2010 American Society of Hematology Annual Meeting 3rd - 7th December

Interview with Dr Neil Shah - University of California, San Francisco, USA

The DASISION chronic myeloid leukaemia trial

IV         Interviewer

NS        Neil Shah

IV        More now from ecancer TV here at the American Society of Hematology Annual Meeting.  Neil Shah has joined me from the UCSS.  Neil, you’ve been a TKI and CML person for quite some time now, you’ve been a real leader here and you’ve got this very interesting study that’s called the DASISION Trial, Dasatinib being the first three letters of that.  Could you tell me what you did in this study?

NS        So, this study was designed to see whether it was possible to do what was probably ten years ago almost unthinkable, and that was to improve upon the success of imatinib in chronic phase CML patients.  Now, we know imatinib revolutionised the way we think about CML and how we management and in the way we think about a number of different cancers.  But nonetheless we know that there are a proportion of patients who don’t respond adequately initially to imatinib or who cannot tolerate imatinib, who are initially – who initially do respond well but then subsequently lose that response.  And so dasatinib was of course developed primarily initially for patients who had loss of response to imatinib or were intolerant to imatinib.  And it was subsequently tested in this study in a head to head fashion to try to see whether it could in fact improve upon the response rates relative to imatinib.

IV         So, you gave either dasatinib or imatinib to your patients?

NS        Correct.

IV         What did you do and what did you find?

NS        So, patients were randomised, newly diagnosed patients that had never before been treated with any Tyrosine Kinase Inhibitor with chronic phase CML were randomised to receive either imatinib or dasatinib.  And the study was basically designed to see what these response rates were specifically, something we call a confirmed complete cytogenetic response rate.  And also to look at other things such as major molecular response rate as well as obviously the safety, the tolerability of the drugs.  And essentially what we found was that dasatinib was superior to imatinib in achieving deep responses at the 12 month time point.  So, more patients had a statistically significant superior complete cytogenetic – confirmed cytogenetic response on dasatinib relative to imatinib as well as a higher proportion had major molecular response.  And the drugs seemed to be on the whole really quite well tolerated.  In fact looking at the side effect profiles was maybe even a little bit better tolerated than imatinib.

IV         And could you run the numbers through me briefly, how many patients were there and what were the ballpark figures for the cytogenetic response and the molecular responses which of course are very interesting?

NS        Sure, so there were close to 258 patients on each arm either receiving dasatinib or imatinib.  And after a 12 months time point the – at the 12 month time point the confirmed complete cytogenetic response rate for dasatinib we previously published was 77% versus 66% with Imatinib.  And now with longer follow up, now we’re presenting 18 month follow up, we’ve seen it remains statistically in favour of dasatinib; it’s now 78% versus 70%.  And the major molecular response rate that’s been observed is 57% with dasatinib as opposed to 41% with imatinib.  So, essentially there’s a 30% higher likelihood of patients having achieved a very deep molecular remission if they were randomised to receive dasatinib with approximately close to 18 months of follow up now.

IV         What might be the implications of getting that molecular response?

NS        So, our data with imatinib is strongly suggesting that the deeper the remission in general the better patients will do.  And as we get longer follow up in patients treated with imatinib, it’s becoming rather clear that patients who have this major molecular response are those that are having the best outcomes, you know, relative even to those patients who have complete cytogenetic responses but don’t have that 3 log reduction which would qualify them as a major molecular responder.  So, we of course will need a longer follow up to see if the prediction holds true in that patients will do better over time, over a period of a few years on dasatinib relative to imatinib, that has not yet been proven.  But certainly the initial response rates are encouraging and give us hope that that will in fact be the case.

IV         So, what are the clinical implications of using this second generation TKI, where might dasatinib stand in the mixture of things?

NS        Right, so it is a second generation drug as you mentioned, meaning that it was… it wasn’t… it came after the initial development of imatinib.  But it’s now been approved based upon this study and based upon the 12 month data that was previously presented for the treatment of newly diagnosed chronic phase patients.  And so this drug along with nilotinib, which is similarly – had such approval.  Based on quite a similar study that was performed with that agent, now physicians and patients actually have three different options for the treatment of newly diagnosed chronic phase CML.  And what’s encouraging to me is that both of these second generation drugs have looked superior to imatinib and the clinical hope is of course that patients will not only have a higher likelihood of responding deeply, but that their responses will be maintained over a longer period of time.

IV         Do you foresee the possibility of chronic myeloid leukaemia becoming a chronic disease, a truly chronic disease that is treated like diabetes?

NS        I certainly see that possibility, yes, because we know the primary reasons whereby which patients may lose response to these drugs.  And we know there are specific mutations that confer resistance to all of the approved Tyrosine Kinase Inhibitors.  What’s very encouraging about the newer ones is that they are quite invulnerable to Kinase Domain Mutation; they’re each clinically vulnerable to about five or six as opposed to imatinib where we know there are close to 100 different mutations that can cause clinical resistance.  So, our hope is that we’ll see less resistance.  And the even better news is that there’s now a third generation drug, ponatinib, which looks like it’s active against – in particular one mutation which had been cross resistant to all three drugs previously which is known as the T315i mutation.  And this drug is looking quite effective in early clinical trial analysis; it also looks to be reasonably well tolerated and is going into a phase two study around the world as we speak.

IV         Based on your experience so far, would you go for imatinib first, then a second generation drug, or would you go from the start with the second generation TKI?

NS        So, my personal preference would be to start with the second generation TKI.  I do believe that the science is quite compelling as far as the likelihood of achieving a deeper response early.  And most of what we know from studying CML with imatinib as well as what we would probably intuit, would tell us that it’s better to get to a deep response faster with any type of cancer.  And again knowing that there are fewer resistance conferring mechanisms for these new drugs, the hope would be that again as long as they’re equivalently tolerable to imatinib, which they certainly seem to be, the hope would be that the responses would be more durable and people would be in general – that people would be more likely to do well over time.  So, my personal preference is for a second generation drug.  Having said that, you know, all three agents are approved at this moment of time and nobody would fault anybody for starting with imatinib at the present time either.

IV         CML is indeed still an exciting area of medicine to be dealing with, what finally messages would you pass on to doctors of advice about how to treat their patients?

NS        Well, I think one of the most important things is that it’s an area under constant flux, there’s a tremendous amount of information that we know about it.  And of course those of us who focus on the disease are able to participate in meetings such as the American Society of Haematology and keep up on the latest.  But of course your average community practitioner, who’s perhaps not only seeing haematology patients, but also lung cancer patients, is going to be seeing a relatively small proportion of these patients relative to breast cancer and colon cancer and everything else that’s out there.  So, but nonetheless we have the capacity with proper management of patients in most cases to achieve deep and durable responses.  And it’s of course a shame if we ever lose that opportunity simply because, you know, a physician hasn’t been able to keep up with the latest news.  And so that would be my encouragement to physicians, to reach out to those of us in academic centres who focus on this disease if they have any questions regarding patients and their response, and making sure that they’re meeting certain treatment milestones, making sure the side effects and compliance or adherence, if you will, are well taken care of.

IV         And thanks to you Neil we’re able to keep up to date here on ecancer TV.  Thanks for taking part.

NS        Thank you very much.