Paediatric ALL with brain metastases

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Published: 5 Oct 2016
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Dr Christina Halsey - University of Glasgow, Glasgow, UK

Dr Halsey speaks with ecancertv at Childhood Cancer 2016 about her research, made possible with a grant from Children with Cancer UK.

She outlines the balancing of risk between relapse and treatment toxicity in paediatric acute lymphoblastic leukaemia (ALL) patients whose diseases has spread to the brain and nervous system.

Dr Halsey hopes that early identification of patients who may be most susceptible to neurotoxicity, based on biomarkers in their cerebrospinal fluid, might be an actionable target for adjuvant therapy and ensure a better quality of life for children through their later life.

 

Childhood Cancer 2016

Paediatric ALL with brain metastases

Dr Christina Halsey - University of Glasgow, Glasgow, UK


My research group in general is interested in one of the, what I consider to be, the remaining challenges in childhood acute lymphoblastic leukaemia which is really how best to manage and treat leukaemia that has spread to the central nervous system, so that’s the brain. We know that although leukaemia originates in the bone marrow, if you don’t actually give treatment directed towards leukemic cells that might have spread from the bone marrow to other sites in the body and particularly to the brain that somewhere between 50-75% of children will have what’s called a relapse or recurrence of their leukaemia within the brain itself. For that reason all children currently receive quite a lot of chemotherapy that’s actually specifically directed to the brain. Although that’s quite effective, the rates of relapse in the brain are relatively, thankfully, low, we know that that therapy is associated with really quite a lot of toxicity and we at the moment don’t really understand very much about CNS leukaemia, the types of treatments that we might need for it and how to limit that toxicity. So our research group works basically on all those aspects of therapy against CNS leukaemia.

What is the grant allowing you to do?

The grant is really exciting, I think. What we’re trying to do is identify children who are at risk of what we call toxicity from the therapy, so neurotoxicity. We know that probably somewhere between 20-50% of children can be susceptible to having some adverse effects of this treatment on things like their ability to concentrate at school, verbal reasoning, processing speed etc., but at the moment we really can’t pick those children out at all so it doesn’t seem to be particularly related to the dose of chemotherapy you get or any other factors that we know about. So some children sail through therapy, we have plenty of children who are cured of leukaemia in childhood who are now doctors and lawyers and university professors and do fantastically but then there’s a smaller group of children that really seem to have some adverse effects of their chemotherapy. So this grant is really trying to see if we can identify ways of picking out these children who are having these adverse effects really early on, at a time when we might be able to prevent them or produce new treatments to try and make those things better and also whether we then might be able to pick out children who require different types of treatment that might not have so many adverse effects on their learning and memory.

What needs to happen before we can see the benefits of these findings in the clinic?

The first thing we want to do is really say can we pick out these children that are going to have the problem or that have the problem really early before it actually causes them a problem. The second thing we have to do is to do something about that. Now this particular grant is not going to give us an instant fix to that but it’s really trying to tie in not just can we pick these children out but can we see why they’re having the problems. So we’re actually taking samples of what’s called the cerebrospinal fluid, which is the fluid around the brain, that that’s actually routinely sampled when these children get their treatment. So the CNS directed therapy is actually giving lumbar punctures, which is spinal taps, and injecting the chemotherapy directly into that fluid. When we have that needle in we always take a sample of the fluid as well, just to look at under the microscope, and we’re taking the left over sample of this and then we’re looking within that to see if we can find out what might be causing this problem with the toxicity in the brain. So we’re looking for markers of damage to cells in the brain but also specific what we call metabolites which are the breakdown products related to the chemotherapy we’re giving. We have really good evidence from what we call preclinical models, so not in patients but in experimental models in the lab, that there might be particular metabolites, these proteins that we find in this fluid, that actually will act on a receptor that might cause this toxicity. The really exciting thing about that is we actually have antidotes to these molecules and one of the antidotes that seems to work in these preclinical models, so it has not been tested in children yet, is actually a common component of cough mixture so it’s a medicine that’s routinely given to children that appears to be safe and that will, in theory, neutralise the adverse effects of the chemotherapy without actually affecting how good it is at fighting the leukaemia. So the breakdown product that causes the toxicity is quite separate from the way that the medicine actually kills the leukemic cells.

So we obviously are super-excited about the idea that that might actually be something that in the future we might be able to give these children a dose of cough mixture before we give them their chemo and that might allow the chemo to work but not have the toxicity. But that’s a long way off, we have to test that in proper trials so I’m not saying this is something that’s just round the corner but this study and this funding enables us to really test whether what we’ve found in the lab is actually true in patients as well which is a really vital step before thinking about new therapies.