CML: Frontline BCR-ABL TKI Therapy


Harry P. Erba, MD: So, let’s move on now and start talking about initial therapy. We’ve made the diagnosis, and we are going to think about an ABL tyrosine kinase inhibitor. And, of course, now we have, for initial therapy, 4 different ones—based on the IRIS trial, imatinib; based on the ENESTnd, nilotinib; based on the DASISION trial, dasatinib; and based on the recent BFORE trial, we had in December 2017 the approval of bosutinib—all for previously untreated patients. So, we have 4 drugs to choose from, and the question that comes up in our daily practice, and we get from referring doctors, is, how do you choose among these 4 drugs?

Let me start the conversation, and then I want to hear from both of you. One first thing to be very careful about is what type of CML you’re talking about. Most patients, 85% of CML patients, will present in chronic phase. So, we’ll get to that discussion. But let’s not forget about the patients who present in advance phases, like accelerated or even blast crisis. There my feeling is that the second-generation drugs are, I believe, superior to imatinib. That is my personal belief. I’d love to hear what you say.

In terms of labeled indications, we know that dasatinib is approved in that setting, bosutinib as well. For nilotinib, it’s in accelerated phase but not in blast crisis, although all 3 have been shown to be active in advanced phases. And the doses of those drugs are often higher to overcome resistance. And if you’re talking about myeloid or especially lymphoid blast crisis, combining those drugs with chemotherapy may be a benefit for patients. And clearly, those are patients whom I would consider for allogeneic transplant once I get them into a response.

But the more common situation is the chronic phase, and I think there are a number of factors that go into picking which drug we are going to start with. One that I use is the so-called risk score. I also will consider patient concerns, things that a patient might be interested in. For example, a young woman who wishes to conceive may want to be on a drug that gets them to a point where they can hold these drugs earlier in their life before the biologic clock stops ticking. So, that could be an important consideration. They all had different side effect profiles and different risks. And so, basing a choice on what risk factors a patient has—for example, for cardiovascular disease or pulmonary hypertension, and pleural disease—these are all important features to mention. So, anything else that you would add?

Jorge E. Cortes, MD: Yes, I’d like to make a couple of comments, Harry. One of them is you mentioned the Sokal index, and it’s one that frequently is advocated as a potential way to decide whether you go with a second-generation drug or with imatinib. And certainly, the patients who have high-risk Sokal or Hasford—because like on the dasatinib study, it was used with Hasford, but they were similar kind of outcomes—the patients treated with imatinib had the worse outcome, the higher the risk score. And that’s why frequently with Sokal or Hasford, high-risk is suggested as one group where you want to use second-generation TKIs.

However, when you look at the data, for example, the probability of achieving a major molecular response, which is what has been reported, improves proportionally, equally, in all Sokal groups. So, although others with a high-risk group have the greatest need, I don’t see why I would deny a lower-risk patient the potential to have a better chance of having a better response. So, although it is a factor, and I think it is important to remember that, it shouldn’t be taken as an absolute thing. It’s a complex interaction of many factors from patient characteristics, comorbidities, disease characteristics, etc.

And that leads me to the other point that I wanted to make, which is the issue of the endpoints. And I think that our endpoints have evolved as the monitoring and the treatment have gotten better. We’re not looking for survival endpoints only, and that’s where some people ask, “Well, you know, you don’t get any better survival with the second generations. Why do you want to use a second-generation drug?” Well, I think if survival is your endpoint, you’re right. But I think we’ve moved beyond the survival benefit. Once you have good survival, is there any other benefits of that? Then you mentioned the deeper responses, the higher probability of getting to meet the criteria for the treatment discontinuation, all these things.

So, I think in the end, what we need to do is to have an honest conversation with the patient and see what the goals for each patient are. Explain them to them because sometimes they are not as familiar with the things that you can achieve and what the meaning of those things are, etc, and see where the goals may be. The goals for a young woman who wants to become pregnant, as you mentioned, may be very different from an older gentleman who wants to just have minimum side effects, for example, or something like that. So, I think it is very important to realize what the goals are and that there are other endpoints that are of clear value to the patients and that we should focus on that if that’s something the patient wants.

Harry P. Erba, MD: I really appreciate you flushing that out. Because what I listed were all these factors, but you’re exactly right. This is a complex interplay of all these features. So, for example, Sokal risk isn’t the only one. Why deny a patient the chance of getting into a deeper remission to get to a treatment-free remission at some point just because they have so-called low risk score? On the other hand, you have a patient who’s 60 years old with a positive family history of myocardial infarction at the age of 40, hypertension, poorly controlled diabetes, and low-risk Sokal score. That might be a patient where you say, “Hey, I’m going to start with imatinib.” Just as an example, I’m saying. So, there’s a complex interplay of all of these, and you have to sit down with the patient. But I agree with what you said, the data for TFR now informs; it’s part of the initial discussion that we’re going to have with patients.

Jorge E. Cortes, MD: Careful with 60-year-old…

Harry P. Erba, MD: I understand, that’s why I picked it.

Michael Mauro, MD: That was going to be my comment. We don’t want to look at age as sort of a deciding factor, but I agree. I mean, 15 years ago, people were happy to have that effective therapy that would save their life, would protect them against transformation, give survival. Now patients may quickly say, “How long do I have to be on this treatment?” which then begets the discussion about the benefits of second-generation inhibitors, the rapidity of response, the depth of response, getting to TFR. There’s nothing that replaces an informed discussion, not only about the benefits and the goals, which I completely agree with, but the toxicities and the journey and the fact that there are multiple TKIs; they have an opportunity to switch and to modify the dose even.

But it’s really about the navigation. There’s something for everybody. There are patients for whom imatinib is still appropriate. There is probably a good majority of patients in whom the second-generation inhibitors may really be the best path. And it’s good to have all these options. And just to close the loop on the age-related fact, the older you live, the older you live. You don’t want to have a patient who is of higher age who wouldn’t benefit tremendously from a newer drug, too.

Harry P. Erba, MD: Yes, I definitely agree with that. And an older patient may run into comorbidities later on in life that may make it difficult to stay on these drugs, so getting them to a treatment-free remission. We all have our personal experience with patients who have financial issues as time goes on and start asking the question, “Hey, when can I come off these drugs?” So, you’re exactly right there.

Transcript Edited for Clarity

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