Activity and toxicity of intramuscular 1000 iu/m² polyethylene glycol‐E. coliL‐asparaginase in the UKALL 2003 and UKALL 2011 clinical trials

Abstract

Summary 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.

The correlation of asparaginase enzyme activity levels after PEG‐asparaginase administration with clinical characteristics and adverse effects in Chinese paediatric patients with acute lymphoblastic leukaemia

“…Infection can lead to increased clearance, 27 however, other factors, including chemotherapeutic agents, patient status, disease burden and the function of mononuclear phagocyte system, 29 may be relevant. PEG-asparaginase inactivation occurred in 19.1% of our patients, similar to the findings of previous reports [23][24][25][30][31][32] Those studies have reported that most patients with drug inactivation experienced hypersensitivity reactions, and the rates of SI were relatively lower, ranging from 2 to 7%. Conversely, the accumulative SI rate was higher (12.5%) than the rate of hypersensitivity (6.6%) in our patient group.…”

“…20 Herein, in patients without PEG-asparaginase inactivation, AEA levels of all samples at the first 2 weeks were >I00 iu/L, which indicates that Chinese-manufactured PEG-asparaginase and the scheduled dose of PEG-asparaginase in CCCG-ALL-2015/2020 protocols enabled our patients to reach the treatment target of asparaginase. Consistent with previous studies, the AEA levels were negatively correlated with patient age, 25 and gradually increased with the number of doses used. [26][27][28] The intervals between the third and fourth doses of PEG-asparaginase were as long as 7-11 weeks.…”

“…We evaluated its association with patient characteristics and PEG-asparaginase-related AEs and presented comprehensive data. Unlike previous studies that mainly analysed trough activity levels, 24,25,29 we also included AEA levels at the end of the first week, generally considered close to peak activity levels. 15 The AEA levels monitored at different time points help to confirm the efficacy or inactivation of PEGasparaginase as recommended by expert consensus.…”

Impact of asparaginase discontinuation on outcomes of children with acute lymphoblastic leukaemia receiving the Japan Association of Childhood Leukaemia Study ALL‐02 protocol

“…Concomitant use of high-dose methotrexate and L-asparaginase was once suspected to be the reason for frequent allergies in sanctuary therapy in the ALL-97 protocol, but this did not seem to be the case in similar situations with lower-dose methotrexate or PEGasparaginase. 3,22,23 Together with suggestions in several previous reports, [24][25][26][27] we believe that our findings support the idea that differences in the corticosteroid schedule at least partially explain why ALL-02 protocols resulted in a very low frequency of allergic reactions to native Lasparaginase. 28 Furthermore, we have also previously suggested that combined use of asparaginase and PSL, rather than dexamethasone, in this protocol might reduce the incidence of osteonecrosis.…”