Barriers To Clinical Trial Enrolment For Teenagers and Young Adults With Acute Lymphoblastic Leukaemia: The Impact of Age Eligibility Criteria
Authors: Fern Lorna Anne , Rowntree Clare , Hough Rachael E , Vora Ajay J , Fielding Adele , Mitchell Chris , Goulden Nicholas , Alston Robert , Birch Jillian , Catherine O'hara , Whelan Jeremy 
Published: October 2019

Abstract

Background
Overall survival (OS) for teenagers and young adults (TYA) aged 15-24 years (yrs) with acute lymphoblastic leukaemia (ALL) is inferior to OS for children. In the UK, five-year OS for children up to 14 years with ALL is 89%, falling to 69% for 15-19 yr olds and 52% for 20-24 yr olds (O'Hara et al, National Cancer Intelligence Network, 2013). Both disease biology and choice of protocol are likely to be important in explaining these differences. However, lower rates of inclusion into clinical trials with increasing age may also be a significant factor.
In the UK 3 national paediatric and adult ALL trials were open to recruitment between 1997-2006 (table 1). In 2006 the upper age eligibility criteria for UKALL2003 was increased from 18 to 24 yrs and the lower age limit of UKALL XII was correspondingly increased to reflect emerging evidence that TYA have improved outcomes when treated on paediatric protocols.

Aims
1. To examine trial accrual rates (AR) by age over a ten year period (1997-2006) to three UK national ALL trials.
2. To determine the influence of amending the age eligibility criteria for UKALL2003 on TYA accrual

Methods
ALL incidence figures for patients aged 1-39 yrs during the study period of 1997-2006 were obtained from a national cancer registry. Incidence data was classified according to the morphology-based coding specifically for TYA (Birch et al, BJC, 2002). Accrual rates (AR) were expressed as the ratio of patients entered onto trials during the same time period compared to incidence cases. Descriptive statistics were applied for an observational dataset where sample size or incidence cases cannot be controlled (Fern et al. BJC, 2008).
We obtained a further incidence data set for cases diagnosed in 2007 and 2008 to examine the impact of age eligibility amendments in 2006 and 2008 to UKALL2003.

Results
ALL was diagnosed in 4,579 patients aged 1-39 yrs between 1997-2006, 2,767 were under 10 yrs. The figure shows the proportion of newly diagnosed ALL patients entering trials 1997-2006. Red arrows show age eligibility criteria of the trials. 65% of all patients were enrolled onto one of the 3 trials. AR were highest for under 10's (71.5%), declining to 55.2% for 15-16 yr olds, 43.4% for 17-18 yr olds and 40% for those aged 21-24 yrs.
The amendments to age inclusion criteria for UKALL2003 and UKALL XII improved AR for 17-18 yr olds to a level equivalent to AR for 15-16 yr olds. AR for 19-20 yr olds also improved to 62.5%. However, recruitment of 21-24 year olds did not change. During 1997-2006 three quarters of 17-18 yr olds recruited to trials were enrolled onto UKALLXII. After protocol amendments, three quarters of 17-18 yrs were recruited to the paediatric trial.

Conclusions
We have shown a decline in trial accrual with increasing age for teenagers and young adults with ALL despite the availability of national trials spanning the age range being available during the time period studied.
Due to close cooperation between adult and paediatric trial management groups, major changes were made to age eligibility criteria for both paediatric and adult trials, following increasing evidence that TYA have better outcomes when treated on paediatric protocols. We have shown an increased accrual of older teenagers to ALL trials in the UK following these changes. No improvements were observed for 21-24 year olds. However, this age group were only eligible for UKALL 2003 during the last year of our analysis. This approach to trial eligibility design may serve as a model for future trials, both in ALL and other cancers.

Disclosures:
No relevant conflicts of interest to declare.