Sidhu Jasmeet, Masurekar Ashish Narayan, Gogoi Manash Pratim, Fong Caroline, Ioannou Tasos, Lodhi Taha, Parker Catriona, Liu Jizhong, Kirkwood Amy A, Moorman Anthony V, Das Kiranmoy, Goulden Nicholas J, Vora Ajay, Saha Vaskar, Krishnan Shekhar
Tata Translational Cancer Research Centre, Tata Medical Center, Kolkata, India.
Department of Paediatric Haematology and Oncology, Tata Medical Center, Kolkata, India.
Br J Haematol. 2022 Jul;198(1):142-150. doi: 10.1111/bjh.18158. Epub 2022 Mar 29.
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/m 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.
在英国针对儿童急性淋巴细胞白血病（ALL）进行的连续临床试验（UKALL 2003、UKALL 2011）中，将1000 iu/m的聚乙二醇缀合大肠杆菌L-天冬酰胺酶（PEG-EcASNase）与风险分层治疗联合进行肌肉注射给药。在诱导期，患者接受两剂PEG-EcASNase，间隔14天。诱导期后，非高危患者（方案A、B）在延迟强化期（DI）接受1 - 2剂，而高危方案C患者接受6 - 10剂PEG-EcASNase，包括DI期的两剂。试验子研究监测了天冬酰胺酶（ASNase）活性、ASNase相关毒性和ASNase相关抗体（共1112例患者）。首次和第二次诱导剂量以及首次DI剂量后，中位（四分位间距）谷值血浆ASNase活性（给药后14±2天）分别为217 iu/l（144 - 307 iu/l）、265 iu/l（165 - 401 iu/l）和292 iu/l（194 - 386 iu/l）；15%（138/910）的样本在任何谷值时间点显示ASNase活性低于阈值（<100 iu/l）。年龄较大与较低的ASNase活性相关（回归系数 -9.5；p < 0.0001），而DI时间点与较高的ASNase活性相关（回归系数29.9；p < 0.0001）。在3.8%（UKALL 2003）和6%（UKALL 2011）的患者中观察到临床过敏反应，在方案C中90%或更多患者出现。在UKALL 2003中观察到沉默失活率为7%（10/149）。UKALL儿童试验中的PEG-EcASNase给药方案毒性较低，但患者间差异较大。治疗药物监测可能通过个体化天冬酰胺酶给药实现优化。
