Improved Outcome for Children and Young Adults with T-Cell Acute Lymphoblastic Leukaemia (ALL): Results of the United Kingdom Medical Research Council (MRC) Trial UKALL 2003.
Authors: Vora Ajay , Wade Rachel , Mitchell Christopher D , Goulden Nicholas , Richards Sue 
Published: October 2019

UKALL 2003 is an ongoing randomised controlled trial investigating whether treatment can be adjusted according to Minimal Residual Disease (MRD) levels measured by RQPCR at the end of induction and week 11 in children and young adults (up to age 25 years) with ALL. Although the results of the randomised interventions remain blinded, we have observed a significant improvement in 4 year event-free (EFS) and overall survival (OS) in the trial overall compared with its predecessor, ALL 97/99. Here we report a comparison of the outcome for T cell patients in the two trials, in whom the majority of events occur within 3 years.

Both UKALL 2003 and ALL97/99 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 and those with poor risk cytogenetics were transferred to Regimen C. The only differences in treatment administered to all patients between the two trials was the use of Pegylated E. Coli Asparaginase (Peg-ASP) (Oncospar, Medac UK) and Dexamethasone in UKALL 2003 instead of native E. Coli Asparaginase and a Dexamethasone vs Prednisolone randomisation respectively 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. Less than 2% of patients, with high risk cytogenetics or day 28 BM3 marrow, were eligible for first remission transplantation.

The outcome for 190 (12%) T-cell patients recruited to UKALL 2003 at 30/10/07 was compared with 92 (10%) patients in ALL97/99. In UKALL 2003, the proportions of T-cell ALL patients treated on the 3 regimens was A= 14%, B= 54% and C= 32% (51%, 26% and 23% respectively in trial overall). For ALL97/99 this was A=14%, B=57% and C=29% (59%, 24% and 16% respectively for the trial overall). EFS and OS are significantly better for T-cell patients in UKALL 2003 (3 year: EFS 86% (se 3.3), OS 90% (se 2.8)) compared with ALL97/99 (EFS 73% (se 4.6), OS 78% (se 4.3)) (p = 0.03 for EFS, p=0.04 for OS). The actuarial incidence of CNS relapse in UKALL 2003 and ALL 97/99 respectively was 3% vs 4% isolated (p=0.7) and 4% vs 7% any CNS (p =0.3). There is a suggestion of a difference in the effect of WCC (<100, ≥ 100) by age on EFS in T-cell patients in both trials, with the effect of WCC not seen in those aged <10, p(heterogeneity)=0.01. Treatment related mortality for T-cell patients was similar in both trials. Only a third of T-cell patients have been entered into the MRD randomisations, hence the observed differences in outcome are unlikely to be due to the randomised interventions.

Over 85% of children and young adults with T-cell ALL at all ages and presenting white cell count can be cured without cranial radiotherapy or high dose methotrexate. The observed improvements in outcome are likely to be due to the use of Dexamethasone and Pegylated asparaginase.