Case Study: Selecting a Tyrosine Kinase Inhibitor in CML

Transcript:Jorge Cortes, MD: Let me go through a case, and put this discussion into practice, just to get your opinion on how you would manage this patient. So let’s say we have a 52-year-old gentleman: he has just a little fatigue, a little weight loss, and some night sweats, and is checked by his primary care physician. He is found to have a high white cell count, let’s say around 200,000. The patient is anemic; may have a hemoglobin of around 7, 7.5; platelets elevated to 720. The differential has 14% basophiles, 9% blasts. You examine the patient; he has splenomegaly. You do the bone marrow biopsy and you confirm that the patient has the Philadelphia chromosome, but no other chromosomal abnormalities. Let me propose that the patient has some comorbidities—hypertension, hyperlipidemia, history of coronary artery disease. I’m sure you’ve done the math very quickly in your mind, but if not, the patient has a high-risk Sokal score of 2.82 and no other abnormalities in the liver, kidney, or anything else. EKG shows nothing special, QTc 420, let’s say. So, Kevin, how would you approach this gentleman with newly diagnosed CML, chronic phase, high-risk Sokal score, and some comorbidities? What would you do?

Kevin Kelly, MD, PhD: Well, there are a few thoughts going through my head. This is definitely a patient with high-risk disease. We would like to give him the best outcomes to prevent progression to accelerated or blast phase disease. So, in that sense, we would like to consider a second-generation tyrosine kinase inhibitor (TKI). I am a little bit concerned about the coronary artery disease and the risk of cardiovascular events in this patient, so I would want to make sure that all those cardiovascular risk factors are optimized before starting a patient on a second-generation TKIs, which have slightly more cardiovascular risks than imatinib. So, if we could feel comfortable that those risk factors are optimized, then we could consider a second-generation TKI for this patient. But certainly there will be a sit down with the patient and the family, and discussing the pros and cons of different approaches. I think from the QTc point of view and electrolytes, we’re good there; so that’s important to make sure that they are optimized before starting a patient on a second-generation TKI, in particular.

Jorge Cortes, MD: So let me put you in the spotlight. What prescription are you going to write?

Kevin Kelly, MD, PhD: I would be between nilotinib and dasatinib.

Javier Pinilla-Ibarz, MD, PhD: But he’s putting you in the spotlight.

Kevin Kelly, MD, PhD: One or the other? I think the data for second-generation TKIs, from the ENESTnd study, is very convincing in terms of prevention of progression to accelerated or blast phase disease, so I would go with nilotinib.

Jorge Cortes, MD: You will go with nilotinib. Javier, what do you do?

Javier Pinilla-Ibarz, MD, PhD: I will go with dasatinib, but the only reason I will in this case is because a 52-year-old may have a more active life, may be working. And in this point of view, I definitely consider and I do exactly the same thing that Kevin do. I really go through, back and forth, on all the side effects. But people at this age, I find, may have better adherence but like the more convenient way to do it. I fully agree that we’re really concerned about the cardiovascular events. And in this case it was not a reason not to go to nilotinib, which I think is fine. I am not really scared away from the cardiovascular events. But in this kind of patient who is of younger age, I may try to [determine what they really prefer.]

Jorge Cortes, MD: So considering the risk features for arterial thrombotic events, anybody, David or Harry, would go with imatinib? I’m not asking whether anybody thinks imatinib is inappropriate. But just, would anybody say, ‘That’s my first choice’?

David Snyder, MD, FACP: No. Based on the Sokal high risk, I would go through the difficult risk-benefit ratios of the various second-generation options. I tend to lean towards nilotinib, but I would want to be sure that the cardiovascular risks are well controlled. But I would not use imatinib.

Harry Erba, MD, PhD: I completely agree with what people have said about the cardiovascular risk factors—hypertension, hyperlipidemia, and coronary artery disease. In the DASISION trial and in ENESTnd trial, they excluded patients with some cardiac comorbidities, but these were very well defined: unstable angina, a recent myocardial infarction, QT prolongation, and bundle branch blocks where you can’t measure the QT—very specific. They didn’t exclude patients who had these risk factors. Now, it’s true that in both of those studies—it was amazing to me how similar they were—the risk of cardiovascular events, arterial occlusive events, was about 2% with imatinib and was about 5% at five years with both nilotinib and dasatinib in two separate well-done studies. It wasn’t zero with any of the drugs, including imatinib. And so I always think about the patient in front of me. Yes, I might have a slightly higher risk of cardiovascular events, but when you look at those patients in both studies, they had very poorly controlled cardiovascular risk factors. So one thing we’ve said today is it’s very important to partner with a good internist to manage those things. I often check these things, hemoglobin A1C and lipid profiles, once a year, not because I know what to do with these things anymore, but I know how to find a good internist [who does]. Have you seen all the drugs for diabetes? It is incredible.

Javier Pinilla-Ibarz, MD, PhD: It’s amazing.

Harry Erba, MD, PhD: That’s another topic. So that would not shy me away from using a second-generation drug. The goal here is prevention of progression in a high-risk patient. And I’m going to now be a little controversial. I would pick nilotinib.

Javier Pinilla-Ibarz, MD, PhD: You’re not controversial. You’re really agreeing with [everyone].

Harry Erba, MD, PhD: Okay, so the on-label dose would be nilotinib 300 mg twice daily, right? But if you look closely at the ENESTnd trial, they had a 400-mg, twice-daily arm. And if you look at [it in] an intent-to-treat way—in other words, patients who started on nilotinib 400 twice daily versus imatinib—actually at five years, there were statistically fewer progressions with that dose of nilotinib that you start with, so fewer progressions. And actually progression-free survival and overall survival were statistically significant as published. So it was 96% with nilotinib at 400 twice daily versus 92% with imatinib once daily—very close numbers. People would say, ‘Well, that’s just the statistical gods playing with us,’ but it is what it is. So I’ll just finish by saying, could I get away with using 400 mg twice daily?

Javier Pinilla-Ibarz, MD, PhD: Let me cut you off there. Tell me, what is the incidence of cardiovascular events in the 400 compared with 300?

Harry Erba, MD, PhD: It was a little bit higher.

Javier Pinilla-Ibarz, MD, PhD: A little bit higher?

Harry Erba, MD, PhD: Just a little bit. How much higher?

Javier Pinilla-Ibarz, MD, PhD: My point is, we were talking about cardiovascular events and now we are talking about that. So I agree that there’s this difference.

Harry Erba, MD, PhD: No, but you didn’t hear the important point. Remember what I said, the overall survival. Isn’t that what we said we cared about? It was 96% versus 92%.

Javier Pinilla-Ibarz, MD, PhD: You said progression.

Harry Erba, MD, PhD: I’ll just finish by saying the patient has 9% blasts, 14% basophiles. This is a person that we’re saying has high-risk CML in chronic phase. It is smelling a little bit like accelerated phase, too.

Javier Pinilla-Ibarz, MD, PhD: Sure, absolutely.

Harry Erba, MD, PhD: And so you could make the argument to use a higher dose of your first-line TKI in a patient who’s coming close to accelerated phase because we don’t know how. These criteria we use are quite arbitrary, and we don’t know yet, biologically, how accelerated phase is defined by some gene expression profile. We don’t have it commercially available so you can’t consider it. So I told you I’d be controversial. But my choice would be nilotinib 300 mg twice daily because that’s what insurance would pay for.

Transcript Edited for Clarity

Related Videos
Andrew Hantel, MD
Jakub Svoboda, MD
Ponatinib in patients with chronic-phase chronic myeloid leukemia and the T315I mutation: 4-year results from OPTIC
Sujith Samarasinghe, MD
Comparative Efficacy of Bruton Tyrosine Kinase Inhibitors in the Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia: A Network Meta-Analysis
Michael R. Grunwald, MD, FACP
Shella Saint Fleur-Lominy, MD, PhD
Manali Kamdar, MD
Matthew Matasar, MD, chief, Division of Blood Disorders, Rutgers Cancer Institute; professor, medicine, Rutgers Robert Wood Johnson Medical School
Sattva S. Neelapu, MD