Developing a test to help treat leukaemia that has spread to the brain

In this project we hope to develop highly accurate tests for leukaemia that has spread to the brain. Ultimately, this work should produce better, gentler treatments with a personalised amount of chemotherapy, tailored to each child’s specific risk of leukaemia recurrence in the brain.

Acute lymphoblastic leukaemia is the commonest childhood cancer. Great treatment advances mean that more than 90% of children now survive, although many suffer significant side-effects from treatment. One particularly challenging area is how best to treat leukaemia that has spread to the brain (the central nervous system, CNS). Current tests for CNS leukaemia are crude, and do not predict CNS recurrence (which is often incurable), so all children receive large amounts of CNS-targeted chemotherapy to try and prevent this. This treatment is unpleasant and has serious side-effects in some children, including seizures and reduced IQ. Better predictive tests are urgently needed in order to identify children that can safely receive less intensive treatment and/or identify those at high risk of leukaemia recurrence in the CNS.

Our current tests for CNS leukaemia rely on detecting leukaemia cells free-floating in the fluid around the brain (cerebrospinal fluid, CSF) using a microscope. The problem with these tests is that the majority of leukaemic cells are stuck to the protective cell layers that surround the brain (the meninges), so the free floating cells are likely to represent only a very small proportion of the overall amount of leukaemia in the CNS.

New technologies can detect tiny amounts of genetic material released from cancers into body fluids (cell-free DNA) and measuring this cell-free DNA can indicate the presence of cancers before they become visible. In addition, it has been shown that levels of cell-free DNA rise prior to clinical relapse of tumours providing an early warning system for impending recurrence.

We will investigate whether we can use cell-free DNA, measured in CSF, to determine the level of CNS leukaemia and also to track how rapidly it responds to treatment. In addition, work in our laboratory has identified a number of small molecules (metabolites) in CSF that seem to indicate the presence of leukaemia, we now want to test how accurate these are on larger numbers of samples.

These new tests have a lot of theoretical advantages over existing tests and are likely to be much better at detecting submicroscopic amounts of leukaemia that accurately reflect the overall leukaemia disease burden. Knowing how much CNS disease is present, and how quickly it responds to therapy, should allow us to determine exactly how much treatment each child needs to completely eradicate all the leukaemia in their brain.