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ARTICLE IN PRESS [mNS;September 10, 2021;1:56]

Review Article

SOHO State of the Art Updates and Next

Questions: Management of Asparaginase Toxicity
in Adolescents and Young Adults with Acute
Lymphoblastic Leukemia
Kjeld Schmiegelow,1,2 Cecilie Utke Rank,3 Wendy Stock,4 Emily Dworkin,4
Inge van der Sluis5
Abstract
Wider use of Asparaginase in adolescents and young adults has led to frequent, burdensome toxicities. We here
review hypersensitivity, hepatotoxicity, hypertriglyceridemia, thromboembolism, pancreatitis, and osteonecro-
sis. The decision to discontinue or modify Asparaginase therapy after these toxicities should balance risk of
toxicity with Asparaginase re-exposure against risk of relapse, as re-exposure with Asparaginase in most cases
is feasible.
A wider use of L-asparaginase in the treatment of children with acute lymphoblastic leukemia has improved cure
rates during recent decades and hence led to introduction of pediatric-inspired treatment protocols for adolescents
and young adults. In parallel, a range of burdensome, often severe and occasionally life-threatening toxicities have
become frequent, including hypersensitivity, hepatotoxicity, hypertriglyceridemia, thromboembolism, pancreatitis, and
osteonecrosis. This often leads to truncation of asparaginase therapy, which at least in the pediatric population has
been clearly associated with a higher risk of leukemic relapse. Many of the asparaginase induced toxicities are far more
common in older patients, but since their relapse rate is still unsatisfactory, the decision to discontinue asparaginase
therapy should balance the risk of toxicity with continued asparaginase therapy against the risk of relapse in the individ-
ual patient. The underlying mechanisms of most of the asparaginase induced side effects are still unclear. In this review
we address the individual toxicities, known risk factors, and their clinical management.

Clinical Lymphoma, Myeloma and Leukemia, Vol. 000, No.xxx, 1–9 © 2021 The Authors. Published by Elsevier Inc.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: Hypersensitivity, Hepatotoxicity, Hyperlipidemia, Thromboembolism, Pancreatitis

Introduction Asp has become a key component of pediatric acute lymphoblas-

L-asparaginase (Asp) is a bacterial enzyme, which for clinical use
is primarily derived from Escherichia coli (E coli) or Erwinia chrysan-
themi (Erwinia). Currently, the long acting pegylated form of E
coli derived Asp (Peg-Asp) is most commonly used in industrialized
countries, and it will be the main drug addressed here.
1
Department of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen
University Hospital, 2100 Copenhagen, Denmark
2
Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen,
Copenhagen, Denmark
3
Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen,
Denmark
4
Department of Medicine, University of Chicago Medicine and Comprehensive
Cancer Center, Chicago, IL
5
Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Submitted: Jun 22, 2021; Revised: Jul 8, 2021; Accepted: Jul 9, 2021; Epub: xxx
Address for correspondence: Kjeld Schmiegelow, MD, DMSci, Department of Pediatrics
and Adolescent Medicine, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
E-mail contact: kjeld.schmiegelow@regionh.dk
tic leukemia (ALL) treatment protocols contributing to the current
excellent event-free survival (Table 1). Accordingly, Asp is increas-
ingly being used in the treatment of adolescents and young adults
(AYA) with ALL, since prospective clinical trials using pediatric
regimens with more extensive exposure to Asp have reported signifi-
cant improvements in cure rate, not least in those who achieve early
minimal residual disease (MRD) negative status.1-3
However, up to thirty percent of children and AYA patients
treated with Asp experience serious toxicities,4-7 which may lead to
truncation of Asp-therapy jeopardizing the chances of cure (Table
1). Due to a higher prevalence of T-cell immunophenotype, poor
risk cytogenetics (eg, ABL-class translocations, low hypodiploidy,
rearranged KMT2A) and a poorer response to remission induction
chemotherapy, AYAs will more frequently be stratified to higher risk
groups, which furthermore adds to the burdensome toxicity profile
experienced by the AYA group.8

2152-2650/$ - see front matter © 2021 The Authors. Published by Elsevier Inc.
This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/)
https://doi.org/10.1016/j.clml.2021.07.009 Clinical Lymphoma, Myeloma and Leukemia 2021 1
Please cite this article as: Kjeld Schmiegelow et al, SOHO State of the Art Updates and Next Questions: Management of Asparaginase Toxicity in Adolescents
and Young Adults with Acute Lymphoblastic Leukemia, Clinical Lymphoma, Myeloma and Leukemia, https://doi.org/10.1016/j.clml.2021.07.009
 JID: CLML
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Asparaginase toxicity in ALL patients

Table 1 Clinical Impact Of Reduced Asparaginase Dose Intensity, Including Shortened Asparaginase (Asp) Therapy

Update on Pieters 2011131 Event-free survival Event-free survival P < .05 References
less-intensive more-intensive
asparaginase therapy asparaginase therapy
Extra 20 wk Asp-in T-ALL POG 8704 55% 68% Yes Amylon 1999132
Extra 20 wk Asp-in T-NHL POG 8704 64% 78% Yes Amylon 1999132
≤ or > 25 wk Asp-DFCI 91–01 73% 90% Yes Silverman 2001119
Extra 20 wk Asp-in IRG AIEOP ALL-91 72% 76% No Rizzari 2001133
Erwinase vs. E coli Asp-EORTC–CLG 58,881 60% 73% Yes Duval 2002134
Extra 20 wk Asp-I-BFM-SG/IDH-ALL-91 79% 88% Yes Pession 2005135
Erwinase vs. E coli Asp-DFCI 95–01 78% 89% Yes Moghrabi 2007136
Truncated vs. continuous Asp (with Erwinia) in Event HR = 1.5 1.1 Yes Gupta 2020137
COG AALL0331/AALL0232
Truncated (including no activity) vs. continuous Relapse risk Relapse risk Yes Gottschalk Højfeldt
Asp-therapy in NOPHO ALL2008 11.1% 6.7% 2020138

Table 2 Guidelines for Switching Asparaginase Formulation in Case of Hypersensitivity

1. Allergy all grades and inactivation a) Switch PEG-asp to Erwinia asparaginase.

b) Switch to E coli asp only when there are no E coli asparaginase antibodies. If the patient also develops an allergy with
inactivation to Erwinia asp, no approved alternative asparaginase preparation is available and asparaginase treatment
needs to be truncated.
c) Do not use steroids or antihistamines prior to administering the next doses, as it will not reverse the inactivation.
d) When no asparaginase activity measurement is available (see 3b), re-expose can be done if an allergic-like reaction is
suspected. If the allergic reaction occurs at the first dose, native E coli can be administered, as antibodies may be
directed towards the Peg moiety or the linker. Otherwise, preparation should be switched or asparaginase therapy
stopped.

2. Silent inactivation a) Switch PEG-asp to Erwinia asparaginase.

b) Switch to E coli asparaginase, when there are no E coli antibodies
c) If the patient also develops an allergy towards or silent inactivation of Erwinia asparaginase, no alternative
asparaginase preparation is currently available and asparaginase treatment needs to be truncated.

3. Allergic-like reaction (no inactivation)
a) a. When the trough asparaginase activity level taken before this dose is adequate you can re-expose carefully to the
same preparation if clinically possible. In these cases, premedication with hydrocortisone and antihistamines are
allowed as well as decreasing the infusion rate.
b) When no trough level is available, check the asparaginase activity level after the dose taking into account how much of
the dose is administered, in case of detectable asparaginase activity you can re-expose carefully to the same
preparation, if clinically possible

Hypersensitivity and Therapeutic
Drug Monitoring
As Asp-is a foreign protein that can elicit an adaptive immune
response, formation of Asp-neutralizing antibodies can occur with
or without clinical signs of hypersensitivity. Three classical types of
hypersensitivity have been defined by the Ponte di Legno Toxicity
Working Group9 : (i) Clinical allergy is a local or general reaction,
ranging from rash to anaphylaxis, which is accompanied by inacti-
vation of Asp-activity. (ii) Patients with silent inactivation do not
experience any symptoms, but neutralize Asp-anyway resulting in
Peg-Asp-levels <0.1 IU/mL day seven post administration or below
the lower limit of quantification day 14. (iii) Finally, patients with
infusion-related/allergic-like reactions lack neutralizing antibodies
and will have adequate Asp-levels, if the full dose is administered.
These three hypersensitivity reactions should be handled differently
(Table 2). Infusion-related/allergic-like reactions may be caused
by very high levels of ammonia, released by the Asp-mediated
breakdown of both asparagine and glutamin.10 , 11 Therapeutic drug
monitoring (TDM) is crucial to identify these three types of hyper-
sensitivity.12
The reported incidences of clinical hypersensitivity reactions vary
widely by age groups (lower in older patients), Asp-preparations,
dosing schedules and treatment phases. When native E coli Asp-is
used, clinical allergy can range from only a few percent in induction
and up to 75% in delayed intensification.13-15 The current upfront
ALL protocols using Peg-Asp-as first line treatment generally report
a lower overall cumulative incidence of clinical allergy reactions of
up to 13%.16 , 17 Overall, silent inactivation has been reported in 4%
to 10% of patients, but is also lower in protocols only using Peg-
asp.17 , 18 The incidence of allergic-like reactions is largely unknown,
because it is either not recognized or not systematically captured by
the ALL toxicity registration platforms.

2 Clinical Lymphoma, Myeloma and Leukemia 2021

Please cite this article as: Kjeld Schmiegelow et al, SOHO State of the Art Updates and Next Questions: Management of Asparaginase Toxicity in Adolescents
and Young Adults with Acute Lymphoblastic Leukemia, Clinical Lymphoma, Myeloma and Leukemia, https://doi.org/10.1016/j.clml.2021.07.009
JID: CLML
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Peg-Asp-is less immunogenic than unpegylated Asp, as the Asp-
epitopes are masked by Peg, but antibodies can still develop not
just against Asp-itself, but also against the Peg moiety or the linker
attaching Peg to Asp.19-21 Besides differences in immunogenicity
between preparations, dosing schedules and treatment phases are
also important determinants of reported differences in frequency of
hypersensitivity reactions. Thus, clinical hypersensitivity reactions
occur more frequently in post-induction than in induction therapy,
most likely reflecting that the extended Asp-free interval induces a
built-up in antibody formation and strong response with Asp-re-
exposure.22
It has been debated whether intravenous administration is a risk
factor for hypersensitivity reactions, but a review of eight papers
comparing intravenous and intramuscular administration of Peg-
Asp-found no difference in the incidences of allergic reactions.23
However, intravenous administration with its rapid rise in ammonia
more frequently causes allergic-like reactions.11 , 24
Premedication with antihistamines, glucocorticosteroids and H2-
receptor antagonist and a decreased infusion rate can prevent
both severe and low-grade hypersensitivity reactions.25 However,
premedication and even high dose glucocorticosteroids do not
prevent inactivation of Asp-by existing neutralizing antibodies.
Thus, premedication should only be used in combination with
TDM of Asp-to avoid masking of allergy. Genetic susceptibility
to hypersensitivity and anti-Asp-antibody formation, such as HLA-
DRB1 × 07:01 and single nucleotide polymorphisms (SNPs) varia-
tions in GRIA1 and CNOT3 have been reported, but the associa-
tion are relatively weak and do not legitimize individual treatment
adaptations.26-28
In patients with hypersensitivity reactions, the decision to switch
to an alternative preparation should depend on anticipated or
measured Asp-activity levels. To distinguish between allergic and
allergic-like reactions, TDM is needed, and only the latter patients
should be re-exposed with premedication coverage or reduction in
the infusion time. Activity levels are hard to interpret after early
interruption of Asp-infusion with little systemic administration, but
with later re-exposure to the full dose therapeutic Asp-activity levels
will be found in patients with allergic-like reactions. When Asp-
activity assays are not available, switching should always be consid-
ered at any grade of hypersensitivity, most commonly to Erwinase,29
since even patients with CTCAE grade 1 allergy reactions have
neutralizing antibodies causing undetectable activity levels.22
There is no cross reactivity of antibodies against E coli Asp-
or Erwinia Asp.14 Importantly, patients treated with Peg-Asp-and
antibodies to the PEG moiety or the linker can switch to native
E coli Asp.20 Reactions towards Peg are relatively more common if
reactions to the first dose occur, as many healthy individuals harbor
anti-Peg antibodies prior to ALL. Measurement of antibodies can
support the type of switch, but is not standard of care and is only
conducted in specialized centers as part of research programs.20 , 30
Hepatotoxicity
Asymptomatic increases in bilirubin and/or transaminases
are quite common with Asp-therapy and may be accompa-
nied by hypoalbuminemia, hypofibrinogenemia, elevated alkaline
phosphate and elevated INR.7 , 31-33 However, clinically severe
Please cite this article as: Kjeld Schmiegelow et al, SOHO State of the Art Updates and Next Questions: Management of Asparaginase Toxicity in Adolescents
and Young Adults with Acute Lymphoblastic Leukemia, Clinical Lymphoma, Myeloma and Leukemia, https://doi.org/10.1016/j.clml.2021.07.009
[mNS;September 10, 2021;1:56]
Kjeld Schmiegelow et al
hepatotoxicity also occurs, not least in AYA patients, and can result
in treatment delays and even fatal complications.
The incidences of Asp-induced hepatotoxicity in the AYA group
and older patients treated on pediatric-inspired regimens have been
reported in the range of 35% to 60%34-36 with rates of grade 3
to 4 hyperbilirubinemia and transaminitis in the range of 10% to
31% and 28% to 63%, respectively.3 , 36-38 Asp-induced hepatotox-
icity occurs most frequently during induction therapy but can also
occur with later Asp-exposure. The UKALL14 trial administered
Peg-Asp 1000 IU/m2 on days four and 18 to patients aged 25 to
65 years (Median: 46 years) and 18% of the patients experienced
induction related mortality, mostly in older adults and after the day
four dose.35 Accordingly, the protocol was amended to remove the
day four dose in patients older than 40 years.
The median reported time to onset of high-grade hyperbiliru-
binemia and transaminitis is typically 13 to 16 days post adminis-
tration.1 , 38-40 Resolution to grade 1 hepatotoxicity can be prolonged
and may take up to a median of 34 to 46 days.1 , 38 Transient grade
1 to 2 hyperbilirubinemia and transaminitis are seen in up to 40%
to 60% of patients37 and will resolve without intervention.
The rate of hepatotoxicity with Erwinia Asp41 , 42 seems lower than
those reported for native l-Asp-and Peg-Asp,36 , 43 , 44 but without
head to head comparisons. Calaspargase pegol has a longer half-
life than Peg-Asp, but rates of hepatotoxicity are very similar.45
The erythrocyte encapsulated l-Asp-reported lower rates of hepatic
disorders compared to native l-Asp, but validation studies are
needed to determine a true difference.46
Asp-induced liver toxicity remains poorly understood, but is
likely a consequence of protein synthesis inhibition and amino acid
depletion resulting in metabolic stress, generation of reactive oxygen
species, mitochondrial permeabilization and apoptosis of hepato-
cytes.47 Asp-degradation of glutamine may play a role, as it can
compromise the ability of healthy cells to synthesize asparagine.48
The mitochondrial stress and dysfunction that ensues can lead to
altered lipid metabolism, accumulation of unoxidized fatty acids
leading to diffuse steatosis and hepatic necrosis.31 , 33 , 49 , 50
Obesity (BMI, body mass index >30) is the best known risk
factor associated with hepatotoxicity.36 , 37 Additional risk factors
reported to be directly or indirectly associated with hepatotoxic-
ity include older age,51 body surface area ≥2 m2 , Asp-dose inten-
sity, baseline platelet count <50 × 109 /L, albumin < 3 g/dL, and
Hispanic ethnicity.37 , 39 Hepatic steatosis is common in obesity,
type II diabetes, metabolic syndrome, and Hispanic populations52
and has been associated with Asp-induced hepatotoxicity in animal
models.53 High grade hypertriglyceridemia during any cycle has also
been associated with high grade hyperbilirubinemia (P = .03) and
non-significantly with high grade transaminitis.38
Germline variants in the superoxide dismutase gene (rs4880) has
been linked to Asp-induced hepatotoxicity,47 which support that
reactive oxygen species plays a role for hepatotoxicity, but otherwise
there is a lack of validated genotype-phenotype associations.
The associations between plasma-Asp-activity levels and Peg-Asp-
efficacy and toxicity among patients with Asp-activity >0.1 IU/ml
remains unclear.51 , 54 , 55 In general, lower dose intensity is associated
with a lower frequency of grade 3 to 4 toxicity, but also lower cure
rates, and in most of the studies TDM has not been performed.
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Asparaginase toxicity in ALL patients
The use of lower Peg-Asp-doses in older patients and patients with
risk factors such as obesity, diabetes and non-alcoholic steatohep-
atitis, may allow for safer administration and extension of pediatric
inspired regimens for this patient population. But the optimal dose
intensity and the benefits of TDM remains to be clarified for the
AYA population.
In the GMALL 07/2003 study, where adult ALL patients received
1000 IU/m2 (N = 826) or 2000 IU/m2 (N = 400), the more inten-
sive dosing was associated with longer remission duration and higher
overall survival at the expense of higher rates of grade 3 to 4 hyper-
bilirubinemia (10% vs. 16%, P = .004).56
Rates of achieving efficacious plasma l-Asp-activity levels
(defined as ≥0.1 IU/mL) increase with Peg-Asp-doses of 500
IU/m2 , 1000 IU/m2 and 2000 IU/m2 , respectively,1 , 54 , 57 as do risk
of toxicity. Still, these studies have led many centers to using lower
doses in older or at risk populations (eg, obese patients, Hispanic
ethnicity) to mitigate the risk of hepatotoxicity.54 , 58 During induc-
tion the percentages of patients who achieved levels ≥0.1 IU/mL at
Peg-Asp-doses of 2000 IU/m2 , 1000 IU/m2 and 500 IU/m2 were
100%, 99% and 86% during the first week post dose, 91%, 77%
and 25% during the second week post dose and 61%, 54% and 0%
during the third week post dose, respectively.57
Higher disease burden with a concomitant inflammatory state,
coincidence with myelosuppression, proximity to anthracycline
dosing and prolonged high dose glucocorticosteroid administration
have been suggested to contribute to the higher rates Asp-toxicity
during induction in the AYA group.1 , 37 , 58 Although the benefits
are not formally proven in randomized trials, delaying Peg-Asp-
administration to the third week of induction has been adapted
by many centers to minimize Asp-associated toxicity. Avoidance of
concurrent hepatotoxic agents may also help to minimize risk of
hepatic injury. Still, larger prospective studies are needed to deter-
mine to optimal dose and frequency of Peg-Asp-in AYA and adult
patients.
Patients who experience grade 1 or 2 hepatotoxicity may continue
therapy without dose reductions or interruption in therapy.7 For
grade 3 hyperbilirubinemia (total bilirubin >3 times upper normal
limit (ULN)59 ) or grade 3 to 4 transaminitis (aminotransferase levels
more than five times the upper normal limit59 ) Asp-therapy should
be withheld until recovery to less than grade 2. In case of isolated
non-progessive grade 3 transaminitis, Asp-therapy may be contin-
ued with close monitoring. For patients who experience grade 4
hepatotoxicity, careful consideration of risks and benefits, including
the anticipated risk of relapse, should be assessed prior to resum-
ing therapy. Smaller studies indicate that half to two thirds of re-
challenged patients who have experienced high-grade hyperbiliru-
binemia or transaminitis may experience recurrence of such hepato-
toxicity.38
In AYA and adult patients with risk factors for Asp-induced
hepatotoxicity preventative strategies should be considered. If Asp-
activity level monitoring is available, individual or general lower-
ing of Peg-Asp-doses to 500 to 1000 IU/m2 should be considered
during induction therapy, as well as delaying Asp-therapy to the
second half of the induction phase.35
Although animal studies have not been clearly supportive,53 , 60
limited clinical data have indicated that l-carnitine administra-
4 Clinical Lymphoma, Myeloma and Leukemia 2021
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and Young Adults with Acute Lymphoblastic Leukemia, Clinical Lymphoma, Myeloma and Leukemia, https://doi.org/10.1016/j.clml.2021.07.009
[mNS;September 10, 2021;1:56]
tion can reduce Asp-induced hepatotoxicity. l-carnitine and vitamin
B complex are necessary cofactors in mitochondrial oxidative
phosphorylation that may be useful in treating drug induced
mitochondrial toxicity.32 , 61 Several case reports and case series have
described the use of l-carnitine with or without vitamin B complex
to treat Peg-Asp-induced hepatotoxicity.32 , 40 , 53 , 61 Response rates are
fairly rapid and improvements in liver function test have been seen
within 1 to 6 days.32 , 40 Importantly, l-carnitine does not appear
to affect Asp-cytotoxicity.53 , 62 In case of grade 3 to 4 hepatotoxi-
city or high risk of hepatotoxicity,40 a loading dose of 50 to 100
mg/kg/intravenously (due to low bioavailability) followed by a shift
to 50 mg/kg/d orally divided in 3 to 4 doses after improvement in
liver function tests. The benefits of co-administration of vitamin
B complex are uncertain, but given the minimal risks associated
with vitamin B complex it may be administered concurrently with
l-carnitine.61 A phase II trial is underway to evaluate the efficacy
of l-carnitine and vitamin B complex in the treatment of Peg-
Asp-and inotuzumab ozogamicin induced hyperbilirubinemia in
patients with ALL (clinicaltrials.gov: NCT03564678).
Ursodiol 300 mg orally divided into two or three doses can
reduce the cholesterol content of bile and has been widely used as
prevention of chemotherapy induced veno-occlusive disease. It has
also been proposed as a prophylactic option38 , 40 for Asp-induced
hepatotoxicity, in patients with baseline elevations in bilirubin or
risk factors for hepatotoxicity, but no clear data exists to support its
wider preventative use.
Hypertriglyceridemia
Hypertriglyceridemia is frequently seen during Asp-therapy, and
the blood may become grossly lipemic with the highly elevated
triglycerides63 and impair the ability to run routine lab work,
and pseudohyponatremia has also been reported with Asp-induced
hypertriglyceridemia.64 The mechanism of Asp-induced hyper-
triglyceridemia likely reflects increased synthesis of very low density
lipoproteins (VLDL VLDL) and decreased lipoprotein lipase activ-
ity.64 , 65 VLDLs are rich in triglycerides and with decreased lipopro-
tein lipase activity the clearance of triglycerides is reduced. The
incidence of grade 3 to 4 Asp-hypertriglyceridemia in AYA and
adult patients has been reported between 11% to 50%.3 , 37 It is
generally asymptomatic, and routine monitoring is not recom-
mended outside research programs. Increased BMI and previ-
ous history of Asp-induced hypertriglyceridemia are potential
risk factors.37 Glucocorticosteroids can contribute to increase
lipid levels. Hypertriglyceridemia may occur already during Asp-
containing induction therapy but is more common results in subse-
quent courses of therapy and may resolve without intervention.37 , 66
Hypertriglyceridemia has been associated with later development
of osteonecrosis.67 , 68 Although hypertriglyceridemia in non-ALL
patients is a known risk factors for pancreatitis, hypertriglyceridemia
has not been clearly linked to an increase risk of Asp-induced
pancreatitis.66
Medical intervention should only be considered for patients
presenting with high grade hypertriglyceridemia (>1000
mg/dL = 11.3 mmol/L) and toxicities,65 , 66 but Asp-therapy
can in general be continued without dose adjustments.7 , 37 , 66
Fibrates, such as gemfibrozil and fenofibrate, and Omega-3 has
JID: CLML
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been recommended as first line in treatment of high grade hyper-
triglyceridemia,66 , 69 , 70 and the latter is being tested in a randomized
trial (clinicaltrials.gov: NCT04209244). More aggressive strategies
such as insulin infusion, heparin infusion and plasmapheresis should
only be used when an immediate decrease in triglycerides is needed,
such as with severe hypertriglyceridemia-induced thrombosis.64 , 71
Thromboembolism
The incidence of thromboembolism (TE) is age-dependent and
ranges from 5% up to 41% among children and adults with ALL,
respectively72 , 73 with the risk being very similar (15%-20%) for
adolescents and young adults up to 45 years of age, when receiv-
ing Asp-heavy treatment.74 This includes a strikingly increased risk
of developing the most serious TE subtypes such as cerebral sinove-
nous thrombosis and pulmonary embolism, when compared with
children younger than 10 years of age.74
TE is mainly of venous origin and is pathophysiologically
believed to arise as a consequence of the Virchow triad, with inter-
plays between (i) abnormalities in blood flow/stasis by, eg, presence
of a mediastinal mass, enlarged lymph nodes, indwelling catheters
and/or immobilization; (ii) hypercoagulability second to distur-
bances in hemostatic/fibrinolytic balance second to impairment of
hepatic protein synthesis as well as inflammatory cytokines released
by leukemic cells, and (iii) chemotherapy-related vessel wall injury.75
The cumulative TE incidence is associated with the number of
Asp-cycles76 , 77 seemingly independent of formulation (native E.coli
versus Peg-Asp).78 Additional risk factors include concurrent infec-
tions, non-O blood group, physical inactivity, obesity, and use of
oral contraceptives, whereas the impact of corticosteroid- and Asp-
induced hypertriglyceridemia remains unclear.79-81
Although both the levels of anticoagulant (antithrombin (AT),
protein C and S); fibrinolytic factors (plasminogen and α2-
antiplasmin) and pro-coagulants proteins (fibrinogen, factor V
and VII–XI) are decreased, a procoagulant state predominates
clinically—in which the Asp-induced AT deficiency is consid-
ered the a major contributor82 , 83 leading to thrombin dysregula-
tion as a result of both ongoing generation and impaired inhibi-
tion.84 In contrast, some patients may experience bleeding tendency,
but cryoprecipitate substitution for hypofibrinogenemia may cause
venous TE and should in general be use cautiously.37
The age-related decline in both anticoagulant and fibrinolytic
factors has been linked to the prothrombotic state in adolescence.85
Corticosteroid treatment may also promote coagulation through
increasing levels of von Willebrand’s Factor and plasminogen activa-
tor inhibitor-1.86 In a retrospective study a lower TE frequency has
been reported, although not validated, with use of dexamethasone
compared with prednisone.87
Various TE risk score models have been published,74 , 88-90 yet
none have been validated in adults with ALL. A recent candidate
gene study including both young children and AYA ALL patients
found that SNPs in F11 (rs2036914) and FFG (rs2066865) was
significantly associated with TE development, being most profound
in the adolescent age group 10.0 to 17.9 years with a hazard rate of
1.6490 .
Although TE-related mortality as well as morbidity depend on
the TE location, long-term sequelae with significant impact on the
quality of life have been described for most TE subtypes.91-93 To
Please cite this article as: Kjeld Schmiegelow et al, SOHO State of the Art Updates and Next Questions: Management of Asparaginase Toxicity in Adolescents
and Young Adults with Acute Lymphoblastic Leukemia, Clinical Lymphoma, Myeloma and Leukemia, https://doi.org/10.1016/j.clml.2021.07.009
[mNS;September 10, 2021;1:56]
Kjeld Schmiegelow et al
date, only one ongoing and two completed RCTs exist investigating
thromboprophylaxis; all in childhood ALL. The ongoing open-label
PREVAPIX-ALL trial is recruiting children with ALL/lymphoblastic
lymphoma to either preemptive direct oral anticoagulant (apixaban)
or no thromboprophylaxis during induction therapy (ClinicalTri-
als.gov identifier: NCT02369653) .94 Recently published findings
from the THROMBOTECT trial (949 children with ALL) showed
significantly reduced TE incidence without any difference in major
bleeding during induction therapy for AT concentrates and low
molecular weight heparin (enoxaparin)—both in comparison with
low dose unfractionated heparin.95 However, concerns have been
raised regarding the open-label design without masking (33%
declined subcutaneous enoxaparin administration) combined with
acceptance of cross-over between the intervention arms. Of note,
the underpowered open-label PARKAA trial enrolling 109 children
found no effect of preemptive AT concentrates on venous TE
incidence during induction treatment.96
Of note, heparins and the synthetic, heparin-derived pentasaccha-
rides directly rely on AT for their mode of action with efficacy being
markedly influenced by low AT levels.97 Thus, activity monitoring
of anti-Xa and AT with activity-adapted AT substitution may be
required to maintain adequate anticoagulation during Asp-therapy.
In addition, vitamin K antagonists may not only deplete vitamin
K-dependent coagulation factors but also natural anticoagulants
protein C and S, which temporarily could make clotting worse in
case of Asp-induced protein C and S deficiency.98 Finally, for AT
prophylaxis cryoprecipitate should not be administered due to its
high content of factor VIII and potential thrombogenicity. In this
context, a higher incidence of leukemic relapse was observed in the
AT concentrates arm of the pediatric THROMBOTECT trial in the
intention-to-treat analysis (but not in the as-treated analysis), which
raises concerns although it remains unexplained.95
At present, the most preferable options for thromboprophylaxis
in AYAs with ALL undergoing Asp-based therapy are low molecu-
lar weight heparin combined with monitoring of anti-Xa and AT
activity, followed by activity-adapted infusion of AT concentrates or
direct oral anticoagulants (eg, apixaban, edoxaban, betrixaban and
rivaroxaban), which act independently of AT. There is an unmet
need for randomized controlled trials testing these approacheds.99
Pancreatitis
Although cases can be mild, Asp-associated pancreatitis (AAP)
is one of the most feared complications of Asp-therapy. During
extended Peg-Asp-therapy (15 doses of Peg-Asp), AAP occurs after a
median of five doses and at a median of ten days after the most recent
dose.100 With efficacious asparagine depletion the Asp-formulations
(native versus pegylated) do not seem to influence the risk of AAP.
The risk is proportional to the number of Peg-Asp-doses adminis-
tered and increases with age2 , 101 , 102 and doubles in children above
aged five years and AYAs compared to younger children, being 10–
11% versus 5% in the Peg-Asp-heavy NOPHO ALL2008 protocol
including patients 1 to 45 years.105 The age-related phenomenon is
also observed for AAP-related complications, including a doubling
of the risk of permanent insulin dependent diabetes (IDDM) among
AYAs compared to younger children from 11% to 21%100 .
Clinical Lymphoma, Myeloma and Leukemia 2021 5
 JID: CLML
ARTICLE IN PRESS [mNS;September 10, 2021;1:56]

Asparaginase toxicity in ALL patients

Even though Asp-is considered the main contributor to AAP
development in ALL patients, the direct mechanism behind this
toxicity remains uncertain. Asp-interferes with the active pancreatic
protein synthesis due to its global impairment of protein synthesis,
where the induction of toxic Ca2+ signaling rather than asparagine
deprivation seems the main pathogenic mechanism,103 , 104 which
has been supported genome-wide association studies.105 Asp-act
on protease-activated receptor 2 mobilizing release of intracel-
lularly stored Ca2+ , which leads to abnormal cytosolic Ca2+
overload followed by excessive Ca2+ entry from the extracellular
space through Ca2+ release-activated Ca2+ channels.103 This Ca2+
overload in turn causes intracellular premature protease activation
with cleavage of trypsinogen into proteolytic trypsin, eliciting a
cascade of acinar cell destruction and necrosis, damaging inflamma-
tory response, and ultimately pancreatic autodigestion.103 , 104 , 106 In
the early phase, pancreatic inflammation with parenchymal edema
as well as peripancreatic fat necrosis dominate the picture (mild
acute AAP). The pancreatic inflammation can evolve into a hemor-
rhagic/necrotizing state (severe AAP), which often includes forma-
tion of pancreatic pseudocysts, ie, encapsulated (peripancreatic)
fluid collections within well-defined inflammatory walls, as well
as sterile or infected walled-off necrosis. Additionally, inflamma-
tory driven cytokines give rise to vasodilation, increase permeability
of the vessels, and promote leucocyte attraction. Combined with
the retroperitoneal location of pancreas without any capsule, the
pancreatic inflammatory process often leads to systemic inflamma-
tory response syndrome in 72% of all patients, and 22% require
mechanical ventilation.100 , 107
Apart from Asp-therapy and older age, established risk factors for
AAP are few.6 , 108 Thus, neither corticosteroid- and Asp-induced
hypertriglyceridemia37 , 79-81 , 109-113 or high body mass index have
been confirmed as risk factors.114 , 115 Although several SNPs have
been found to be associated with alcoholic or familial pancreatitis,
only rs13228878 and rs10273639 have been validated in a child-
hood ALL setting leading to elevated expression of the gene PRSS1
encoding for trypsinogen.105
Although the direct mortality in only a few percent, serious
acute as well as long-term morbidities (long-term pancreatitis,
IDDM107 , 116 ) are common. Accordingly, Peg-Asp-therapy is often
truncated, not least since the incidence of a second AAP following
Asp-re-challenge is 44% to 63%.100 , 107 , 117 However, decision deter-
minants for re-exposure should take the anticipated risk of leukemic
relapse into account, as this is significantly increased with truncated
Peg-Asp-therapy.118-120 In addition, no risk factors have been identi-
fied for development of a second AAP, including age, severity of the
first AAP, or presence of AAP-related complications.107 Importantly,
14% of children but 33% of AYAs experienced a second event of
AAP after the first Asp-re-exposure dose, and given the high risk of
IDDM in AYAs after AAP,100 Asp-re-exposure should be avoided in
AYAs with a favorable ALL prognosis, such as those being MRD
negative at the end of induction therapy (personal correspondence,
CU Rank; NOPHO ALL2008 data).
In addition to temporary or permanent discontinuation of Asp,
treatment of AAP is mainly supportive including antibiotics (until
sepsis as differential diagnosis is ruled out), fluid resuscitation,
analgesia and parenteral feeding. In case reports and smaller ALL
patient cohorts, octreotide, a synthetic somatostatin analog, has
proven safe and potentially effective both as therapeutic,121 , 122 as
well as prophylactic treatment to preventing AAP recurrence after
Asp-re-exposure.123 , 124 In one study, continuous regional arterial
infusion of protease inhibitors with concomitant antibiotics for
severe AAP also seemed beneficial.125 Ca2+ channel inhibitors,
protease-activated receptor 2 blockers, and pyruvate have demon-
strated promising efficacy in reducing Asp-induced Ca2+ entry
and/or the extent of necrosis in preclinical studies.103
Osteonecrosis
Although few risk factors, beyond older age, women gender and
germline SNPS have been identified for osteonecrosis in patients
with ALL,126-128 several studies have associated osteonecrosis devel-
opment with hyperlipidemia during the earlier Asp-containing
phases of chemotherapy in ALL and other patients.67 , 68 Further-
more, lipid-lowering therapy has is preclinical models been shown to
reduce the risk of glucocorticosteroid induced osteonecrosis.129 , 130
However, lipid-lowering therapy such as fibrates and should only
been given within randomized, controlled, clinical trials.
Future Perspectives
Although longer acting and potentially less immunogenic Asp
formulation will come to market, their mechanism of action will
be uniform, i.e. depletion of asparagine. Thus, the pattern of toxic-
ities remains the same. The three major strategies to reduce the
frequency of Asp-associated toxicities will be less Asp therapy to
patient with excellent responses to induction therapy (i.e. negative
MRD), testing in randomized trial of preemptive interventions to
prevent or ameliorate clinical hypersensitivity (with TDM), hepato-
toxicity, TE, AAP and osteonecrosis, and development of superior
risk score algorithms based on clinical features and host genome
variants to modify Asp treatment intensity and decide on Asp re-
exposure after a toxic event based on individual risk scores
Clinical Practice Points
A significant proportion of adolescents and young adults (AYA)
with acute lymphoblastic leukemia or lymphoma develop burden-
some and severe toxicities when treated with asparaginase. Due to
the lack of clear guidelines many clinicians truncate asparaginase
therapy following such toxicities. Although AYA studies are still
lacking, many pediatric trials have shown that truncation of asparag-
inase therapy may increase the risk of relapse. In this report we
review the current evidence from pediatric and adult studies and
recommend that the decision to continue of discontinue asparagi-
nase therapy should take into account both the severity of the toxic-
ity and the risk of relapse in the individual patient. More focus on
the fact that most patients tolerate re-exposure to asparaginase after a
toxic episode could lead to higher cure rates in the AYA population.
Acknowledgments
This work was supported by the Danish Cancer Society (R257-
A14720) and the Danish Childhood Cancer Foundation (2019–
5934 and 2020–5769).

6 Clinical Lymphoma, Myeloma and Leukemia 2021

Please cite this article as: Kjeld Schmiegelow et al, SOHO State of the Art Updates and Next Questions: Management of Asparaginase Toxicity in Adolescents
and Young Adults with Acute Lymphoblastic Leukemia, Clinical Lymphoma, Myeloma and Leukemia, https://doi.org/10.1016/j.clml.2021.07.009
JID: CLML
ARTICLE IN PRESS
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Please cite this article as: Kjeld Schmiegelow et al, SOHO State of the Art Updates and Next Questions: Management of Asparaginase Toxicity in Adolescents
and Young Adults with Acute Lymphoblastic Leukemia, Clinical Lymphoma, Myeloma and Leukemia, https://doi.org/10.1016/j.clml.2021.07.009
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