8B. Improving therapy for childhood ALL by therapeutic drug monitoring

The intensity of asparaginase therapy plays an important role in the improved outcome of  acute lymphoblastic leukemia (ALL). We performed real-time therapeutic drug monitoring (TDM) of asparaginase in the DCOG ALL11 protocol and found a non-significant trend towards lower asparaginase activity levels in induction and higher relapse rate. Due to the limited number of relapses and limited number of patients included  in the DCOG ALL11 protocol it was not possible to correct for possible confounders such as age, cytogenetic subgroups, immunophenotype, and major treatment modifications. There was also a trend towards higher minimal residual disease at end of induction in patients with lower asparaginase activity levels. No association was found between the asparaginase activity levels and relapse risk in other treatment phases.
Higher asparaginase activity levels might be associated with increased toxicity. This needs to be taken into account when defining a safe target level for individualised treatment. Besides the association between asparaginase activity level and outcome, the association between asparaginase activity levels and pancreatitis, deep venous thrombosis, (fungal) infections and hepatotoxicity will be studied.

You will be able to conduct this study in patients treated according to ALLTogether1, a treatment protocol for newly diagnosed children and young adults with ALL. Patients from ALL study groups in the UK, The Nordic countries, Germany, Belgium, Portugal, France, Ireland  and the Netherlands will participate. These study groups will include over 1400 ALL patients per year. Therapeutic drug monitoring is implemented as standard of care. Prior to start therapeutic drug monitoring with individualized dosing we need to study the association between activity levels using a fixed dose asparaginase and outcome (relapse, MRD and survival) in a larger cohort and define a safe and efficacious target level. Results of this study will be implemented in the TDM program of the next ALLTogether protocol.