a) CASE REPORT: A 55-year-old woman developed severe hyperkalemia with associated ECG changes while receiving asparaginase for acute lymphatic leukemia. The patient received doses of 100 to 200 IU/kg/day for 4 of 5 days in combination with dexamethasone and allopurinol. On the fifth day the patient developed diffuse muscular tremors, hypotension, dyspnea, and hyperkalemia (up to 9.5 mEq/L). Hyperuricemia increased from 8.4 to 12 mg % and ECG revealed a disappearance of atrial activity and prolongation of the QRS interval (0.2 msec) with increases in T-wave amplitude and voltage (Bottoni & Volpato, 1974). Asparaginase was discontinued resulting in normalization of ECG and potassium levels.

a) CASE REPORT: Asparaginase-induced occlusive coronary thrombosis was suspected in a 21-year-old man receiving combination chemotherapy for ALL. On day 14 of antineoplastic therapy the patient received his daily dose of asparaginase 9000 IU, and 12 hours later developed an acute myocardial infarction. The patient continued chemotherapy without asparaginase and without further sequel (Fragasso et al, 1995).

a) Seizures have been reported with asparaginase therapy (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013; Oettgen et al, 1970; Ohnuma et al, 1969).

a) Asparaginase has been associated with CNS symptoms including somnolence (Oettgen et al, 1970; Ohnuma et al, 1969).

a) Posterior reversible encephalopathy syndrome (PRES) has been reported with the use of asparaginase combined with other chemotherapeutic agents. Symptoms may include headache, seizure, visual disturbances, altered mental status, or hypertension (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).

a) CASE REPORT: A 15-year-old boy, with acute lymphoblastic leukemia, presented with a severe headache and persistent vomiting approximately one month after receiving asparaginase and dexamethasone as reinduction phase therapy. Four days after presentation, the patient developed an acute cerebral focal convulsion. An MRI showed total cerebral sinus occlusion. Laboratory analysis revealed elevated D-dimer levels (initial concentration 749 mcg/L) and a prolonged prothrombin time (42 seconds). His serum triglyceride concentrations were also elevated, approximately 30-fold (59 mmol/L). Following low molecular weight heparin therapy and administration of bezafibrate, an antihyperlipidemic agent, the patient's cerebral occlusion resolved, without neurologic sequelae, and his triglyceride levels normalized (DeSilva et al, 2007).

a) CNS hemorrhages have been reported with asparaginase therapy (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).
b) CASE REPORT: A 15-year-old girl developed seizures, hypotension (80/50 mmHg), and tachycardia (160 bpm) after receiving 4 doses of L-asparaginase for treatment of acute lymphocytic leukemia (ALL). Laboratory data revealed prothrombin time and activated partial thromboplastin time of greater than 60 seconds and greater than 120 seconds, respectively (normal range 10.8 to 13.9 seconds and 26.6 to 40.3 seconds, respectively), and low fibrinogen levels (less than 10 mg/dL; normal range 156 to 400 mg/dL). A brain CT scan showed parenchymal hemorrhage bilaterally at the frontal and right posterior parietal areas. Administration of recombinant factor VIIa resulted in resolution of the patient's signs and symptoms and normalization of prothrombin time. A repeat brain CT scan, performed 10 days later, showed resorption of the parenchymal hemorrhage, although ischemic lesions continued to be present (Ucar & Caliskan, 2006).

a) Asparaginase administration has been associated with abnormal EEG changes, such as decreased alpha activity and increased theta and delta activity (Moure et al, 1970). EEG abnormalities were described in 3 patients following total doses of asparaginase of 190,000 to 300,000 international units over a period of 6 to 19 days. Abnormalities consisted of slowing of basal rhythm, predominance of theta and delta waves with and without paroxysmal appearance. These effects were coexistent with hyperammonemia in 2 patients receiving higher doses (240,000 units and 300,000 units total for 6 days and 15 days, respectively) (Oberling et al, 1971).
b) Asparaginase increases blood ammonia levels secondary to conversion of asparagine to aspartic acid and ammonia. Moderate to marked EEG abnormalities (decreased alpha activity or increased theta and delta activity) were observed in 6 of 7 patients with blood ammonia levels from 600 to greater than 800 mcg/100 mL and 10 of 14 patients with blood ammonia levels of 200 to 600 mcg/100 mL (Moure et al, 1970).

a) Coma has been reported with asparaginase therapy (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013; Anon, 1972).
b) The cerebral dysfunction manifested by confusion, stupor, or coma may occur in up to 25% of those receiving the drug (DeVita et al, 1989).

a) Allergic meningitis occurred in a 19-year-old man following intrathecal asparaginase therapy (total of 35,000 international units) for acute lymphoblastic leukemia. The patient was also receiving cytarabine. Ten minutes following the last injection of asparaginase, the patient developed intense headache, vomiting, photophobia, stiffness of the neck, and a fever of 39.5 degrees C. Within a few hours, the patient developed psychomotor agitation and confusion. Symptoms subsided within 1 day. Six days later the patient received a single IV infusion of 1000 international units/kg and developed fever, malaise, and arterial hypotension. The symptoms subsided upon discontinuation of the infusion. This is apparently the first report of an allergic meningitis secondary to intrathecal asparaginase (Goudemand et al, 1972).

a) CASE REPORT/CHILD: Asparaginase induction therapy of acute lymphocytic leukemia in a 5-year-old girl led to the development of acute, hemorrhagic pancreatitis that progressed to systemic inflammatory response syndrome (SIRS), and hypovolemic shock. Supportive care, including aggressive volume replacement, imipenem, narcotic analgesia, histamine-2 antagonist therapy, and total parenteral nutrition, brought about a full recovery (Lamelas et al, 1999).

a) Pancreatitis, sometimes fulminant and fatal, has been reported with the use of asparaginase (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013; Lamelas et al, 1999; Sahu et al, 1998l; Sadoff et al, 1997; Anon, 1972; Oettgen et al, 1970; Ohnuma et al, 1970; Keung et al, 1999). Acute pancreatitis may occur during therapy or after discontinuation. In one case series, 58% of patients were able to receive subsequent Erwinia asparaginase without further complications (Sahu et al, 1998l).
b) CASE SERIES: Acute pancreatitis was observed in 19 pediatric patients (median age, 5.5 years) receiving L-asparaginase (dose unspecified) to treat acute lymphoblastic leukemia. In the majority of these cases (63%), onset of pancreatitis occurred during the induction phase. Clinical presentation was characterized by anorexia, nausea/vomiting, fever, icterus, increased urination, and abdominal pain, distention, or tenderness. Eight patients had gastrointestinal bleeding. Signs and symptoms lasted for a median of 4 weeks, while the median durations of elevated amylase and lipase were 3 weeks and 2.5 weeks, respectively. On average, biochemical changes were evident 2 days after the onset of symptoms. Five patients developed pancreatic pseudocysts, which were managed conservatively. Among the remaining 14 patients, 4 eventually died as a result of pancreatitis. Eleven patients were switched to Erwinia asparaginase without any further pancreatic complication. Surviving patients suffered no long-term adverse sequelae (Sahu et al, 1998l).
c) Pancreatitis was reported in 4% of patients (n=940) who received asparaginase Erwinia chrysanthemi IV or IM during the Erwinaze Master Treatment Protocol (EMTP) clinical trial (Prod Info ERWINAZE(R) intramuscular intravenous injection, 2014).

a) Complications of pancreatitis, including pancreatic pseudocyst, have been reported with the use of asparaginase (Prod Info ELSPAR(R) injection, 2006; Karabulut et al, 2005).

a) Nausea and vomiting were reported in 2% and 3% of patients (n=940), respectively, who received asparaginase Erwinia chrysanthemi IV or IM during the Erwinaze Master Treatment Protocol (EMTP) clinical trial (Prod Info ERWINAZE(R) intramuscular intravenous injection, 2014).

a) Diarrhea was reported in 1% of patients (n=940) who received asparaginase Erwinia chrysanthemi IV or IM during the Erwinaze Master Treatment Protocol (EMTP) clinical trial (Prod Info ERWINAZE(R) intramuscular intravenous injection, 2014).

a) Abdominal pain/discomfort was reported in 1% of patients (n=940) who received asparaginase Erwinia chrysanthemi IV or IM during the Erwinaze Master Treatment Protocol (EMTP) clinical trial (Prod Info ERWINAZE(R) intramuscular intravenous injection, 2014).

a) Mucositis was reported in 1% of patients (n=940) who received asparaginase Erwinia chrysanthemi IV or IM during the Erwinaze Master Treatment Protocol (EMTP) clinical trial (Prod Info ERWINAZE(R) intramuscular intravenous injection, 2014).

a) Liver abnormalities have been reported with asparaginase therapy, including AST (SGOT), ALT (SGPT), alkaline phosphatase, and bilirubin elevations, and serum albumin and fibrinogen decreases (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).
b) Hepatotoxicity of asparaginase has been reported in children with advanced leukemia (Anon, 1972). In 105 children receiving intravenous asparaginase 200 IU/kg/day intermittently over a period of 26 days or 200 IU/kg every other day for 15 days, abnormal liver enzymes were reported in 76, bilirubin increases in 16, and icterus in 3. Fatty changes in the liver were noted upon autopsy in 18 children. There was no significant correlation between dosage regimen and hepatotoxic effects.
c) Fatty metamorphosis of the liver was described in 31 children upon necropsy (Pratt & Johnson, 1971).
d) Elevated transaminase concentrations were reported in 4% of patients (n=940) who received asparaginase Erwinia chrysanthemi IV or IM during the Erwinaze Master Treatment Protocol (EMTP) clinical trial (Prod Info ERWINAZE(R) intramuscular intravenous injection, 2014).

a) CASE REPORT: Fatal liver failure with accompanying multi-organ failure was reported in an adult patient being treated with L-asparaginase for acute lymphoblastic leukemia. Histopathology showed mixed liver injury with microvesicular hepatic steatosis. The mechanism of liver injury is unknown (Bodmer et al, 2006).

a) Azotemia, has been reported with asparaginase therapy (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).

a) Thrombosis, fatal bleeding, consumption coagulopathy, and intracranial hemorrhage in association with low fibrinogen levels have all been reported in those receiving asparaginase infusions (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013; Ucar & Caliskan, 2006; DeVita et al, 1989a). In patients with acute lymphoid leukemia, the risk of thrombosis is 4.9 fold higher in patients being treated with L-asparaginase than those not treated with this particular drug (DeStefano et al, 2005).
b) The asparaginase component of a combination chemotherapeutic regimen for acute lymphocytic leukemia was implicated as the probable cause of hemostatic complications in a retrospective review of 1100 pediatric patients. The overall incidence was 2.8%, of which 19 cases (61% of total) involved thrombosis and 12 cases (39% of total) involved hemorrhage. Three cases were fatal. The most frequently affected sites were the central nervous system (42%) and subclavian vein (29%). Almost all episodes occurred during the induction period when concomitant asparaginase and glucocorticoids were administered (Sutor et al, 1999).
c) The effect of asparaginase on coagulation factors was studied during initiation of chemotherapy in 26 patients with acute lymphoblastic leukemia. Fibrinogen levels decreased to less than 0.2 gm in all patients with prolongation of PTT to greater than 45 seconds at 2 to 12 days of therapy in 23 patients. Coagulation factors IX and XI were decreased to less than 70% in 9 and 14 patients, respectively. Factor VIII was elevated in 13 patients. Coagulation factors returned to normal within 3 to 11 days after discontinuation of asparaginase (Ramsay et al, 1977).
d) Several cases of complications due to clotting abnormalities have been reported following L-asparaginase therapy. Dural sinus thrombosis developed in 2 children with ALL during induction treatment with vincristine, prednisone and asparaginase (Steinherz et al, 1981); a 15-year-old boy developed cerebral sinus thrombosis and hypertriglyceridemia during treatment of acute lymphoblastic leukemia with asparaginase and dexamethasone (Dietel et al, 2007); a 9-year-old boy developed sigmoid sinus thrombosis with ocular complication of optic disc edema and right sixth nerve palsy during treatment with L-asparaginase for acute lymphocytic leukemia (Foroozan, 2005); a retrospective review of children in a non-urban area with ischemic stroke identified one child (out of 27) with ischemic stroke due to L-asparaginase (Bowen et al, 2005); 2 patients developed clinical features of intracranial bleeding during induction for ALL (Urban & Sager, 1981); and 2 children developed intracranial hemorrhagic infarcts with focal seizures and hemiparesis following induction therapy for ALL (Cairo et al, 1980).
e) Hemostatic changes were reported in children with acute lymphoblastic leukemia (ALL) according to 2 different L-asparaginase schedules (Miniero et al, 1986). L-asparaginase-induced coagulopathy is most commonly associated with vincristine and prednisone. Thus the risk/benefit ratio for the use of L-asparaginase early in the induction of children with low risk ALL needs to be further evaluated.

a) Leukopenia has been reported during asparaginase therapy (Mathe et al, 1970; Oehlers et al, 1969; Kolarz & Pietschmann, 1971; Johnston et al, 1974; Lorie et al, 1973).
b) CASE REPORT: Profound leukopenia was reported in a 25-year-old man who received intravenous asparaginase 12,500 IU daily for 4 days for acute lymphoblastic leukemia . After 2 days of therapy, the patient developed nausea, vomiting and high fever in addition to chest pain and left-sided pleural effusion. Leukocytes decreased to 550/mm(3). Asparaginase was discontinued, and the patient was given penicillin G with cephaloridine for the development of infection and nystatin for Candida infection. However, the patient remained thrombocytopenic and leukopenic and died 15 days later in cardiac failure. Autopsy revealed a decrease in bulk of leukemia tissue and depressed normal cellular elements of bone marrow (Oehlers et al, 1969).

a) Thrombocytopenia has been reported during asparaginase therapy (Mathe et al, 1970; Oettgen et al, 1970).

a) Urticaria has been reported with asparaginase use and may occur in the absence of a positive skin test, or during continued maintenance therapy (Oettgen et al, 1970; Jaffe et al, 1971).

a) Several patients have developed diabetes mellitus during asparaginase therapy, including severe diabetic ketoacidosis with insulin dependence (Jaffe, 1972b; Ouais et al, 3312; Butenandt et al, 1970; Gillette et al, 1972; Falletta et al, 1972). Hyperglycemia due to decreased serum insulin usually responds to discontinuation of the drug, intravenous fluids and insulin, but death has occurred in some cases (Butenandt et al, 1970; DeVita et al, 1989).
b) The exact mechanism of asparaginase-induced diabetes mellitus is unclear, but is likely related to interference with insulin production caused by protein synthesis inhibition (Ouais et al, 3312; Ettinger et al, 1997a). It has been suggested that L-asparaginase induces nonketotic hyperglycemia with hypoinsulinemia and hyperglucagonemia from a combined effect on alpha and beta cell function (Rao & Castells, 1986).
c) INCIDENCE: Pui et al (Pui et al, 1981) determined retrospectively the frequency and risk of hyperglycemia in 421 children with leukemia who had L-asparaginase and prednisone as part of their remission induction therapy. Of those patients, 9.7% developed this complication (41 of 421) with 39 within 1 week after the first dose. Age, obesity and Down syndrome each had a significant bearing on the frequency of hyperglycemia with children over 10 years of age more likely to develop the complication.
d) Ten children with acute lymphocytic leukemia developed transient diabetes mellitus during treatment with L-asparaginase and prednisone. They had relative hyperglucagonemia similar to other patients with diabetes mellitus (Turner et al, 1983).
e) Hyperglycemia was reported in 4% of patients (n=940) who received asparaginase Erwinia chrysanthemi IV or IM during the Erwinaze Master Treatment Protocol (EMTP) clinical trial (Prod Info ERWINAZE(R) intramuscular intravenous injection, 2014).

a) CASE REPORT: Hypertriglyceridemia with acute pancreatitis occurred in an 18-year-old man with acute lymphoblastic leukemia treated with asparaginase as part of a multi-drug chemotherapeutic regimen including daunorubicin, vincristine, prednisone, teniposide, and cytarabine. Two weeks after his third exposure to asparaginase, the patient presented with acute abdominal pain, a serum triglyceride of 1742 mg/dL, serum amylase of 284 IU/L, and serum lipase of 3256 IU/L. The patient was treated conservatively and discharged 2 weeks later with a serum triglyceride level of 243 mg/dL (Keung et al, 1999).
b) Hyperlipidemia has occurred with asparaginase (with or without prednisone) in patients undergoing induction therapy for ALL. A 10-year-old girl developed peak plasma triglyceride and cholesterol levels of 20,600 mg/dL and 1640 mg/dL, respectively following asparaginase plus prednisone induction therapy. On a review of patients receiving New York-II protocol (asparaginase plus prednisone pulses for ALL induction), 5 of 60 patients experienced transient, marked, benign hyperlipidemia (Steinherz, 1994).
c) CASE REPORT: Hypertriglyceridemia (59 mmol/L and 51 mmol/L upon repetitive determination) was reported in a 15-year-old boy, with acute lymphoblastic leukemia, after receiving asparaginase and dexamethasone as reinduction phase therapy. The patient's triglyceride concentrations normalized within one month following administration of bezafibrate, an antihyperlipidemic agent (DeSilva et al, 2007).

a) Hypersensitivity reactions, including serious allergic reactions, have occurred commonly during asparaginase therapy. There is a higher risk of serious allergic reactions in patients with previous exposure to asparaginase or other E coli L-asparaginase products, but serious reactions have also occurred with the first dose (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).
b) Intermittent analysis of antibodies in patients receiving asparaginase may be useful in predicting hypersensitivity. In a clinical study of 35 children receiving asparaginase to treat acute lymphoblastic leukemia, anti-asparaginase antibody levels were higher at all comparable time points in patients with hypersensitivity reactions (n=22) than in control patients (n=13) receiving an identical treatment regimen. Initial reactions occurred after a median of 11.5 doses of E. coli asparaginase, and half of the reacting patients were switched to Erwinia asparaginase. Reactions occurring after Erwinia asparaginase developed after a median of 4 doses. In reacting patients, the median anti-asparaginase antibody levels increased from 0.039 (optical density, 1 to 3200 dilution ratio) at baseline to 0.506 after hypersensitivity reactions (p=0.0002). In nonreacting control patients, these levels increased from 0.011 to 0.032 after 25 doses of asparaginase (p=0.02). After induction, 59% of reacting patients had anti-asparaginase antibody levels that were 3 times greater than background levels in blood samples from human volunteers, and 91% exhibited these increases after reinduction. Postinduction antibody levels among nonreacting patients did not differ significantly from those of normal control volunteers (Woo et al, 1998).
c) Hypersensitivity reactions were reported in 14% of patients (n=940) who received asparaginase Erwinia chrysanthemi IV or IM during the Erwinaze Master Treatment Protocol (EMTP) clinical trial (Prod Info ERWINAZE(R) intramuscular intravenous injection, 2014).

a) Serious allergic reactions, including anaphylaxis, have occurred commonly during asparaginase therapy. There is a higher risk in patients with previous exposure to asparaginase or other E coli L-asparaginase products, but serious allergic reactions have also occurred with the first dose. Treatment should be discontinued in patients with serious allergic reactions (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).
b) The incidence and clinical characteristics of anaphylactoid reactions to IV asparaginase were assessed in 196 patients given E coli asparaginase and 49 patients given Erwinia asparaginase. Twenty-nine of 196 patients (14.8%) given E coli asparaginase had an anaphylactoid reaction, occurring after their first through 12th doses. The risk of an anaphylactoid reaction to E coli asparaginase was significantly greater in patients who were not receiving concomitant prednisone-vincristine therapy and patients who had a hiatus of at least 1 month between courses. Seven of 49 patients (14%) treated with Erwinia asparaginase had an anaphylactoid reaction; all had been treated with E coli asparaginase earlier (Evans et al, 1982).
c) Anaphylaxis may occur in the absence of a positive skin test, or during continued maintenance therapy (DeVita et al, 1989).

a) MICE, RATS: Asparaginase, in mice and rats, has been shown to retard the weight gain of mothers and fetuses when given in doses of more than 1000 international units/kg (the recommended human dose). Resorptions, gross abnormalities, and skeletal abnormalities were observed (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).
b) RABBITS: In pregnant rabbits, the IV administration of 50 or 100 international units/kg of asparaginase (approximately 10% to 20% of the human dose) on Day 8 and 9 of gestation resulted in dose dependent embryotoxicity and gross abnormalities (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).

a) RATS, RABBITS: Embryofetal toxicities and fetal abnormalities were seen in embryofetal development studies of rats and rabbits. Maternal toxicity appeared as decreased body weight gain in pregnant rats, and partially undescended thymic tissue in fetuses occurred with rats given IM doses of 2000 international units (IU)/kg) (approximately 50% the maximum recommended human dose [MRHD], on a body surface area basis), every other day, during organogenesis. Similarly, 1 rabbit study showed maternal toxicity of decreased body weight with doses of 40 IU/kg (approximating 2% the MRHD, based on body surface area). A decreased number of live fetuses, a rise in postimplantation loss, and gross abnormalities (absent kidney, absent accessory lung lob, additional subclavian artery, and delayed ossification) were seen in rabbits given doses of at least 10 IU/kg (approximately 0.5% the MRHD, adjusted for body surface area) (Prod Info ERWINAZE(R) intramuscular injection, 2014)

a) RABBITS: In pregnant rabbits, the IV administration of 50 or 100 international units/kg of asparaginase (approximately 10% to 20% of the human dose) on Day 8 and 9 of gestation resulted in dose dependent embryotoxicity (Prod Info ELSPAR(R) intravenous injection, intramuscular injection, 2013).

a) RABBITS: A decreased number of live fetuses, a rise in postimplantation loss, and gross abnormalities (absent kidney, absent accessory lung lob, additional subclavian artery, and delayed ossification) were seen in rabbits given doses of at least 10 IU/kg (approximately 0.5% the MRHD, adjusted for body surface area) (Prod Info ERWINAZE(R) intramuscular injection, 2014)

a) No effect on male or female fertility was seen in an embryonic development and fertility study in rats with IM doses up to 2000 international units (IU)/kg (approximately 50% the recommended human dose [RHD], based on body surface area), administered every other day, for 35 total doses. However, a decreased sperm count was seen in male rats administered approximately more than 500 IU/kg (approximately 12% of the RHD) (Prod Info ERWINAZE(R) intramuscular injection, 2014).

a) At the time of this review, the manufacturer does not report any carcinogenic potential for asparaginase Erwinia chrysanthemi in humans (Prod Info ERWINAZE(TM) lyophilized powder for intramuscular injection, 2011).

a) Development of melanomas and aplastic nevi were reported in a 17-year-old boy 2 to 3 months after combination chemotherapy for pre-B-cell acute lymphocytic leukemia which included E. coli-derived L-asparaginase (Reutter et al, 2007).

a) Monitor vital signs, including temperature, and mental status.