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© 2001 American Society for Clinical Oncology Effect of Protracted High-Dose L-Asparaginase Given as a Second Exposure in a Berlin-Frankfurt-Münster–Based Treatment: Results of the Randomized 9102 Intermediate-Risk Childhood Acute Lymphoblastic Leukemia Study—A Report From the Associazione Italiana Ematologia Oncologia PediatricaFrom the Clinica Pediatrica dell’Università di Milano, Ospedale S. Gerardo, Monza; Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia; Ospedale Infantile Regina Margherita, Torino; II Università, Servizio Autonomo di Oncologia Pediatrica, Napoli; Divisione di Onco-Ematologia Pediatrica, Catania; Bologna; Padova; Bari; Cattedra di Ematologia, Università La Sapienza, Roma; and Dipartimento di Medicina e Sanità Pubblica, Università di Verona, Verona, Italy. Address reprint requests to C. Rizzari, MD, Clinica Pediatrica, Ospedale Nuovo S. Gerardo, Via Donizetti 106, 20052 Monza, Italy; email: masera{at}xquasar.it/gmasera@libero.it
PURPOSE: To assess in a randomized study the therapeutic effect of the addition of high-dose L-asparaginase (HD ASP) in the context of a Berlin-Frankfurt-Münster (BFM)–based chemotherapy regimen for intermediate risk (IR) childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: From March 1991 to April 1995, a total of 705 patients, with 59% of the cohort of patients fewer than 15 years old, with newly diagnosed non-B ALL, enrolled onto the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-91 study, were assigned to the IR group. Patients in remission at the beginning of the reinduction phase were randomized either to the standard treatment (SD ASP arm) or the experimental treatment (HD ASP arm; weekly intramuscular administration of HD ASP 25,000 IU/m2 repeated for a total of 20 weeks). Most of the patients (90%) were treated with Erwinia chrysanthemi L-asparaginase product. RESULTS: Among the 610 patients randomized to the SD ASP arm (n = 322) or to the HD ASP arm (n = 288), relapse occurred at a median time of 24 months after randomization in 76 (24%) and in 64 children (22%), respectively. Most of the relapses occurred in the marrow (100 isolated, 21 combined). There was no significant difference between the disease-free survival in the two treatment arms (P = .64), with estimated values at 7 years from randomization of 72.4% (SE 3.1) v 75.7% (SE 2.6) in the SD ASP and HD ASP arms, respectively. CONCLUSION: No advantage was observed for IR ALL children treated with BFM-based intensive chemotherapy who received protracted E chrysanthemi HD ASP during reinduction and the early continuation phase.
RESULTS OBTAINED in childhood acute lymphoblastic leukemia (ALL) by several cooperative study groups with different intensive chemotherapy schedules have been largely superimposable over the last decade, with approximately 70% long-term event-free survival (EFS) rates.1-8 A direct comparison of results obtained by two groups with sharply different treatment modalities, ie, the Berlin-Frankfurt-Münster (BFM) schedule (based on two multidrug intensive elements: protocols I and II) versus the Dana-Farber Cancer Institute (DFCI) studies (largely based on a traditional four-drug induction phase followed by the protracted, intensive use of L-asparaginase [L-ASP]) showed the same results.9 On the basis of these data, it has been suggested that treatment intensification is the key to improving the results, allowing the statement that more is better10 and that "the integration of major components of each program into a single, new protocol to improve the outcome" could be considered.9 In addition, the peculiar mechanism of action of L-ASP, with its limited immune and myelosuppressive activity, makes this drug suitable for addition in the context of intensive chemotherapy schedules. Overall results of the BFM-based1 Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-91 study have already been reported8; the intermediate-risk (IR) patients, accounting for 59% of the total patient population, were randomized to receive or not receive, during reinduction (protocol II) and early maintenance, a weekly high-dose L-ASP (HD ASP) schedule derived from the DFCI experience.4 In this article, the results of this randomized study are presented.
Patients From March 1991 to April 1995, 1,267 untreated patients younger than 15 years old, with newly diagnosed non-B ALL, were registered from 37 AIEOP institutions. Twenty-two patients were only registered, and 25 were not eligible for the study protocol (because of Down’s syndrome [n = 14], acute undifferentiated leukemia [n = 1], acute myeloid leukemia [n = 2], age > 15 years [n = 7], or antiblastic drug pretreatment [n = 1]); 26 were not assessable because of missing data. Thus, 1,194 patients were eligible for the study, as already reported.8
A total of 705 patients (59%) were assigned to the IR group. Inclusion criteria for IR were BFM risk factor1 (calculated at diagnosis as 0.2 x log10 [blast cell count + 1] + 0.06 x centimeters of palpable liver + 0.04 x centimeters of palpable spleen) Among the 705 IR patients, 36 patients were not eligible for randomization because of corticosteroid pretreatment (n = 21) or erroneous stratification (patients with either standard or high-risk features who were treated as IR patients, n = 15). In addition, 19 patients did not reach the point of randomization because they died during induction (n = 2), relapsed (n = 11) or died in CR (n = 2), or were lost to follow-up during induction (n = 3) or soon after CR was achieved (n = 1). Among the remaining 650 patients, 40 (6%) were not randomized because of parents’ refusal (n = 4), clinical decision (n = 29), or other unknown cause (n = 7). Of these 40 patients, 10 relapsed and one died in CR. This work is focused on the 610 randomized patients.
Diagnostic Studies Immunophenotyping was performed by flow cytometry by using a large panel of commercial monoclonal antibodies directed against the following surface and intracellular antigens: CD1a (OKT6; Ortho Diagnostic Systems, Raritan, NJ), CD3 (Leu4; Becton Dickinson, Mountain View, CA), CD4 (OKT4A; Ortho), CD5 (Leu1; Becton Dickinson), CD7 (3A1; Coulter, Miami, FL), CD10 (J5; Coulter), CD13 (My7; Coulter), CD14 (My4; Coulter), CD15 (LeuM1; Becton Dickinson), CD19 (B4; Coulter), CD20 (B1; Coulter), CD24 (OKB2; Ortho), CD33 (My9; Coulter), CD34 (HPCA 1; Becton Dickinson), CDw65 (Vim2; Caltag Laboratories, San Francisco, CA), HLA-DR (Ortho), immunoglobulin M chain (Southern Biotechnology, Birmingham, AL), and terminal deoxynucleotidyl transferase (TdT; Supertechs Inc, Bethesda, MD). The positivity criteria were defined according to the BFM-family criteria, with the limit of 20% for surface antigens and 10% for intracellular markers.12
Definition of Remission
Treatment
Randomized Therapy All eligible patients who were in CR at the beginning of the reinduction phase (23 weeks after the diagnosis) were centrally randomized after informed consent had been obtained from the parents or legal guardian. After checking the eligibility criteria, a computer program allocated each patient either to the standard treatment (SD ASP arm) or to the experimental treatment (HD ASP arm). Patients on the standard treatment arm received, during the reinduction phase, four doses (on days 8, 11, 15, and 18) of L-ASP 10,000 IU/m2. Patients on the experimental treatment arm received, during the reinduction phase and early continuation phase, a weekly administration of HD ASP 25,000 IU/m2 repeated for a total of 20 weeks. L-ASP was administered intramuscularly. Random allocation was implemented according to a minimization approach.13 A technical mistake in the software was discovered during recruitment and partially corrected thereafter. This explains the imbalance in the number of patients allocated in the two arms (322 v 288 patients). Patients’ features in the two arms were, however, very similar. At the beginning of the study, the Escherichia coli product (Crasnitin; Bayer, Leverkusen, Germany) became unavailable in Italy. Thus, only fewer than 10% of the patients received this product, whereas the other 90% received the Erwinia chrysanthemi product (Erwinase; Speywood, Maidenhead, United Kingdom).
Toxicity Survey
Pharmacologic Studies
Statistical Analysis
Follow-up was updated as of August 31, 1999. Four randomized patients (0.7%) were lost to follow-up while in CCR. The main analysis of treatment effect was performed according to the intention-to-treat principle. The log-rank test was applied for comparing the outcome of the randomized groups. In addition, the Cox regression model15 was applied to estimate treatment effect adjusting for known prognostic variables (WBC count < 10,000, 10 to 50,000, and
The median follow-up time of the 705 patients enrolled onto the IR group of the AIEOP ALL-91 study was 71 months. The 7-year EFS (SE) was 72.7% (1.8%), with a survival of 81.0% (1.8%). As explained in Patients and Methods, 610 patients were randomized to the SD ASP arm (n = 322) or to the HD ASP arm (n = 288). Their presenting clinical and laboratory features are listed in Table 2, according to randomized treatment. Their median follow-up time from randomization was 66 months.
Relapse was the most common cause of treatment failure. It occurred in 76 children (24%) in the SD ASP arm and in 64 children (22%) in the HD ASP arm, at a median time of 24 months after randomization (range, 0 to 80 months). Sites of relapse are listed in Table 3. Most of the relapses occurred in the marrow (100 isolated, 21 combined). Isolated CNS relapse occurred in 12 children (2%) (eight during treatment); isolated testicular relapses occurred in five children (1.5% of boys).
There was no significant difference between the DFS (SE) in the two treatment arms (P = .64), with estimated values at 7 years from randomization of 72.4% (3.1%) and 75.7% (2.6%) in the SD ASP and HD ASP arms, respectively ( Fig 1).
When treatment comparison was adjusted by prognostic factors in a Cox regression model, similar results were obtained: the RR estimate was not significantly different from 1 (HD ASP v SD ASP; RR = 0.92, P = .62). Of the covariates considered in this analysis, age and immunophenotype significantly influenced the outcome. Namely, almost twice the risk of an adverse event was experienced by patients with age  10 years or infants (age < 1 year), as compared with patients aged 1 to 9 years (RR = 1.67, P = .01). Patients with T-cell ALL had twice the risk of failure compared with the remaining IR patients (RR = 1.99, P = .004). No significant difference in the DFS by sex or by WBC count was detected. We also tested, by adding interaction terms in the model, whether treatment had a different effect in different subgroups defined by each covariate in turn. None of these analyses gave an indication of a significant interaction. Indeed, also with the univariate analysis, no significant difference between arms was present in the subgroups identified by sex, WBC count, age, and immunophenotype. Results on treatment comparison obtained when the analysis was performed by treatment actually given were similar to those obtained with the intention-to-treat analysis and reported above. A limited number of shifts had occurred (17 patients randomly assigned to the HD ASP arm were given the SD ASP treatment, and in one patient the opposite occurred) and two patients had erroneously been randomized in relapse (in the experimental arm) and were excluded from this analysis. Data on a subset of 245 patients were available for evaluation of toxicity (Table 4). Among the 119 patients from the SD ASP arm, a mean duration of reinduction therapy of 76 days (expected duration, 63 days), 122 episodes of neutropenia in 72 patients, and 31 episodes of thrombocytopenia in 26 patients were observed; conversely, among the 126 patients from the HD ASP arm, a mean duration of reinduction therapy of 82 days (P not significant), 218 episodes of neutropenia in 102 patients (P < .001), and 67 episodes of thrombocytopenia in 51 patients (P = .002) were observed. Reduction of the AT III levels to less than 50% was observed in zero and three patients (P not significant), whereas AT III levels between 50% and less than 70% were observed in two and 13 patients (P = .005) in the SD ASP arm versus the HD ASP arm, respectively. Replacement therapy with AT III was given to six patients, with a total of nine episodes in the HD ASP arm versus none in the SD ASP arm. Severe allergic reactions were observed in three patients (one systemic, two local) in the SD ASP arm versus 10 (five systemic, five local) in the HD ASP arm (P not significant). Transient hyperglycemia requiring the use of insulin therapy was observed in only two patients from the HD ASP arm. No patients developed diabetes, thrombosis, or pancreatitis.
Treatment with HD ASP was discontinued in nine (7%) of 126 patients because of severe allergic reactions (n = 5), prolonged myelosuppression (n = 2), and seizures or liver dysfunction (one case each). In the SD ASP arm, the drug was discontinued in one (0.8%) of 119 patients (P = .01).
The overall results achieved by the AIEOP ALL 9102 study for IR childhood ALL patients with an EFS at 7 years of 72.7% (SE 1.8%) are comparable to those achieved by other major cooperative groups.1-7 The design of the AIEOP ALL 9102 randomized study was based on the concept that the protracted administration of HD ASP could be considered the ideal type of treatment intensification because of its efficacy, particularly as observed in the DFCI studies,4,9,10 and limited hematologic toxicity. These characteristics could have thus allowed the exploitation of the therapeutic potential of HD ASP for improving the outcome of patients treated with a BFM-based intensive chemotherapy schedule.9 The two major forms of native L-ASP mainly used in clinical practice derive from two different bacterial species (ie, E coli and E chrysanthemi). These products have, however, different pharmacokinetic and immunogenic properties, with the E chrysanthemi product displaying a mean half-life shorter than that of the E coli product (0.65 ± 0.13 v 1.24 ± 0.17 days, respectively) and being mainly used as second-line treatment for patients experiencing severe allergic reactions to E coli preparations.16,17 For many years, the E coli product Crasnitin was the only E coli-derived L-ASP preparation available in Europe, and thus L-ASP treatment schedules adopted in clinical trials conducted in Europe were based on the pharmacokinetic properties of this drug. When the AIEOP ALL-91 study was started, Crasnitin was no longer available in Europe. Because Erwinase had been already used in other studies as front-line product with clinical results considered comparable to those obtained with Crasnitin,18-20 in the AIEOP ALL-91 study Erwinase was used at the same dose and schedule as Crasnitin. Limited toxic effects were seen in our patients treated with HD ASP: only six of 126 needed substitutive therapy with AT III. An increase of neutropenia and thrombocytopenia episodes was observed in the HD ASP arm; this information suggests that ASP added at high doses may increase the hematologic toxicity of an intensive chemotherapy schedule, even in the absence of effective asparagine depletion. Incidence of allergic reactions was very low, whereas other typical L-ASP–related side effects, such as diabetes, thrombosis, or pancreatitis, were never seen. These findings are in keeping with the lower toxicity pattern recently reported by DFCI ALL Consortium investigators in children randomized to receive in induction the E chrysanthemi product compared with those treated with an E coli product.21 This study reported that no significant difference in DFS was observed between patients randomized to receive or not receive the protracted HD ASP schedule. This finding was confirmed not only in the overall study population but also in the analysis of the subgroups identified by sex, WBC count, or immunophenotype. These findings may lead to the conclusion that the therapeutic effect deriving from the application of an intensive regimen such as BFM1,2,9 is already maximal and thus cannot be improved by the addition of protracted HD L-ASP. Data reported in the present study are apparently not in keeping with those obtained in a recent randomized study (Pediatric Oncology Group 8704) in which an E coli preparation (Elspar; MS&D, West Point, PA) was administered at high doses 3 months after diagnosis in the context of an intensive and effective rotating-agents backbone. This schedule has proven to be effective for a large cohort of children with T-ALL and advanced lymphoblastic lymphoma.22 In another Pediatric Oncology Group study, however, HD ASP did not provide any benefits for B-precursor ALL children.23 Conversely, it could also be possible that in our study HD ASP may not have been used in the optimal way. This hypothesis is supported by pharmacologic studies performed in the framework of the AIEOP ALL-91 study that showed that L-asparagine plasma14 or CSF24 depletion (which is considered the major biologic correlate of L-ASP efficacy) was observed in only 25% of cases during the second (reinduction phase) exposure to Erwinase given either at conventional or high doses. This is further confirmed by a dose optimization study under pharmacokinetic control in patients treated with Erwinase as second exposure, in which it was found that increased dosage and more frequent administrations were necessary to ensure adequate ASP activity levels and asparagine depletion during the reinduction phase.25 Reduction of Erwinase activity may be caused by the specific pharmacokinetic characteristics of the drug, inactivating factors of immunologic origin, or both. For this reason, it should also be taken into consideration that timing of ASP treatment may be important in determining a maximal therapeutic effect from this treatment. In DFCI studies, HD ASP treatment was administered shortly after the start of chemotherapy treatment and represented the first exposure of patients to the drug; the timing may thus influence both the incidence of immunologic reactions (leading to clinical complications or to silent inactivation) and the therapeutic efficacy.4,9,10 We have already reported that in a retrospective nonrandomized comparison performed in IR ALL children treated with Erwinase or with the previously available E coli product Crasnitin, similar DFS estimates were found.26 In this context, it must be considered that pharmacologic17,24,25 and clinical data27,28 indicate that the activity of Erwinase or Crasnitin is inferior to that of other E coli products (such as medac ASP) currently used, which, in turn, could have a different impact on clinical outcome. In particular, patients enrolled onto the European Organization for Research and Treatment of Cancer 58881 trial (based on a BFM backbone) and randomized to receive the E coli medac ASP product had a significantly better outcome compared with those randomized to receive the E chrysanthemi product.27,28 However, in the BFM ALL-90 study, no difference in terms of DFS was found in IR ALL children randomized to receive or not receive HD medac ASP (25,000 IU/m2 every 2 weeks for 4 weeks) during the consolidation phase (ie, after each high-dose methotrexate cycle infusion).2 A more extensive use of these drugs could theoretically lead to an improvement of clinical results; however, the excess of enzymatic activity caused by more intensive ASP schedules or more potent products may also lead to increased toxicity.29-31 Careful attention must thus be given in the design of clinical studies, not only to the schedule, but also to the activity of the L-ASP products used. In conclusion, our study did not provide evidence of an advantage for patients receiving protracted E chrysanthemi HD L-ASP. However, because of the above-mentioned reasons, it is possible that other currently used L-ASP products or different L-ASP treatment schedules could have a different impact also in the context of BFM-based therapies.
This work was conducted within the framework of Ministero Università Ricerca Scientifica Tecnologica grant no. 12-02/5030/6, 1999-40%, and with the contribution of the Fondazione Tettamanti per lo studio delle Leucemie ed Emopatie Infantili, Fondazione Città della Speranza, and of the Associazione Italiana Ricerca Cancro. We gratefully acknowledge the competent contribution of D. Silvestri to the conduction of this study.
1. Reiter A, Schrappe M, Ludwig R, et al: Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: Results and conclusions of the multicenter trial ALL-BFM 86. Blood 84: 3122-3333, 1994
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Schrappe M, Reiter A, Ludwig W-D, et al: Improved outcome in childhood ALL despite reduced use of anthracyclines and of cranial radiotherapy: Results of trial ALL-BFM 90. Blood 95: 3310-3320, 2000 3. Rivera GK, Raimondi SC, Hancock ML, et al: Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet 337: 61-66, 1991[Medline] 4. Clavell LA, Gelber RD, Cohen HJ, et al: Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 315: 657-663, 1986[Abstract]
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Nachman J, Sather HN, Gaynon PS, et al: Augmented Berlin-Frankfurt-Munster therapy abrogates the adverse prognostic significance of slow early response to induction chemotherapy for children and adolescents with acute lymphoblastic leukemia and unfavorable presenting features: A report from the Children’s Cancer Group. J Clin Oncol 15: 2222-2230, 1997
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Mahoney DH Jr, Shuster JJ, Nitschke R, et al: Intensification with intermediate-dose intravenous methotrexate is effective therapy for children with lower-risk B-precursor acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol 18: 1285-1294, 2000 7. Richards S, Burrett J, Hann I, et al: Improved survival with early intensification: Combined results from the Medical Research Council childhood ALL randomized trials. UKALL X and UKALL XI. Medical Research Council Working Party on Childhood Leukaemia. Leukemia 12: 1031-1036, 1998[Medline] 8. Conter V, AricòM, Valsecchi MG, et al: Intensive BFM chemotherapy for childhood ALL: Interim analysis of the AIEOP-ALL 91 study. Haematologica 83: 699-707, 1998
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Niemeyer CM, Reiter A, Riehm H, et al: Comparative results of two intensive treatment programs for childhood acute lymphoblastic leukemia: The Berlin-Frankfurt-Münster and Dana-Farber Cancer Institute protocols. Ann Oncol 2: 745-749, 1991 10. Sallan SE, Gelber RD, Kinball V, et al: More is better! Update of DFCI ALL trials, in Büchner T, Schellong G, Hiddemann W, et al (eds): Acute Leukemias II: Prognostic Factors and Treatment Strategies. Berlin, Germany, Springer Verlag, 1990, pp 459-466 11. Bennett JM, Catovsky D, Daniel M-T, et al: Proposals for the classification of the acute leukemias. French-American-British Cooperative group. Br J Haematol 33: 451-458, 1986 12. van der Does-van den Berg A, Bartram CR, Basso G, et al: Minimal requirements for the diagnosis, classification, and evaluation of the treatment of childhood acute lymphoblastic leukemia (ALL) in the "BFM Family" Cooperative Group. Med Pediatr Oncol 20: 497-505, 1992[Medline] 13. Pocock SJ: Clinical Trials: A Practical Approach. Chichester, United Kingdom, John Wiley & Sons, 1983
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Gentili D, Conter V, Rizzari C, et al: L-asparagine depletion in plasma and cerebro-spinal fluid of children with acute lymphoblastic leukemia during subsequent exposures to Erwinia L-asparaginase. Ann Oncol 7: 725-730, 1996 15. Cox DR: Regression models and life-tables (with discussion). J R Stat Soc B 34: 187-220, 1972
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Asselin BL, Whitin JC, Coppola DJ, et al: Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol 11: 1780-1786, 1993 17. Müller HJ, Boos J: Use of L-asparaginase in childhood ALL. Crit Rev Oncol Hematol 28: 97-113, 1998[Medline] 18. Eden OB, Shaw MP, Lilleyman JS, et al: Non-randomized study comparing toxicity of Escherichia coli and Erwinia asparaginase in children with leukemia. Med Pediatr Oncol 18: 497-502, 1990[Medline] 19. Barron AC, Luke KH, Hsu E, et al: The use of Erwinia L-asparaginase as first line therapy for childhood acute lymphocytic leukemia. Int J Pediatr Haematol Oncol 2: 7-10, 1995 20. O’Meara A, Daly M, Hallinan FH: Increased antithrombin III concentration in children with acute lymphoblastic leukemia receiving L-asparaginase therapy. Med Pediatr Oncol 16: 169-174, 1988[Medline] 21. Silverman LB, Kimball Dalton VM, Zou G, et al: Erwinia asparaginase is less toxic than E. coli asparaginase in children with acute lymphoblastic leukemia (ALL): Results from the Dana-Farber Cancer Institute ALL Consortium. Blood 94: 209a, 1999 (abstr) 22. Amylon MD, Shuster J, Pullen J, et al: Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: A Pediatric Oncology Group study. Leukemia 13: 335-342, 1999[Medline] 23. Harris MB, Shuster JJ, Pullen DJ, et al: Consolidation with anti-metabolite based therapy in standard risk acute lymphoblastic leukemia: A Pediatric Oncology Group study. J Clin Oncol 16: 2840-2847, 1998[Abstract]
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Dibenedetto SP, Di Cataldo A, Ragusa R, et al: Levels of L-asparagine in CSF after intramuscular administration of asparaginase from Erwinia in children with acute lymphoblastic leukemia. J Clin Oncol 13: 339-344, 1995 25. Vieira Pinheiro JP, Ahlke E, Nowak-Gottl U, et al: Pharmacokinetic dose adjustment of Erwinia asparaginase in protocol II of the paediatric ALL/NHL-BFM treatment protocols. Br J Haematol 104: 313-320, 1999[Medline]
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Rizzari C, Conter V, D’Incalci M, et al: L-Asparagine depletion: Another opinion. Ann Oncol 8: 204-206, 1997 27. Otten J, Suciu S, Lutz P, et al: The importance of L-asparaginase (A’ASE) in the treatment of acute lymphoblastic leukemia (ALL) in children: Results of the EORTC 58881 randomized phase III trial showing greater efficiency of Escherichia coli (E. coli) as compared with Erwinia (ERW) A’ASE. Blood 88: 669, 1996 (suppl 1, abstr) 28. Paquement H, Philippe N, Mechinaud F, et al: Importance of L-asparaginase, detrimental effects of additional cytosine arabinoside and of I.V. mercaptopurine in the treatment of lymphoblastic non-Hodgkin lymphoma. Med Pediatr Oncol 29: 429, 1997 (abstr P-160) 29. Nowak-Göttl U, Boos J, Wolff JEA, et al: Influence of two different E. coli asparaginases preparations on coagulation and fibrinolysis: A randomized trial. Fibrinolysis 8: 66-68, 1994 (suppl 2) 30. Sutor AH, Niemeyer C, Sauter S, et al: Gerinnungsveranderungen bei Behandlung mit den Protokollen ALL BFM 90 und NHL-BFM-90. Klin Padiatr 204: 264-273, 1992[Medline] 31. Liang D-C, Hung I-J, Yang C-P, et al: Unexpected mortality from the use of E. coli L-asparaginase during remission induction therapy for childhood acute lymphoblastic leukemia: A report from the Taiwan Pediatric Oncology Group. 13: 155-160, 1999 Submitted June 1, 2000; accepted November 14, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
