UNITED KINGDOM CHILDHOOD ACUTE LYMPHOBLASTIC LEUKAEMIA RANDOMISED TRIAL 2003 (MRC UKALL 2003)

Acute Lymphoblastic Leukaemia is the single most common cause of cancer in children. Clinical trials conducted by a network of childhood cancer specialists supported by the Medical Research Council have contributed to the current relatively good cure rate for this leukaemia. However, initial treatment fails in around 25% of patients and they require very toxic and expensive further therapy which is not effective for many children. Also, some of those who are cured develop physical, mental and social problems in adult life due to the toxicity of their leukaemia therapy. This trial seeks to make two improvements in the treatment of children with ALL. First, to increase the success of initial treatment so that the disease recurs (comes back) in fewer patients. Second, reduce the treatment for patients who have a low risk of recurrence so that they have less immediate and late treatment-related problems. Both these aims could be fulfilled by tailoring treatment to the risk of recurrence using a new test called Minimal Residual Disease (MRD) which allows a very accurate prediction of this risk. Using genetic technology for measuring Minimal Residual Disease, we can detect and quantify 1 leukaemic cell mixed in with 10,000 normal cells. The level of leukaemia detected by this technique after 28 days of treatment accurately separates those patients with a greater than 90% chance of cure (good risk) from those with a less than 75% chance (high risk). This trial will ask the following two questions: (1) Can patients defined as good risk by the MRD test achieve the same cure rate as at present but with less treatment so that they have fewer immediate and late side-effects of therapy? (2)Can the chance of cure for patients defined as high risk by the MRD test be improved by giving them more treatment? In addition to looking at the chances of survival and leukaemia recurrence, we will also assess the impact of these treatment changes on patient and family quality of life and health service economics.

On-treatment monitoring and detection of sub-microscopic levels of leukaemia (Minimal Residual Disease or MRD assessment) is the best predictor of relapse risk in children with Acute Lymphoblastic leukaemia (ALL). The primary aim of this randomised trial will be to optimise treatment of childhood ALL and minimise its toxicity by using Minimal Residual Disease (MRD) assessment for stratification of treatment according to relapse risk. The treatment randomisations will test two hypotheses. First, that post-remission therapy can be reduced (along with its acute and long-term side-effects) for a sub-group of patients with rapid clearance of MRD during induction therapy without compromising their current excellent cure rate. Second, that patients with slow clearance of MRD will benefit from further intensification of post-remission therapy. Over its 6 year life span, the trial will accrue over 90% of newly diagnosed children with ALL in the UK and Ireland (approximately 350/annum). Minimal Residual Disease will be assessed at day 28 of treatment by a centrally co-ordinated network of 5 laboratories in the UK working to a standardised Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR) method for detection of clonal antigen receptor gene rearrangements. Stratification and randomised allocation of treatment based on the day 28 MRD result will be done centrally by the Oxford Clinical Trial Service Unit. Primary end-points of the trial will be event-free and overall survival by randomised treatment. Secondary end-points will include health economic and quality of life assessments.

Additional studies will address questions relating to asparaginase and thiopurine therapy, and biological, pharmacogenetic and pharmacokinetic determinants of treatment response.