Medications | Asparaginase Dosing, Monitoring, and Toxicity Management – Adult/Pediatric – Inpatient/Ambulatory
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Asparaginase Dosing, Monitoring, and Toxicity
Management – Adult/Pediatric –
Inpatient/Ambulatory
Clinical Practice Guideline
Note: Active Table of Contents – Click each header below to jump to the section of interest
Table of Contents
INTRODUCTION ............................................................................................................. 3
SCOPE ............................................................................................................................ 3
DEFINITIONS ................................................................................................................. 4
RECOMMENDATIONS ................................................................................................... 5
METHODOLOGY .......................................................................................................... 14
COLLATERAL TOOLS & RESOURCES (AS APPROPRIATE) .................................. 17
APPENDIX A. GRADING OF COMMON ASPARAGINASE TOXICITIES ................... 18
APPENDIX B. ASPARAGINASE TOXICITY MONITORING STRATEGY SUMMARY 19
APPENDIX C. ASPARAGINASE TOXICITY MANAGEMENT SUMMARY .................. 20
REFERENCES .............................................................................................................. 21
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Content Expert(s):
Name: Mike Fallon, PharmD – Pharmacy
Phone Number: (608) 263-1290
Email Address: mfallon@uwhealth.org
Contact for Changes:
Name: Philip Trapskin, PharmD – Pharmacy
Phone Number: (608) 263-1328
Email Address: ptrapskin@uwhealth.org
Guideline Author(s):
Jared Borlagdan, PharmD – Pharmacy
Mike Fallon, PharmD – Pharmacy
Nicole Lubcke, PharmD – Pharmacy
Workgroup Members:
Carol Diamond, MD – Pediatric Hematology/Oncology
Ryan Mattison, MD – Adult Hematology/Oncology
Committee Approval(s):
Pediatric Clinical Ops (01/22/18)
Leukemia (DOT) (02/16/18)
Laboratory Committee (02/21/18)
Chemotherapy Council Subcommittee (03/14/18)
Pharmacy & Therapeutics Committee (04/19/18)
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Introduction
Asparaginase products pegylated-asparaginase (pegaspargase) and asparaginase Erwinia
chrysanthemi (Erwinia asparaginase) are medications utilized in treatment protocols for various
hematologic malignancies. These products have been an integral aspect of multiagent therapy
yielding high survival rates in pediatric acute lymphoblastic leukemia (ALL).1, 2 Of the two
available asparaginase products in the US, pegaspargase is recommended as first-line therapy
due to its longer duration of action, less frequent administration, and flexibility in route of
administration (i.e., intramuscular and intravenous).3-9
The limiting factors to using asparaginase for both adult and pediatric patients are the toxicities
associated with the drug, which include hypersensitivity, pancreatitis, hyperglycemia,
hypertriglyceridemia, hepatotoxicity, hyperbilirubinemia, hyperammonemia, and thrombotic
events.1, 9-13 In pediatric patients, hyperammonemia and hypersensitivity are among the most
common toxicities that occur. The Children’s Oncology Group (COG) discourages pre-
medication with antihistamines as this may mask a possible systemic allergy to pegaspargase,
which often signals the presence of asparaginase neutralizing antibodies. Many pediatric
patients are often switched to Erwinia asparaginase at the first sign of a hypersensitivity
reaction, regardless of the severity.6, 7
Compared to pediatric patients, adult patients being treated for ALL have traditionally used little
to no asparaginase in their treatment regimens. This is because the toxicities associated with
asparaginase have been reported more frequently in adults than in children, and it has been
shown that toxicity frequency with asparaginase has a proportional relationship with patient
age.9, 13 Depending on the grade of these toxicities, patients may temporarily discontinue
asparaginase therapy and initiate at a later date, switch asparaginase products, or simply
discontinue asparagine-depleting therapy altogether.3, 5-7, 9 Along with discontinuation of
asparaginase therapy correlating with a higher mortality rate, inappropriately switching patients
to Erwinia asparaginase has been shown to be associated with higher health care spending due
to drug acquisition cost and a more frequent dosing regimen.14 The historical lack of
asparaginase in adult ALL regimens is believed to be a strong contributing factor to the worse
prognosis of adults being treated for ALL compared to pediatric patients.1, 9, 10, 12, 15 Much of the
recent literature has looked at treating adults with “pediatric-inspired” regimens to elucidate the
toxicity profile in adults and showcase various strategies, such as changing dosing, monitoring
practices, or toxicity management, to allow adult patients to better tolerate the toxicities of
asparaginase products, ultimately decreasing mortality through prolonged asparaginase
therapy.1, 4, 9-12, 14-21
Scope
Intended User(s): Advanced Practice Providers, Pharmacists, Physicians, Registered Nurses
Objective(s): To maximize outcomes and minimize toxicity associated with asparaginase-
containing regimens. In addition, this guideline aims to avoid inappropriate use of Erwinia
asparaginase.
Target Population: Adult and pediatric oncology inpatients and clinic patients receiving
asparaginase products
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Clinical Questions Considered:
• What are appropriate monitoring practices for adult and pediatric patients on
asparaginase products?
• What types of hypersensitivity reactions are appropriate to facilitate transition of patients
from pegaspargase to Erwinia asparaginase?
• What grades of hypersensitivity reactions facilitate obtaining an asparaginase enzyme
activity level in a patient?
• How should an asparaginase enzyme activity level be interpreted and what should the
resulting action be?
• What are appropriate management practices for patients experiencing various toxicities
(hepatotoxicity, pancreatitis, hyperglycemia, CNS/non-CNS thrombosis, CNS/non-CNS
bleeding, hyperammonemia) due to asparaginase therapy?
Definitions
Table 1 – Interpretation of Asparaginase Enzyme Activity Levels1, 22-25
Enzyme Activity Level Interpretation
< 0.1 IU/mL Subtherapeutic
0.1 – 1 IU/mL Therapeutic, re-draw level within 14 days
> 1 IU/mL Therapeutic, continue therapy
1. CTCAE: Common Terminology Criteria for Adverse Events26
2. BSA: Body Surface Area
3. COG: Children’s Oncology Group
4. PT: prothrombin time
5. PTT: partial thromboplastin time
6. FFP: fresh frozen plasma
7. LMWH: low molecular weight heparin
8. ULN: upper limit of normal
9. ADL: activities of daily living
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Recommendations
1. Asparaginase product choice
1.1 It is recommended that pegaspargase be utilized as a first-line agent for
asparaginase therapy in adult and pediatric patients.3-9 (UW Health very low quality
evidence, strong recommendation)
1.2 It is recommended to switch from pegaspargase to Erwinia asparaginase in adult
and pediatric patients that have experienced a severe grade 2 hypersensitivity
reaction or a true grade 3 or 4 hypersensitivity reaction.3-7, 9, 22, 27 (UW Health low
quality evidence, strong recommendation)
1.3 The substitution of Erwinia asparaginase for pegaspargase after adverse events
other than hypersensitivity should be avoided.3, 5-7 (UW Health very low quality
evidence, strong recommendation)
2. Asparaginase product dosing and administration
2.1 Pegaspargase should be dosed based on UW Health protocols utilized for the
treatment of various hematologic malignancies.5-7 (UW Health very low quality
evidence, strong recommendation)
2.2 In adult patients, intramuscular administration should be recommended over
intravenous administration due to the potential increased risk and faster onset of
hypersensitivity of intravenously-administered pegaspargase.5 (UW Health very low
quality evidence, strong recommendation)
2.3 In pediatric patients, intravenous infusion over 2 hours should be utilized to
minimize hypersensitivity, hyperammonemia, and injection site trauma associated
with intramuscular injections of pegaspargase.6, 7, 28 (UW Health very low quality
evidence, strong recommendation)
2.4 Erwinia asparaginase should be dosed based on protocols UW Health utilizes for
treatment of various hematologic malignancies.5-7 (UW Health very low quality
evidence, strong recommendation)
2.5 Dose adjustments for both adult and pediatric patients should be guided by the
patient’s treatment protocol and the grade of toxicity that the patient experienced.3, 5-
7 (UW Health very low quality evidence, strong recommendation)
2.6 It is reasonable to consider capping the dose at 1 vial (3750 IU/m2) or banding the
dose to 10% as it has been shown to yield effective asparagine depletion while
having a potentially lower toxicity risk in adult patients due to decreased drug
exposure.1, 9, 10, 17 (UW Health very low quality evidence, strong recommendation)
3. Monitoring of toxicity for patients receiving asparaginase products
3.1 Pediatric patients with a BSA > 1.6 m2 should be monitored with the same
frequency as adults due to an increased risk for toxicity.1, 10, 16, 18 (UW Health very
low quality evidence, strong recommendation)
3.2 Asparaginase toxicity grades may be determined using CTCAE and the expert
recommendations by Stock et al (see Appendix A).9, 26 (UW Health very low quality
evidence, weak/conditional recommendation)
3.3 Hypersensitivity
3.3.1 It is recommended that the patient be observed for 1 hour after administration
of an asparaginase product and have an anaphylaxis kit available if needed.
3-7, 9 (UW Health very low quality evidence, strong recommendation)
3.3.2 Adult patients
3.3.2.1 It is recommended that patients receive pre-medication with oral
acetaminophen 650 mg and oral diphenhydramine 25 mg prior to
asparaginase doses to decrease the risk of allergic reactions.5, 9 (UW
Health very low quality evidence, strong recommendation)
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3.3.2.2 It is recommended to draw an asparaginase enzyme activity level after
seven days of the first administered dose of pegaspargase to assess
neutralizing antibodies and identify possible silent inactivation.1, 9, 22-25
3.3.2.3 If the asparaginase enzyme activity level after seven days is less than
0.1 IU/mL, consider switch to Erwinia asparaginase.1, 22-25 (UW Health
very low quality evidence, weak/conditional recommendation)
3.3.2.4 If asparaginase enzyme activity level is between 0.1 and 1 IU/mL after
seven days, redraw the level at 14 days post-dose to assess
accelerated clearance1, 9, 22-25 (UW Health very low quality evidence,
weak/conditional recommendation)
3.3.3 Pediatric patients
3.3.3.1 COG discourages pre-medication to decrease the risk of allergic
reactions as this may mask the appearance of systemic allergy,
indicating the possible presence of asparaginase neutralizing
antibodies.6, 7 (UW Health very low quality evidence, weak/conditional
recommendation)
3.3.3.2 If a patient is pre-medicated to decrease the risk of allergic reactions
and possible hypersensitivity, it is recommended to draw an
asparaginase enzyme activity level after seven days of the first
administered dose of pegaspargase to assess drug activity and identify
possible silent inactivation according to Table 2.1, 6, 7, 18, 22-25, 29 (UW
Health very low quality evidence, weak/conditional recommendation)
3.4 Liver Function Tests
3.4.1 It is recommended to monitor liver function tests and total bilirubin prior to
asparaginase administration in all patients.5-7, 9 (UW Health very low quality
evidence, strong recommendation)
3.4.2 Adult patients
3.4.2.1 It is recommended to monitor liver function tests following
pegaspargase administration once weekly for two weeks and prior to
subsequent doses of chemotherapy that can cause an increased risk for
hepatotoxicity.5, 9 (UW Health very low quality evidence,
weak/conditional recommendation)
3.4.3 Pediatric patients
3.4.3.1 It is reasonable to consider monitoring liver function tests following
pegaspargase administration for patients who have pre-existing
hyperbilirubinemia or elevated baseline liver function tests.3, 6, 7 (UW
Health very low quality evidence, weak/conditional recommendation)
3.5 Pancreatitis
3.5.1 Amylase, lipase, and triglycerides should be checked in all patients prior to
administration of the first pegaspargase dose.5-7, 9 (UW Health very low quality
evidence, strong recommendation)
3.5.2 Adult patients
3.5.2.1 During induction, amylase, lipase, and triglycerides should be checked
weekly for two weeks following the first dose of pegaspargase.3, 5, 9 (UW
Health very low quality evidence, strong recommendation)
3.5.2.2 For further doses of asparaginase products, amylase, lipase, and
triglycerides should be checked prior to administration and once seven
days post-asparaginase administration due to potential for development
beyond induction of chemotherapy.25, 30 (UW Health low quality
evidence, weak/conditional recommendation)
3.5.3 Pediatric patients
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3.5.3.1 For further doses of asparaginase products, triglycerides should be
checked prior to administration.25 (UW Health very low quality evidence,
weak/conditional recommendation)
3.5.3.2 It is reasonable to consider checking amylase, lipase, and triglycerides
seven days post-asparaginase administration if the patient has
previously experienced grade 2 or 3 pancreatitis or grade 2-4
hypertriglyceridemia. 3, 5-7, 9 (UW Health very low quality evidence,
weak/conditional recommendation)
3.6 Glucose
3.6.1 It is recommended to monitor serum glucose in patients receiving asparaginase
products periodically based on the specific treatment protocol being used to treat
the patient. 3, 5-7, 9 (UW Health very low quality evidence, weak/conditional
recommendation)
3.7 Blood and coagulation
3.7.1 For all patients, it is recommended to monitor a complete blood count with
differential and fibrinogen prior to administration of any asparaginase dose.3, 5-9, 16
(UW Health very low quality evidence, strong recommendation)
3.7.2 Adult patients
3.7.2.1 Platelets and fibrinogen should be monitored twice weekly for one week
following each dose of asparaginase.3, 5, 9 (UW Health very low quality
evidence, strong recommendation)
3.7.2.2 It is reasonable to omit monitoring PT and PTT as part of the
coagulation lab workup unless fibrinogen levels are below 100 mg/dL.
(UW Health very low quality evidence, weak/conditional
recommendation)
3.7.3 Pediatric patients
3.7.3.1 Platelets should be monitored at least weekly following each dose of
asparaginase.3, 6, 7 (UW Health very low quality evidence,
weak/conditional recommendation)
3.7.3.2 If patients develop a thrombosis while on asparaginase therapy,
platelets and fibrinogen should be monitored with the same frequency
as adult patients to help prevent thrombosis recurrence. 3 (UW Health
very low quality evidence, weak/conditional recommendation)
3.7.3.3 It is reasonable to omit monitoring PT and PTT as part of the
coagulation lab workup.6, 7 (UW Health very low quality evidence,
weak/conditional recommendation)
3.8 Ammonia
3.8.1 In patients that present with symptoms of altered mental status, unexplained
fatigue, somnolence, or seizures, serum ammonia should be monitored weekly
until symptom resolution.3, 9 (UW Health very low quality evidence,
weak/conditional recommendation)
3.9 Patients that resume or retrial asparaginase therapy after experiencing an adverse event
should be more closely monitored for recurrence of that event.3, 5-7, 9 (UW Health very low
quality evidence, strong recommendation)
4. Management of asparaginase-related toxicities
4.1 Dosing based on asparaginase enzyme activity levels
4.1.1 Adult patients
4.1.1.1 For patients that experience severe non-hypersensitivity adverse effects
and have asparaginase enzyme activity documented as therapeutic, it is
reasonable to consider dose reduction of 20% as clinically indicated.
With any dose reduction, re-check asparaginase enzyme activity weekly
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for two weeks post-dose.1, 9, 18, 19, 22-25, 29 (UW Health very low quality
evidence, weak/conditional recommendation)
4.2 Hypersensitivity
4.2.1 Pegaspargase should be continued in patients that experience a grade 2 or lower
hypersensitivity reaction.1, 3, 9, 15 (UW Health very low quality evidence,
weak/conditional recommendation)
4.2.2 Refer to Table 2 for grade 2 or lower hypersensitivity management for pediatric
patients. (UW Health very low quality evidence, weak/conditional
recommendation)
Table 2. Pediatric grade 1/2 hypersensitivity management strategies24
Hypersensitivity
Grade
Symptoms Management Strategy
Grade 1 • Transient
flushing/rash
• Temperature < 38°C
• Acceptable to give diphenhydramine PO x 1 dose
• Continue pegaspargase infusion
• Draw an ammonia level to rule out
hyperammonemia
Grade 2
(non-severe)
• Urticaria without
respiratory
symptoms
• Hypotension
• Edema
• Give medications to treat symptoms
• Finish pegaspargase infusion if possible
• Draw an ammonia level to rule out
hyperammonemia
• If at least ¼ (one-fourth) of the dose was given,
draw asparaginase enzyme activity level 4-7 days
post-dose to test for silent inactivation.
If level is:
o < 0.1 IU/mL – initiate Erwinia asparaginase as
soon as possible
o > 0.1 IU/mL – re-draw at 14 days post-dose
o > 1 IU/mL – use pegaspargase with pre-
medication for next cycle
• If giving future doses of pegaspargase: consider
pre-medication with diphenhydramine followed by
asparaginase enzyme activity levels
4.2.3 Pegaspargase should be discontinued in patients that experience a severe grade
2 hypersensitivity reaction or a true grade 3 or 4 hypersensitivity reaction.1, 3-7, 9, 15
(UW Health low quality evidence, strong recommendation)
4.2.4 Patients should switch from pegaspargase to Erwinia asparaginase if the patient
experienced hypersensitivity reactions that required parenteral intervention due
to administration of pegaspargase.3, 5-7, 9-15 (UW Health very low quality evidence,
strong recommendation)
4.2.5 For patients that have an asparaginase enzyme activity level of greater than 1
IU/mL while on pegaspargase, it is recommended that they continue
pegaspargase therapy for their next scheduled dose as this represents an
appropriate therapeutic level.1, 22-25 (UW Health very low quality evidence,
weak/conditional recommendation)
4.2.6 For patients that have an asparaginase enzyme activity between 0.1 – 1 IU/mL
while on pegaspargase, it is recommended that a repeat level be redrawn at 14
days post-dose to detect silent inactivation and/or accelerated clearance. 1, 22-25
(UW Health very low quality evidence, weak/conditional recommendation)
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4.2.7 For patients that have an asparaginase enzyme activity level of less than 0.1
IU/mL while on pegaspargase, it is recommended that they switch to Erwinia
asparaginase as this represents the presence of neutralizing antibodies causing
silent inactivation.1, 22-25 (UW Health very low quality evidence, weak/conditional
recommendation)
4.2.8 Patients that are switched to Erwinia asparaginase should have an asparaginase
enzyme activity level drawn within 24-48 hours after a dose of Erwinia
administration to assess drug activity and detect silent inactivation if they
experience a non-severe grade 2 or lower hypersensitivity reaction.1 (UW Health
very low quality evidence, weak/conditional recommendation)
4.2.9 For patients that have an asparaginase enzyme activity level of less than < 0.1
IU/mL while on Erwinia asparaginase, asparaginase therapy should be
discontinued permanently.1, 22-25 (UW Health very low quality evidence,
weak/conditional recommendation)
4.2.10 Erwinia asparaginase should be discontinued in patients that experience a
severe grade 2 or a true grade 3 or 4 hypersensitivity reaction.1, 3-7, 9 (UW Health
very low quality evidence, strong recommendation)
4.3 Hepatotoxicity
4.3.1 It is recommended to continue scheduled administration of asparaginase
products for patients who present with grade 1 or 2 hepatotoxicity.3, 9 (UW Health
very low quality evidence, weak/conditional recommendation)
4.3.2 For patients that present with grade 3 hepatotoxicity, either due to asparaginase,
concomitant chemotherapy, or other hepatotoxic medications, it is reasonable to
delay the next dose of asparaginase until the patient’s hepatotoxicity returns to
below grade 2.3, 9 (UW Health very low quality evidence, weak/conditional
recommendation)
4.3.3 For patients that present with grade 4 hepatotoxicity, either due to asparaginase,
concomitant chemotherapy, or other hepatotoxic medications, it is reasonable to
discontinue asparaginase permanently or resume asparaginase therapy with
close monitoring if the patient’s hepatotoxicity does not return to below grade 2
within one week.3, 9 (UW Health very low quality evidence, weak/conditional
recommendation)
4.3.4 A review of the patient’s medication list should be conducted to assess for
hepatotoxic medications, which should be held until the patient’s liver function
tests return to baseline values. (UW Health very low quality evidence,
weak/conditional recommendation)
4.3.5 Patients that are re-trialed on asparaginase therapy after experiencing grade 3 or
4 hepatotoxicity should be monitored more closely.3, 9 (UW Health very low quality
evidence, strong recommendation)
4.3.6 It is recommended to continue asparaginase therapy in patients that present with
grade 1 or 2 hyperbilirubinemia.3, 9 (UW Health very low quality evidence,
weak/conditional recommendation)
4.3.7 It is reasonable to hold asparaginase therapy if direct bilirubin is greater than 3.1
mg/dL and resume once direct bilirubin is below 2.0 mg/dL.3, 9 (UW Health very
low quality evidence, weak/conditional recommendation)
4.3.8 Adult patients
4.3.8.1 It is reasonable to consider the administration of levocarnitine 50 mg/kg
IV daily and over the counter Vitamin B Complex 1 tab orally daily until
liver function tests approach normal values patients who present with
grade 3 or 4 hepatotoxicity.1, 31-34 (UW Health very low quality evidence,
weak/conditional recommendation)
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4.4 Pancreatitis
4.4.1 It is recommended to continue asparaginase therapy with close monitoring for
patients that experience grade 2 or lower pancreatitis.3, 9 (UW Health very low
quality evidence, weak/conditional recommendation)
4.4.2 It is recommended to permanently discontinue asparaginase therapy in patients
that experience grade 4 pancreatitis (i.e. hemorrhagic pancreatitis, severe
abdominal pain, intractable vomiting, grade 4 elevated amylase and/or lipase).3, 9
(UW Health very low quality evidence, strong recommendation)
4.4.3 Adult Patients
4.4.3.1 It is reasonable to consider holding asparaginase if triglycerides are
elevated beyond 1000 mg/dL and then resume the dose at the prior
level once triglycerides return to the patient’s normal range.3, 9, 35 (UW
Health very low quality evidence, weak/conditional recommendation)
4.4.3.2 It is reasonable to consider the use of micronized fenofibrate 67 mg
daily (maximum dose 200 mg/day) in patients with grade 2 through
grade 4 hypertriglyceridemia.1, 36 (UW Health very low quality evidence,
weak/conditional recommendation)
4.4.4 Pediatric Patients
4.4.4.1 It is reasonable to consider the use of intravenous octreotide either by
continuous or intermittent infusion for patients who are admitted with
grade 4 pancreatitis.37 (UW Health very low quality evidence,
weak/conditional recommendation)
4.4.4.2 It is reasonable to continue asparaginase therapy without dose
modifications for elevated triglycerides.3, 6, 7, 35 (UW Health very low
quality evidence, weak/conditional recommendation)
4.5 Hyperglycemia
4.5.1 Adult Patients
4.5.1.1 It is recommended to continue asparaginase therapy in patients that
present with grade 2 or lower hyperglycemia.3, 9 (UW Health very low
quality evidence, strong recommendation)
4.5.1.2 For patients that require insulin therapy, it is reasonable to hold
asparaginase and glucocorticoid therapy until the blood glucose is
regulated.3, 9 (UW Health very low quality evidence, weak/conditional
recommendation)
4.5.1.3 For patients that present with grade 4 hyperglycemia and are restarted
on asparaginase therapy, it is recommended to not make up for missed
doses.3, 9 (UW Health very low quality evidence, weak/conditional
recommendation)
4.5.2 Pediatric Patients
4.5.2.1 It is reasonable to continue asparaginase therapy for hyperglycemia
and treat with insulin if warranted.6, 7 (UW Health very low quality
evidence, weak/conditional recommendation)
4.6 Thrombosis
4.6.1 The goal fibrinogen level for patients on asparaginase therapy is greater than or
equal to 100 mg/dL. (UW Health very low quality of evidence, weak/conditional
recommendation) If clinically indicated it is reasonable to consider administration
simultaneous administration of FFP and cryoprecipitate, as the FFP helps to
balance the pro-coagulant effect of the cryoprecipitate and the asparagine
present in FFP will immediately get cleaved by pre-existing asparaginase present
in the body.38, 39 (UW Health very low quality evidence, weak/conditional
recommendation)
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4.6.2 Patients administered cryoprecipitate and FFP should have their fibrinogen level
checked the next day. (UW Health very low quality of evidence, strong
recommendation)
4.6.3 FFP and cryoprecipitate should not be administered as prophylaxis against
thrombosis due to a lack of clinical benefit shown in the current literature.40 (UW
Health low quality evidence, weak/conditional recommendation)
4.6.4 LMWH as prophylaxis against potential thrombotic events in all patients on
asparaginase therapy should be avoided due to a lack of mortality benefit.41-43
(UW Health low quality evidence, weak/conditional recommendation)
4.6.5 Non-central nervous system thrombosis
4.6.5.1 Patients with symptomatic grade 2-4 thrombosis should hold
asparaginase therapy until clinically stable with appropriate
antithrombotic therapy.3, 5-7, 9, 44 (UW Health very low quality evidence,
weak/conditional recommendation)
4.6.5.2 Once the thrombosis is clinically stable, it is reasonable to consider
resuming asparaginase therapy with closer monitoring while on
appropriate antithrombotic therapy or LMWH.3, 5-7, 9, 44 (UW Health very
low quality evidence, weak/conditional recommendation)
4.6.5.3 It is reasonable to consider continuation of asparaginase therapy in
patients that present with abnormal coagulation laboratory findings
without correlated clinical symptoms.3, 5-7, 9, 44 (UW Health very low
quality evidence, weak/conditional recommendation)
4.6.6 Central nervous system (CNS) thrombosis
4.6.6.1 Adult patients
4.6.6.1.1 Patients that present with grade 4 CNS thrombosis should
discontinue all asparaginase products permanently.3, 9 (UW
Health very low quality evidence, strong recommendation)
4.6.6.1.2 Adult patients that present with grade 3 or less CNS thrombosis
should discontinue therapy and treat with appropriate
antithrombotic therapy.3, 9 (UW Health very low quality evidence,
weak/conditional recommendation)
4.6.6.1.3 For grade 3 or less CNS thrombosis, it is reasonable to consider
resuming asparaginase at lower doses and/or longer intervals
between doses.3, 9 (UW Health very low quality evidence,
weak/conditional recommendation)
4.6.6.2 Pediatric patients
4.6.6.2.1 Asparaginase should be held and treated with appropriate
antithrombotic therapy.3, 6, 7, 45, 46 (UW Health very low quality
evidence, weak/conditional recommendation)
4.6.6.2.2 It is reasonable to consider resuming asparaginase therapy at
full dose when all symptoms have resolved and evidence of
recanalization by CT or MRI imaging has been shown.3, 6, 7, 45, 46
(UW Health very low quality evidence, weak/conditional
recommendation)
4.7 Bleeding
4.7.1 Non-CNS bleeding
4.7.1.1 Adult patients
4.7.1.1.1 For patients that present with grade 2-4 bleeding, it is
recommended to withhold asparaginase therapy until the
bleeding is < grade 1, until acute toxicity and clinical signs
resolve, and coagulant replacement therapy is stable or
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completed, then resume.3, 9 (UW Health very low quality
evidence, weak/conditional recommendation)
4.7.1.1.2 For patients that present with grade 2 bleeding based on
abnormal lab findings without a clinical correlate, asparaginase
therapy should not be withheld.3, 9 (UW Health very low quality
evidence, weak/conditional recommendation)
4.7.1.1.3 It is reasonable to consider the use of oral aminocaproic acid (1
gram four times a day) or tranexamic acid (1300 mg three times
daily). (UW Health very low quality evidence, weak/conditional
recommendation)
4.7.1.2 Pediatric patients
4.7.1.2.1 Symptomatic patients should be treated with appropriate factor
or procoagulant replacement. Asparaginase dose should be held
and resumed with the next scheduled dose.3, 6, 7, 45, 46 (UW Health
very low quality evidence, weak/conditional recommendation)
4.7.1.2.2 Asparaginase therapy should not be withheld in patients with
abnormal laboratory findings without a clinical correlate.3, 6, 7, 45, 46
(UW Health very low quality evidence, weak/conditional
recommendation)
4.7.2 CNS bleeding
4.7.2.1 Adult patients
4.7.2.1.1 For patients that present with grade 3 or lower hemorrhage, it is
recommended to discontinue asparaginase therapy until
symptoms/signs have fully resolved.3, 9 (UW Health very low
quality evidence, weak/conditional recommendation)
4.7.2.1.2 For patients that present with grade 4 hemorrhage, it is
recommended that asparaginase therapy be permanently
discontinued.3, 9 (UW Health very low quality evidence,
weak/conditional recommendation)
4.7.2.1.3 It is reasonable to consider coagulation factor replacement in
patients with grade 3 or lower hemorrhage.3, 9 (UW Health very
low quality evidence, weak/conditional recommendation)
4.7.2.1.4 It is reasonable to consider resuming asparaginase at lower
doses and/or longer intervals between doses.3, 9 (UW Health
very low quality evidence, weak/conditional recommendation)
4.7.2.2 Pediatric patients
4.7.2.2.1 Symptomatic patients should be treated with appropriate factor
or procoagulant replacement and have their asparaginase dose
held and resumed with the next scheduled dose.3, 6, 7, 45, 46 (UW
Health very low quality evidence, weak/conditional
recommendation)
4.7.2.2.2 Asparaginase therapy should not be withheld in patients with
abnormal laboratory findings without a clinical correlate.3, 6, 7, 45, 46
(UW Health very low quality evidence, weak/conditional
recommendation)
4.8 Hyperammonemia
4.8.1 It is recommended to administer lactulose in patients who present with
symptomatic hyperammonemia (altered mental status, unexplained fatigue,
somnolence, or seizures) starting at 20g by mouth three times daily with further
titration to produce 2 to 3 soft stools daily.3, 9 (UW Health very low quality
evidence, weak/conditional recommendation)
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13
4.8.2 Adult patients
4.8.2.1 Patients should continue therapy as normal for grade 2
hyperammonemia.3, 9 (UW Health very low quality evidence,
weak/conditional recommendation)
4.8.2.2 Full doses can be resumed in patients with grade 3 and 4
hyperammonemia once the toxicity becomes grade 2 or lower.3, 9 (UW
Health very low quality evidence, weak/conditional recommendation)
4.8.3 Pediatric Patients
4.8.3.1 Pediatric patients < 20 kg: start dosing at 10g by mouth three times
daily. (UW Health very low quality evidence, weak/conditional
recommendation)
Disclaimer
Clinical practice guidelines assist clinicians by providing a framework for the evaluation and
treatment of patients. This guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is
understood that some patients will not fit the clinical condition contemplated by a guideline and
that a guideline will rarely establish the only appropriate approach to a problem.
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14
Methodology
Development Process
Each guideline is reviewed and updated a minimum of every 3 years. All guidelines are
developed using the guiding principles, standard processes, and styling outlined in the UW
Health Clinical Practice Guideline Resource Guide. This includes expectations for workgroup
composition and recruitment strategies, disclosure and management of conflict of interest for
participating workgroup members, literature review techniques, evidence grading resources,
required approval bodies, and suggestions for communication and implementation.
Methods Used to Collect the Evidence:
The following criteria were used by the guideline author(s) and workgroup members to conduct
electronic database searches in the collection of evidence for review.
Literature Sources:
• PubMed
• American Society of Hematology Annual Meeting Abstracts
• Children’s Oncology Group Protocols
Time Period: All published literature through December 2017
Search Terms:
• Pegaspargase OR pegasparaginase OR asparaginase OR Erwinia
• Hypersensitivity OR allergic reaction
• Hepatotoxicity OR liver toxicity
• Pancreatitis
• Dyslipidemia OR hypertriglyceridemia
• Thrombosis
• Hyperammonemia
• Hyperglycemia
• Pediatric
• Adult
• Acute lymphoblastic leukemia
Methods to Select the Evidence:
Electronic database searches (PubMed, abstracts from the American Society of Hematology
Annual Meeting, and Children Oncology’s Group protocols) were conducted by the guideline
author(s) and workgroup members to collect evidence for review. External practices from other
institutions, expert opinion, and clinical experience were also considered during discussions of
the evidence.
Methods Used to Formulate the Recommendations:
The workgroup members agreed to adopt recommendations developed by external
organizations and/or created recommendations internally via a consensus process using
discussion of the literature and expert experience/opinion. If issues or controversies arose
where consensus could not be reached, the topic was escalated appropriately per the guiding
principles outlined in the UW Health Clinical Practice Guideline Resource Guide.
Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations:
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15
Recommendations developed by external organizations maintained the evidence grade
assigned within the original source document and were adopted for use at UW Health.
Internally developed recommendations, or those adopted from external sources without an
assigned evidence grade, were evaluated by the guideline workgroup using an algorithm
adapted from the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) methodology (see Figure 1).
Figure 1. GRADE Methodology adapted by UW Health
Rating Scheme for the Strength of the Evidence/Recommendations:
GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate
We are quite confident that the effect in the study is close to the true effect, but
it is also possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.
GRADE Ratings for Recommendations For or Against Practice
Strong
The net benefit of the treatment is clear, patient values and
circumstances are unlikely to affect the decision.
Weak/conditional
Recommendation may be conditional upon patient values and
preferences, the resources available, or the setting in which the
intervention will be implemented.
Cost Analysis:
A cost analysis was done by Tong et al in 2013 on a set of patients enrolled in the Dutch
Childhood Oncology Group ALL-10 medium-risk group intensification protocol. Treatment costs
were calculated based on 84 patients and compared patients who had no allergies to
pegaspargase to those that did have allergies to pegaspargase and required a switch to Erwinia
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16
asparaginase. From their analysis, they found that the total costs of the intensification course of
30 weeks were $57,893 (n=64) in patients without a pegaspargase allergy, while patients that
required a switch to Erwinia asparaginase incurred costs of $113,558 (n=20). Decision tree
analyses and simulations of part of the treatment were required in order to calculate these
values.14
Table 3. UW Health Acquisition Cost Table
Pegaspargase (3750 unit vial) Erwinia asparaginase (10000 unit
vial)
Cost per Cycle 2500 units/m2 x 1 dose
25000 units/m2 x 6 doses
Cost per Vial $14,399.09* $3,799.46*
Cost per Cycle
(1.7 m2 patient)
$28,798.18 $113,983.80
*Based on acquisition cost in December 2017
Recognition of Potential Health Care Disparities:
Health care disparities exist in cancer care. Patients that are uninsured are less likely to receive
proper cancer screening and express lower rates of delayed follow-up after any abnormal test
results, which lead to diagnosis at more advanced stages. Furthermore, institutions most likely
to serve minorities may not have as much access to state of the art diagnostic and therapeutic
measures and the ability to participate in cancer clinical trials, affecting the overall quality of
care. Additional factors that may influence outcomes of minorities include distrust of the health
care system, stigmas related to cancer and death, literacy and language barriers, and poor
expectations regarding the outcome from cancer care.47
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17
Collateral Tools & Resources
The following collateral tools and resources support staff execution and performance of the
evidence-based guideline recommendations in everyday clinical practice.
Metrics
• Adherence to the clinical practice guideline
• Number of doses of pegaspargase used at UW Health
• Number of doses of asparaginase (Erwinia) used at UW Health
• Incidence and severity of asparaginase toxicities as identified through voluntary reporting and
retrospective chart review
Beacon Protocols
1. AFCH ONC RSCH/SOC AALL1231 ARM A and B INTERIM MAINTENANCE (CMTX – AL
PATIENTS) (56D) – T-ALL AND T-NHL [5584]
2. AFCH ONC SOC PHILADELPHIA CHROMOSOME POSITIVE LEUKEMIA INDUCTION [6149]
3. CSC HEM ALL CALGB 10403 CONSOLIDATION (56D) [5815]
4. CSC HEM ALL CALGB 10403 EXTENDED REMISSION (15D) [5802]
5. CSC HEM INPT/OP
DEXAMETHASONE/ETOPOSIDE/IFOSFAMIDE/METHOTREXATE/PEGASPARGASE [4390]
6. CSC HEM INPT/OUTPT CALGB 10403 INDUCTION (29D) [5751]
7. CSC-R AALL1231 (ADULT) ARM A AND B INTERIM MAINTENANCE (CMTX – ALL PATIENTS)
(56D) – T-ALL AND T-NHL [6126]
8. PATIENT SPECIFIC TEMPLATE AFCH AALL0631 REINDUCTION (ARM A)) [5999]
9. PATIENT SPECIFIC TEMPLATE CSC HEM INPT/OP
DEXAMETHASONE/ETOPOSIDE/IFOSFAMIDE/IT CHEMO/
METHOTREXATE/PEGASPARGASE/VINCRISTINE (CCG-1941) [5760]
10. AFCH ONC SC ERWINIA ASPARAGINASE [4728]
11. AFCH SOC AALL0631 INDUCTION (PT GREATER THAN OR EQUAL TO 6 MO OLD AT DX) (35D)
[5848]
12. AFCH SOC AALL0631 INDUCTION (PT GREATER THAN OR EQUAL TO 7 D AND LESS THAN 6
MO OLD AT DX) (35D) [5094]
Clinical Practice Guidelines
1. Perioperative Medication Management - Adult/Pediatric - Inpatient/Ambulatory
2. Intravenous Administration of Formulary Medications – Adult – Inpatient/Ambulatory
3. Intravenous Administration of Formulary Medications – Pediatric/Neonatal – Inpatient/Ambulatory
Patient Resources
1. Health and Nutrition Facts for You #6079: What to Do for an Allergic Reaction to Asparaginase
Chemotherapy
2. Medication Fact Sheet: Asparaginase
3. Lexicomp: Pegaspargase
4. Lexicomp: Asparaginase (Erwinia)
Policies
1. UWHC Policy 6.1.1: Chemotherapy Processes: Informed Consent, Ordering, Verification,
Administration, Documentation, and Patient/Family Education
2. UWHC Policy 6.1.14: Approval of Core and Patient-Specific Chemotherapy Regimens for the
Treatment of Adult Malignancy
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18
Appendix A. Grading of Common Asparaginase Toxicities
Adverse Event Grade 1 Grade 2 Grade 3 Grade 4
Hypersensitivity
(Allergic reaction /
Anaphylaxis)
Transient flush
or rash, drug
fever < 38
degrees C (<
100.4 degrees
F); intervention
not indicated
Urticaria without
bronchospasm,
hypotension,
edema, or need for
parenteral
intervention
Symptomatic
bronchospasm with or
without urticaria,
indicated parenteral
intervention,
angioedema, or
hypotension
Life-threatening
consequences; urgent
intervention indicated
Hepatotoxicity >ULN – 3.0 x
ULN
>3.0 – 5.0 x ULN > 5.0 – 20.0 x ULN > 20.0 x ULN
Pancreatitis - Enzyme elevation
or radiologic
findings only
Severe pain; vomiting;
medical intervention
indicated (e.g.
analgesia, nutritional
support)
Life-threatening
consequences; urgent
intervention indicated
Elevated Serum
Amylase
> ULN – 1.5 x
ULN
> 1.5 – 2.0 x ULN > 2.0 – 5.0 X ULN > 5.0 x ULN
Elevated Serum
Lipase
> ULN – 1.5 x
ULN
> 1.5 – 2.0 x ULN > 2.0 – 5.0 X ULN > 5.0 x ULN
Hyperbilirubinemia > ULN – 1.5 x
ULN
> 1.5 – 3.0 x ULN > 3.0 – 10.0 x ULN > 10.0 x ULN
Hypertriglyceridemia 150 mg/dL –
300 mg/dL
> 300 mg/dL – 500
mg/dL
> 500 mg/dL – 1000
mg/dL
> 1000 mg/dL; life
threatening
consequences
Hyperglycemia Fasting glucose
value > ULN –
160 mg/dL
Fasting glucose
value > 160 – 250
mg/dL
> 250 – 500 mg/dL;
hospitalization
indicated
> 500 mg/dL; life-
threatening
consequences
Thromboembolic
Event
Venous
thrombosis (e.g.
superficial
thrombosis)
Venous thrombosis
(e.g. uncomplicated
deep vein
thrombosis),
medical intervention
indicated
Thrombosis (e.g.
uncomplicated
pulmonary embolism
[venous], non-embolic
cardiac mural [arterial]
thrombus), medical
intervention indicated
Life-threatening (e.g.
pulmonary embolism,
cerebrovascular event,
arterial insufficiency);
hemodynamic or
neurologic instability;
urgent intervention
indicated
Hemorrhage Mild;
intervention not
indicated
Moderate
symptoms; medical
intervention or
minor cauterization
indicated
Transfusion,
radiologic,
endoscopic, or
operative intervention
indicated
Life-threatening
consequences; urgent
intervention indicated
Hyperammonemia /
Encephalopathy
Mild Symptoms Moderate
symptoms; limiting
instrumental ADL
Severe symptoms;
limiting self-care ADL
Life-threatening
consequences; urgent
intervention indicated
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19
APPENDIX B. Asparaginase Toxicity Monitoring Strategy Summary
Adults Pediatrics
Hypersensitivity • Draw asparaginase enzyme
activity level after seven days of
first administered dose
• Only draw asparaginase enzyme level if
patient is pre-medicated or if patient receives
at least ¼ of dose prior to development of
hypersensitivity reaction (see Table 2)
Liver Function
Tests
• Monitor alkaline phosphatase,
AST, ALT, and total bilirubin prior
to administration
• Monitor following administration
weekly for two weeks and prior to
doses of chemotherapy with
increased risks for hepatotoxicity
• Monitor alkaline phosphatase, AST, ALT, and
total bilirubin prior to administration
• Consider monitoring following administration if
patient has pre-existing hyperbilirubinemia or
elevated baseline liver function tests
Pancreatitis • Amylase, lipase, and triglycerides
prior to first dose
• First dose: check labs weekly for
two weeks following first
pegaspargase dose
• Subsequent doses: Check labs
prior to administration and once
seven days after dose
• Amylase, lipase, and triglycerides prior to first
dose
• Further doses: check triglycerides prior to
administration
• Consider checking all labs seven days post-
administration if patient has previously
experienced grade 2-3 pancreatitis or grade 2-
4 hypertriglyceridemia
Glucose • Monitor periodically • Monitor periodically
Blood and
Coagulation
• Complete blood count with
differential and fibrinogen prior to
any dose
• Platelets and fibrinogen twice
weekly for one week post-dose
• Complete blood count with differential and
fibrinogen prior to any dose
• Platelets weekly post-dose
• If thrombosis occurs, platelets and fibrinogen
twice weekly for one week post-dose
• Omit PT and PTT
Ammonia • Weekly if patient is symptomatic
(i.e. altered mental status,
somnolence) until symptom
resolution
• Weekly if patient is symptomatic (i.e. altered
mental status, somnolence) until symptom
resolution
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20
APPENDIX C. Asparaginase Toxicity Management Summary
Adults Pediatrics
Hypersensitivity • Always pre-medicate
• Grade 1-2: continue therapy
• Grade 3-4: switch therapy or discontinue if on
Erwinia asparaginase
• Pre-medication not recommended by COG, but
can do so if an asparaginase enzyme activity
level is checked
• Grade 1-2 (non-severe): refer to Table 2
• Grade 2 (severe) or higher: switch therapy or
discontinue if on Erwinia asparaginase
Hepatotoxicity • Grade 1-2: continue
• Grade 3: delay until grade <2
• Grade 4: discontinue permanently or resume
with close follow up if grade <2 not achieved
within one week
• Can consider IV levocarnitine + PO vitamin B
complex
• Grade 1-2: continue
• Grade 3-4: delay until grade <2 within one
week
Hyperbilirubinemia • Grade 1-2: continue
• Hold if > 3.1 mg/dL and resume when below 2.0
mg/dL
• Grade 1-2: continue
• Hold if > 3.1 mg/dL and resume when below
2.0 mg/dL
Pancreatitis • Grade 1-2: continue
• Discontinue permanently if grade 4
• Grade 1-2: continue
• Discontinue permanently if grade 4
• Can consider IV octreotide via continuous or
intermittent infusion if admitted inpatient with
grade 4
Hypertriglyceridemia • Hold therapy if triglycerides > 1000 mg/dL and
resume at same dose when triglycerides
normalize
• Can consider micronized fenofibrate for grade
2-4
• Continue without dose modifications for
elevated triglycerides
Hyperglycemia • Grade 1-2: continue
• Reasonable to hold therapy if insulin therapy is
required until levels are regulated
• Treat with insulin if warranted and continue
therapy
Non-CNS Thrombosis • Hold therapy if symptomatic grade 2-4 until
stable on antithrombotic therapy
• Can consider resuming therapy with closer
monitoring while on antithrombotic therapy or
LMWH
• Continue treatment in patients with abnormal
lab findings without correlated clinical
symptoms
• Hold therapy if symptomatic grade 2-4 until
stable on antithrombotic therapy
• Can consider resuming therapy with closer
monitoring while on antithrombotic therapy or
LMWH
• Continue treatment in patients with abnormal
lab findings without correlated clinical
symptoms
CNS Thrombosis • Grade 1-3: discontinue and treat with
antithrombotic therapy
• Can consider resuming therapy in lower doses
and/or longer intervals
• Grade 4 – discontinue all asparaginase
products permanently
• Hold therapy and treat with antithrombotic
therapy
• Can consider resuming therapy at full dose
when symptomatically resolved and imaging
shows recanalization
Non-CNS Bleeding • Grade 2 via lab findings: Do not withhold
therapy without a clinical correlate
• Grade 2-4: hold therapy until bleeding is lower
than grade 1
• Treat with appropriate factor or pro-coagulant
blood product replacement
• Hold dose and resume with next scheduled
dose
• Do not withhold dose without clinical correlate
CNS Bleeding • Grade 1-3: discontinue therapy until full
symptomatic resolution
• Grade 1-3: Can consider coagulation factor
replacement and resuming at lower doses
and/or longer intervals
• Grade 4: permanently discontinue therapy
• Treat symptomatic patients with appropriate
factor or procoagulant replacement
• Hold dose and resume with next scheduled
dose
• Do not withhold dose without clinical correlate
Hyperammonemia • Lactulose if symptomatic
• Do not withhold dose without clinical correlate
• Grade 1-2: continue therapy as normal
• Grade 3-4: dose reduce per protocol, resume
full dose once grade 2 or lower
• Lactulose if symptomatic
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21
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