Precision diagnosis for tailored therapy in acute lymphoblastic leukaemia

Dr Jean-Pierre Bourquin - University Children’s Hospital, Zurich, Switzerland

The scope of the presentation was to discuss new possibilities to improve the information we have for patients with very resistant disease, acute lymphoblastic leukaemia, by adding new functional assays to evaluate the response of cells from patients to all sorts of different drugs. So I’ve shown that it is possible to obtain responses for a large collection of agents in a time frame that’s suitable for clinical application at the same time one takes the decision for these patients in this particular clinical situation. So within about one week one can get very solid information how the leukaemia cells look in terms of their profiles of sensitivity but also of resistance to a selection of drugs that are to be considered then for application in that particular clinical situation.

I have shown several examples, in particular for this subtype of leukaemia, T acute lymphoblastic leukaemia, so T-cell, derived from T-cells. These patients at relapse in paediatrics but also adults have a very poor outcome with our more conventional approaches, including very intensive treatments such as bone marrow transplantation, stem cell transplantation. So I’ve shown several examples of how we could classify possible targets by combining information from genomic assays, so the profiling of the mutation the patients have, and functional assays.

Could you tell us more about these assays?

The principle is to maintain the cells that have been collected at particular time points during the treatment in a system that maintains them alive and dividing for a sufficient time to really test properly the activity of drugs. In our approach we have chosen to grow the cells on a layer of support cells from the bone marrow stroma. This is an established line that can be reproducibly used. Then this allows us to put the cells in a plate for high throughput readouts. The cells can then be exposed to this collection of drugs and the readout for what is happening is done by automated microscopy which allows us to follow at the single cell level what is happening over a longer period of time to the cell, looking at the viability but also with the possibility to look at other markers of response.

Are these assays currently being used in the clinic?

These assays are now entering, really, the clinic. There are different groups including this along clinical treatment protocols. There is a first study that has been reported from the group in Vienna for adult hematologic malignancies demonstrating that by choosing a salvage approach with this type of functional assay it is possible to get much more efficient responses than with a conventional decision tree.

We have already, in the last two years now, used our platform to assist physicians that are making decisions for patients with refractory disease in paediatric leukaemia and have several examples with promising responses.

Is there anything you would like to add?

I think it is that we are only at the beginning of this type of approach, we are going to meet a number of challenges. The one thing is the more precisely we look at subsets in this leukaemia population the more complex it gets and the smaller these groups become so it is impossible to think along the traditional lines that we had so far – how to build a clinical trial, how to get the clinical evidence that the approach is working, that’s one thing. The other is that we need to take into consideration a number of different agents at the same time for a framework of a clinical trial or a clinical registry which in the regulatory framework nowadays is a huge challenge as well. So there we will have to come up with innovative, more permissive, solutions and that’s also a plea to everybody to contribute to this.