Lawrence J. Ettinger
Emanuel D. Lerner*
Mamta V. Manglani
From
the Divisions of Pediatric Hematology-Oncology and *General
Pediatrics, University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert
Wood Johnson Medical School, New Brunswick, New Jersey, USA.
Reprint
requests: Dr. Lawrence J. Ettinger, Chief, Division of Pediatric
Hematology-Oncology, Saint Peter’s University Hospital, 254
Easton Avenue,
P.O. Box 591, New Brunswick, NJ 08903-0591, USA.
E-mail: [email protected]
Manuscript received: March 18, 1999;
Initial review completed: June 21, 1999;
Revision accepted: November 11, 1999
L-asparaginase
is an active agent in the treatment of childhood acute lymphoblastic
leukemia (ALL)(1,2). Toxicities related to its use include
abnormalities in hemostasis, pancreatitis, hyperglycemia,
hepatotoxicity, neurotoxocity, and hypersensitivity reactions. The
latter are the most common limiting factor in the use of
L-asparaginase(1,2). Polyethylene glycol (PEG) conjugation of L-asparaginase
not only extends its biologic half-life, but also appears to
diminish its imunogenicity(1,2). Pegaspargase appears to be safe and
effective in patients with ALL, as has been shown in prior clinical
trials(2-4). The toxicity profile has been similar to that of native
L-asparagi-nase(1,2,5). The present study was conducted to further
characterize the toxicity of pega-spargase when given in combination
chemo-therapy protocols to children with ALL.
Patients
Between July, 1992
and October, 1993, patients below 24 years of age, with ALL (newly
diagnosed, relapsed or in remission) were enrolled into the study
(ASP-307), if asparaginase was intended to be included in their
treatment protocol and they were not eligible for participation in a
cooperative group protocol. Patients included in this analysis were
those treated at UMDNJ-Robert Wood Johnson Medical School. Patients
with compromised renal, hepatic, or pancreatic function were
excluded from study. An informed consent to participate in this
study was obtained in accordance with federal and institutional
guidelines.
Drug Administration
All patients received
pegaspargase at a dose of 2500 IU/m2 intramuscularly. Additional
doses were substituted for native L-asparaginase in the protocols,
at intervals of at least 14 days. Other chemotherapeutic agents were
given based upon the patient’s individual treatment protocol and
phase of therapy. Protocols that were adapted for use in this study
included standard 3 and 4-drug (re)induction (vincristine,
prednisone, asparaginase, ±doxo-rubicin), augmented BFM(6),
standard BFM(7), NY-I(7), and NY-II(8). In all cases, pegaspargase
was substituted for native E. coli L-asparaginase. One
patient with ALL in bone marrow relapse received carboplatin,
ida-rubicin, dexamethasone, and pegaspargase.
Patient Monitoring
During Study
Patients were
monitored clinically for any symptoms or signs of toxicities related
to treatment. The following laboratory parameters were monitored
throughout pegaspargase therapy: Prothrombine time (PT), partial
thromboplastin time (aPTT), fibrinogen, plasminogen, antithrombin
III (AT-III), serum amylase, lipase, glucose, albumin, total
bili-rubin, serum glutamic oxaloacetic transaminase (SGOT) and serum
glutamic pyruvic trans-aminase (SGPT). Those laboratory parameters
that became abnormal were followed until they returned to normal.
Definition of
Toxicity
The Common Toxicity
Criteria of the National Cancer Institute (USA) were used to define
the laboratory and clinical toxicities encountered. These are graded
1 to 4, with grade 4 being the most significant. Lipase, plasminogen
and AT-III are not included in the Common Toxicity Criteria.
Toxicity criteria for lipase was defined on the basis of criteria
for amylase. Toxicity grading for plasminogen and AT-III were
devised based upon mean normal activity of 100%: for plasminogen,
grade 1< 75%, grade 2 < 56%, grade 3 < 37%
and grade 4 <19%; for AT-III, grade 1< 84%, grade 2
< 63%, grade 3 < 42% and grade 4 < 21%.
Patient
Characteristics
Fourteen patients
were enrolled into the study. Their age ranged from 4 to 23 years
(median, 11 years). Nine (64%) were females and 5 (36%) were males.
Eight patients were newly diagnosed with ALL, 3 were in bone marrow
relapse, one each had testicular and CNS relapse, and one patient
was in remission. Five (36%) patients had received native L-asparaginase
(E. coli) as a part of prior chemo-therapy protocols; none
had hypersensitivity reactions to native L-asparaginase. The number
of pegaspargase doses received ranged from a single dose to 9 doses
with a total of 58 doses administered in the study.
Toxicities
Table I documents
the observed toxicities. Grades 3 and 4 abnormalities of hemostatic
parameters–decreased fibrinogen (71%), decreased plasminogen
(33%), and decreased AT-III (23%) were the most commonly encountered
toxicities. PT and PTT were prolonged (grade 3) in one patient (7%)
who had disseminated intravascular coagulation (DIC) with septic
shock. None of the patients had clinical evidence of hemorrhage or
throm-bosis. Patients with hemostatic abnormalities were variably
managed with blood component therapy (fresh frozen plasma,
cryoprecipitate and/or AT-III concentrates), at the discretion of
the investigator.
The most significant
clinical toxicities seen were hypersensitivity reactions in 3
patients (21%) and pancreatitis in one (7%). Thirty minutes
following the third dose of pega-spargase, one patient developed
red, "burning", swollen ears, generalized urticaria,
abdominal pain, emesis, and hypotension. Wheezing and respiratory
difficulty did not occur. Treatment with epinephrine,
diphenhydramine, hydro-cortisone and methylprednisolone resulted in
rapid resolution of this hypersensitivity reaction. Urticaria
recurred in between doses of the above medications but resolved
within one day. Ten minutes following the second dose of
pegaspargase, another patient developed swelling of the lips and
tongue, urticaria, and nasal flaring; however, neither wheezing nor
hypotension developed. Rapid recovery, without return of symptoms,
followed a dose of epinephrine, hydrocortisone and diphenhydramine.
Within 1 hour of receiving the fourth dose of pegaspargase, another
patient developed tightness in the throat, facial flushing and
puffiness, and hypotension. Wheezing did not occur. Treatment with
vasopressors, intravenous hydration, glucocorticoid therapy and
hydroxyzine was successfully instituted. However, vasopressor
support could not be discontinued until the third day. Only the
second patient described above had received E. coli L-asparaginase
previously. All 3 patients with hypersensitivity reactions to
pegaspargase tolerated Erwinia-L-asparaginase subsequently
without hypersensitivity reactions.
Clinical and
biochemical pancreatitis was seen in 1 (7%) patient 17 days
following the second dose of pegaspargase. Her serum amylase and
lipase peaked at 702 U/L (n: 44-128 U/L) and 1331 IU/L (N: 10-54 IU/L,)
respectively. CT scan findings were consistent with pancreatitis.
This patient recovered with supportive care. Transient elevation in
serum glucose was noted in 10 (71%) patients, most of whom were
receiving prednisone concomitantly. Of these, 2 (14%) had grade 3
elevation; only one of these (with septic shock) required insulin
for a short period of time. All patients became normoglycemic,
usually following discontinuation of intravenous hydration and or
steroid therapy. Further doses of pegaspargase were given without
significant toxicity. Grades 3 and 4 hepatotoxicity was manifest
predominantly by hyperbilirubinemia (50%) with a lesser frequency of
transaminase (21%) elevation and hypoalbuminemia (7%). Both patients
who had grade 4 hyperbili-rubinemia were also in septic shock at
that time. All laboratory values normalized over a short period of
time. None of the 14 patients had any significant evidence of
central nervous system dysfunction during the study period.
There were no obvious
differences in toxicity between those patients who had or had not
received native L-asparaginase prior to entry onto this study.
Table I: Toxicities
Related to Pegaspargase
| |
Toxicity
|
Evaluable Patients [Prior Native
Asp - Y/N] |
Grade of Toxicity
|
|
0
|
1
|
2
|
3
|
4
|
|
Coagulopathy
|
PT
|
14 [5/9]
|
2[2/0] (40/0)
|
10 [3/7]
(60/78)
|
1 [0/1]
(0/11) |
1 [0/1] (0/11)
|
0
|
| |
PTT
|
14 [5/9]
|
3 [2/1] (40/11)
|
10 [3/7] (60/78)
|
0
|
1
[0/1] (0/11) |
0
|
| |
Fibrinogen
|
14 [5/9]
|
0
|
0
|
4 [3/1]
(6/11) |
7 [2/5]
(40/56)
|
3 [0/3] (0/33)
|
| |
Plasminogen
|
12 [5/7]
|
4 [1/3] (20/43)
|
1 [0/1]
(0/14)
|
3 [2/1] (40/14)
|
4 [2/2] (40/29)
|
0
|
| |
AT-III
|
13 [5/8]
|
4 [2/2] (40/25)
|
4 [1/3] (20/38)
|
2 [0/2] (0/25)
|
3
[2/1] (40/13)
|
0
|
|
Pancreatitis
|
Clinical Pancreatitis
|
14 [5/9]
|
13
[5/8] (100/89)
|
0
|
0
|
0
|
1 [0/1] (0/11)
|
| |
Amylase
|
13 [5/8]
|
10 [4/6] (80/75)
|
2 [1/1] (20/13)
|
0
|
0
|
1 [0/1] (0/13]
|
| |
Lipase
|
13 [5/8]
|
8 [5/3] (100/38)
|
2 [0/2] (0/25)
|
2
[0/2] (0/25) |
0
|
1 [0/1] (0/13)
|
|
Hyperglycemia
|
Glucose
|
14 [5/9]
|
4 [1/3] (20/33)
|
3
[1/2] (20/22) |
5
[2/3] (40/33)
|
2 [1/1] (20/11)
|
0
|
|
Hepatotoxicity
|
Albumin |
14 [5/9]
|
3 [2/1] (40/11)
|
5
[3/2] (60/22)
|
5 [0/5]
(0/56)
|
1 [0/1] (0/11)
|
0
|
| |
Bilirubin
|
14 [5/9]
|
4 [2/2] (40/22)
|
3 [2/1]
(40/11)
|
0
|
5 [0/5] (0/56)
|
2 [1/1] (20/11)
|
| |
SGOT
|
14 [5/9]
|
6 [3/3] (60/33)
|
5 [0/5] (0/56)
|
1
[1/0] (20/0)
|
2 [1/1] (20/11)
|
0
|
| |
SGPT
|
13 [5/8]
|
5 [2/3]
(40/38)
|
3 [1/2] (20/25)
|
2
[0/2] (0/25)
|
3 [2/1] (40/13)
|
0
|
|
Allergic Reaction
|
Hypersensitivity
|
14 [5/9]
|
11
[4/7] (80/78)
|
See text for details of reactions
|
|
[1/2] (20/22)
|
|
Figures in brackets [ ] = number of patients who
did/did not receive prior native L-asparaginase. Figures in
parentheses ( ) = percentage of patients who did/did not receive
prior L-asparaginase.
PT - prothrombin time, PTT - partial thromboplastin time, AT-III
- antithrombin III; SGOT - serum glutamic oxaloacetic transaminase,
SGPT - serum glutamic pyruvic transaminase.
Biochemical
coagulopathy is one of the most common toxicities noted with the use
of L-asparaginase(2,9-11). Laboratory abnorma-lities of antithrombin
III, clotting factors, fibrinogen, plasminogen, protein C, protein
S, and von willebrand factor have been reported. Similar
abnormalities have been caused by pegaspargase(3-5). However,
clinically signi-ficant thrombosis or hemorrhage is uncommon and is
seen only in 1-2% of patients(2,9,12). Reduced fibrinogen,
plas-minogen, AT-III and prolonged PT and PTT were observed in the
present study (Table I). However, none of our patients had
any clinical evidence of hemorrhage or thrombosis. This might have
been due to the prophylactic use of blood components whenever it was
considered appropriate(12,13).
L-asparaginase may
cause pancreatitis in as many as 16% of patients treated(9). A
single patient (7%) developed pancreatitis in this study. Therefore,
the incidence is comparable to earlier data(4,5) in patients who had
received pegaspargase.
Hyperglycemia was
seen in 71% of our patients, including all 8 patients >10 years
of age and 2 of 6 patients below 10 years of age. Of the 8 patients
>10 years, 6 had grade >1 hyperglycemia. The higher incidence
of hyperglycemia in patients >10 years has been reported by Pui et
al.(14). in patients treated with native asparaginase, although
they found an overall incidence of only 9.7%; 30% of these were
>10 years. The longer half-life of pegaspargase may be
responsible for an even higher incidence seen in the present study.
Chemical evidence of
hepatotoxicity in the form of elevated serum transaminases, total
bilirubin, and reduced albumin has been reported in up to 35%, 60%
and 70%, respectively, in patients treated with native forms of
L-asparaginase(9). A similar incidence of these abnormalities was
seen in the present study. However, no significant hepatotoxicity
attributable to pegaspargase was seen.
Hypersensitivity
reactions to native L-asparaginase have been the most frequent
reasons for discontinuation of the drug and are seen in 15-35% of
patients; however, mortality due to anaphylaxis is less than 1% of
treated patients(9,15). Three (21%) of our 14 patients developed
hypersensitivity reactions; there was no correlation between
hypersensitivity reactions and prior exposure to L-asparaginase.
Prior reports suggest that pegaspargase is well tolerated by
patients with prior hypersensitivity to native L-asparaginase(2).
Central nervous
system dysfunction in the form of mental status changes, seizures,
personality changes, coma, etc. have been frequently reported
in the adult literature. These are uncommon in children, and were
not seen in the present study, although occasional reports suggest a
high incidence of these changes in children(2,9).
In conclusion, the
toxicity profile seen with pegaspargase in the present study is
similar to that seen with native L-asparaginase. Pegaspargase
appears to have no excess of clinically significant side effects.
Additionally, its longer half-life allows less frequent dosing
("patient-friendly") and as has been reported in the
literature, it can be relatively safely administered to patients who
are hypersensitive to its native form. Nevertheless, a large,
randomized trial comparing native L-asparaginase and pegaspargase
with the remainder of the chemotherapeutic regimen being constant is
required to definitively determine their comparative efficacies and
toxicities.
|
Key Messages |
-
The toxicity profile seen with
pegaspargase is similar to that seen with native L-asparaginase.
-
Pegaspargase appears to have no
excess of clinically significant side effects.
-
The longer half-life of pegaspargase
allows less frequent dosing ("patient-friendly")
and it can be relatively safely administered to patients who
are hypersensitive to its native form.
-
A large, randomized trial comparing native L-asparaginase
and pegaspargase with the remainder of the chemotherapeutic
regimen being constant is required to definitively determine
their comparative efficacies and toxicities.
|
This study was
supported in part by a grant from Enzon, Inc., Piscataway, NJ, USA.
Contributors:
LJE was the principal investigator of the study and was responsible
for the clinical care, enrollment, monitoring and evaluation of all
patients entered onto the study. He made revisions to prior drafts
of the paper and he will act as the guarantor for the paper. EDL
participated in the data collection and analysis and wrote the first
draft of the paper. MVM made extensive revisions to the first draft
of the paper.
Funding:
Supported in part by a grant from Enzon, Inc., Piscataway, NJ, USA.
Competing interests:
None stated.
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