Upfront Treatment of Chronic Myeloid Leukemia CML

Transcript:Jorge Cortes, MD: So, that discussion then brings us to the point of when do you choose, then, a first generation TKI, imatinib or a second-generation TKI, we have two approved, dasatinib and nilotinib. Kevin, in which situations would you choose one versus the other? How do you go about this?

Kevin Kelly, MD, PhD: Well, I agree 100% with Harry. When I have newly diagnosed patients with chronic myeloid leukemia, I look to see what drug can prevent progressions to accelerated or blast phase disease. And certainly it’s been shown in two large randomized controlled trials that second-generation TKIs have fewer progressions to accelerated or blast phase disease compared to Gleevec. All three drugs are very effective, but there is a slight benefit to the second-generation drugs.

Certainly, the second-generation drugs are slightly better tolerated, as well, compared to Gleevec. If I sit down with the patient, we have a discussion, very much two-way street, and I assess the comorbidities of the patient. If they have a certain number of comorbidities, I may shy away from one TKI compared to the other. But all things being equal, I try to offer a second-generation tyrosine kinase in the upfront setting.

Now, if I was in a resource- poor setting, where maybe we’re looking at a year or two time when Gleevec is available as a generic form, we may be in a situation where we offer Gleevec as a frontline treatment and then switch to second-generation tyrosine kinase inhibitor if we’re not reaching predefined endpoints, so that could be another potential strategy. But, certainly, for the higher risk patients, the higher-risk Sokal score, there is definite evidence that those patients have a higher chance of getting into a major molecular response, into that safe haven phase at the one year time point compared to the first generation TKIs.

Jorge Cortes, MD: Okay. One of the advantages that we’ve seen in all these studies, in the randomized studies in particular, dasatinib versus imatinib and nilotinib versus imatinib is these deeper molecular responses and they are achieved faster. So, I mean, you look at these curves and the deeper responses, they separate very early. What does that mean? David, can you tell us, is there relevance to achieving these early responses? Maybe you get them to the same level, but later. Does it matter to get deeper and faster?

David Snyder, MD, FACP: Some people would argue that it doesn’t matter, because if you get to say MMR after nine months or if it takes 12 or 15 months, eventually you get there and that’s what’s important. But I would argue it on the other side and I would echo what Harry and Kevin have said, that to me, the prevention of progression to accelerated phase or blast crisis is the most important endpoint clinically.

I have a zero- tolerance approach in my practice, meaning I want to do whatever I can to minimize the risk of a patient progressing, and that means using a second-generation TKI up front because the risk of progression to accelerated phase or blast crisis is lower. It also allows you with the deeper, faster response, you more quickly reduce the substrate of remaining residual leukemic cells that are at risk potentially to evolve mutations which then can make it more complicated to treat the patient later. But, in terms of risk stratifying from the ENESTnd and the DASISION trial.

My understanding is that the events that occurred in terms of accelerated phase, blast crisis were in patients who were intermediate or at a high-risk on Sokal or by Hasford, respectively. So, certainly, for a patient who is intermediate or at high risk by Sokal diagnosis, there’s no question that I would be using a second-generation TKI. For a patient who is low risk, you might make more of an argument that imatinib could be appropriate, especially if you’re ready to make a change if you don’t reach the desired milestones.

Harry Erba, MD, PhD: I’d like to add something to that discussion though about these deeper responses. And I agree with everything you said about where we are right now, but for the future, the other potential for getting deeper responses is all this discussion about TKI discontinuation or treatment-free remissions. So, of course, we don’t recommend, in routine practice, to discontinue TKIs when a patient becomes negative on your sensitive quantitative PCR.

However, there are situations, especially in younger patients, where we might still consider it. And the specific situation I would bring up is young women who want to conceive. We’re all nodding our heads because we’ve seen this. It’s a very common question, so one potential benefit of a second-generation drug is that you get into quicker, deeper responses. In fact, with both dasatinib and nilotinib, the number is about 50% of patients will go into a complete molecular remission using the assays that are typically used now.

And, so that might be a situation where we might feel a little bit more comfortable monitoring a young woman very closely while she attempts to conceive and carry a child.

Jorge Cortes, MD: Yeah. Now, we’re talking about these deeper and faster responses. What is deep and what is fast? David, let me ask you because you brought up the point, and I think we all kind of agreed that deeper and faster is good but what is it?

David Snyder, MD, FACP: Right. Well, I think the depth of response that I would like to achieve is MMR, the 3-log reduction, because I think that’s been shown to be clinically relevant. The patients who achieve that level of response have very low, if not zero risk of progressing to accelerated phase and blast crisis. So that’s my initial goal. And how fast? With the second-generation TKIs, you can get there sometimes by six months, nine months typically, and, again, that shortens the window of time that patients are exposed to the risk of progression, and also more deeply, quickly reduces the remaining pool of leukemic cells that are left.

Javier Pinilla-Ibarz, MD, PhD: However, David, you don’t think that the assessment of early molecular response at three months is also is a nice marker to predict overall survival and progression-free survival as many trials have shown?

David Snyder, MD, FACP: For sure and reaching 10% or below by three months. But I think that most patients would probably reach that with imatinib or a second-generation, so I’m not sure that’s enough of a discriminator in this regard.

Transcript Edited for Clarity