ALL is, yes, a very big success story, particularly in children because now the survival rates have reached nine out of ten children diagnosed with the disease. But unfortunately, hence talking about adults, they don’t have the same success, it’s more like 50% survival in adults.
What can you tell us about the progress in beating acute lymphoblastic lymphoma?
Essentially you’re right, there have been no new drugs for the last forty years but what has changed is the doses, the combinations, the timings of the doses and looking at the features of the patient, their clinical features, their age, their white blood cell count, their levels of minimal residual disease and their genetics. To put them into groups that you will determine their response to the treatment, so you would have those who would be defined as good risk and those who would be defined as poor risk in terms of response. You tweak, then, the treatment accordingly.
In adult ALL poor risk groups are identified with what benefit?
Poor risk groups now, one being the Philadelphia chromosome positive acute lymphoblastic leukaemia, based on findings from chronic myeloid leukaemia that a drug, a tyrosine kinase inhibitor, the initial one named imatinib or Gleevac, was used with success to eradicate the Philadelphia chromosome population. It’s now being used in adults and children carrying the Philadelphia chromosome which in this disease is a very, very aggressive disease, in combination with their conventional therapy, after long-term follow-up what we’re seeing is a vastly improved prolonged long-term remission which is a success, or the beginnings of a success, for treatment of adult disease.
As a geneticist looking at the genome do you see any new targets?
Yes, we’re finding, we’re finding new targets. Partly because we have a lot of novel technology available now – next generation sequencing techniques are allowing us to find things that we just wouldn’t have known before. We’re looking at genetics as a broad picture, so a gene fits into a pathway so it has a whole pathway of genes and you look at the genes in the pathway instead of just individual genes and then we can learn about molecules which will target this pathway. So now there’s an increasing list of experimental data that shows responses to a larger number of translocations or chromosome rearrangements and these are being trialled or going into clinical trials. So the hope for the future is very promising.
Could you be hindered by the complexity of the genomic picture?
Of course, that’s always a problem. You might target one pathway but cancer in general is a very complex disease where it involves many pathways so you conquer one only to give rise to another one. In a way that’s why our job is not yet done; I think we’ll go on discovering new things, learning how these new things interact with the things we already know and build up an increasingly complex picture.
How can this affect things now?
I’m very heartened in that I’m a geneticist but we work very, very closely with clinicians now, more and more. We sit down together, we talk about the sort of things that we’re finding, we have drug chemists working alongside us and the clinicians. I think because of that things are happening a lot quicker, we can go from bench to bedside a lot quicker than we could years ago. We also have a lot of experience on which we can build because you can take data from another type of cancer and if you’ve got similar overlapping genes that are involved in ALL you can try that therapy because you know how the patient is going to respond, side effects etc.
Do you have any promising targets?
Yes, we have and similar to the tyrosine kinases on the ABL of the BCR-ABL of the Philadelphia chromosome. There are other ABL partners and also a gene called platelet derived growth factor beta which is a very important gene in chronic myeloproliferative disorders. These patients, chronic myeloproliferative patients, have been shown to respond really well to TKI and particularly imatinib. So we’re now finding these platelet derived growth factor beta rearrangements occur in ALL and we’re starting to use imatinib on those patients with success and we’ve now got a whole group of patients with a particular PDGFR beta translocation completely refractory to conventional chemotherapy, normally would die, they’re being treated with imatinib and they’re showing at least a short term response of about one or two years is the latest data. So we’re very excited.
And quite recently, even here at the European Haematology Association, we’ve been hearing about some molecular keys that have made big differences in progression free survival and overall survival in certain leukaemias and lymphomas.
Yes, that’s true and I think that in the next few years we’ll see similar things with the worrying population – adults with ALL.
What would be your message to doctors?
I think that there are new things being identified and they should be reassured that we’re trying our best because there are beautiful experimental models now we can use in culture dishes, putting cells into culture and treating them in culture, which really do mirror what happens in the patient. So we can get a very good indication and go rapidly from the laboratory into the clinic.
