkaline phosphatase 480 U/L (Table).  A liver biopsy showed diffuse microvesicular steatosis with minimal inflammation, necrosis or fibrosis.  Several days later, he became progressively somnolent and was transferred to the intensive care unit.  Serum ammonia levels were high (227 µmol/L: normal <35), but lactate and glucose levels were normal.  He developed progressive coma, sepsis, renal failure and died 54 days after starting therapy and 4 weeks after stopping all chemotherapy.

 

Key Points

Medication: Asparaginase (dose not given)
Pattern: Cholestatic (R=0.7)
Severity: 5+ (jaundice, hepatic failure and death)
Latency: 26 days
Recovery: None
Other medications:Chemotherapy for leukemia included prednisone, daunorubicin, vincristine, methotrexate, and cyclophosphamide.

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
0pre501592.4Started chemotherapy
5 days1441410.8
11 days1821101.0
19 days124641.0
26 days012248010.9Chemotherapy stopped
28 days2 days11158811.9Liver biopsy
32 days6 days13298219.5Somnolence
42 days16 days526273520.9Coma
50 days24 days184268832.0
54 days28 daysDied of hepatic and multiorgan failure
Normal Values<38<107<1.2

Comment

While this patient was receiving 6 chemotherapeutic agents concurrently, the hepatic injury most closely resembled asparaginase hepatotoxicity, which typically arises after 2 to 3 weeks of therapy and is marked by gradual elevations in alkaline phosphatase to high levels with variable increases in serum bilirubin and aminotransferase levels.  Some cases are severe and associated with hepatomegaly, fatty metamorphosis, severe hepatic dysfunction, progressive jaundice and hepatic coma.  The condition can progress for several weeks after stopping therapy and several fatal instances such as the current case have been described.  This toxicity is not actually idiosyncratic, but there is variable susceptibility to the injury.  Higher doses of asparaginase and comorbidities may predispose to hepatotoxicity.  Early in the course, the fatty metamorphosis may be largely microvesicular steatosis, whereas later, a mixed or fully macrovesicular steatosis may be present.  Unlike the acute fatty liver with hepatic failure that occurs with Reye syndrome and mitochondrial injury due to nucleoside analogues, the steatosis and liver injury associated with asparaginase is less commonly associated with lactic acidosis, although it can be accompanied by pancreatitis. 

 

 

Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review.  Most of these reference cases are from the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case.  All cases have been reviewed and cleared of personal identifiers and a brief comment added by the LiverTox editors.  Click on the following link to view the submitted case reports that have been made publically available.


Submitted Cases on Asparaginase

 

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PRODUCT INFORMATION
Asparaginase

 

REPRESENTATIVE TRADE NAMES
Asparaginase – Erwinaze®
Pegaspargase – Oncaspar®

 

DRUG CLASS
Antineoplastic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Asparaginase 9015-68-3 Large protein Unavailable
Pegaspargase 130167-69-0 Large protein Unavailable

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REFERENCES
Asparaginase

 

References updated: 25 July 2017

  1. Zimmerman HJ. Hepatotoxic effects of oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 673-708.  (Expert review of hepatotoxicity of neoplastic agents published in 1999 mentions high incidence of hepatic and pancreatic side effects from asparaginase, liver injury marked by steatosis which is found in 50-90% of patients and worsens with duration of treatment).

  2. DeLeve L. L-asparaginase. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 557.  (Review of hepatotoxicity of anticancer drugs states that the rate of liver test abnormalities and clinically apparent liver injury due to asparaginase therapy is considerably lower in the recent literature, although severe cases are still reported).

  3. Chabner BA, Bertino J, Clearly J, Ortiz T, Lane A, Supko JG, Ryan DP. Cytotoxic agents. Chemotherapy of neoplastic diseases. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1677-1730.  (Textbook of pharmacology and therapeutics mentions that the toxicity of asparaginase is due to its antigenicity and to its actions in inhibiting protein synthesis).

  4. Haskell CM, Canellos GP, Leventhal BG, Carbone PP, Block JB, Serpick AA, Selawry OS. L-asparaginase: therapeutic and toxic effects in patients with neoplastic disease. N Engl J Med 1969; 281: 1028-34. PubMed Citation  (Early experience with asparaginase in 55 patients with cancer or leukemia, given iv for 3 weeks; common side effects were nausea, fever, hypersensitivity reactions, clotting abnormalities, pancreatitis and CNS toxicity; the most frequent side effect was liver dysfunction characterized by decreases in serum albumin and slight elevations in Alk P, ALT and bilirubin, in one instance liver injury was severe).

  5. Gross MA, Speer RJ, Hill JM. Hepatic lipidosis associated with L-asparaginase treatment. Proc Soc Exp Biol Med 1969; 130: 733-6. PubMed Citation  (Study in mice given different doses of asparaginase with different degrees of purity; highest purity samples had little hepatotoxicity).

  6. Pratt CB, Simone JV, Zee P, Aur RJ, Johnson WW. Comparison of daily versus weekly L-asparaginase for the treatment of childhood acute leukemia. J Pediatr 1970; 77: 474-83. PubMed Citation  (Comparison of daily versus weekly infusions of asparaginase in 19 children with acute leukemia; evidence of hepatotoxicity occurred in all patients with decrease in albumin in 68%, increase in AST in 63%, Alk P in 16%, bilirubin in 47%, liver changes found on autopsies were "vacuolization of hepatocytes").

  7. Leventhal BG, Skeel RT, Yankee RA, Henderson ES. L-asparaginase(NSC- 09229) plus azaserine(NSC-742) in acute lymphatic leukemia. Cancer Chemother Rep 1970; 54: 47-51. PubMed Citation  (Result of use of asparaginase and azaserine in 27 children with acute lymphocytic leukemia; hypersensitivity reactions occurred in 33%, Alk P elevations in 77%, decreases in albumin in 59%, clotting abnormalities in 88%).

  8. Oettgen HF, Stephenson PA, Schwartz MK, Leeper RD, Tallai L, Tan CC, Clarkson BD, et al. Toxicity of E. coli L-asparaginase in man. Cancer 1970; 25: 253-78. PubMed Citation  (Analysis of toxicity of asparaginase in 131 children and 143 adults with neoplastic disease; elevations in Alk P occurred in 31-47% of patients, AST in 46-63%, bilirubin in 29-51%, and decreases in albumin in 71-82%, usually arising during the 2nd to 3rd week of therapy and resolving upon stopping; fatty metamorphosis found in 73% of autopsies).

  9. Bernard J, Jacquillat C, Boiron M, Weil M, Bussel A, Larrieu MJ, Delobel J, et al. [Treatment of acute leukemia with the L-asparaginase. Preliminary results based on 84 cases]. Presse Med 1970 78: 161-6. French. PubMed Citation  (Analysis of results of treating 75 patients with acute leukemia with asparaginase; liver toxicity was frequent and marked by falls in serum albumin and cholesterol with rises in Alk P, while ALT elevations were rare; two patients developed hepatic insufficiency which may have contributed to their deaths).

  10. Burchenal JH. A summary of the clinical status of asparaginase. Recent Results Cancer Res 1970; 33: 350-4. PubMed Citation  (Summary of a workshop on asparaginase).

  11. Jacquillat C, Weil M, Bussel A, Loisel JP, Rouesse T, Larrieu MJ, Boiron M, et al. Treatment of acute leukemia with L-asparaginase--preliminary results on 84 cases. Recent Results Cancer Res 1970; 33: 263-78. PubMed Citation  (Among 84 patients with acute leukemia given asparaginase, early toxicities included hypersensitivity reactions [fever, urticaria and anaphylaxis], and late toxicities where often hepatic with weight loss and elevations in bilirubin, Alk P [50%] and ALT [36%], with decrease in albumin [60%], cholesterol [72%] and fibrinogen, usually arising after the first week of therapy and beginning to resolve within a week of stopping).

  12. Marmont AM, Damasio EE. Some clinical observations on the treatment with L-asparaginase of the acute leukemias. Recent Results Cancer Res 1970; 33: 296-315. PubMed Citation  (Discussion of side effects of asparaginase: "there can be no doubt that L-ase profoundly affects the liver cell").

  13. Carbone PP, Haskell CM, Leventhal BG, Block JB, Selawry OS. Clinical experience with L-asparaginase. Recent Results Cancer Res 1970; 33: 236-43. PubMed Citation  (Summary of results using asparaginase, similar to report by Haskell [1969]).

  14. Zubrod CG. The clinical toxicities of L-asparaginase in treatment of leukemia and lymphoma. Pediatrics 1970; 45: 555-9. PubMed Citation  (Review of toxicities of asparaginase, hepatic abnormalities being the most common).

  15. Beard ME, Crowther D, Galton DA, Guyer RJ, Fairley GH, Kay HE, Knapton PJ, et al. L-asparaginase in treatment of acute leukaemia and lymphosarcoma. Br Med J 1970; 1(5690): 191-5. PubMed Citation  (Among 40 patients treated with L-asparaginase, nausea and vomiting were common as were "slight abnormalities in liver function tests").

  16. Pratt CB, Johnson WW. Duration and severity of fatty metamorphosis of the liver following L-asparaginase therapy. Cancer 1971; 28: 361-4. PubMed Citation  (Analysis of liver histology from autopsies in 31 children after asparaginase therapy, 27 [87%] had fatty metamorphosis for periods of up to 261 days after last dose, severity decreasing 60 days after dosing, but fatty change also found in 51% of children with leukemia who did not receive asparaginase).

  17. Biggs JC, Chesterman CN, Holliday J. L-asparaginase--clinical experience in leukaemia, lymphoma and carcinoma.  Aust N Z J Med 1971; 1: 1-7. PubMed Citation  (Among 11 patients with leukemia or cancer treated with asparaginase, mild elevations in ALT and Alk P [2-4 times ULN] occurred in 4).

  18. Revol L, Fière D, Guyon JM. [Accidents due to asparaginase]. J Med Lyon 1971; 52: 831-3. French. PubMed Citation 

  19. Oberling F, Cazenave JP, Lang JM, Kurtz D, Mayer G, Waitz R. [Apropos of certain toxic effects of L-asparaginase in human therapy]. Sem Hop 1971; 47: 1421-5. French. PubMed Citation 

  20. Land VJ, Sutow WW, Fernbach DJ, Lane DM, Williams TE. Toxicity of L-asparginase in children with advanced leukemia. Cancer 1972; 30: 339-47. PubMed Citation  (Among 105 patients with leukemia treated with asparaginase, liver test abnormalities occurred in most patients and were fatal in two [fatty liver]).

  21. Hasegawa Y, Suzuki T, Motegi F, Takanashi R. [Severe toxicity of L-asparaginase in the treatment of acute leukemia--the hepatocerebral lesions (author's transl)]. Rinsho Ketsueki 1973; 14: 917-24. Japanese. PubMed Citation 

  22. Haghbin M, Tan CC, Clarkson BD, Miké V, Burchenal JH, Murphy ML. Intensive chemotherapy in children with acute lymphoblastic leukemia (L-2 protocol). Cancer 1974; 33: 1491-8. PubMed Citation  (Experience in treating 75 children with leukemia with intensive chemotherapy including asparaginase; two died of serum hepatitis from platelet transfusions; hepatotoxicity not discussed).

  23. Rutter DA. Letter: Toxicity of asparaginases. Lancet 1975; 1 (7919): 1293-4. PubMed Citation  (Retrospective review of 77 courses of either E. coli or Erwinia carotovora derived asparaginase in patients with acute leukemia seen at 3 London hospitals, found slightly higher rates of side effects with E. coli product [liver injury not mentioned]; 10 patients with hypersensitivity reactions to one tolerated the other).

  24. Olive D, Cartault F, Legras B, Neimann N. [Evaluation in children of the clinical, biological and electroencephalographic side effects of L-asparaginase]. Pediatrie 1976; 31: 259-78. French. PubMed Citation  

  25. Woods WG, O'Leary M, Nesbit ME. Life-threatening neuropathy and hepatotoxicity in infants during induction therapy for acute lymphoblastic leukemia. J Pediatr 1981; 98: 642-5. PubMed Citation  (Two children [ages 16 and 14 months] developed neuropathy and hepatic failure during 4th week of chemotherapy with regimens including asparaginase for acute lymphocytic leukemia, with liver biopsies showing fat, focal necrosis and mild inflammation, one survived and one died of hepatic failure).

  26. Haskell CM. L-Asparaginase: human toxicology and single agent activity in nonleukemic neoplasms. Cancer Treat Rep 1981; 65 Suppl 4: 57-9. PubMed Citation  (Unlike other antineoplastic agents, asparaginase has little bone marrow toxicity and its main side effects are on liver, kidneys, pancreas, central nervous and clotting system; hypersensitivity reactions can also occur and can be severe).

  27. Cairo MS. Adverse reactions of L-asparaginase. Am J Pediatr Hematol Oncol 1982 Fall; 4: 335-9. PubMed Citation  (Review of toxicity of asparaginase; hepatic injury is most common and is marked by changes in AST, Alk P, bilirubin and albumin).

  28. Distasio JA, Salazar AM, Nadji M, Durden DL. Glutaminase-free asparaginase from vibrio succinogenes: an antilymphoma enzyme lacking hepatotoxicity. Int J Cancer 1982; 30: 343-7. PubMed Citation  (Unlike standard, E coli-derived asparaginase, a glutaminase-free preparation did not cause hepatotoxicity or fatty liver in mice, suggesting that the hepatotoxicity of asparaginase is due to a contaminant).

  29. Durden DL, Salazar AM, Distasio JA. Kinetic analysis of hepatotoxicity associated with antineoplastic asparaginases. Cancer Res 1983; 43: 1602-5. PubMed Citation  (Comparison of glutaminase-free and standard asparaginase in a mouse model found little hepatotoxicity, even with 3-4 weeks of therapy).

  30. Kafkewitz D, Bendich A. Enzyme-induced asparagine and glutamine depletion and immune system function. Am J Clin Nutr 1983; 37: 1025-30. PubMed Citation  (Induced immune deficiency in mice given E. coli derived asparaginase was associated with decrease in glutamine, which did not occur with V. succinogenes derived product that is free of glutaminase).

  31. Jenkins R, Perlin E. Severe hepatotoxicity from Escherichia coli L-asparaginase. J Natl Med Assoc 1987; 79: 775, 779. PubMed Citation  (51 year old woman with diabetes and acute lymphocytic leukemia developed jaundice at the end of a 10 day course of asparaginase [bilirubin 9.0 rising to 25.5 mg/dL, AST 344 to 1920 U/L, Alk P 400 to 1650 U/L, with high ammonia and decreased fibrinogen], but gradually improved and all tests were normal 4 months later).

  32. Bessho F, Kinumaki H, Yokota S, Hayashi Y, Kobayashi M, Kamoshita S. Liver function studies in children with acute lymphocytic leukemia after cessation of therapy. Med Pediatr Oncol 1994; 23: 111-5. PubMed Citation  (Among 27 children with acute leukemia, serum ALT levels were often elevated during induction and maintenance therapy, but were normal or near normal in all 3 months after stopping therapy and remained normal in long term follow up).

  33. Wróbel G, Dobaczewski G, Kazanowska B, Boguslawska-Jaworska J, Balwierz W, Balcerska A, Bubala H, et al. [Adverse reactions associated with the use of L-asparaginase during therapy of patients with B non-Hodgkin's lymphoma. Report of the Polish Paediatric Leukaemia/Lymphoma Study Group]. Med Wieku Rozwoj 2000; 4 (1 Suppl 2): 67-72. Polish. PubMed Citation  (Abstract: among 66 children with non- Hodgkin lymphoma treated with asparaginase, 20 [30%] developed adverse reactions, mostly typically coagulation abnormalities [18%] and "impairment of liver function" [9%]).

  34. Sahoo S, Hart J. Histopathological features of L-asparaginase-induced liver disease. Semin Liver Dis 2003; 23: 295-9. PubMed Citation  (Four patients developed hepatomegaly and abnormal liver tests 2-20 days after starting asparaginase [bilirubin 1.6-39.0 mg/dL, ALT 69-3916 U/L, Alk P 118-1075 U/L, albumin 2.2-2.6 g/dL] and had diffuse macro- and micro-vesicular steatosis on liver biopsy; one patient had acute liver failure and died).

  35. Graham ML. Pegaspargase: a review of clinical studies. Adv Drug Deliv Rev 2003; 55: 1293-302. PubMed Citation  (Review of clinical trials of pegylated asparaginase; toxicities were similar to the standard product and included hypoalbuminemia, lipoprotein abnormalities and elevations in ALT, Alk P and bilirubin).

  36. Bodmer M, Sulz M, Stadlmann S, Droll A, Terracciano L, Krähenbühl S.  Fatal liver failure in an adult patient with acute lymphoblastic leukemia following treatment with L-asparaginase. Digestion 2006; 74: 28-32. PubMed Citation  (68 year old man developed jaundice after 26 days of chemotherapy which included asparaginase [bilirubin 10.9 rising to 32.2 mg/dL, ALT 122 rising to 526 U/L, Alk P 480 rising to 2688 U/L], with progressive somnolence, hyperammonemia, coagulopathy, coma and death from liver failure 4 weeks later: Case 1).

  37. Flores-Calderón J, Exiga-Gonzaléz E, Morán-Villota S, Martín-Trejo J, Yamamoto-Nagano A. Acute pancreatitis in children with acute lymphoblastic leukemia treated with L-asparaginase. J Pediatr Hematol Oncol 2009; 31: 790-3. PubMed Citation  (Among 266 children given chemotherapy [including asparaginase with prednisone, vincristine, daunorubicin and methotrexate] for acute lymphocytic leukemia over a 6 year period, 18 [7%] developed pancreatitis arising 1-18 days after last dose of asparaginase [amylase 19-2893 U/L]; no fatalities, but 3 developed a pseudocyst and chronic symptoms and 3 required long term insulin).

  38. Yong W, Zheng W, Zhu J, Zhang Y, Wang X, Xie Y, Lin N, et al. L-asparaginase in the treatment of refractory and relapsed extranodal NK/T-cell lymphoma, nasal type. Ann Hematol 2009; 88: 647-52. PubMed Citation  (Among 45 adult patients receiving asparaginase for refractory and relapsed NKT cell leukemia, side effects included elevations in ALT in 51%, bilirubin in 33% and decreases in albumin in 9%).

  39. Ladas EJ, Kroll DJ, Oberlies NH, Cheng B, Ndao DH, Rheingold SR, Kelly KM. A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia (ALL). Cancer 2010; 116: 506-13. PubMed Citation  (Among 50 children with acute leukemia given maintenance chemotherapy [vincristine, mercaptopurine, methotrexate and prednisone] who had ALT elevations and who were treated with either milk thistle or placebo, there were few differences in subsequent ALT, AST and bilirubin levels, and elevations of serum ALT or AST above 5 times ULN occurred equally with or without milk thistle).

  40. Raetz EA, Salzer WL. Tolerability and efficacy of L-asparaginase therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2010; 32: 554-63. PubMed Citation  (Review of safety and efficacy of asparaginase in children with ALL discusses hypersensitivity reactions and toxicity caused by inhibition of protein synthesis, which includes pancreatitis, thrombosis, and liver dysfunction, some degree of which occurs in most patients, with hepatic steatosis in 87% which often persists for months after discontinuation).

  41. Tsutsui M, Koike M, Komatsu N. [Fulminant hepatitis possibly caused by L-asparaginase during induction chemotherapy in a patient with acute lymphoblastic leukemia]. Rinsho Ketsuek. 2012; 53: 531-4. Japanese. PubMed Citation  (44 year old man with ALL developed abnormal liver tests 10 days after starting asparaginase with progressive injury and death by day 32).

  42. Okamura A, Nishimura M, Sanada Y, Yakushijin K, Matsuoka H, Yamamoto K, Minami H. L-Asparaginase-induced fulminating liver dysfunction. Int J Hematol 2013; 98: 6-7. PubMed Citation  (49 year old woman with ALL developed liver test abnormalities 20 days after starting therapy with CHOP and 5 doses of asparaginase [bilirubin 2.2 mg/dL, ALT 43 U/L, Alk P not given] with hepatomegaly and marked fatty liver by CT scan; recovery by day 100).

  43. Roesmann A, Afify M, Panse J, Eisert A, Steitz J, Tolba RH. L-carnitine ameliorates L-asparaginase-induced acute liver toxicity in steatotic rat livers. Chemotherapy 2013; 59: 167-75. PubMed Citation  (Pretreatment with L-carnitinde decreased the liver injury and steatosis of isolated perfused rat livers exposed to asparaginase).

  44. Vetro C, Giulietti G, Calafiore V, Romano A, Di Raimondo F. A snapshot of asparaginase-induced liver insufficiency. Eur J Haematol 2014; 92: 271-2. PubMed Citation  (39 year old man with ALL and renal transplant developed hepatomegaly and marked fatty liver [by CT scan] 25 days after starting pegaspargase [bilirubin not given; AST 90 U/L, Alk P 167 U/L, albumin 2.3 g/dL, fibrinogen 0, antithrombin III 19%], with progressive liver failure and death).

  45. Al-Nawakil C, Willems L, Mauprivez C, Laffy B, Benm'rad M, Tamburini J, Fontaine H, et al. Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors. Leuk Lymphoma 2014; 55: 1670-4. PubMed Citation  (Three patients, ages 51-64 years, developed severe liver injury 11-22 days after starting asparaginase therapy for ALL [peak bilirubin 6.1-50.4 mg/dL, ALT 480-1150 U/L, Alk P 550-2400 U/L, CT scan showing hepatomegaly and fatty liver], all 3 recovering after L-carnitine and vitamin B therapy).

  46. Saison J, Berger F, Lebosse F, Audoual R, Thomas X, Michallet M. Hepatomegaly and fever at the time of neutrophil recovery revealing L-asparaginase toxicity in the treatment of acute lymphoblastic leukemia. Am J Case Rep 2014; 15: 13-7. PubMed Citation  (52 year old man with ALL developed fever and hepatomegaly by day 25 of chemotherapy and, after 5 injections of asparaginase [bilirubin 7.5 mg/dL, ALT 148 U/L, Alk P 148 U/L], rising for 2 weeks and then returning to normal within 2 months, biopsy showing marked steatosis and mild necrosis).

  47. Douer D, Aldoss I, Lunning MA, Burke PW, Ramezani L, Mark L, Vrona J, et al. Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia. J Clin Oncol 2014; 32: 905-11. PubMed Citation  (Among 51 adults with ALL treated with 192 doses of intravenous pegaspargase, ALT or AST elevations occurred in all patients [above 5 times ULN in 63%], and bilirubin in 26 patients [above 3 times ULN in 31%], but all resolved spontaneously [within 6-83 days], although therapy was delayed in 10 patients for high bilirubin and 11 for ALT or AST elevations).

  48. Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol 2014; 13: 231-9. PubMed Citation  (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, none were attributed to asparaginase or pegaspargase).

  49. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 cases [5%] were attributed to antineoplastic agents including 2 to asparaginase and 2 to pegaspargase, all 4 of which were jaundiced, but none were fatal).

  50. Horvat TZ, Pecoraro JJ, Daley RJ, Buie LW, King AC, Rampal RK, Tallman MS, et al. The use of Erwinia asparaginase for adult patients with acute lymphoblastic leukemia after pegaspargase intolerance. Leuk Res 2016; 50: 17-20. PubMed Citation  (Ten adults with ALL with hypersensitivity or intolerance of pegaspargase were able to tolerate Erwinia aspaginase without hypersensivity reactions and with only mild-to-moderate hepatotoxicity).

  51. Göpel W, Schnetzke U, Hochhaus A, Scholl S. Functional acute liver failure after treatment with pegylated asparaginase in a patient with acute lymphoblastic leukemia: potential impact of plasmapheresis. Ann Hematol 2016; 95: 1899-901. PubMed Citation  (44 year old man with ALL developed liver failure 3 days after receiving pegaspargase [bilirubin rising to ~29 mg/dL, ALTto 2.5 times ULN, GGT to 16 times ULN], recovering over 3 week period folloinwg plasmapheresis).

  52. Alshiekh-Nasany R, Douer D. L-Carnitine for treatment of pegasparaginase-induced hepatotoxicity. Acta Haematol 2016; 135: 208-10. PubMed Citation  (56 year old man with ALL developed jaundice  after a single infusion of pegaspargase [peak bilirubin 26.6 mg/dL, ALT ~230 U/L, Alk P not given], resolving after a 6 day course of L-carnitine).

  53. Hijiya N, van der Sluis IM. Asparaginase-associated toxicity in children with acute lymphoblastic leukemia. Leuk Lymphoma 2016; 57: 748-57. PubMed Citation  (Review of the mechanism of action of asparaginase and its toxicity in children).

  54. Blackman A, Boutin A, Shimanovsky A, Baker WJ, Forcello N. Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: A case report and review of the literature. J Oncol Pharm Pract 2017 Jan 1. [Epub ahead of print] PubMed Citation  (36 year old woman with ALL developed jaundice 4 days after a second dose of pegaspargase [days 4 and 17 of therapy] [bilirubin 11.5 mg/dL, ALT 2493 U/L, Alk P 270 U/L, INR 1.0], improving rapidly with L-carnitine [50 mg/k/day for 8 days] and vitamin B therapy and tolerating a reduced dose of pegaspargase, and resumption of chemotherapy with recurrence of liver injury 6 weeks later).

  55. Toksvang LN, De Pietri S, Nielsen SN, Nersting J, Albertsen BK, Wehner PS, Rosthøj S, et al. Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites. Pediatr Blood Cancer 2017; 64. e26519. PubMed Citation  (Among 130 children with ALL recieving a complex chemotherapy regimen that included 8-15 biweekly pegaspargase infusions, 29 developed liver injury diagnosed as sinusoidal obstruction syndrome [SOS] by clinical criteria alone, possibly due to asparaginase effects on mercaptopurine metabolism, but all children recovered).

  56. Liu Y, Fernandez CA, Smith C, Yang W, Cheng C, Panetta JC, Kornegay N, et al. Genome-wide study links PNPLA3 variant with elevated hepatic transaminase after acute lymphoblastic leukemia therapy. Clin Pharmacol Ther 2017 Jan 16. [Epub ahead of print] PubMed Citation  (Testing of two cohorts of patients receiving asparaginase found associations of posttreatment ALT levels and the PNPLA3 variant that has been linked to ALT elevations in the general population and with alcoholic and nonalcoholic fatty liver disease).

  57. Özdemir ZC, Turhan AB, Eren M, Bor Ö. Is N-acetylcysteine infusion an effective treatment option in L-asparaginase associated hepatotoxicity? Blood Res 2017; 52: 69-71. PubMed Citation  (2 year old with ALL developed liver test abnormalities after a fifth infusion of an E. coli derived asparaginase [bilirubin 7 mg/dL, ALT 501 U/L, Alk P 246 U/L, GGT 1297 U/L], with recovery after 6 days of N-acetylcysteine infusions and minimal hepatotoxicity with later chemotherapy using Erwinia asparaginase).

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