Acute lymphoblastic leukaemia (ALL) is the most common form of childhood cancer. It accounts for 80% of all childhood leukaemias, affecting up to 400 children a year in the UK. Children under the age of five years are at greatest risk, with half of all cases occurring in this age group.
As recently as the early 1960s, childhood leukaemia was considered incurable. By the late 1970s, more than 50% of those diagnosed with ALL were surviving for at least five years. And survival has continued to increase decade by decade ever since, to the point that the survival rate is now above 90%.
Surprisingly, no new drugs have been introduced for four decades, with the increased survival having been brought about by intensifying combinations of existing drugs. Whilst effective in curing the disease, these intensive treatments are toxic and expose young patients to a range of side-effects, some of which can be life-threatening. And of course, there is still a core of children, some 30-40 children a year in the UK, who still lose their lives to ALL.
A major focus of current research is on tailoring treatments to more precisely meet the needs of individual children. The last national clinical trial, UKALL 2003, introduced MRD testing as a way of stratifying children into different treatment categories. MRD stands for minimal residual disease, which is the amount of disease remaining in a child’s bone marrow after the first stage of treatment. The trial confirmed that children with low levels of MRD are at lower risk of relapse and can safely be given less intensive treatment, without increasing their risk of relapse. It also confirmed that children with high MRD benefit from receiving more intensive therapy, helping them to avoid relapse. MRD testing is now routinely used as part of the treatment for ALL to enable doctors to tailor children’s therapy.
Whilst MRD has been shown to be a sensitive and reliable marker of treatment response, it provides no mechanistic explanation. Differences in drug metabolism between different patients may explain differences in treatment response and the current approach to treatment does not take this into account. This means that therapy may be sub-optimal in some children, resulting in disease recurrence whilst, in others, reduced drug clearance may lead to excess toxicity.