Efficacy and Toxicity of Pegylated Asparaginase in the Treatment of Children and Young Adults with Acute Lymphoblastic Leukaemia: Results of the United Kingdom Medical Research Council (MRC) Trial UKALL 2003.

Pegylated E. Coli Asparaginase (Peg-ASP) (Oncospar, Medac UK) 1000 units/m² administered intra-muscularly replaced native E. Coli Asparaginase (Elspar, MSD) throughout treatment in the current UK trial for children and young adults with ALL, UKALL 2003. The trial opened in October 2003 to patients aged 1 – 21 years (increased to 25 years recently). Included in these analyses are the 1542 patients enrolled and followed up to 31/10/2007. Standard and Intermediate risk patients receive two doses Peg-ASP in induction at days 4 and 18 and a single dose on day 4 of each of two delayed intensifications. High risk patients receive an additional 8 doses during consolidation, interim maintenance and 2 delayed intensification courses. Although results of the randomised interventions remain blinded, overall event free survival (EFS) is significantly better for patients in UKALL 2003 compared with its predecessor, ALL 97/99 (3 year EFS: 92% (se 0.9) vs 87% (se 1.1) - p=0.005), particularly for patients in NCI high risk, T cell and slow early response categories.

Both trials included risk stratification by NCI risk, blast karyotype, and morphological marrow response at day 8/15 of induction to allocate patients to one of 3 treatment regimens (A, B and C – escalating intensity from A to C). NCI standard risk (SR) patients received a 3 drug induction whilst high risk (SR) patients received 4 drugs including daunorubicin. Patients with a slow early response at day 8 (NCI HR) or day 15 (NCI SR) of induction were transferred to Regimen C. The only difference between the trials in treatment administered to all patients was the use of Peg-ASP and dexamethasone in UKALL 2003 instead of native E. Coli asparaginase and a dexamethasone vs prednisolone randomisation in ALL97/99. Only patients with overt CNS disease (CNS3) at presentation received cranial radiotherapy, and high dose Methotrexate was not part of the protocol in either trial. CNS directed therapy comprised 19 – 26 doses of intrathecal methotrexate given over 2 – 3 years depending on regimen and gender.

Comparison of cohorts receiving otherwise similar treatment in the two trials suggests that Peg-ASP is an important contributor to the improved outcome seen in the high risk subgroups. In NCI HR patients, EFS is significantly better in UKALL2003 (3 year EFS: 88% (se 1.6)) compared with ALL97/99 patients who received Elspar and dexamethasone (79% (se 3.8)) (p=0.01). For T-cell patients, 3 year EFS in UKALL2003 is 86% (se 3.3), and 72% (se 9.0) in ALL97/99 (p=0.1). The incidence of Peg-ASP related serious toxicities has been relatively low: thrombosis 3% (CNS <1%), clinical hypersensitivity 1.5% and pancreatitis 1%. There is no indication that older children and young adults are at higher risk of these toxicities except possibly pancreatitis, although numbers are too small to permit statistical analysis.

As part of an intensive front-line treatment protocol, Peg-ASP has contributed to improved outcome with acceptable toxicity in a large cohort of children and young adults with ALL.