TY - JOUR
T1 - Activity and toxicity of intramuscular 1000 iu/m2 polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials
AU - Sidhu, Jasmeet
AU - Masurekar, Ashish Narayan
AU - Gogoi, Manash Pratim
AU - Fong, Caroline
AU - Ioannou, Tasos
AU - Lodhi, Taha
AU - Parker, Catriona
AU - Liu, Jizhong
AU - Kirkwood, Amy A.
AU - Moorman, Anthony V.
AU - Das, Kiranmoy
AU - Goulden, Nicholas J.
AU - Vora, Ajay
AU - Saha, Vaskar
AU - Krishnan, Shekhar
N1 - Funding Information:
The study was supported by a programme grant from Cancer Research UK (CRUK A6791) (Vaskar Saha) and grants from Blood Cancer UK (formerly Leukaemia Lymphoma Research) (08070) (Vaskar Saha); Great Ormond Street Hospital Charity (V1356); and Servier (016-33724). Vaskar Saha is a recipient of an India Alliance DBT-Wellcome Margdarshi Fellowship (IA/M/12/1/500261). The UKALL 2003 study was funded by the Medical Research Council (Ajay Vora) and the UKALL 2011 study by Blood Cancer UK. We thank patients and families for participating in the study and the participating centres for recruiting patients and providing samples.
Funding Information:
The study was supported by a programme grant from Cancer Research UK (CRUK A6791) (Vaskar Saha) and grants from Blood Cancer UK (formerly Leukaemia Lymphoma Research) (08070) (Vaskar Saha); Great Ormond Street Hospital Charity (V1356); and Servier (016‐33724). Vaskar Saha is a recipient of an India Alliance DBT‐Wellcome Margdarshi Fellowship (IA/M/12/1/500261). The UKALL 2003 study was funded by the Medical Research Council (Ajay Vora) and the UKALL 2011 study by Blood Cancer UK. We thank patients and families for participating in the study and the participating centres for recruiting patients and providing samples.
Publisher Copyright:
© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
PY - 2022/7
Y1 - 2022/7
N2 - In successive UK clinical trials (UKALL 2003, UKALL 2011) for paediatric acute lymphoblastic leukaemia (ALL), polyethylene glycol-conjugated E. coli L-asparaginase (PEG-EcASNase) 1000 iu/m2 was administered intramuscularly with risk-stratified treatment. In induction, patients received two PEG-EcASNase doses, 14 days apart. Post-induction, non-high-risk patients (Regimens A, B) received 1–2 doses in delayed intensification (DI) while high-risk Regimen C patients received 6–10 PEG-EcASNase doses, including two in DI. Trial substudies monitored asparaginase (ASNase) activity, ASNase-related toxicity and ASNase-associated antibodies (total, 1112 patients). Median (interquartile range) trough plasma ASNase activity (14 ± 2 days post dose) following first and second induction doses and first DI dose was respectively 217 iu/l (144–307 iu/l), 265 iu/l (165–401 iu/l) and 292 iu/l (194–386 iu/l); 15% (138/910) samples showed subthreshold ASNase activity (<100 iu/l) at any trough time point. Older age was associated with lower (regression coefficient −9.5; p < 0.0001) and DI time point with higher ASNase activity (regression coefficient 29.9; p < 0.0001). Clinical hypersensitivity was observed in 3.8% (UKALL 2003) and 6% (UKALL 2011) of patients, and in 90% or more in Regimen C. A 7% (10/149) silent inactivation rate was observed in UKALL 2003. PEG-EcASNase schedule in UKALL paediatric trials is associated with low toxicity but wide interpatient variability. Therapeutic drug monitoring potentially permits optimisation through individualised asparaginase dosing.
AB - In successive UK clinical trials (UKALL 2003, UKALL 2011) for paediatric acute lymphoblastic leukaemia (ALL), polyethylene glycol-conjugated E. coli L-asparaginase (PEG-EcASNase) 1000 iu/m2 was administered intramuscularly with risk-stratified treatment. In induction, patients received two PEG-EcASNase doses, 14 days apart. Post-induction, non-high-risk patients (Regimens A, B) received 1–2 doses in delayed intensification (DI) while high-risk Regimen C patients received 6–10 PEG-EcASNase doses, including two in DI. Trial substudies monitored asparaginase (ASNase) activity, ASNase-related toxicity and ASNase-associated antibodies (total, 1112 patients). Median (interquartile range) trough plasma ASNase activity (14 ± 2 days post dose) following first and second induction doses and first DI dose was respectively 217 iu/l (144–307 iu/l), 265 iu/l (165–401 iu/l) and 292 iu/l (194–386 iu/l); 15% (138/910) samples showed subthreshold ASNase activity (<100 iu/l) at any trough time point. Older age was associated with lower (regression coefficient −9.5; p < 0.0001) and DI time point with higher ASNase activity (regression coefficient 29.9; p < 0.0001). Clinical hypersensitivity was observed in 3.8% (UKALL 2003) and 6% (UKALL 2011) of patients, and in 90% or more in Regimen C. A 7% (10/149) silent inactivation rate was observed in UKALL 2003. PEG-EcASNase schedule in UKALL paediatric trials is associated with low toxicity but wide interpatient variability. Therapeutic drug monitoring potentially permits optimisation through individualised asparaginase dosing.
KW - PEG-asparaginase
KW - acute lymphoblastic leukaemia
KW - children
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U2 - 10.1111/bjh.18158
DO - 10.1111/bjh.18158
M3 - Article
C2 - 35348200
AN - SCOPUS:85127301099
SN - 0007-1048
VL - 198
SP - 142
EP - 150
JO - British journal of haematology
JF - British journal of haematology
IS - 1
ER -