Comparison of Side Effects between L-asparaginase and PEG-L-asparaginase in Pediatric Acute Lymphoblastic Leukemia Patients

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Abstract : L-asparaginase (L-asp) is an essential drug for the treatment of acute lymphoblastic leukemia (ALL). However, it requires attention for several side effects. PEG-L-asparaginase (PEG-L-asp), which is formed by the covalent linkage of L-asp to polyethylene glycol (PEG), is also not safe from side effects.

In this study, we considered 6 side effects (hypersensitivity, acute pancreatitis, coagulopathy, hyperglycemia, hepatotoxicity and elevation of blood ammonia levels) from 60 pediatric ALL patients who received L-asp and PEG-L-asp in severance hospitals between 2006 and 2010.

Among them, 22 patients received only L-asp, and 38 patients were converted from L-asp to PEG-L-asp. Differences were evaluated by the chi-square test and Fisher exact test on the SAS software (version 9.2).

Elevation of blood ammonia levels (P=0.0050), hypersensitivity (P=0.1219), bleeding risk

L-asparaginase와 PEG-L-asparaginase를 투여한 소아 급성 림프구성 백혈병 치료시 부작용 비교

연세대학교 세브란스병원 약무국

Comparison of Side Effects between L-asparaginase and PEG-L-asparaginase in Pediatric Acute Lymphoblastic

Leukemia Patients

Min Jung Geum, In Hye Park, Jong Hee Ko , Ji Hyune Ahn, Sung Eun Kim, Hyun Ju Seok

Department of Pharmacy, Yonsei University Healthcare System 50 Yonsei-ro, Seodeamun-gu, Seoul, 120-752, Korea

회원학술보고

투고일자 2013. 5. 29; 심사완료일자 2013. 6. 18; 게재확정일자 2013. 7. 23

�교신저자 고종희 Tel:02-2227-4861 E-mail:[email protected]

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Background and Purpose

The amino acid, L-asparagine, is a nutritional requirement of both normal and cancer cells.

Unlike normal cells, certain leukemic cells can- not synthesize asparagine and rely on an exter- nal supply. L-asparaginase(L-asp) destroys this free source of asparagines. Therefore, L-asp is an essential drug for the treatment of acute lymphoblastic leukemia(ALL).

However, there are several side effects. The major side effects are hypersensitivity, acute pancreatitis, coagulopathy, hyperglycemia, hepatotoxicity, and elevation of blood ammo- nia levels. It requires attention before and after the patients administrated L-asp.

PEG-L-asparaginase(PEG-L-asp), which is formed by the covalent linkage of L-asp to monomethoxy polyethylene glycol(PEG), pro- longed half-life from 24 hours to 6 days and

reduced administration frequency and proce- dure-related pain.

But, patients who were administrated PEG-L-asp are still experiencing similar side effects to L-asp, and there are not enough long term clinical data in Korea. By analyz- ing major side effects of L-asp and PEG-L- asp, we would like to get supportive evidence and contribute to safe drug using for children with ALL.

Pat ient s and Met hods

Patients

Between January 2006 and December 2010, total 60 pediatric patients with ALL were treated in Severance hospital. 22 of 60 patients treated with only native L-asparag- inase(L-asp), 38 of 60 patients who had been (P=0.2839), and hyperglycemia (P=0.6194) were more frequent in the L-asp group. Hepatotoxicity (P=0.1968), thromboembolism (P=0.6432), and acute pancreatitis (P=0.7321) were more frequent in the PEG-L-asp group. The incidence for each side effect depends not only on the drug itself, but also on the patients’risk, treatment phase and so on. Hypersensitivity by treatment phase (P=0.0109) and bleeding tendency by patients’risk (P=0.0057) show statistical differences.

Through this study, we would like to obtain supportive evidence and contribute to the safe consumption of drugs for children with ALL.

[Key words] Pediatric ALL, L-asparaginase, PEG-L-asparaginase, Side effects

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Age (years), at diagnosis Mean

Range Sex, n (%) Male Female Risk, n (%)

Infant high-risk Standard-risk High-risk

Immunophenotype, n (%) B cell-lineage T cell-lineage others Karyotype, n (%)

Successful examination T(9;22)

T(4;11) dupMLL TEL/AML1 Hyperdiploidy Normal and others CNS involvement, n (%)

7.0 1~15

10 (45.5) 12 (54.5)

4 (18.2) 2 (9.1) 16 (72.7)

6 (27.3) 3 (13.6) 13 (59.1)

19 (86.4) 1 (5.3)*

- 5 (26.3)*

4 (21.1)*

- 9 (47.4)*

4 (18.2)

7.7 2~19

26 (68.4) 12 (31.6)

- 14 (36.8) 24 (63.2)

15 (39.5) 3 (7.9) 20 (52.6)

26 (68.4) 5 (19.2)*

- 8 (30.8)*

1 (3.8)*

6 (23.1)*

1 (2.63)

N

Native L-asp 22

PEG-L-asp 38 Table 1. Patients characteristics

*Percentages were computed on successful examination.

treated with native L-asp were changed to treatment with PEG-L-asparaginase(PEG- L-asp). Patients were aged 1 through 19 years, and eligible with initial diagnosis.

Treatment

Treatment started with 4 weeks of induction, and followed to consolidation, interim mainte- nance, intensification, maintenance therapy.

At the start of induction, patients assigned to

receive L-asp were given Leunase

^�

intramus-

cularly (IM) at a dose of 6,000 U/m

²

, 3 times

per week, for 9 doses in induction. And

patients assigned to receive PEG-L-asp were

given Oncaspar

^�

IM at a dose of 2,500 U/m

²

on

day 3 and 17. In most cases of PEG-L-asp

group, patients had been received 3 doses of

native L-asp first, and then a dose of PEG-L-

asp replaced the rest 6 doses of L-asp.

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Side effects monitoring

The major 6 side effects were analyzed ret- rospectively. The incidence of side effects and the level of change from baseline laboratory parameters were used to evaluate adverse events. The occurrence time, any procedure related with adverse events, and the progress of adverse events were also considered.

1) Hypersensitivity 2) Acute pancreatitis 3) Coagulopathy 4) Hyperglycemia 5) Hepatotoxicity

6) Elevation of blood ammonia levels

Statistical analysis

Differences between the native L-asp group and the PEG-L-asp group in side effects were examined by the chi-square test and Fisher exact test. All tests were performed by using SAS software (Version 9.2).

Result s

Patient characteristics (Table 1)

For this study, 60 patients were enrolled. 60 patients divided into the native L-asp group and the changed PEG-L-asp group.

Of those each group, higher percentage of patients was treated according to the high- risk group. The high-risk group based on at least one of the following criteria: age between 1 and 2, or older than 10 year old, WBC ≥ 50,000/μ L, and MLL rearrangement.

The eligibility criteria of standard-risk group included age between 2 and 10, initial WBC <

50,000/μ L, and TEL-AML rearrangement.

And the patients who were younger than 6 months at diagnosis are defined as infant high-risk group.

In the immunophenotypic analysis, 21 patients were B cell lineage, 6 patients were T cell lineage, and the others were non-spe- cific lineage. And 45 patients succeeded in the karyotype examination. In addition, there were central nervous system involvements in 5 patients at the time of diagnosis.

Side effects monitoring (Fig. 1)

1) Hypersensitivity

Hypersensitivity was more frequent in the L-asp group than in the PEG-L-asp group (P=0.1219). The number of patients who showed hypersensitivity was 8(36.4%) in the native L-asp group and 7(18.4%) in the PEG- L-asp group. The signs of hypersensitivity included hypotension, urticaria, erythema, rash, angioedema, etc. There was not a life- threatening anaphylaxis. The antihistamines were used to relieve symptoms, and L-asp or PEG-L-asp was changed to drugs of other

Fig. 1 Side effects incidence of L-asparagi-

nase and PEG-L-asparaginase

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types since next dose. There was statistical significance about hypersensitivity incidence by treatment phase(P=0.0109). The hypersen- sitivity of the native L-asp group occurred more early treatment stage, while more than half of the PEG-L-asp group shows hyper- sensitivity in the delayed intensification

stage(Table 2).

2) Acute pancreatitis

The number of patients who experienced acute pancreatitis was 3(13.6%) in the native L-asp group and 7(18.4%) in the PEG-L-asp

Stage of symptom manifestation, n (%)*

Induction Consolidation Interim maintenance Delayed intensification

3 (37.5%)*

2 (25.0%)*

3 (37.5%)*

-

- 3 (42.9%)*

- 4 (57.1%)*

N (%)

Native L-asp N=22 (100%) 8 (36.4%)

PEG-L-asp N=38 (100%)

7 (18.4%) Table 2. Incidence of hypersensitivity

*Percentages were computed on cases of hypersensitivity.

Induction Consolidation Interim maintenance Delayed intensification Symptom, n (%)*

Nausea, vomiting, abdominal pain None

Abnormal level expression (days)^� Amylase level, mean (range) Lipase level, mean (range)

1 (33.3%)*

- 1 (33.3%)*

3 (100%)*

-

6.3 (2~15) 8.3 (1~14)

4 (57.1%)*

2 (28.6%)*

- 1 (14.3%)*

6 (85.7%)*

1 (14.3%)*

7.0 (1~20) 6.9 (0~20)

N (%)

Native L-asp N=22 (100%) 3 (13.6%)

PEG-L-asp N=38 (100%)

7 (18.4%) Table 3. Incidence of acute pancreatitis

*Percentages were computed on cases of acute pancreatitis.

�Amylase (normal range: 20~120 U/L), Lipase (normal range: 10~120 U/L)

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group(P=0.7321). Most of them complained abdominal sharp pain, nausea and vomiting, and the level of amylase and lipase were increased. The Incidence of acute pancreatitis in PEG-L-asp group was higher at induction phase than other phases. But there was no significant difference of pancreatitis inci- dence by treatment stage(P=1.0000)(Table 3).

Patients recovered by stopping suspicious medication and receiving proteolytic agent.

There was no case that leads to severe condi- tion or changes to other types of drugs.

3) Coagulopathy

3-1) Thromboembolism

The number of patients who showed signs of thromboembolism was 1(4.5%) in the native L-asp group and 4(10.5%) in the PEG-L-asp group(P=0.6432). The incidence of throm- boembolism in PEG-L-asp group was higher at induction than other stages, but there was no statistical significance(P=0.4000). Most of thromboembolism cases were related with

existence of central-line(P=0.1643) and accompanied by swelling and edema(Table 4).

In the cases of thromboembolism, symptoms of the native L-asp group was mild and there was no treatment, but patients of the PEG- L-asp group was removed central-line and administrated heparin, and 2 of them took warfarin for 4 to 6 months. Only 3 of the PEG-L-asp group who experienced throm- boembolism in induction phase was assigned to change asparaginase to other types of drug.

3-2) Bleeding tendency

According to the laboratory testing, 13(59.1%) of the native L-asp group and 17(44.7%) of the PEG-L-asp group showed PT/PTT prolongation and fibrinogen level of them were lower than normal range. Patients’

increased bleeding risk was more frequent in the L-asp group than in the PEG-L-asp group(P=0.2839). Of them, 2(15.4%) of the L- asp group(1 epistaxis and 1 petechia) and 7(41.2%) of the PEG-L-asp group(3 epistaxis,

Induction Consolidation

Body part of thromboembolism, n (%)*

Upper extremity

Lower extremity / Line associated Pulmonary embolism

Existing central-line insertion

- 1 (100%)*

1 (100%)*

- - -

3 (75%)*

1 (25%)*

- 3 (75%)*

1 (25%)*

4 (100%)*

N (%)

Native L-asp N=22 (100%)

1 (4.5%)

PEG-L-asp N=38 (100%)

4 (10.5%) Table 4. Incidence of thromboembolism

*Percentages were computed on cases of thromboembolism

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3 petechia, 1 cerebral hemorrhage) experi- enced symptoms(Table 5). Increase of bleeding tendency was more occurred in high risk group, and there was statistical significance (P=0.0057)(Fig. 2). In the cases of increasing bleeding tendency, patients were administrat- ed vitamin K1 or antithrombin. There was no case that leads to changes to other types of drugs.

4) Hyperglycemia

The number of patients who diagnosed with hyperglycemia was 2(9.1%) in the native L- asp group and 2(5.3%) in the PEG-L-asp group(P=0.6194). All of them were older than 10 years old. About those 4 patients who were diagnosed with hyperglycemia, the average of period blood glucose level above 200 mg/dL was 10 days per person in the Fig. 2 Bleeding tendency incidence by risk group.

Specific criteria, n (%)*

PT/PTT prolongation

Fibrinogen level (≤ 200 mg/dL)^� Symptom, n (%)*

Epistaxis Petechia

Cerebral hemorrhage

13 (100%)*

12 (92.3%)*

1 (7.7%)*

17 (100%)*

3 (17.6%)*

1 (5.9%)*

N (%)

Native L-asp N=22 (100%) 13 (59.1%)

PEG-L-asp N=38 (100%)

17 (44.7%) Table 5. Increase of bleeding tendency

*Percentages were computed on cases of increased bleeding tendency.

�Fibrinogen (normal range: 200~400 mg/dL)

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native L-asp group, and 21.5 days per person in the PEG-L-asp group. Patients treated by insulin for 8 days and 16.5 days in each group. There was no case that leads to severe condition or changes to other types of drugs.

5) Hepatotoxicity

Hepatotoxicity defined as above the upper normal limit of total bilirubin(0.2~1.2 mg/dL) or above 1.5 times of the upper normal limit of ALT(0~2 months: 8~78 IU/L, above 2 months: 8~36 IU/L), AST(infant: 18~74 IU/L, child: 15~46 IU/L), ALKP(newborn: 60~130 IU/L, 0~16 years: 85~400 IU/L, above 16 years: 30~115 IU/L). Hepatotoxicity was more frequent in the PEG-L-asp group(P=0.1968).

15(68.2%) of the native L-asp group and 32(84.2%) of the PEG-L-asp group showed hepatotoxicity. And hepatotoxicity was more occurred in high risk group, but there was no statistical significance(P=0.2744)(Fig. 3).

Patients recovered by stopping suspicious medication and receiving liver preparations.

There was no case that changes to other types of drugs.

6) Elevation of blood ammonia levels

Elevation of blood ammonia level was defined as above the upper normal limit of blood ammonia level(40~120 μ g/dL). It was more frequent in the L-asp group than in the PEG-L-asp group(P=0.0050). The number of patients who elevated in blood ammonia level was 18(81.8%) in the native L-asp group and 17(44.7%) in the PEG-L-asp group. About those 35 patients who were experienced ele- vation of blood ammonia levels, the average numbers of times above upper normal limit was 6.6 times per person in the native L-asp group, and 4.3 times per person in the PEG- L-asp group. Patients treated by lactulose syrup. There was no case that leads to coma or changes to other types of drugs.

Discussion and Conclusion

Hypersensitivity reaction is the most com-

mon side effect of L-asp. But the hypersen-

sitivity of PEG-L-asp has been expected to

be reduced.

¹⁾

The outcome also showed that

the PEG-L-asp group lead to less occurrence

of hypersensitivity reaction than the native

Fig. 3 Hepatotoxicity incidence by risk group

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L-asp group. There was not a study of anti- body, we could not analyze about silent hypersensitivity. In the case of hypersensi- tivity, all groups changed L-asp or PEG-L- asp to drug of other types and there was no cross hypersensitivity reaction.

As reported, PEG-L-asp group showed more occurrence of acute pancreatitis.

²⁾

Acute pan- creatitis by L-asp and PEG-L-asp was known to occur early in treatment schedule,

³⁾

and this study showed that only PEG-L-asp group demonstrated acute pancreatitis in early stage of treatment.

Thromboembolism by L-asp was more occurred in high risk group, central line inser- tion group, and upper 10 years of age group.

⁴⁾

Though this study showed higher occurrence rate of thromboembolism in PEG-L-asp group, it could not be ruled out of influence of previously administrated L-asp. All patients who experienced thromboembolism were related with central line and treated as high- risk level. A report said that serum fibrinogen level below 50 ㎎/dL increase the risk of thromboembolism.

⁵⁾

But only one patient showed below 50 ㎎/dL of serum fibrinogen level in this study, and there was no correla- tion between thromboembolism of L-asp or PEG-L-asp and fibrinogen level.

According to other study, increase of bleed- ing tendency which was caused by decrease of coagulation factor synthesis was mani- fested abnormal PT or PTT.

⁶⁾

About half of each group appears to increase of bleeding tendency, and the PEG-L-asp group showed fewer occurrences than the L-asp group.

There was no relation between treatment stage and bleeding tendency. But because of the characteristic of the disease, there was limitation that some patient had already been

increased bleeding tendency.

As the risk factor of hyperglycemia in ALL treatment, female, upper 10 years of age and combined treatment with steroids are well known.

⁷⁾

But this study didn’ t show the cor- relation of gender and hyperglycemia.

Though the L-asp group showed 4% higher than the PEG-L-asp group, the PEG-L-asp group had twice as much as the L-asp group for average periods of glucose levels over 200 mg/dL. It seemed to be related with half-life of the drug. Although two groups appeared about 20% of hyperglycemia occurrence rate, all of hyperglycemia patients were over ten years old. Hyperglycemia of L-asp and PEG- L-asp was responded to insulin therapy and did not develop into diabetes.

The hepatotoxicity was observed in both of groups and the PEG-L-asp group showed higher incidence. The limitation was that the PEG-L-asp group had more high-risk patients than the L-asp group and high-risk patient had to be administrated more anti- cancer drugs. There were no cases that lead to serious hepatic insufficiency.

The elevation of blood ammonia levels is a specific side effect which is explained by cre- ation of secondary product of asparagines breakdown. The L-asp group showed higher incidence than the PEG-L-asp group. There was no case that leads to coma and all case returned to normal levels by taking lactulose syrup.

In this study, the overall patterns of side

effects had similar result with the L-asp group

and the PEG-L-asp group, but hypersensitivi-

ty incidence by treatment phase(P=0.0109),

bleeding tendency by patients’risk(P=0.0057),

and elevation of blood ammonia levels inci-

dence by group(P=0.0050) showed statistical

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difference. The other finding from this study was hepatotoxicity, acute pancreatitis and thromboembolism were more occurred in PEG- L-asp group despite the low administration frequency. Through this study, we hope to help the medical team prepare appropriate treatment for the side effect by each patient, based on the findings.

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