EHA 2015

Measuring molecular responses to tyrosine kinase inhibitors in chronic myeloid leukaemia

Prof Susan Branford - Adelaide University Adelaide, Australia

You’ve been looking at decisions for discontinuation of a TKI among patients being treated for chronic myeloid leukaemia. What is this research all about, what you were trying to do?

Patients have been treated with tyrosine kinase inhibitors for many years now and patients who can achieve a very deep molecular response, and this is sustained for two years, can go on to a trial of discontinuation of their kinase inhibitor. Studies over the last few years have shown that about 50% of patients, when they stop after sustained deep molecular response 50% of them will have disease recurrence whereas the other 50% will maintain remission. These remissions now in some patients have lasted out to ten years.

I suppose part of this is the definition of deep molecular response because it can be deep or it could be deeper, couldn’t it?

The criteria that we use to determine the molecular response is essentially based on a log reduction from a standardised base line level that is set at 100%. So we’re measuring the abnormal gene in this disease, which is BCR-ABL, we’re measuring the BCR-ABL messenger RNA, we have an international reporting scale. So a level of 0.1% is termed a major molecular response, that’s approximately a 3 log reduction from the diagnosis level. We know that those patients who can achieve a major molecular response have a very good outcome, it’s very rare that patients, their disease will progress.

So when you’re in this low risk category, you can then discontinue. Is that the case?

Well when you reach this low risk category of 0.1% what happens is that the BCR-ABL levels continue to decline and they can decline another 1 to 2 logs. Studies over the last six or seven years have shown that those patients who reach these very, very low levels that we call deep molecular response, which is about 1 log lower than the major molecular response, and if that’s sustained for about two years then those patients can go on to a trial of discontinuation. About half of those who do stop will maintain remission and the longest person now is about ten years off therapy. But about half of them will relapse and their disease recurs and they have to go back onto drug.

Is this irrespective of which TKI you use, second generation or imatinib?

Imatinib is where the studies have been taken so far. So there are two major studies using imatinib, they were very successful so now there are other studies using more potent inhibitors, they’re nilotinib, dasatinib. So they are ongoing.

What does this mean to cancer doctors, then, for treating these patients?

I think it means a lot, both to their doctors and to the patients. The doctors would like to see their patients coming off therapy, particularly if they are having long-term side effects. It’s very difficult for young patients who face a lifetime prospect of being on a drug, a daily drug that they have to take. It really does impact their lifestyle.

Patients want to get off drugs, how many of them are you getting off drugs?

Not enough. We did a study a few years ago where we worked out on imatinib just how many patients will we get off therapy and successfully off therapy. After eight years of imatinib it was only about 12% of patients. So not very many. So now there are a lot of studies ongoing to see how can we get more patients to reach these very deep molecular responses, so more patients can come off therapy.

Do you have any ideas of how this might be achieved?

Yes, this can be achieved with switching, in some cases, to more potent inhibitors. Or it may be achieved by starting with more potent inhibitors. We do know that patients can reach these deeper responses faster and a study just published last year showed that those patients who switched from imatinib to a more potent inhibitor did have a higher rate of reaching these deep molecular responses. But the problem is that for patients who are already tolerating imatinib and they switch to nilotinib it may introduce some further side effects and there are also some other potentially quite toxic side effects with these more potent inhibitors. So I think, for a patient who is tolerating imatinib, a question is should they switch to nilotinib or dasatinib or should they just continue on imatinib. What are their chances of reaching a deep molecular response?

What are your interim comments, then, for the clinical ramifications and how doctors in the real world should be applying this?

Our study that we’re presenting at the EHA meeting is to show that there are some patients who are already at a level where if they continue on imatinib they have a very high probability of then reaching their deep molecular response levels and then qualifying, whereas others who may just be slightly higher, even with five years of follow-up they won’t reach those deep responses.

And busy cancer doctors do have a chance of distinguishing those patients and knowing which ones can have the prospect of getting off the drugs?

Absolutely. So we hope that this study will help clinicians to decide should my patient continue on imatinib, is there any hope or should we go to a more potent inhibitor?