Outcomes Of Teenagers and Young Adults On The UKALL 2003 Paediatric Trial For Children and Young People With Acute Lymphoblastic Leukaemia

Outcomes for adults with acute lymphoblastic leukaemia (ALL) have traditionally been inferior to outcomes for children, with differences in survival being noted from adolescence onwards. The reasons for the declining cure rates with increasing age are likely to be multi factorial but the choice of treatment protocol has been shown to play an important role in outcomes for teenagers and young adults (TYAs) with ALL. Over the past decade there has been increasing evidence of better outcomes for TYAs treated on paediatric regimens compared to adult regimens. Historically, 15-17 year olds treated on the adult UKALL XII trial had about 15% lower 5-year probability of both overall survival (OS) and event-free survival (EFS) compared to those treated on the corresponding paediatric ALL 97/99 trial during the same period, with the EFS difference not accounted for by age, gender, WBC or Ph status. (Ramanujachar et al. Pediatr Blood Cancer. 2007 Mar;48(3):254-61).

UKALL 2003 was a randomised controlled trial investigating treatment modification according to Minimal Residual Disease (MRD) status at the end of induction and week 11, in consecutively diagnosed children and young people with Philadelphia negative ALL recruited from the UK and Republic of Ireland between October 2003 and June 2011. The trial was initially open to children up to the age of 18 years but the upper age limit was increased to 20^th birthday in 2006 and 25^th birthday in 2007. Here we report the outcomes for the 16 – 24 year old teenage and young adult (TYA) patients recruited to the trial from 2003-2011.

A total of 229 out of 3126 patients entered were aged 16-24 years (7.3%), although only 56 patients were over 20 years of age at diagnosis. With follow up to October 2012, the 5-year EFS for the 16-24 year old cohort was 72% (95% CI: 66-79%) compared to an EFS for 1-10 year olds and 10-15 year olds of 90% (88-91%) and 84% (80-87%) respectively, p(trend)<0.0001. At the last analysis, 37 TYA patients had relapsed with a 5-year cumulative risk of relapse of 21% (14-27%), compared to 11% (8-14%) for the 10-15 year olds and 7% (6-9%) for the 1-10 year olds, p(trend)<0.0001.

Within UKALL 2003 there was no significant increase in reported toxicities in the 16-24 year age group compared to the 10-15 year age group. The induction death rate was 2.2% for 16-24 year olds, 2.1% for 10-15 year olds and 1.2% for under 10 year olds. 53% of TYA patients had one or more serious adverse event (SAE) reported compared to 56% for 10-15 year olds and 31% for under 10 years. The SAEs reported were primarily infections and expected toxicities related to steroids, pegylated asparaginase and methotrexate. There was a trend (p=0.05) towards an increase in deaths in remission in the TYA age group at 6.1% compared to 3.1% in the 10-15 year olds.

Outcomes in TYAs were analysed by MRD status as previously described (Vora et al. Lancet Oncol. 2013 Mar;14(3):199-209). There was an increase in the proportion of TYA patients with persistent MRD positivity compared to the younger patient groups; 49% were MRD high risk, 24% were MRD low risk and 27% MRD indeterminate compared to 32%, 36% and 32% respectively for patients under 16 years, p<0.0001. MRD was highly predictive of outcome in the TYA age group, as in the trial overall. Five-year EFS for those aged 16-24 was 64% (95% CI: 54-74%) for MRD high risk patients, 71% (58-84%) for MRD indeterminate and 93% (86-100%) for MRD low risk; MRD high risk vs low risk, p=0.0003. The TYA EFS compares favourably with the 10-15 year old cohort with EFS of 74% (68-81%), 83% (77-88%) and 95% (91-99%) respectively.

This large randomised study provides evidence that TYAs with ALL can be treated on a national paediatric trial with toxicities similar to those seen in younger teenagers. Outcomes are significantly improved using this approach in TYAs compared to the historical, transplant focused adult ALL regimens. MRD based risk stratification in this age group remains a valid approach with low risk patients having an unprecedented 93% EFS at 5 years. Further intensification of therapy for MRD high risk patients, possibly including transplantation may be required for the MRD high risk TYA patients and this question is being examined in the next national trial, UKALL 2011.

No relevant conflicts of interest to declare.