Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older...

2237

Leukemia & Lymphoma, December 2011; 52(12): 2237–2253© 2011 Informa UK, Ltd.

ISSN: 1042-8194 print / 1029-2403 online

DOI: 10.3109/10428194.2011.596963

Correspondence: Archie Bleyer, MD, Pediatric & Young Adult Oncology, 2884 NW Horizon Dr., Bend, OR 97701, USA. E-mail: [email protected]

Received 12 November 2010 ; revised 2 May 2011 ; accepted 6 June 2011

REVIEW

Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel

Wendy Stock 1 , Dan Douer 2 , Daniel J. DeAngelo 3 , Martha Arellano 4 , Anjali Advani 5 , Lloyd Damon 6 , Tibor Kovacsovics 7 , Mark Litzow 8 , Michael Rytting 9 , Gautam Borthakur 9 & Archie Bleyer 7,10,11

1 University of Chicago, Chicago, IL, USA, 2 Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3 Dana-Farber Cancer

Institute and Harvard University, Boston, MA, USA, 4 Emory University, Atlanta, GA, USA, 5 Cleveland Clinic, Cleveland, OH, USA,

6 University of California at San Francisco, San Francisco, CA, USA, 7 Oregon Health and Science University, Portland, OR, USA,

8 Mayo Clinic, Rochester, MN, USA, 9 University of Texas M. D. Anderson Cancer Center, Houston, TX, USA, 10 St. Charles Health

System, Bend, OR, USA, and 11 University of Texas Medical School at Houston, Houston, TX, USA

Introduction

Th e survival of patients with acute lymphoblastic leukemia

(ALL) has a striking dependence on the age of the patient at

diagnosis, with a dramatic decline as a function of age begin-

ning in late childhood, plummeting during adolescence, and

declining steadily thereafter (Figure 1). Th e discontinuity in

the survival-versus-age relationship, noted especially in the

USA during the past decade (Figure 1), suggests a treatment

eff ect in that the sudden decrement coincides with the age

at which the pediatric-versus-adult therapy regimen occurs.

Diff erences in the treatment that has been used in older

versus younger patients have been described as a signifi cant

contributing factor [1 – 9]. One of the key components of suc-

cessful pediatric therapy is the intensive use of l -asparaginase

(ASNase) [10–12]. Th e drug has been a mainstay in pediatric

therapy since the 1960s, and there are multiple reports of

ASNase-containing regimens used in pediatric ALL therapy

achieving a greater survival rate that non-ASNase treatment

regimens used in adult and older adolescent patients. Th e

most impressive of these is probably the Dana-Farber Can-

cer Institute (DFCI) clinical trial 77-01, in which pediatric

patients with non-T-cell ALL were randomized to receive or

not receive ASNase intensifi cation [10]. After a median of 9.4

years, event-free survival was 71 � 9% (SE) with ASNase and

31 � 11% (SE) without ASNase [10]. After more than 20 years

of follow-up, the ASNase-treated group had a 25% higher pla-

teau on their survival curve than those who did not receive

ASNase (Sallan S, personal communication). In contrast,

the lack or minimal use of ASNase in many adult treatment

regimens may be one of the major treatment diff erences that

account for treatment outcome disparities between the pedi-

atric and adult ALL regimens.

Th e degree to which ASNase can kill a patient ’ s ALL cells

in vitro is highly predictive of long-term outcome, more so

than perhaps any other single agent. In children, in vitro re-

sponse versus no-response was correlated with a 57% vs. 5%

relapse rate, respectively [13].

Th ere is also evidence that the benefi t of the drug is depen-

dent on how much of the drug is given, and that stopping AS-

Nase therapy for toxicity may jeopardize cure rates [14]. With

much more limited data on the value of including ASNase in

treatment regimens for adults with ALL, the contribution of

Abstract

The rapidly increasing use of pegasparaginase (pegASNase) in

adults, after a half century of use of asparaginase (ASNase) in

children, has prompted a need for guidelines in the management

and prevention of toxicities of asparagine depletion in adults.

Accordingly, an initial set of recommendations are provided

herein. Major advantages of pegASNase are its 2 – 3-week duration

of action, in contrast to less than 3 days with native ASNase, and

the fl exibility of intravenous or intramuscular administration of

pegASNase and associated patient and physician convenience.

The most frequent toxicities of both types of ASNase are hepatic

and pancreatic, with pancreatitis being the most serious. Other

toxicities are hypersensitivity reactions, thrombosis, nausea/

vomi ting, and fatigue. Whether or not the replacement of one

dose of pegASNase for 6 – 9 doses of native ASNase can be achieved

in adults with similar effi cacy and acceptable toxicities to those

achieved in children remains to be established.

Keywords: Asparaginase , pegasparaginase , toxicities ,

guidelines , adults

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2238 W. Stock et al.

ASNase per se to the treatment of adult patients with ALL is

not yet known, but the potential for improved survival with

this agent has been strongly suggested by recent studies in

adult patients that have included ASNase or increased the

amount delivered [15 – 23].

Th e primary reason for the lack of ASNase in the adult

regimens is historic, with an early adverse experience in the

initial trials in adults in the late 1960s [24] and early 1970s

and the subsequent development of adult ALL trials that

minimized or avoided use of ASNase completely. With

improvements in the purity of the drug, introduction of

pegylation technology to provide a long-acting form of the

drug [25,26], fl exibility in administration of pegasparaginase

(pegASNase) by either intramuscular (IM) or intravenous

(IV) routes, and increasing evidence that ASNase is one of the

best drugs in the treatment of childhood ALL, there has been

a resurgence of interest in including ASNase in chemotherapy

regimens for adults with ALL, especially with the long-acting

pegASNase. Intravenous pegASNase has a plasma half-life

(t½) of about 6 days, which is far longer than the 0.65-day t ½

of Erwinia ASNase and the 1.24-day t ½ of native Escherichia

coli ASNase [27]. In pediatric patients, including older ado-

lescents, the toxicity profi le of IV pegASNase has been docu-

mented to be comparable to that of IM pegASNase [12,28].

Th e renewed interest in exploring the use of ASNase in

adults with ALL has heightened the interest in understand-

ing better its toxicities in the adult ALL population. Toxicities

may not be as problematic as they were with the native bacte-

rial ASNase preparations of the past that were contaminated

by other bacterial proteins and impurities, and when only a

crude IV form of administrations was available. Some of the

reasons for avoiding ASNase in adult patients have been de-

scribed as myths [29], at least as applied to younger adults.

Nonetheless, ASNase does appear to cause more toxicities

in older patients that in general are directly proportional to

patient age. Even within the pediatric age range, adolescents

are more likely than younger children to develop hepatic and

pancreatic dysfunction, including hyperglycemia in con-

junction with corticosteroid therapy that is also a critical

component of ALL therapy.

Hence, a panel of principal investigators studying the

inclusion of pegASNase in adult patients was assembled to

review their collective experience and the reports and lit-

erature of toxicity to date, and to provide guidelines for the

prevention and management of ASNase toxicities and com-

plications in older adolescent and adult patients. A table of

ASNase and pegASNase dose recommendations for specifi c

organ-system related toxicities is provided toward the end of

this article (Table II).

Methods

All of the authors assembled in Chicago on 28 April 2009 to

review the literature and their clinical experience of ASNase

and pegASNase in adult and pediatric patients. Th e authors

subsequently divided into small groups to evaluate specifi c

toxicities by organ system, review and summarize the medi-

cal literature, compare and contrast their own experiences,

and subsequently develop a summary of these data and a

set of recommendations for anticipation, management, and

potentially prevention of ASNase- and pegASNase-related

toxicities and complications. At least two experts at diff er-

ent academic centers were assigned to each type of clinical

toxicity. Th e subgroups were Drs. Stock and Douer for hyper-

sensitivity reactions, Drs. Rytting, Douer, and Arellano for

pancreatic toxicities, Drs. Arellano, Douer, and Rytting for

hyperglycemia, Drs. Advani and DeAngelo for hepatotoxicities,

Drs. Kovacsovics, Damon, and Litzow for thrombosis and

bleeding, and Drs. Bleyer, Borthakur and Rytting for central

nervous system toxicities. In general, a computerized lit-

erature search of the PubMed and Medline databases in the

English language was performed with relevant keywords to

fi nd clinical reports on ASNase and pegASNase. Relevant re-

ports presented at annual meetings of the American Society

of Hematology and American Society of Clinical Oncology

were also reviewed. Before the manuscript was fi nalized, all

of the authors had an opportunity to review the manuscript

in its entirety.

Patient age and ASNase/pegASNase-associated toxicities

As described above, the initial experience with ASNase a half

century ago created the impression that it was unacceptably

toxic in adults. It is now apparent that most of the toxicities

of ASNase are qualitatively similar in children and adults

(Figure 2) [30 – 33], especially if the age-dependent, adverse

reactions are adjusted for co-existing morbidities. Toxicities

attributable to pegASNase-related toxicities were evalu-

ated among the fi rst 76 adults with newly diagnosed ALL to

be treated with IV pegASNase at the Cleveland Clinic, the

M. D. Anderson Cancer Center, and the University of South-

ern California, and compared with those for 1274 pediatric

patients treated with 6670 doses of IM pegASNase at member

Figure 1. Five-year observed survival rate of patients with acute lym-phoblastic leukemia diagnosed in the USA between 2000 and 2007, by age at diagnosis of 2-year intervals. Slopes are linear regressions for ages 4–17 and 18–83 years. Data from Surveillance, Epidemiology and End Results (SEER) 17, accessed 2 May 2010. Relative survival has an essentially identical pattern.

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Peg/asparaginase toxicity guidelines 2239

institutions of the Children ’ s Oncology Group (COG). Quali-

tatively, the toxicity profi le in the 76 adult patients evaluated,

of median (range) age of 30 (14 – 68) years, was similar to that

of the pediatric patients. Quantitatively, however, the fre-

quency of grade 3 – 4 toxicities was greater in adult patients for

hepatic and pancreatic dysfunction and greater in children

for allergic reactions (Figure 2), the latter of which is par-

tially explained by the greater number of doses per patient.

Other toxicities were similar in adult and pediatric patients

and in comparison to the rates published in the Physician ’ s

Desk Reference ® (PDR), with the exception of a higher rate of

hyperbilirubinemia as described in the section on hepato-

toxicity below [30].

Grade 2 – 4 toxicity rates were reported in a follow-up of this

study with an expansion of the adult patient experience to 92

patients, 14 – 71 years of age, treated at the same centers with a

total of 330 pegASNase doses [31]. Th e most common symp-

tomatic toxicities, in order of patient occurrence, were throm-

bosis, fatigue, pancreatitis, nausea/vomiting, and allergic

reactions (Table I). For asymptomatic toxicities, detected by

laboratory-based abnormalities, liver and pancreatic toxi cities

were re-iterated, with hepatotoxicity predominating (Table I).

It is, however, the co-existing morbidities, particularly of

the liver and pancreas (Figure 2), that create a higher quanti-

tative rate of adverse eff ects of ASNase in adult patients. Con-

comitant use of alcohol or other hepato- and pancreato-toxic

drugs and underlying hepatitis C are particularly likely to

cause more ASNase-related liver and pancreatic toxicities. In

general, however, healthy adults appear to tolerate ASNase/

pegASNase comparably to younger patients. Age-dependent,

organ-specific differences are described below, albeit in

most instances awaiting a more signifi cant knowledge base

founded on clinical evidence.

Evidence-based recommendations for management of ASNase/pegASNase toxicities

Hypersensitivity As a foreign protein, ASNase hypersensitivity reactions are a

common and serious toxicity, particularly with re-exposure to

repeated doses of the enzyme. Th e risk of hypersensitivity varies

with prior exposure, concomitant or prior immunosuppressive

therapy, and the individual patient. Th e type of reaction is also

highly heterogeneous, ranging from a reaction at the injection

site, often diffi cult to distinguish from a non-allergic infl amma-

tory response, to frank anaphylaxis with fatal potential.

Incidence Th e incidence of hypersensitivity reactions to ASNase depends

on the number of prior exposures to ASNase, the type of

ASNase, concomitant corticosteroid therapy as part of the

Figure 2. Proportion of adult and pediatric patients with ALL with apparent* grade 3–4 pegASNase related toxicities. Data from poster presentation by Advani and associates [30]. *Apparent refers to the diffi culty in determining whether the observed toxicity was due to pegASNase or to another agent in the multidrug regimen of ALL therapy, or to a combination of drugs that would not have occurred with pegASNase alone.

Table I. Proportion of 92 adults with apparent pegASNase-related toxicities while treated at the Cleveland Clinic, University of Texas M. D. Anderson Cancer Center, and University of Southern California [31]*.

Toxicity Grade 2–4 toxicity rate

Symptomatic Th rombosis 13% Fatigue 12% Clinical pancreatitis 9% Nausea/vomiting 8% Allergy 5% Stroke-like symptoms 3% Neuropathy 2%Asymptomatic (laboratory) Hepatic transaminasemia (transferasemia) 52% Hyperglycemia 33% Hyperbilirubinemia 24% Hypfi brinogenemia 9% Prolonged prothrombin time 1%

*Modifi ed from Rytting [33].

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sitivity reactions declined. Th is experience suggests that the

pediatric regimen should also provide steroid pre-medication

for doses of ASNase that occur during phases that do not

include corticosteroid anti-leukemic therapy. Since silent

neutralizing antibody appears to be much less problematic

with pegASNase (see the next two paragraphs), the pediatric

regimens may similarly benefi t and allow more patients to

receive sustained asparagine depletion.

Neutralizing anti-ASNase antibody can form with or with-

out clinical allergic reaction, the latter referred to as silent

hypersensitivity. Antibody formation to native ASNase and

to the ASNase or polyethylene glycol portion of pegASNase

has been shown to alter the pharmacokinetics of the drug

[37 – 41]. Such antibodies can inhibit ASNase from depleting

asparagine, and if silent may be continued unknowingly with-

out the benefi t of ASNase and yet continued risk of toxicity.

In children, the frequency of neutralizing antibody to native

E. coli ASNase has ranged from 18% [40] to 50% [41].

PegASNase appears to have a signifi cantly lower rate

of inducing neutralizing antibody than the native enzyme

[37 – 42]. In children with newly diagnosed ALL who were

randomized to receive native E. coli ASNase or pegASNase,

26% of those treated with the native ASNase regimen had

high-titer antibodies, whereas only 2% of pegASNase pa-

tients had those levels [37]. High-titer antibodies were asso-

ciated with low ASNase activity in the native arm but not in

patients treated with the pegASNase regimen [37]. Among

11 children treated with pegASNase for relapsed ALL after

clinically signifi cant hypersensitivity reactions to native

ASNase, enzymatic activity of pegASNase was not diff erent

from that in previously treated children with no evidence

for allergic reactions [43]. Th ree of four children on the ALL/

NHL-BFM 95 study who previously had allergic reactions

to E. coli ASNase demonstrated no evidence for neutral-

izing antibody against pegASNase [35]. In adult patients

treated by IM or subcutaneous injection of four doses of

pegASNase, two that were admini stered during induction

and two during intensifi cation, neutralizing antibody was

detected in 10% of patients [16]. Among the fi rst 43 adult

patients who received 77 doses of IV pegASNase and were

tested for neutralizing antibody, only one patient was found

to have evidence of such antibody [44]. In a follow-up study

with 10 adults receiving six doses of pegASNase and 11

adults receiving four doses, only one patient had evidence

of neutralizing antibody, and this patient developed a rash

after receiving a subsequent dose [45]. One of 26 adult

patients treated with low doses of pegASNase (500 – 1000

IU/m 2 ) developed evidence for neutralizing activity [22].

Patients with silent antibodies may benefi t from a switch

to Erwinia ASNase [46], or theoretically from more frequent

dosing of pegASNase, in that enough antigen (ASNase) may

saturate the antibody and overcome the neutralizing capac-

ity. Patients with antibodies to polyethylene glycol may also

clear the drug more rapidly than normal patients [38]. Since

polyethylene glycol is used in a variety of commonly encoun-

tered products including cosmetics and processed foods, ex-

posure to polyethylene glycol and subsequent development

of polyethylene glycol antibodies could, hypothetically, be

increasing in the general population [33].

leukemia therapy, and host immunocompetence. In pediatric

patients at Th e Children ’ s Hospital of Boston who were ran-

domized to either 30 weekly IM injections of E. coli ASNase or

15 IM doses of pegASNase every other week, 15% had allergic

reactions [14]. Th ere were fewer low-grade hypersensitivity

reactions with pegASNase but no diff erence in dose-limiting

hypersensitivity reactions. Th ere was also no diff erence in

age (children versus adolescents) in the incidence of hyper-

sensitivity reactions. Th ere was a highly signifi cant correla-

tion between disease-free survival and number of doses of

ASNase delivered. Patients who tolerated 25 or fewer weeks

of ASNase had a signifi cantly worse outcome than those who

received at least 26 weeks of ASNase ( p � 0.01).

In the COG Children ’ s Cancer Study Group (CCG)-1961

trial, nine doses of E. coli ASNase were given during induc-

tion therapy and six or 10 doses of pegASNase, depending

on the regimen to which the patient was randomized, dur-

ing post-remission consolidation, interim maintenance, and

intensifi cation therapies. Half of the patients experienced

an allergic reaction to pegASNase during the post-remission

intensifi cation phase [34]. Because many of the hypersensi-

tivity reactions may have been due to the prior exposure to

the E. coli ASNase, successor COG studies provide pegASNase

during induction as well as in subsequent phases.

Th e incidence of severe reactions to pegASNase in other

pediatric studies that have been published is somewhat diffi -

cult to interpret. In the German ALL/non-Hodgkin lympho-

ma Berlin – Frankfurt – M ü nster (NHL-BFM) 95 study, none

of 70 children who had a dose of pegASNase during repeat

induction therapy had an allergic reaction despite having

had four doses of E. coli ASNase during induction [35], and

in four of whom a clinical hypersensitivity reaction with

E. coli ASNase had occurred.

In adult patients, no large body of data exists, but the inci-

dence of clinically signifi cant hypersensitivity probably aver-

ages between 10 and 15%. In Cancer and Leukemia Group B

(CALGB) 8811, Larson et al . reported an incidence of severe

hypersensitivity reactions to native ASNase in 21 of 197 (11%)

adults entered onto trial [36]. Fourteen doses of ASNase were

scheduled in this trial; however, the severity of hypersensitiv-

ity in these 21 patients required discontinuation of the drug.

Twenty of these patients received Erwinia ASNase and 12 of

20 completed all required ASNase doses. Th ese patients did

not have a shorter leukemia-free survival when compared to

the other adults treated on this trial.

Among the first 61 adult patients treated with IV

pegASNase (seven scheduled doses) on the CALGB/Southwest

Oncology Group (SWOG)/Eastern Cooperative Oncology

Group (ECOG) C10403 trial for 15 – 39-year-old patients with

newly diagnosed ALL, grade 3 – 4 hypersensitivity reactions

occurred in nine patients (15%) (Stock W, review of US Nati-

onal Cancer Institute Adverse Event Expedited Reporting

System [NCI ADEERS] reports, personal communication).

Th e protocol for this study initially did not recommend pre-

medication to prevent allergic reactions, and concurrent ste-

roid therapy does not occur for fi ve of the required seven doses.

Subsequently, the protocol was amended to recommend

pre-medication with hydrocortisone, diphenhydramine, and

acetaminophen, following which the incidence of hypersen-

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Current management strategies Th e goal is to minimize the incidence of hypersensitiv-

ity reactions and yet allow for maximal exposure to ASNase.

Also, recommendations that will not result in signifi cant

alterations to protocol-based therapy are preferred. Th ere

is a strong clinical impression that pretreating patients with

corticosteroids is eff ective in preventing clinically signifi cant

allergic reactions. Since steroids are anti-leukemic and used

in most ALL treatment regimens, timing the steroid exposure

with the ASNase doses makes sense. When dexamethasone

is used, a drug – drug interaction may occur in that ASNase-

induced hypoalbuminemia has been reported to decrease

the clearance of dexamethasone [47]. Dexamethasone has

been increasingly used in ALL therapy as a result of the tri-

als that randomized prednisone and dexamethasone and

showed that dexamethasone had a stronger anti-leukemic

eff ect [48]. In adolescents, however, avascular necrosis of the

hip and other weight-bearing joints (osteonecrosis) has been

a major drug-limiting toxicity. To what extent this occurs

in adults with a mature skeleton has yet to be determined,

albeit the early indications are that osteonecrosis is less

problematic.

With native ASNase treatment, clinical hypersensitivity

reactions are frequently a surrogate for neutralizing anti-

ASNase antibody formation. Whether or not this also applies

to pegASNase is not known, in part because the incidence of

clinical allergy has been suffi ciently low to limit this evalu-

ation. Routine pre-medication with steroids to suppress

clinical hypersensitivity reactions is avoided in children, in

case a clinical allergic reaction indicates the development

of neutralizing antibody. In adult patients, however, pre-

medication with hydrocortisone is recommended in some of

the clinical trials.

Recommendations For each dose of ASNase or pegASNase, an anaphylaxis kit

should be available at the bedside and the patient should

be observed for 1 h after either IV or IM administration.

Steroids, antihistamines, oxygen, and epinephrine should

be admini stered as clinically indicated. For any potentially

life-threatening reaction with either native E. coli ASNase or

pegASNase, further treatment with either is contraindicated.

Erwinia ASNase may be substituted for native E. coli ASNase

or pegASNase in patients, including those with grade 3 or 4

hypersensitivity reactions (Table II), provided the aforemen-

tioned precautions are taken.

Prevention When ASNase and daily corticosteroids are both used in a

treatment phase, the ASNase should be delayed for 3 – 4 days

after the start of steroid therapy to reduce the risk of a serious

hypersensitivity reaction. In an adult patient who is not on

concurrent corticosteroids, pre-medication with hydrocorti-

sone, 100 mg IV prior to each dose of pegASNase, is recom-

mended. Acetaminophen and diphenhydramine may also

be given with the hydrocortisone. Other than prior ASNase or

pegASNase therapy, there are no known risk factors for pre-

dicting ASNase-related hypersensitivity. A test dose for pre-

existing hypersensitivity is not routinely performed. Th ere is

currently no known eff ective strategy to prevent silent hyper-

sensitivity occurring with neutralizing antibody, other than

using pegASNase instead of native E. coli ASNase, since the

former appears to be signifi cantly less immunogenic. Anti-

body assays for neutralizing antibody are currently available

only at research laboratories, but are more straightforward to

assess than ASNase levels.

Anecdotal experience suggests that lengthening IV ad-

ministration of pegASNase from 1 to 2 h reduces the risk of

a hypersensitivity reaction. Whereas this practice is not yet

evidence-based, the slower rate may result in less immu-

nogen having been infused when the reaction occurs and is

thereby potentially more reversible.

Pancreatic toxicities Despite three decades since ASNase-related pancreatitis

was fi rst described, the mechanism of this toxicity is still un-

known [49]. Fortunately, this form of toxicity is usually not

life-threatening, generally responds favorably to aggressive

medical therapy when indicated [32,50], and usually resolves

without long-term sequelae [51]. In children, the reported

incidence of pancreatitis associated with the various ASNase

preparations ranges from zero to as high as 18%, with large

trials reporting an incidence of less than 10% [52 – 54] and with

adolescents more likely than children to develop this com-

plication [51]. Acute pancreatitis associated with pegASNase

also appears to occur in fewer than 10% of patients, although

one group of investigators has expressed concern about

increased episodes of pancreatitis using pegASNase [55].

Pancreatitis tends to occur early in treatment, after the fi rst

few doses of asparaginase, suggesting a predisposition to this

complication rather than a cumulative drug eff ect [51]. In

contradistinction to hyperglycemia, which is more likely to

occur with concomitant steroid therapy as described above,

ASNase-related pancreatitis is not dependent on concurrent

steroid therapy [56]. Re-treatment with asparaginase after

resolution of an episode of clinically signifi cant pancreatitis

was associated with a high risk of recurrent pancreatitis [51].

Incidence Among the adult centers investigating pediatric-based ALL

treatment regimens in young adults, the incidence of acute

pancreatitis in adult patients given pegASNase has been low

[33]. Th is is despite the expected increase in both alcohol use

and of gallstones, and thus pancreatitis, in this population as

compared to children and adolescents.

Current management strategies Octreotide, a synthetic somatostatin analog with a prolonged

half-life, has been demonstrated to be safe and eff ective for

use in the management of pancreatitis in both children and

adults [57 – 59]. A recent study suggests that severe pancreati-

tis may be eff ectively managed with continuous regional arte-

rial infusion of a protease inhibitor, nafamostat mesylate, and

concomitant imipenem antibiotic therapy [57,58,60 – 62].

Recommendations Th e guidelines below provide a framework for physicians

treating adult patients with ALL who develop fi ndings of

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Table II. ASNase/pegASNase dose modifi cation recommendations* for ASNase-induced toxicities in adults and older adolescents.

Toxicity

Toxicity grade†

2 3 4

Hypersensitivity‡

Urticaria, wheezing, laryngospasm, hypotension, etc.

For urticaria without bronchospasm, hypotension, edema, or need for parenteral intervention, continue ASNase

For wheezing or other symptomatic bronchospasm with or without urticaria, indicated parenteral intervention, angioedema, or hypotension, discontinue ASNase. If Erwinia ASNase available, replace each pegASNase dose with 6 doses of Erwinia ASNase, 25 000 IU/m2 IM every other day including weekend days

For life-threatening consequences or indicated urgent intervention, discontinue ASNase. If Erwinia ASNase available, replace each pegASNase dose with 6 doses of Erwinia ASNase, 25 000 IU/m2 IM every other day including weekend days

Pancreatitis Pancreatitis Continue ASNase

for asymptomatic amylase or lipase elevation � 3.0 � ULN (chemical pancreatitis) or only radiologic abnormalities; observe closely for rising amylase or lipase levels

Continue pegASNase for non-symptomatic chemical pancreatitis but observe patient closely for development of symptomatic pancreatitis for early treatment. Hold native ASNase for amylase or lipase elevation � 3.0 � ULN until enzyme levels stabilize or are declining. Permanently discontinue ASNase for symptomatic pancreatitis (see grade 4 recommendation)

Permanently discontinue all ASNase for clinical pancreatitis (vomiting, severe abdominal pain) with amylase or lipase elevation � 3 � ULN for � 3 days or/and development of pancreatic pseudocyst

Hypertriglyeridemia Hypertriglyceridemia If serum triglyceride

level � 1000 mg/dL, continue ASNase but follow patient closely for evolving pancreatitis

Hold ASNase for triglyceride � 1000 mg/dL; follow closely for pancreatitis; resume ASNase at prior dose level after patient’s triglyceride level returns to his/her normal range

Hold ASNase for triglyceride � 1000 mg/dL; follow closely for pancreatitis; resume ASNase at prior dose level after patient’s triglyceride level returns to his/her normal range

Hyperglycemia Hyperglycemia,

ketoacidosisContinue ASNase for

uncomplicated hyperglycemia

For hyperglycemia with requiring insulin therapy, hold ASNase (and glucosteroid therapy) until blood glucose regulated with insulin; resume ASNase at prior dose level

For hyperglycemia with life-threatening consequences or indicated urgent intervention, hold ASNase (and glucosteroid therapy) until blood glucose is regulated with insulin; resume ASNase and do not make up for missed doses

Hepatic toxicity Hepatic

transferasemia (transaminasemia)

For alanine or glutamine aminotransferase elevation � 3.0�5.0 � ULN, continue ASNase

For alanine or glutamine aminotransferase elevation � 5.0�20.0 � ULN, delay next dose of ASNase until grade � 2

For alanine or glutamine aminotransferase elevation � 20.0 � ULN, discontinue ASNase if toxicity reduction to grade � 2 takes� 1 week

Hyperbilirubinemia Continue ASNase if direct bilirubin � 3.0 mg/dL

If direct bilirubin 3.1–5.0 mg/dL, hold ASNase and resume when direct bilirubin is � 2.0 mg/dL. Consider switching to native ASNase

If direct bilirubin � 5.0 mg/dL, discontinue all ASNase and do not make up for missed doses

Th rombosis and bleeding, including CNS Non-CNS thrombosis For abnormal laboratory

fi ndings without clinical correlates, continue ASNase

Withhold ASNase until acute toxicity and clinical signs resolve and anticoagulant therapy stable or completed; do not withhold ASNase for abnormal laboratory fi ndings without a clinical correlate

Withhold ASNase until acute toxicity and clinical signs resolve and anticoagulant therapy stable or completed

Non-CNS hemorrhage For bleeding in conjunction with hypofi brinogenemia, withhold ASNase until bleeding � grade 1; do not withhold ASNase for abnormal laboratory fi ndings without a clinical correlate

Withhold ASNase until bleeding � grade 1, until acute toxicity and clinical signs resolve, and coagulant replacement therapy stable or completed

Withhold ASNase until bleeding � grade 1, until acute toxicity and clinical signs resolve, and coagulant replacement therapy stable or completed

(Continued)

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• Patients should be educated to promptly report ab-

dominal pain, especially in association with vomiting,

so that amylase and lipase can be checked and pan-

creatitis diagnosed as early as possible.

• Isolated elevations of amylase or lipase, if obtained and

worrisome, may be further evaluated radiographically.

In the unlikely event of elevated pancreatic enzymes

and positive radiographic fi ndings of pancreatitis in a

patient with no symptoms, ASNase therapy should be

stopped.

• For severe pancreatitis, continuous regional arterial

infusion of a protease inhibitor such as nafamostat me-

sylate and concomitant imipenem antibiotic therapy

for severe pancreatitis [57] should be considered.

• Subsequent pseudocyst development can be assessed

with follow-up abdominal computed tomography (CT)

scans.

• In general, re-challenging patients with ASNase prep-

arations following resolution of an attack of acute clini-

cal pancreatitis is contraindicated. Re-challenge after

intermediate degrees of clinical pancreatitis (Table II)

has nonetheless been successful.

Prevention Avoidance of alcohol is a key preventive measure. Octreotide

may be useful for preventing pancreatitis in recovering patients

[58]. Hypertriglyceridemia can be a harbinger of pancreatitis,

and if treated with gemfi brozil when the serum triglyceride

exceeds 1000 mg/dL may obviate acute pancreatitis (Table II).

Hyperglycemia Endocrine complications are commonly seen in patients un-

dergoing treatment for ALL. Hyperglycemia (random plasma

glucose � 200 mg/dL or fasting � 140 mg/dL) due to insulin

resistance is a common consequence of steroid use and

pancreatitis while receiving ASNase. Th ey are conservative

and are intended to maintain ASNase exposure while pro-

tecting patients from severe toxicity.

• Since stopping the drug may be associated with poorer

survival, as demonstrated in pediatric patients with ALL

[10,14], the diagnosis of pancreatitis should be well

defi ned before eliminating ASNase from the treatment

regimen.

• Abdominal pain without elevation of pancreatic en-

zymes is unlikely to represent acute pancreatitis and

likely represents other disorders such as acute gastritis.

Administration of ASNase and pegASNase can con-

tinue in such patients.

• ASNase or pegASNase need not be discontinued for

chemical pancreatitis (i.e. elevation of amylase and/or

lipase) without symptoms and physical or radiologic

fi ndings of clinical pancreatitis and regardless of the

degree of amylasemia or lipasemia (Table II) [63].

• ASNase (or pegASNase) therapy should be discontinued

for symptoms (e.g. abdominal pain, vomiting), amy-

lasemia, and/or lipasemia, and physical or radiologic

fi ndings consistent with acute pancreatitis. As more

specifi cally recommended in Table II, ASNase should

be withheld until symptoms resolve and amylase/lipase

levels return to normal, and permanently discontinued

for abdominal pain with grade 3 or 4 amylase/lipase

elevation for more than 3 days or/and development of

pancreatic pseudocyst.

• Treatment of clinically signifi cant pancreatitis includes

hospitalization, nothing-by-mouth status, nasogastric

decompression, for recurrent vomiting IV hydration

and if necessary alimentation, analgesia, octreotide,

and antibiotics; these measure are more eff ective when

started with the first symptoms and signs of acute

pancreatitis.

Toxicity

Toxicity grade†

2 3 4

CNS thrombosis For abnormal laboratory fi ndings without a clinical correlate, continue ASNase

Discontinue all ASNase; if CNS symptoms and signs are fully resolved and signifi cant ASNase remains to be administered, may resume ASNase therapy at a lower dose and/or longer intervals between doses

Permanently discontinue all ASNase

CNS hemorrhage Discontinue ASNase; do not withhold ASNase for abnormal laboratory fi ndings without a clinical correlate

Discontinue all ASNase; if CNS symptoms and signs are fully resolved and signifi cant ASNase remains to be administered, may resume ASNase therapy at a lower dose and/or longer intervals between doses

Permanently discontinue all ASNase

Hyperammonemia Hyperammonemia-

related fatigue (‘ASNase blues’)

Continue ASNase Reduce ASNase dose 25%; resume full dose when toxicity � grade 2; make up for missed doses

Reduce ASNase dose 50%; resume full dose when toxicity � grade 2; make up for missed doses

ASNase/pegASNase, asparaginase/pegasparaginase; CNS, central nervous system; ULN, upper limit of normal; IM, intramuscular.*Only ASNase (and pegASNase) dose changes are specifi ed; the text provides other treatment recommendations. ASNase dose changes apply to both native E. coli ASNase and pegASNase.†Grade according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, with the exception of pancreatitis which is applied by the authors with some modifi cations.‡Local infl ammatory reactions to intramuscularly injected ASNase must be distinguished from true hypersensitivity reactions.

Table II. (Continued)

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diets should be avoided, as anorexia and weight loss are fre-

quent side eff ects of ALL and its treatment.

Improving glycemic control through diet and exercise,

monitoring urine glucose, and controlling blood glucose

with insulin therapy in severe cases improves the outcome of

hyperglycemia caused by asparagine depletion [72]. ASNase

should be discontinued and judicious intravenous fluids

administered for grade 3 – 4 hyperglycemia (fasting blood

glucose � 250 mg/dL) (Table II) or less severe hyperglycemia

in symptomatic or azotemic patients. Patients with severe

hyperosmolar hyperglycemia should be hospitalized and

insulin therapy initiated until circulating ASNase or, more

slowly, pegASNase is cleared and glucose homeostasis re-

stored. Careful monitoring for resolution and worsening with

careful review of systems and serum glucose measurements

at home and in the clinic should be instituted. Th e target

blood glucose level is not defi ned, but a modest range (fast-

ing glucose 120 – 180 mg/dL) is preferable to avoid the risk of

hypoglycemia. Also unclear are when isolated post-prandial

glucose elevations or fasting glucose elevations should be

monitored, and how to assess ASNase/pegASNase-induced

glucose dysregulation such as formal glucose tolerance tests,

2 h post-prandial glucose levels, or hemoglobin A1C levels.

ASNase/pegASNase should not be permanently discon-

tinued for hyperglycemia per se , even for grade 3 – 4 toxicity,

given its effi cacy in ALL (Table II). Maintenance insulin ther-

apy may be needed during continued asparagine depletion.

Diet and exercise recommendations, as mentioned next,

should be off ered.

Prevention Exercise, diabetic dietary modifi cations, and educating the

patient about signs and symptoms of hyperglycemia remain

the only prevention strategies. Judicious monitoring may de-

tect hyperglycemia prior to the onset of symptoms. A high

index of suspicion for those who are at risk and emphasizing

diabetic education for patients with pre-existing diabetes are

warranted. Expect an increase in the insulin dose in patients

who were previously using insulin, or initiation of insulin in

those who were diet-controlled.

Hepatotoxicity Very few clinical trials have reported on the incidence of he-

patotoxicity secondary to ASNase. Even fewer studies have

reported on the follow-up of abnormalities after the course

of treatment. Th e reason for this paucity of data is in part re-

lated to the diffi culty in determining the reason for abnormal

liver function tests when the underlying disease, infection,

co-morbidities, and other hepatotoxic agents, including other

chemotherapeutic agents in the multidrug regimen of ALL

therapy, can all be inciting factors. Infection in particular

confounds the evaluation in that patients with ALL often de-

velop sepsis or are prophylactically treated with antibiotics,

such as antifungal antibiotics, that are hepatotoxic.

Rarely has hepatic dysfunction associated with ASNase

resulted in severe or fatal complications [73]. Th e most com-

mon abnormalities are in the serum hepatic transferases

(transaminases), alkaline phosphatase, bilirubin, and albu-

min [74]. Other manifestations include hypofi brinogenemia,

can also occur during treatment with ASNase, as a conse-

quence of decreased insulin production [64,65] and perhaps

a defi ciency or modifi cation of insulin receptors [66]. Th e

concomitant use of both drugs has been shown to synergisti-

cally increase the occurrence of hyperglycemia [67]. ASNase-

induced hyperglycemia can result in acute complications

such as delayed wound healing and, rarely, non-ketotic,

hyperosmolar coma. Although long-term complications of

hyperglycemia are rare in children, the prevalence in adults

is unknown. It is therefore imperative to diagnose and treat

ASNase-related hyperglycemia.

Incidence Th e incidence of hyperglycemia attributed to ASNase therapy

in pediatric patients has been reported to be as high as 23%

[68], at least when given in combination with anti-leukemic

corticosteroid therapy. For pegASNase, the reported rates

are 5 – 17% for pediatric patients [25,69] and up to 76% (16%

grade 3 – 4) for adult patients [31,70]. In a study of 421 chil-

dren and adolescents with ALL undergoing therapy with

E. coli ASNase and prednisone, 10% of the patients developed

hyperglycemia, all but two within 1 week of the fi rst dose of

ASNase [71]. Hyperglycemia resolved in all patients, and in

78% by the end of the 4-week induction phase. In 71%, the

hyperglycemia was severe enough to require insulin therapy.

ASNase was continued in all patients despite hyperglycemia,

and did not recur or worsen in 61%. Th e greatest risk factor

appears to be concomitant steroid therapy, for ASNase by

itself appears to have little hyperglycemic potential. Among

pediatric patients, other risk factors are older age (adolescence

greater than childhood), obesity, a family history of diabetes

mellitus, and Down syndrome. Th e increased incidence with

age continues into adult ages as shown for pegASNase in

Figure 2.

Clinical presentation Th e symptoms are polyuria and polydipsia, accompanied by

glucosuria. Polyphagia and azotemia may occur, but ketone-

mia is rare. Th e majority of adult patients with pegASNase-

related hyperglycemia are asymptomatic; 84% in the most

recent report had grade 1 – 2 toxicity [31].

Current management strategies Clinical protocols recommend periodic monitoring of serum

glucose and less commonly checking for glucosuria. The

hyperglycemia syndrome responds to intravenous fl uids and

insulin administration but there are no clear guidelines as to

when to use insulin. As reported in children, the syndrome

resolves upon discontinuation of pegASNase, does not con-

traindicate ASNase retreatment, and in fact may not recur

with re-administration.

Recommendations Vigilance regarding known risk factors for ASNase/

pegASNase-induced hyperglycemia is important, as patients

at higher risk may warrant closer monitoring. Therefore

obtaining a thorough family history and physical exam prior

to initiating therapy is important. Patients should be coun-

seled about exercise and healthy diet, but highly restricted

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ASNase [16]. Th e variable hepatotoxicity noted in the stud-

ies may be due to several factors including patient age (older

patients in the latter two studies), increased number of doses

of ASNase (in the latter two studies), or diff erences in thera-

peutic regimens.

Although it was previously thought that pegASNase may

be associated with increased hepatotoxicity, these data have

not held in clinical trials. In a large randomized study of

Erwinia versus native E. coli ASNase during induction, with

350 children in each regimen, the incidence of grade 3 – 4

hepatotoxicity was relatively low and similar in both arms

(3.8 – 4.5%) [27]. In the CCG study (study 1), grade 3 – 4 transam-

inases were seen in 3% of patients treated with pegASNase

and 7% of patients treated with native E. coli ASNase [30].

In the three-institution survey of pegASNase toxicities pre-

viously cited (Figure 2) [30], hepatotoxicity was the most

common grade 3 – 4 toxicity, with elevation of serum liver

enzymes, hypofibrinogenemia, and hyperbilirubinemia

in 36%, 16%, and 14% of evaluable patients, respectively.

Hyperglycemia and chemical pancreatitis were the next most

common toxicities, occurring at grade 3 – 4 levels in 25% and

5% of patients, respectively. Hyperbilirubinemia was more

common in adult patients than stated in the PDR. Successful

re-challenge with ASNase in a patient who recovered from

grade 3 hepatotoxicity has been reported [22].

Current management strategies Formal recommendations regarding the management of

hepatotoxicity in adult patients would be premature, given

that nearly all reported experience has been anecdotal.

Nonetheless, in order to provide some guidelines, the follow-

ing management strategy is off ered.

Recommendations Clinical experience and the literature to date warrant recom-

mending holding ASNase when grade 3 – 4 hepatotoxicity

develops and then re-challenging with careful monitoring if

toxicity resolves to grade 1 (Table II). Th e risk of re-challenge

seems to be more a result of recurrent hepatotoxicity that

delays subsequent scheduled administration of drugs that

are metabolized or cleared by the liver, such as anthracy-

clines and vincristine, than hepatic failure per se . Th ere are

currently no data to suggest the need for reducing the dose

of pegASNase after recovering from hepatotoxicity. Liver

function tests should be checked before each dose of ASNase

or pegASNase, as well as any dose of a drug scheduled for

administration after ASNase/pegASNase that is cleared or

metabolized by the liver, such as a vinca alkaloid, anthracy-

cline, or antifungal azol.

Prevention Preventive treatment strategies to decrease hepatotoxicity

include avoiding the concurrent use of alcohol and hepa-

totoxic drugs, including azol antifungal antibiotics [80 – 83].

Hepatotoxic chemotherapy agents such as methotrexate

and cytarabine may not be avoidable, depending on the ALL

regimen, but the prescribing oncologist should be aware that

their concomitant use with ASNase is likely to increase the

risk of hepatic dysfunction. Other measures include avoiding

decreased antithrombin III [74], and increased cholesterol,

phospholipids, and triglycerides [75]. Th e mechanism of

ASNase hepatotoxicity has been speculated to be due to

decreased protein synthesis or impaired liver mitochondrial

function, and alterations in very-low-density lipoprotein

metabolism and secretion have also been implicated, as well

as the development of severe fatty metamorphosis and infi l-

tration [73,74,76]. Liver biopsies after 2 – 20 days in four adults

with hepatomegaly and elevated liver function tests after

ASNase as part of a combination chemotherapy regimen all

showed diff use steatosis [74]. Other changes included patchy

hepatic necrosis, mixed infl ammatory cell infi ltrates in the

portal tracts, and hepatocellular/canalicular cholestasis. In

another report, an adult patient who died of liver failure had

mixed liver injury and predominantly microvesicular hepatic

steatosis [76].

Whereas hyperglycemia is usually a manifestation of con-

comitant ASNase and corticosteroid therapy (as described

above), ASNase-related steatosis is not similarly co-dependent.

In pediatric patients, ASNase induces hypertriglyceridemia,

but not hypercholesterolemia, without concomitant steroid

therapy [72]. ASNase alone appears suffi ciently hepatotoxic to

cause hypertriglyceridemia as high as 1000 mg/dL in 25% of

patients by itself, but without associated pancreatitis [72].

Incidence Among reports of largest series of children or adults treated

with native E. coli ASNase, elevations in the hepatic trans-

ferase (serum glutamic oxaloacetic transaminase; SGOT),

alkaline phosphatase, and bilirubin were noted in 35 – 45%,

30 – 35%, and 30 – 60% of patients, respectively [24,73,77 – 79].

A decreased serum albumin has been reported in as many

as 70% of children and adults studied [24,73]. It is diffi cult

to know, however, whether or not ASNase contributed to

this decrease, since patients with ALL frequently have other

causes of hypoalbuminemia, and albumin is also known to

be an acute phase reactant. Th e incidence of grade 3 – 4 tox-

icities varies with the treatment regimen, and with the dose

of ASNase. Early studies used higher doses of native E. coli

ASNase (10 doses of 1000 IU/kg), during which the incidence

of hepatotoxicity was higher [80]. Th e use of lower doses of

ASNase has reduced the incidence of hepatic complications,

but hepatic dysfunction still occurs [80].

In patients 18 – 55 years of age treated with one dose of IV

pegASNase, 2000 IU/m 2 , during induction chemotherapy

that included prednisone, 16% developed grade 3 – 4 transam-

inasemia and 11% developed hyperbilirubinemia [70]. In 92

adult patients treated with an average of 3.4 doses, the in-

cidence of grade 3 – 4 toxicity was 52% for transaminasemia

and 24% for hyperbilirubinemia (Table I). Th e increase in

transaminasemia with repeated exposure is probably not

clinically signifi cant, since the enzyme elevations nearly al-

ways resolved spontaneously [31]. Th e hyperbilirubinemia

is more signifi cant in that it can delay the delivery of those

chemotherapy agents that require dosage interruption or

reduction in the presence of bilirubin elevations, such as the

vinca alkaloids and anthracyclines. In CALGB 9511, which

did not have an upper age limit, grade 4 hyperbilirubine-

mia occurred in 54% of patients who received 1 – 4 doses of

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ASNase therapy in patients with underlying chronic hepatic

dysfunction, especially due to alcoholism and viral hepatitis.

Milk thistle has been reported to be eff ective in preventing

hepatotoxicity of the non-ASNase maintenance phase of

therapy in children with ALL [84]. Lower doses of ASNase

are also used in some protocols in part to reduce the risk of

hepatotoxicity.

Thrombosis and bleeding Th e simultaneous eff ects of ASNase on both procoagulant

and thrombolytic proteins increase the risk of both thrombo-

sis and bleeding, with thrombosis generally more problem-

atic. ASNase leads to asparagine depletion in serum, which

results in the decreased synthesis of fi brinogen, plasmino-

gen, and the anti-coagulation factors antithrombin III (AT),

protein C, and protein S. AT and fi brinogen are particularly

aff ected [85 – 87], with the former leading to an increase in

thrombin generation [87]. ASNase does not aff ect the cleav-

age of AT in serum, but leads to decreased secretion of AT

[88] and fi brinogen [85], possibly by leading to AT aggregates

in cells [89]. Interestingly, the formation of AT aggregates

appears more pronounced in the presence of prednisone

than of dexamethasone [90]. In one study of 11 patients, all

of them had decrements in their AT levels for 5 – 21 days after

pegASNase, which correlated with the duration of ASNase

plasma enzymatic activity [70].

Th e mechanism of cranial venous sinus thrombosis (CVST)

is primarily thrombin generation as a consequence of AT

depletion [87,91 – 93]. However, an increase in factor VIII and

a decrease in protein S have also been implicated. Depletion

of serum fi brinogen due to disseminated intravascular coag-

ulation may worsen ASNase-related central nervous system

(CNS) hemorrhage. CT and magnetic resonance (MR) studies

can detect CVST in cranial venous sinuses [94], and frequently

CVST is associated with parenchymal hemorrhage.

Incidence Th e incidence of ASNase-associated thrombotic complica-

tions is clearly age-dependent [95]. In children, the overall

incidence of ASNase-related thrombosis is 3 – 5% [87,93,95 –

99]. In clinical trials in newly diagnosed patients with ALL

treated at the Dana-Farber Cancer Institute between 1991

and 2008 with intensive ASNase therapy, 5% of pediatric

patients, 34% of adult patients, and 42% of adults 30 years

of age or older had venous thromboembolic events, and age

was the only signifi cant predictor of these events [100]. In a

pooled analysis of reports on adult patients, the incidence

of clinically apparent thrombosis was 6% [95]. Less intensive

ASNase regimens in adult patients have reported lower

rates of thrombotic complications [101,103]. Th e data on

pegASNase-related deep venous thrombosis (DVT) in adults

suggests that DVTs may be less frequent after E. coli ASNase,

but original data are limited and come mainly from reports

on small numbers of patients [18,31,45,70]. In UKALL 2003,

children with DVTs were routinely retreated with pegASNase

and concurrent heparin prophylaxis without recurrence of

thrombosis [99].

Th e majority of clinically signifi cant thrombotic events

can be divided into those related to venous catheters and

those in the central nervous system. When extensive screen-

ing is performed and catheter-related clots are included, the

incidence is considerably greater, but the vast majority of

these are asymptomatic. Th e majority (90%) of thromboses

in both children and adults occur during induction [104].

In the GOELAMS (Groupe Ouest – Est des Leuc é mies et des

Autres Maladies du Sang) study, 9% of adults had a thrombo-

sis during induction [103].

An incidence of CVST of 2 – 3% in children was observed in

both regimens of a randomized study of native ASNase versus

pegASNase [37]. A BFM type remission induction regimen in

adult patients with ALL replaced 14 doses of native ASNase

with one dose of pegASNase. No grade 3 or 4 neurotoxicity

was noted [70]. Among 238 adult patients with a median age

of 29 years (range 12 – 68) treated with the GIMEMA (Gruppo

Italiano Malattie EMatologiche dell ’ Adulto) protocol ALL

0288 (including E. coli ASNase in the induction phase at a

dosage of 6000 IU/m 2 /day for 7 days starting on day 15), CNS

thrombotic events occurred in seven (3%) patients, of whom

fi ve had CVST and two developed cerebral artery thrombosis

[104]. In children, older age ( � 10 years) and a higher initial

white cell count ( � 50 000/ μ L) at diagnosis may predict for

higher risk of developing CVST [105]. Depletion of AT and

fi brinogen may also identify patients with high risk of CNS

thrombohemorrhagic complications.

Confounding factors include increasing age (at least in

pediatric ALL [107]), presence of indwelling venous catheters

[102], oral contraceptives [103], and prednisone versus dex-

amethasone therapy, with lower thrombosis rates reported

for dexamethasone [108]. Inherited prothrombotic factors

(factor V Leiden, protein S, protein C) are likely also impor-

tant, but the data in children are confl icting, with an impact

in a German study of children treated according to the ALL-

BFM 90/95 [109] but not in the North American PARKAA

study (Prophylactic Antithrombin Replacement in Kids with

ALL treated with Asparaginase) [110]. Similar studies in

adults have not been reported.

Current management strategies For intracranial thrombohemorrhagic complications, the

use of antithrombin III concentrates and/or cryoprecipitates

to replace AT and fi brinogen, respectively, is a reasonable

strategy. Should antithrombin III concentrates not be avail-

able, fresh frozen plasma at a dose of 20 mL/kg can raise

the antithrombin III level by approximately 20%, but it also

may replete asparagine and counteract the anti-leukemic

effect of ASNase. Patients with thrombotic complications

are anticoagulated with low-molecular-weight heparin and

subsequent coumadin. There is no clear indication from

the literature about whether further administration of

ASNase should be stopped in adults. In children, ASNase

is continued with low-molecular-weight heparin. Patients

with CNS thrombotic events after ASNase have been suc-

cessfully re-challenged (after eff ective anticoagulation) with

ASNase without recurrence of complications [103]. While

prophylactic or therapeutic use of AT concentrate to prevent

thrombotic complications in patients receiving ASNase has

been studied [110], it has not been systematically proven to

be of benefi t.

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majority of events take place, rather than for subsequent

administrations.

With respect to CNS thrombosis, a retrospective com-

parison of patients at two centers in Canada indicated that

a cohort prophylactically administered fresh frozen plasma

and/or cryoprecipitate did not develop CVST [106]. As higher

white blood cell count and older age are risk factors for CVST,

prophylactic use of AT or cryoprecipitate may be directed to

this subgroup of patients. Re-challenge with ASNase after a

CNS thrombohemorrhagic event has resolved may be con-

sidered but is in general not recommended.

Potential prophylaxis modalities include: AT supplementa-

tion, and anticoagulation with either low-molecular-weight

heparin or heparin alone or in conjunction with AT and/or

with cryoprecipitate administration. Recommendations based

on the limited available data may be provided as follows.

Anticoagulant therapy: low-molecular-weight heparin with

AT supplementation if AT level low . Th is is based on a 0%

incidence of DVT with combined low-molecular-weight

heparin treatment/AT replacement versus a 12.7% inci-

dence with AT replacement alone in a study in pediatric pa-

tients [112]. Th e French Group for Research on Adult Acute

Lymphoblastic Leukemia (GRAALL) also recommends an-

ticoagulation plus AT replacement for adult patients [103].

Th e general recommendation is to start with low-molecular-

weight heparin fi rst and add AT when the AT result becomes

available and is � 60%. Factor Xa levels may be used to

modify this recommendation.

AT replacement: replace for AT level � 60% . In the French

GRAALL study in adult patients, the incidence of thrombo-

sis after AT administration was 4.8% vs. 12.2% without AT

supplementation [103]. Th ese guidelines were also used by

investigators in the German adult ALL group, who observed

a 2% incidence of DVT in patients receiving AT supplemen-

tation [18]. In a pediatric trial [110], and a German – Swiss

pediatric study (Th rombotect trial) [113], the incidence of

thrombosis was 28% in patients with AT supplementation

versus 37% in patients without AT supplementation. On-

cologists at the Mayo Clinic supplement AT for levels � 70%.

Fresh frozen plasma is not recommended since it contains

asparagine and may thereby counteract the anti-leukemic

eff ect of ASNase.

Bleeding prophylaxis: if prophylactic therapy is desired, cryo-

precipitate and not fresh frozen plasma should be administered

and the use of cryoprecipitate should be conservative. Since

cryoprecipitate contains high concentrations of factor VIII it

is therefore particularly thrombogenic, and because ASNase-

related thrombosis is more problematic than bleeding, con-

servative use of cryoprecipitate is recommended. Pediatric

patients are not treated prophylactically for hypofi brinogen-

emia. For adult patients, the French GRAALL recommends

cryoprecipitate therapy for fi brinogen levels below 50 mg/dL

[103]. Th e Mayo Clinic ’ s threshold is 100 mg/dL. Others replace

fi brinogen only in bleeding patients. Th us, a defi nitive recom-

mendation is elusive. If cryoprecipitate is used prophylacti-

cally in adult patients, a conservative threshold of fi brinogen

In the Dana-Farber Cancer Institute review cited above

[100], 74% of patients received low-molecular-weight hepa-

rin after venous thromboembolic events. Complications of

anticoagulation included epistaxis (9%), bruising (2%), and,

in two adult patients, major bleeding. Th irty patients (70%)

ultimately received at least 85% of the intended doses of as-

paraginase. Some 33% of patients experienced recurrent ve-

nous thromboembolic events (pediatric 17% vs. adults 47%,

p 0.07). Th e 48-month event-free survival for patients with

venous thromboembolic events was 85 � 6% compared with

88 � 2% for those without venous thromboembolic events

( p 0.36). This study confirms that, after venous throm-

boembolic events, asparaginase can be restarted with closely

monitored anticoagulation after imaging demonstrates clot

stabilization or improvement. With this management strat-

egy, a history of venous thromboembolic events does not

appear to adversely impact prognosis.

Recommendations In adults, activated partial thromboplastin time ( APTT),

International Normalized Ratio (INR), AT, and fi brinogen

levels should be measured prior to ASNase therapy to have

available as baseline assessments. Between doses of native

ASNase and for 1 week after pegASNase therapy, these tests,

as well as factor Xa, should be obtained as clinically indi-

cated. AT concentrates and cryoprecipitate infusions should

be considered to treat thrombohemorrhagic events due to

AT and fi brinogen defi ciency, respectively. For non-urgent

thrombohemorrhagic episodes, fresh frozen plasma should

be avoided since it contains asparagine and may counteract

the anti-leukemic eff ect of ASNase. For a clinically signifi cant

DVT, the patient should be anticoagulated with or without

AT supplementation, and whether or not it is associated with

a central venous line. Early diagnostic imaging should be

performed in patients with a suspected CNS event related to

ASNase therapy. For CNS thrombosis, the patient should be

anticoagulated with or without AT supplementation. Anti-

seizure medications in patients with thrombohemorrhagic

complications should be administered prophylactically or

therapeutically as appropriate.

ASNase is discontinued for all clinically signifi cant bleeding

or thrombosis; whether it is resumed depends on the nature

and resolution of the thrombohemorrhagic event (Table II).

Prevention In children and adolescents, prophylaxis is rarely undertaken,

even with dose-intense schedules of ASNase [100,111],

albeit there is some evidence that antithrombin concentrate

may decrease the incidence of thrombosis [97,110]. Most

pediatric centers do not monitor clotting and AT level status

unless and until the patient develops clinical evidence for

thrombosis or bleeding. In a historically controlled study

of adult patients, the incidence of venous thrombosis was

lower in a cohort who received prophylactic AT concentrate,

but the study was not powered to establish effi cacy [110]. It

is also diffi cult to recommend prophylaxis in adult patients

when the risk of thrombosis and bleeding has been inad-

equately characterized. If prophylaxis is desired it is best

applied during the induction phase of therapy when the

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last of which is recommended in the pegASNase package

insert and used in pediatric patients [37,118], and in sev-

eral adult ALL protocols such as the CALGB/SWOG/ECOG

C10403 trial and the Dana-Farber Cancer Institute ALL Con-

sortium trials [20]. Dosing intervals have ranged from 2 to

4 weeks and variably when dose administrations are timed with

phases of leukemia therapy. Th e package insert recommends

no more frequently than every 14 days. Th e DFCI trials have

attempted to deliver 15 consecutive full doses (2500 IU/m 2 )

of pegASNase at 2-week intervals in both children [14] and

adults up to the age of 50 [20]. More than 90% of children

and adolescents up to the age of 18 [9,14] have been able to

tolerate all 15 doses; in adults, however, excessive hyperbili-

rubinemia has limited this schedule, at least in older adults

(DeAngelo, personal communication).

Th us, the optimal starting dose and frequency of pegASNase

administration in adults are yet to be determined. In children

with relapsed ALL, a dose of pegASNase of 500 IU/m 2 resulted

in more than 30% of the patients having a therapeutically

signifi cant drug concentration for less than a week after admi-

nistration [43]. In adults, a dose of 2000 IU/m 2 provided

asparagine depletion levels for more than 2 weeks when given

IV [18] or subcutaneously (SC) [16]. Consecutive doses of 500

and 1000 IU/m 2 2 weeks apart in 22 adult patients resulted

in suboptimal concentrations in half of the patients after the

fi rst (500 IU/m 2 ) dose, and incrementally better concentra-

tions after the second dose (1000 IU/m 2 ) [22]. Because of the

persistent enzymatic activity and asparagine depletion for

3 weeks or more after pegASNase administration in almost

all adult patients [42], and since excessive hyperbilirubine-

mia has been encountered in adults, a drug interval of no less

than 3 – 4 weeks may be prudent, especially in older adults.

Allergic reactions do not appear to be dose-related with

either pegylated or native ASNase, as expected for a foreign

protein. Other toxicities do seem dose-related, with less hepatic,

hemostatic, pancreatic, and neural toxicities at lower doses.

Only two of 26 adults treated with 500 and 1000 IU/m 2 of

pegASNase as described above had hepatic toxicity and none

had pancreatic or CNS toxicity. Yet, dose reduction to avoid

non-allergic toxicities obviously risks a signifi cant reduction

in anti-leukemic activity.

When an adult patient develops unacceptable hepatic

dysfunction or other dose-related toxicity, the usual issue is

whether continued therapy should be administered at a lower

dose or at less frequent intervals, or both. Since sustained

asparagine depletion is more aff ected by dose interval than

the dose per se , and since the anti-leukemic eff ect is depen-

dent on the duration of asparagine depletion, reduction in

dose rather than prolongation of the interval between doses

would seem to be the fi rst step in dose modifi cation. For

asymptomatic chemical pancreatitis, pegASNase can be con-

tinued if the amylase and lipase elevations are stable or

decreasing. For symptomatic pancreatitis, all ASNase therapy

should be permanently discontinued, and a switch to native

ASNase is not recommended. For severe hepatotoxicity, it is

unclear whether pegASNase should be continued or a switch

made to the shorter-acting native moiety. Ideally, therapeutic

drug monitoring of ASNase levels and, even more preferably,

asparagine in the presence of ASNase should be conducted

level (e.g. � 50 mg/dL) should be applied and concurrent an-

ticoagulant therapy administered. Fresh frozen plasma is not

recommended for coagulant prophylaxis since it contains

asparagine and may counteract the benefi t of ASNase.

Oral contraception in female patients: provide another form of

contraceptive prophylaxis or discontinue contraception . Th e

choice depends on which is feasible and on the overall mag-

nitude of thrombosis risk.

Central nervous system toxicities (other than thrombosis or hemorrhage) Both native and pegylated ASNase can cause altered mental

status, somnolence, seizures, and coma. In addition to the

cerebrovascular complications described above, ASNase

therapy may cause hyperammonemia with a diff use enceph-

alopathy [114] or reversible posterior leukoencephalopathy

syndrome, albeit hyperammonemia per se , even at high levels,

has been reported to have no clinical signifi cance [13,56]. Hy-

perammonemia results from the catabolism of asparagine by

ASNase to aspartic acid and ammonia, and to a lesser extent

by the intrinsic glutaminase activity of ASNase to convert glu-

tamine to glutamic acid and ammonia. Th e general CNS de-

pression that results when enough ammonia is liberated has

been referred to as the ‘ asparaginase blues. ’ Reversible pos-

terior leukoencephalopathy syndrome is characterized by T2

and fl uid attenuated inversion recovery (FLAIR) hyperintense

signals in MR studies in occipital parenchyma [115,116].

Incidence Th e incidence of clinically signifi cant hyperammonemia is

unclear in children but may be in the 10% range in adults if the

reported grade 3 – 4 level of fatigue in adults [31] is indicative of

this complication. A study in pediatric patients with ALL us-

ing vincristine, ASNase, daunorubicin, and prednisone as an

induction regimen reported a high incidence (25/138, 18%)

of acute neurotoxicity mostly manifested as seizures [117].

Folate replacement mitigated this toxicity in several patients,

suggesting a causal role of methotrexate rather than ASNase.

Current management strategies In patients with hyperammonemia, use of lactulose to reduce

intestinal production of ammonia is indicated. No active

treatment is available for patients with reversible posterior

leukoencephalopathy syndrome.

Recommendations Serum ammonia should be obtained in patients with altered

mental status, unexplained fatigue, somnolence, or seizures.

Discontinuation of ASNase (Table II) and supportive care

should be suffi cient for recovery from these forms of toxicity.

Prevention Other than the possibility of prophylactic lactulose therapy,

there is no known preventive treatment.

PegASNase dosage, dosing interval, and therapeutic drug monitoring

Doses of pegASNase that have been used in both pediatric

and adult patients are 500, 1000, 2000, and 2500 IU/m 2 , the

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after the start of steroid therapy to reduce the risk of a seri-

ous hypersensitivity reaction. Patients should be observed

for anaphylaxis for 1 h after a dose administration of ASNase,

with resuscitative equipment and medications available. All

patients should be monitored for delayed hypersensitivity

(1 – 2 days after a dose), hyperglycemia, coagulopathies, cere-

brovascular episodes, and pancreatitis symptoms.

Concerning future studies needed to better understand

the diff erences of ASNase therapy in pediatric and adult

patients, the pharmacokinetics of the various preparations

of ASNase per se have not been rigorously evaluated as a

function of age over the pediatric – adult life span. In chil-

dren, the pharmacokinetics of pegASNase is similar to that of

native ASNase in that both have a one-compartment distri-

bution, a monophasic half-life, and a single elimination

phase [46,52,63]. Th ey are strikingly dissimilar in both chil-

dren and adults, however, in their half-lives. PegASNase

has a t ½ of about 6 days, which is far longer than the 0.65-day

t ½ of Erwinia ASNase and the 1.24-day t ½ of native E. coli

ASNase. Th is prolonged t ½ allows one dose of pegASNase

to replace multiple injections of the non-pegylated formu-

lations. Whether or not the customary replacement of one

dose of pegASNase for 6 – 9 nine doses of native ASNase can

be achieved in adults at the same effi cacy and toxicities as

has occurred in children remains to be established. Also, drug

interactions such as decreased clearance of dexamethasone

by ASNase noted in children [47] have not been studied in

adult patients. Th e drug interactions of clinical signifi cance

are more likely to occur in adults, since they customarily

are on more medications than children. Monitoring ASNase

toxicity with serum albumin may also ultimately be useful

(Relling M, personal communication) [47].

As to the fi nancial ‘ toxicity ’ of ASNase therapy, only

one pharmacoeconomic analysis has been reported in the

peer-reviewed literature that compared the economic cost

of pegASNase versus native E. coli ASNase in adults [119].

Th e conclusion was that every-other-week pegASNase was

signifi cantly less costly to payers on an inpatient or outpatient

basis when drug costs, administration and preparation fees,

and offi ce visit charges were considered. Th e analysis was for

frontline ALL therapy in adults and did not assume any savings

from a lower hypersensitivity rate with pegASNase.

Not discussed above is the apparent lack of mutagen-

icity of ASNase. ASNase may be one of only two drugs —

methotrexate is the other mutagenicity-free chemotherapy

agent — used in human cancer therapy that have not been

observed to be carcinogenic in either laboratory studies or

animal models, or in the clinical experience over the half

century that ASNase has been available to oncologists. Th e

one potentially contradictory observation is the higher rate

of secondary malignancies in children randomized to in-

tensifi cation therapy with E. coli ASNase than on the control

regimen [11]. All patients in this trial received the epipodo-

phyllotoxin teniposide, however, which was subsequently

shown to be the primary reason for second cancers. Because

epipodophyllotoxins are extensively bound to plasma pro-

teins, inhibition of protein synthesis by ASNase may have

increased the concentration of free teniposide in plasma and

thereby indirectly led to secondary malignancies [12].

to assure complete asparagine depletion and avoid useless

continuation of the drug. Th e authors recommend such an

assay. Table II recommends specifi c dose modifi cation for

organ and organ-system toxicities that are based on, and should

be applied in accordance with, these considerations.

Many of these uncertainties could be alleviated by an

assay for ASNase activity, or better yet, an assay for aspar-

agine, neither of which are available outside of research

laboratories. Th e problem with the latter is that measuring

asparagine in a sample containing ASNase requires instant

inhibition or separation of the enzyme immediately after the

sample is procured, and this has proven diffi cult at the bed-

side. Th e authors recommend that a commercially available

assay be developed and provided for general application.

Conclusions and discussion

Whether or not the customary replacement of one dose of

pegASNase for 6 – 9 doses of native ASNase can be achieved

in adults at the same effi cacy and acceptable toxicities as

achieved in children remains to be established. Meanwhile,

pegASNase, in combination with other ALL chemotherapy

agents, has a comparable toxicity profi le in adult patients to

that of pegASNase in pediatric patients, and warrants increased

use in adult patients with ALL. Based on the initial experi-

ence at major comprehensive cancer centers, the majority of

young and middle-aged adults tolerate pediatric ALL treatment

regimens that include ASNase. Th e most frequent toxici-

ties of ASNase are hepatic and pancreatic, with pancreatitis

being the most serious. In adults, transient serum hepatic

transaminase and bilirubin elevations occur with pegASNase

in about one-third of patients and can be dramatic and pro-

longed in a few percent. Similar to pediatric patients, other

clinically signifi cant toxicities occur at a rate of 10% or less in

frequency, and the most common of these are hypersensitiv-

ity reactions, thrombosis, nausea/vomiting, and fatigue.

In patients previously unexposed to ASNase, pegASNase is

less likely than native ASNase to cause hypersensitivity reac-

tions in that the non-severe reactions are less frequent and

fewer injections are required for asparagine depletion. Both

forms of the enzyme can cause severe and life-threatening

reactions; however, the reactions occur at a lower incidence

with both drugs when concurrent immunosuppressive medi-

cations, particularly glucocorticoids, are administered.

In comparing IV versus IM pegASNase, the toxicity profi le

is comparable, except for local rashes that occur with IM injec-

tions and are non-existent with IV administration unless the

agent extravasates. Th e fl exibility of IV and IM pegASNase and

the associated patient and physician convenience can and

should be applied to both pediatric and adult patients. Th e

non-overlapping toxicities with other agents that are used in

ALL therapy, and particularly the lack of myelosuppression,

are reasons to include asparagine depletion in both pediatric

and adult regimens. Adults with lymphoblastic lymphoma

should also be considered for ASNase therapy, analogous to its

inclusion in pediatric non-Hodgkin lymphoma regimens, with

the same caveats for toxicity prevention and management.

When ASNase and daily corticosteroids are both used in a

treatment phase, the ASNase should be delayed for 3 – 4 days

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Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols. J Clin Oncol 2007;25:813 – 819.

[10] Sallan SE, Gelber RD, Kimball V, Donnelly M, Cohen HJ. More is better! Update of Dana-Farber Cancer Institute/Children ’ s Hospital childhood acute lymphoblastic leukemia trials. Haematol Blood Transfus 1990;33:459 – 466.

Amylon MD, Shuster J, Pullen J. Intensive high-dose asparaginase [11] consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood 2000;96:335 – 342.

Raetz EA, Salzer WL. Tolerability and effi cacy of L-asparaginase [12] therapy in pediatric patients with acute lymphoblastic leukemia. J Pediatr Hemat Oncol 2010;32:554 – 563.

Asselin BL, Kreissman S, Coppola DJ, Bernal SD, Leavitt PR, Gelber [13] RD, Sallan SE, Cohen HJ. Prognostic signifi cance of early response to a single dose of asparaginase in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 1999;21(1):6 – 12.

Silverman L, Gelber RD, Dalton VK, et al. Improved outcome for [14] children with acute lymphoblastic leukemia:results of Dana-Farber consortium protocol 91-01. Blood 2001:97;1211 – 1218.

Nachman JB, La MK, Hunger SP, et al. Young adults with acute [15] lymphoblastic leukemia have an excellent outcome with chemo therapy alone and benefi t from intensive postinduction treatment: a report from the Children ’ s Oncology Group. J Clin Oncol 2009;27:5189 – 5194.

Wetzler M, Sanford BL, Kurtzburg J, et al. Eff ective asparagine [16] depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood 2007;109:4164 – 4167.

Huguet F, Leguay T, Raff oux E, et al. Pediatric-inspired therapy in [17] adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009;27:911 – 918.

Goekbuget N, Baumann A, Beck J, et al. PEG-asparaginase in [18] adult acute lymphoblastic leukemia: efficacy and feasibility analysis with increasing dose levels. Blood 2008;112(Suppl. 1): Abstract 302.

DeAngelo DJ. Th e treatment of adolescents and young adults with [19] acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2005:123 – 130.

DeAngelo DJ, Stone RM. New agents for the treatment of [20] patients with acute lymphoblastic leukemia. Curr Hematol Malig Rep 2008;3:135 – 143.

Aguayo A, Cortes J, Thomas D, et al. Combination therapy [21] with methotrexate, vincristine, polyethylene-glycol conjugated-asparaginase, and prednisone in the treatment of patients with refractory or recurrent acute lymphoblastic leukemia. Cancer 1999;86:1203 – 1209.

Rosen O, Muller HJ, Gokbuget N, et al. Pegylated asparaginase in [22] combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in fi rst remission: a pilot study. Br J Haematol 2003;123:836 – 841.

Storring J, Minden M, Kao S, et al. Treatment of adults with [23] BCR-ABL negative acute lymphoblastic leukaemia with a modifi ed paediatric regimen. Br J Haematol 2009;146:76 – 85.

Oettgen HF, Stephenson PA, Schwartz MK, et al. Toxicity of E.coli [24] l-asparaginase in man. Cancer 1970;25:253 – 278.

Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R. [25] FDA drug approval summary: pegaspargase (Oncaspar) for the fi rst-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist 2007;12:991 – 998.

Graham ML. Pegaspargase: a review of clinical studies. Adv Drug [26] Deliv Rev 2003;55:1293 – 1302.

Duval M, Suciu S, Ferster A, et al. Comparison of Escherichia coli-[27] asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer Children ’ s Leukemia Group phase 3 trial. Blood 2002;99:2734 – 2739.

Ettinger LJ, Kurtzberg J, Voute PA, et al. An open-label, multicenter [28] study of polyethylene glycol-L-asparaginase of the treatment of acute lymphoblastic leukemia. Cancer 1995;75:1176 – 1181.

Sallan SE. Myths and lessons from the adult/pediatric interface [29] in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2006:128 – 132.

Advani A, Earl M, Douer D, Rytting M, Bleyer A. Toxicities [30] of intravenous pegasparaginase (Oncaspar) in adults with acute lymphoblastic leukemia. Blood 2007;110(Suppl. 1): Abstract 2811.

Rytting M, Earl M, Douer D, Muriera B, Advani A, Bleyer A. [31] Toxicities in adults with acute lymphoblastic leukemia treated with regimens using pegasparaginase. Blood 2008;112(Suppl. 1): Abstract 1924.

Th e development of new ASNase formulations is a poten-

tial therapeutic strategy [120]. Th e toxic eff ects of microbial

ASNases may be the result of their ability to hydrolyze both

asparagine and glutamine amino acids due to glutaminase

activity present in the ASNase preparation [121 – 123]. Pa-

tients treated with E. coli and Erwinia ASNase have a marked

decrease in glutamine as well as asparagine [124]. Glutamine

deprivation may block the biosynthetic pathway by which

normal cells escape the toxic eff ects of asparagine depletion

[123]. A glutaminase-free ASNase isolated from Vibrio suc-

cinogenes that is not hepatotoxic after prolonged therapy has

been reported [80].

In any event, more experience with ASNase in adults will

accrue rapidly as the agent is included in adult treatment

regimens and pediatric regimens are applied to adult pa-

tients [125]. It is likely that many of the recommendations ex-

pressed herein will be modifi ed as knowledge about ASNase,

and particularly pegASNase, is acquired.

Acknowledgements

Th e authors thank the many pediatric and adult patients

with ALL and their families and care providers for teaching

us about the challenges of treating this disease.

Potential confl ict of interest: Disclosure forms provided

by the authors are available with the full text of this article at

www.informahealthcare.com/lal.

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Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older...

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