ASCO 2015

Outcomes of dasatinib for Philadelphia chromosome-positive acute lymphoblastic leukaemia

Dr William Slayton - University of Florida, Florida, USA

You’re looking at a very special group of kids who have acute lymphoblastic leukaemia. Could you tell me what was the challenge that you were taking on with this study that you’re now reporting?

At this point we’re able to cure about 90% of children with acute lymphoblastic leukaemia. So there’s a lot of focus on that 10% of children who actually relapse. One subgroup of very high risk patients is children with the Philadelphia chromosome. The Philadelphia chromosome is a translocation that brings BCR and ABL together, these are two proteins that when they come together dysregulate ABL and cause the cells to become malignant.

And that’s the same molecular feature as in chronic myeloid leukaemia.

Very true. It’s the same and they’ve developed these drugs now that bind to that abnormal protein and block its activity. These targeted therapies have proven to be very effective.

So basically imatinib is an option here, isn’t it? But also you’ve got chemotherapy and the possibility of stem cell transplant. How did those feature in your study?

Chemotherapy has been the way patients have historically been treated with leukaemia. It turns out if you use chemotherapy alone in this group of patients about 30% of them will be cured, so it’s a very low cure rate with chemo alone relative to 90% with most children with ALL. A stem cell transplant can provide a cure in about 60% of the patients but you know that cure is bought with some risks of dying from the toxicity of the transplant and things like graft versus host disease and long term side effects.

Enter imatinib which, of course, did well but now you’re looking at dasatinib?

Yes. The imatinib story is important to know that giving patients imatinib plus intensive chemo has provided a cure for about 70% of the patients without a stem cell transplant. So that was a major home run because you’re curing these patients without having the long-term side effects of the transplant.

Now you’re taking that one stage further and you’re trying a different TKI, dasatinib. What did you do?

Dasatinib, yes, it’s a drug that has some potential, it may be potentially better than imatinib. At least in chronic myelogenous leukaemia it gets patients into remission more quickly. It’s more effective in tissue culture, it penetrates into the central nervous system better. It also works for imatinib resistant leukemic clones so we thought it might be a better drug for children with ALL.

So what did you do in the study and what did you find?

Essentially we took dasatinib and we paired it with the same intensive chemotherapy backbone that the Children’s Oncology Group used with imatinib. We really were interested in whether it was feasible to use this combination so we were looking at the side effect profile and then we’re now looking at the long-term outcome in these patients.

What did you find?

So we found that it was very feasible to use the dasatinib with intensive chemotherapy. We did have to modify the backbone a little bit in order to make it tolerable. We took a dose of high dose methotrexate out of one of the blocks and we also altered… we took one dose of chemotherapy that was given into the central nervous system. Once we did those two little tweaks to the backbone the therapy was very well tolerated. We had no toxic deaths on the study and everybody is now in the follow-up phase of their treatment.

What about the choice of whether to go with imatinib or to switch to dasatinib; mutations come into this, don’t they?

Yes, I think the biggest thing right now is that we don’t know yet what the long-term outcomes of using dasatinib with this chemo backbone are. In the very short term, at three years, they look pretty similar in terms of the outcomes but as we’re following these patients a little longer we’re still seeing patients relapsing on the dasatinib trial and those data are not mature yet. So really, at this point, imatinib is still the gold standard in childhood ALL combined with this chemotherapy backbone with longer follow-up. And also there is a nice follow-up study that will provide additional data to help us decide whether to use dasatinib or imatinib as the preferential tyrosine kinase inhibitor.

Now you’ve got a fairly small group, 60 patients or thereabouts, what can you now definitely say to doctors first of all about dasatinib – looking reasonably good but needs a bit more evidence?

Yes, I think what we can say is that it’s safe to give it along with the chemotherapy backbone. We also have kind of confirmed that you can cure patients without transplant. The prior study showed that but I think some people were still doubting that. Our study was in line with what they saw in the prior study where patients are faring well without transplant.

So what’s the bottom line message to take home from ASCO from your presentation here, then, for doctors?

Sure. I think this drug is a very promising drug for patients with Philadelphia chromosome positive disease in general. I think there’s a possibility that it’s a drug that we will move to in the future but for now people should be cautious about using it outside of a clinical trial setting in children with Ph positive ALL.