Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): A randomised, open-label phase 3 trial

Andrew E. Place, Kristen E. Stevenson, Lynda M. Vrooman, Marian H. Harris, Sarah K. Hunt, Jane E. O'Brien, Jeffrey G. Supko, Barbara L. Asselin, Uma H. Athale, Luis A. Clavell, Peter D. Cole, Kara M. Kelly, Caroline Laverdiere, Jean Marie Leclerc, Bruno Michon, Marshall A. Schorin, Jennifer J G Welch, Steven E. Lipshultz, Jeffery L. Kutok, Traci M. BlonquistDonna S. Neuberg, Stephen E. Sallan, Lewis B. Silverman

Research output: Contribution to journalArticle

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Abstract

Background: l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. Methods: DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m2 every 2 weeks) or intramuscular native E coli l-asparaginase (30 doses of 25 000 IU/m2 weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. Findings: Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E coli l-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E coli l-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E coli l-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E coli l-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E coli l-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E coli l-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). Interpretation: Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E coli l-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. Funding: National Cancer Institute and Enzon Pharmaceuticals.

Original languageEnglish (US)
JournalThe Lancet Oncology
DOIs
StateAccepted/In press - 2015

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Asparaginase
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Escherichia coli
Remission Induction
Hypersensitivity
Pancreatitis
Disease-Free Survival

ASJC Scopus subject areas

  • Oncology

Cite this

Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001) : A randomised, open-label phase 3 trial. / Place, Andrew E.; Stevenson, Kristen E.; Vrooman, Lynda M.; Harris, Marian H.; Hunt, Sarah K.; O'Brien, Jane E.; Supko, Jeffrey G.; Asselin, Barbara L.; Athale, Uma H.; Clavell, Luis A.; Cole, Peter D.; Kelly, Kara M.; Laverdiere, Caroline; Leclerc, Jean Marie; Michon, Bruno; Schorin, Marshall A.; Welch, Jennifer J G; Lipshultz, Steven E.; Kutok, Jeffery L.; Blonquist, Traci M.; Neuberg, Donna S.; Sallan, Stephen E.; Silverman, Lewis B.

In: The Lancet Oncology, 2015.

Research output: Contribution to journalArticle

Place, AE, Stevenson, KE, Vrooman, LM, Harris, MH, Hunt, SK, O'Brien, JE, Supko, JG, Asselin, BL, Athale, UH, Clavell, LA, Cole, PD, Kelly, KM, Laverdiere, C, Leclerc, JM, Michon, B, Schorin, MA, Welch, JJG, Lipshultz, SE, Kutok, JL, Blonquist, TM, Neuberg, DS, Sallan, SE & Silverman, LB 2015, 'Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): A randomised, open-label phase 3 trial', The Lancet Oncology. https://doi.org/10.1016/S1470-2045(15)00363-0
Place, Andrew E. ; Stevenson, Kristen E. ; Vrooman, Lynda M. ; Harris, Marian H. ; Hunt, Sarah K. ; O'Brien, Jane E. ; Supko, Jeffrey G. ; Asselin, Barbara L. ; Athale, Uma H. ; Clavell, Luis A. ; Cole, Peter D. ; Kelly, Kara M. ; Laverdiere, Caroline ; Leclerc, Jean Marie ; Michon, Bruno ; Schorin, Marshall A. ; Welch, Jennifer J G ; Lipshultz, Steven E. ; Kutok, Jeffery L. ; Blonquist, Traci M. ; Neuberg, Donna S. ; Sallan, Stephen E. ; Silverman, Lewis B. / Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001) : A randomised, open-label phase 3 trial. In: The Lancet Oncology. 2015.
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title = "Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): A randomised, open-label phase 3 trial",
abstract = "Background: l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. Methods: DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m2 every 2 weeks) or intramuscular native E coli l-asparaginase (30 doses of 25 000 IU/m2 weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. Findings: Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E coli l-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28{\%}] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26{\%}] of 231 patients in the intramuscular native E coli l-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90{\%} (95{\%} CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89{\%} (85-93) for those assigned to intramuscular native E coli l-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E coli l-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E coli l-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20{\%}] of 232 in the intravenous PEG-asparaginase group vs 51 [22{\%}] of 231 patients in the intramuscular E coli l-asparaginase group) and asparaginase-related allergic reactions (14 [6{\%}] vs 6 [3{\%}]). Interpretation: Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E coli l-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. Funding: National Cancer Institute and Enzon Pharmaceuticals.",
author = "Place, {Andrew E.} and Stevenson, {Kristen E.} and Vrooman, {Lynda M.} and Harris, {Marian H.} and Hunt, {Sarah K.} and O'Brien, {Jane E.} and Supko, {Jeffrey G.} and Asselin, {Barbara L.} and Athale, {Uma H.} and Clavell, {Luis A.} and Cole, {Peter D.} and Kelly, {Kara M.} and Caroline Laverdiere and Leclerc, {Jean Marie} and Bruno Michon and Schorin, {Marshall A.} and Welch, {Jennifer J G} and Lipshultz, {Steven E.} and Kutok, {Jeffery L.} and Blonquist, {Traci M.} and Neuberg, {Donna S.} and Sallan, {Stephen E.} and Silverman, {Lewis B.}",
year = "2015",
doi = "10.1016/S1470-2045(15)00363-0",
language = "English (US)",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",

}

TY - JOUR

T1 - Intravenous pegylated asparaginase versus intramuscular native Escherichia coli l-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001)

T2 - A randomised, open-label phase 3 trial

AU - Place, Andrew E.

AU - Stevenson, Kristen E.

AU - Vrooman, Lynda M.

AU - Harris, Marian H.

AU - Hunt, Sarah K.

AU - O'Brien, Jane E.

AU - Supko, Jeffrey G.

AU - Asselin, Barbara L.

AU - Athale, Uma H.

AU - Clavell, Luis A.

AU - Cole, Peter D.

AU - Kelly, Kara M.

AU - Laverdiere, Caroline

AU - Leclerc, Jean Marie

AU - Michon, Bruno

AU - Schorin, Marshall A.

AU - Welch, Jennifer J G

AU - Lipshultz, Steven E.

AU - Kutok, Jeffery L.

AU - Blonquist, Traci M.

AU - Neuberg, Donna S.

AU - Sallan, Stephen E.

AU - Silverman, Lewis B.

PY - 2015

Y1 - 2015

N2 - Background: l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. Methods: DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m2 every 2 weeks) or intramuscular native E coli l-asparaginase (30 doses of 25 000 IU/m2 weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. Findings: Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E coli l-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E coli l-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E coli l-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E coli l-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E coli l-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E coli l-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). Interpretation: Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E coli l-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. Funding: National Cancer Institute and Enzon Pharmaceuticals.

AB - Background: l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. Methods: DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m2 every 2 weeks) or intramuscular native E coli l-asparaginase (30 doses of 25 000 IU/m2 weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. Findings: Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E coli l-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E coli l-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E coli l-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E coli l-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E coli l-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E coli l-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). Interpretation: Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E coli l-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. Funding: National Cancer Institute and Enzon Pharmaceuticals.

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