© Borgis - Postępy Nauk Medycznych 4/2014, s. 231-237
*Małgorzata Czogała1, Krystyna Sztefko2, Iwona Rogatko2, Walentyna Balwierz1, 3
Ocena wpływu obniżenia aktywności L-asparaginazy i reakcji alergicznej na wyniki leczenia ostrej białaczki limfoblastycznej u dzieci
Analysis of the influence of decrease of L-asparaginase activity and hypersensitivity reaction on the treatment outcome in children with acute lymphoblastic leukemia
1Department of Pediatric Oncology and Hematology, Children’s University Hospital, Kraków
Head of Department: prof. Walentyna Balwierz, MD, PhD
2Department of Clinical Biochemistry, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Kraków
Head of Department: prof. Krystyna Sztefko, MD, PhD
3Department of Pediatric Oncology and Hematology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Kraków
Head of Department: prof. Walentyna Balwierz, MD, PhD
Streszczenie
Wstęp. L-asparaginaza (L-ASPA) to jeden z podstawowych leków stosowanych w terapii ostrej białaczki limfoblastycznej (ALL) u dzieci.
Cel pracy. Celem pracy była ocena wpływu obniżenia aktywności L-ASPA i reakcji alergicznej w odpowiedzi na ten lek na wyniki leczenia ALL u dzieci.
Materiał i metody. Do badania włączono 87 dzieci leczonych według protokołu ALL IC-BFM 2002. Podczas indukcji oznaczano aktywność L-ASPA. W trakcie wszystkich cykli chemioterapii zawierających L-ASPA obserwowano pacjentów w kierunku wystąpienia reakcji alergicznej na ten lek. Po okresie obserwacji trwającym od 62 do 102 miesięcy oceniono wyniki leczenia.
Wyniki. Aktywność L-ASPA poniżej wartości terapeutycznych (100 IU/l) stwierdzono u 19 (21%) pacjentów, w tym u 7 (8%) dzieci stwierdzano aktywność nieoznaczalną (< 30 U/l). Wskaźnik ponad 5-letniego przeżycia wolnego od choroby (DFS) nie różnił się istotnie pomiędzy grupą pacjentów z aktywnością L-ASPA poniżej 100 IU/l a pacjentami z aktywnością terapeutyczną (DFS odpowiednio 88,9 i 84,5%; p = 0,69). Reakcja alergiczna wystąpiła u 42 (49%) pacjentów. Szczególne ryzyko wystąpienia reakcji nadwrażliwości dotyczyło pacjentów z niską i nieoznaczalną aktywnością leku (współczynnik ryzyka HR odpowiednio: 1,86 i 2,23). Wystąpienie reakcji nadwrażliwości na L-ASPA nie wiązało się z istotnym pogorszeniem wyników leczenia u obserwowanych pacjentów (ponad 5-letnie DFS: 85 i 85,8%; p = 0,94).
Wnioski. Obniżenie się aktywności L-ASPA u dzieci leczonych z powodu ALL nie wiązało się z pogorszeniem wyników leczenia, natomiast istotnie zwiększało ryzyko wystąpienia reakcji nadwrażliwości na ten lek.
Summary
Introduction. L-asparaginase (L-ASPA) is one of the basic drug in the treatment of the acute lymphoblastic leukemia (ALL) in children.
Aim. The aim of the study was to analyze the influence of decrease of L-ASPA activity and allergic reaction on the treatment outcome in children with ALL.
Material and methods. Eighty seven patients treated with ALL IC-BFM 2002 Protocol were enrolled to the study. L-ASPA activity was measured during induction. In course of all chemotherapy cycles comprising L-ASPA symptoms of allergic reactions to the drug were registered. Treatment outcome was assessed after observation lasting 62-102 months.
Results. Activity below therapeutic values (< 100 IU/l) was noticed in 19 (21%) patients, including 7 (8%) patients with undetectable activity (< 30 IU/l). Disease free survival (DFS) did not differ significantly between the groups with therapeutic and low L-ASPA activity (5-years DFS 88.9 and 84.5% respectively; p = 0.69). Allergic reaction occurred in 42 (49%) patients. Children with low and undetectable L-ASPA activity were at especially high risk of allergic reaction (hazard ratio respectively: 1.86 and 2.23). Occurrence of hypersensitivity to L-ASPA was not associated with outcome deterioration (5-years DFS in patients with allergic reaction 85%; in patients without hypersensitivity: 85.8%; p = 0.94).
Conclusions. Decrease in L-ASPA activity in children treated for ALL was not associated with outcome deterioration but was significant risk factor of hypersensitivity to this drug.
Introduction
L-asparaginase (L-ASPA) is one of the basic agents in the treatment of acute lymphoblastic leukemia (ALL). Efficacy of L-ASPA therapy is related to the grade and duration of asparagine decrease in serum and cerebrospinal fluid (CSF), which depends on the enzyme activity. Activity above 100 IU/l, assuring complete asparagine depletion, is concerned as therapeutic (1). Although, total removal of asparagine was observed in some patients with L-ASPA activity below 100 IU/l (2-4).
L-ASPA as a protein of bacterial origin can cause development of antibodies, which leads to allergy with local or generalized symptoms (5-7), or to inactivation of the enzyme and shortening of its half-life without symptoms of hypersensitivity (“silent inactivation”) (5-9). The reported frequency of anti-asparaginase antibodies is variable and ranges up to 70% (7-10). The frequency of hypersensitivity reactions ranges from 0 to 45% (7-10). Incidence of the hypersensitivity reaction depends on preparation of L-ASPA, doses, way of administration, number of L-ASPA administrations during one treatment phase (4-7, 9, 11-13). It is recommended to change L-ASPA preparation when hypersensitivity or silent inactivation occurs. Conflicting data exist regarding influence of immunologic reaction to L-ASPA on the treatment outcome (7, 14-17). Effects of the hypersensitivity can be minimized by fast switching to another preparation after allergy occurrence (7).
Aim
The aim of the study was analysis of the influence of decrease of L-ASPA activity and allergic reaction to this drug on the treatment outcome in children treated for ALL.
Material and methods
Ninety seven children with ALL began the treatment according to the international protocol ALL IC-BFM-2002 in the Department of Pediatric Oncology and Hematology in the Children’s University Hospital in Cracow from 1th June 2005 to 31th October 2008. Eighty seven patients were eligible to the study (10 were excluded because not enough blood samples were available for L-ASPA activity measurement). General characteristic of the analyzed children is shown in table 1.
Table 1. Clinical characteristics of the 87 patients with acute lymphoblastic leukemia analyzed in the study.
| Parameters | cALL | proB-ALL | Transitional ALL | T-ALL | All |
| Number of patients (percentage) | 71 (81.6) | 3 (3.4) | 2 (2.3) | 11 (12.7) | 87 (100) |
Age: median (range)
[years] | 5.5
(1.7-17) | 14
(3.5-16) | 1,5
(1.2-1.9) | 7.5
(2-13.5) | 6
(1.2-17) |
| | Number of patients (percentage) |
Risk groups | SRG | 25 (35) | 1 (33) | 2 (100) | 0 | 28 (32) |
| IRG | 31 (44) | 2 (67) | 0 | 7 (64) | 40 (46) |
| HRG | 15 (21) | 0 | 0 | 4 (36) | 19 (22) |
| Down syndrome | 4 (5.6) | 0 | 0 | 0 | 4 (4.6) |
| HSCT in the treatment of first line | 2 (2.8) | 0 | 0 | 3 (27) | 5 (5.7) |
| Relapses | 10 (14) | 1 (33) | 0 | 0 | 11 (12.6) |
| Progression before remission | 1 (1.4) | 0 | 0 | 0 | 1 (1.1) |
| Lasting first remission | 59 (83) | 2 (67) | 1 (50) | 10 (91) | 72 (82.7) |
| Lasting second remission | 4 (5.6) | 0 | 0 | 0 | 4 (4.6) |
Deaths
– of ALL
– of toxicities | 7 (9.8)
3 (4.2)
4 (5.6) | 1 (33)
1 (33)
0 | 1 (50)
0
1 (50) | 1 (9)
0
1 (9) | 10 (11.5)
4 (4.6)
6 (6.9) |
Observation was finished on 31th December 2013. Median follow-up was 87 months (range: 62-102 months). On the day of the finish of observation 72 patients remained in first complete remission (I CR), lasting 60-100 (median 82) months.
L-ASPA was administrated during induction (Protocol I), reinduction (Protocols II and III) and HR cycles (tab. 2). Blood for L-ASPA activity test was collected before each administration of the drug during Protocol I. Plasma was centrifuged and frozen in -80°C till examination. L-ASPA activity was assessed using MAAT test (Medac Asparaginase-Aktivitäts-Test) test in the Department of Clinical Biochemistry of the Polish-American Institute of Pediatrics (Jagiellonian University Medical College, Kraków). For each patient average value of L-ASPA activity in induction was counted, and this value was used in specified analysis.
Table 2. Treatment protocols comprising L-ASPA.
| Protocol I | 5000 IU/m2/24 h – day 12., 15., 18., 21., 24., 27., 30., 33. |
| Protocol II | 10 000 IU/m2/24 h – day 8., 11., 15., 18. |
| Protocol III | 10 000 IU/m2/24 h – day 1., 4., 8., 11. |
| HR1-3 cycles | 25 000 IU/m2/24 h – day 6. and 11. |
Patients were strictly observed for early recognition of the symptom of hypersensitivity to L-ASPA during all treatment protocols with L-ASPA administrations.
Early response to the chemotherapy was assessed basing on the percentage of blasts in bone marrow on the day 33 of induction therapy. Treatment outcome was estimated on the basis of survival rates: overall survival (OS) counted from the date of the beginning of the treatment to the date of the finish of observation or to the death, event free survival (EFS) – from the beginning of the treatment to the finish of the observation or to the unfavorable event (progression, relapse, death of any reason), disease free survival (DFS) – from beginning of the treatment to the finish of observation or to the treatment failure (early progression, relapse), relapse free survival (RFS) – from remission to the finish of observation or to relapse. Comparative analysis concerning influence of low (< 100 IU/l), undetectable (< 30 IU/l) L-ASPA activity and hypersensitivity reaction on DFS was performed.
STATISTICA 8 software was used for statistical analysis. U Mann-Whitney test, chi-square test, Yates’ corrected chi square test, V-square test, Fisher’s exact test, Kaplan-Meier survival curves analysis and log-rank test were performed.
Results
From 87 enrolled patients 84 received all L-ASPA doses scheduled in the ALL IC-BFM-2002 program. Two children died before finishing the treatment with L-ASPA, during HR cycles. In one patient L-ASPA was contraindicated after acute pancreatitis which occurred after 7th dose of L-ASPA during induction therapy.
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