BCR-ABL1 TKIs in Relapsed/Refractory CML - Episode 3

Response Monitoring of Patients With CML Treated With TKIs

June 24, 2019

Harry Erba, MD, PhD:The goal of our therapy in CML [chronic myelocytic leukemia] has been to prevent progression to the terminal phase, accelerated phase, and finally blast crisis. You start a patient on anABLTKI [tyrosine kinase inhibitor]. We’ll get to how you choose between them, but what kind of responses are you looking for to judge whether the patient is in, let’s say, a safe zone that they’re protected from progression?

Jorge Cortes, MD:I will say that our goals have evolved as our treatments have improved. If you remember in the days of hydroxyurea and busulfan, controlling the symptoms was our goal because that’s the best we could do. Nowadays, it’s not only that but even other goals—get them off therapy and that kind of thing. But certainly, preventing the transformation is important because even though these drugs also work in transformation, the efficacy is much less, not only in terms of the rate but in the durability of the responses and all that.

Once you can prevent them from transforming, these patients are going to most likely have a normal life expectancy. We have identified hallmarks at the given time points, so we know that when a patient gets to that level of response at that time, that is associated with negligible probability of transformation. These have to do with both the time and the depth of their response. The critical time points are the early time points. We have at 3 months, at 6 months, and at 12 months. For example, at 3 months, getting less than 10% transcripts is associated with excellent progression-free survival and excellent overall survival. At 6 months, getting to less than 1% of the transcripts, it gets to that same level.

That’s why it’s very important—always, of course, but certainly in the first year—to make sure that your patient is progressing. It’s particularly so if you’re using, for example, imatinib, and you have the option to go to a second-generation. It’s fine to use imatinib, in some instances that’s what you have to do, but then you have to see that your patient is progressing well into the response goals, so that you minimize that risk of transformation.

Harry Erba, MD, PhD:One thing that often confuses people is you’ve talked about the 3-month and the 6-month milestones that we look for. But a place where the guidelines differ is in the 12-month milestone. ELN [European LeukemiaNet] suggests that a major molecular response with aBCR-ABLlevel of less than 0.1% is—and I’ll use the word they use—optimal. But in NCCN [National Comprehensive Cancer Network], a guideline says that if you’re in a complete cytogenetic remission with a level of about 1%, that’s acceptable. How do you come to terms with these different recommendations for your own patients?

Jorge Cortes, MD:I think that the difference is mostly in what your long-term goal is. I think that I agree with the NCCN in terms of that when the patient gets to a complete cytogenetic response by 12 months, the probability of transformation and of course survival are going to be excellent. In that regard, the patient is fine. The NCCN has taken it further because they’re focusing on if they’re going to get to the deepest molecular response and all that, and that’s fine. I think as a goal, it’s good.

But I think we shouldn’t confuse the 2 things because, No 1, the value of the deeper molecular responses can be debated into what they mean for every patient. There are benefits, but it doesn’t prolong the survival anymore. Things like that. No 2 is that sometimes developing these criteria creates a perception that if I don’t have it, I have to change. There isn’t always data to suggest that the change in a given scenario would be beneficial. In some instances, you may even expose the patient to other toxicities and adverse events. If the patient has a complete cytogenetic response by 12 months, and you know their likelihood of transformation is minimal and their survival is going to be that of the general population, I don’t want to change my patient to another therapy. This is because what if I give them something that now is going to give them another adverse effect, but right now they’re fine? I think that it depends on what exactly you’re aiming for.

Harry Erba, MD, PhD:I practice the exact same way, and I think our audience actually might be surprised to hear that from so-called experts—that we might be satisfied, and often are satisfied, in some of our patients with a complete cytogenetic remission, especially in older patients who are just barely maybe tolerating some of these. I agree with you, you can pick another drug, but you don’t know if they’re going to tolerate that 1 or be more compliant with it.

Jorge Cortes, MD:Oh, absolutely, yeah.

Harry Erba, MD, PhD:What do you recommend, then, in terms of monitoring of patients onABLTKIs? How do you do it?

Jorge Cortes, MD:The way I do it, and there are variations of these in the guidelines, but the way I do it is the first year I do it every 3 months. You could question the 9 months because we don’t have a milestone to follow. But just to make it easy for the patient to have a calendar, I do it every 3 months for the first year. If by the end of the first year, my patient already has at least a complete cytogenetic response and certainly a deeper molecular response, I continue every 6 months. In the first year, I do PCR [polymerase chain reaction] tests, and I like to do at least 1 or 2 bone marrows—certainly at 12 months, maybe at 6 months. There’s a small percentage of patients, about 10%, 15% of patients who develop chromosomal abnormalities in Philadelphia chromosome; Ph—negative metaphases, so I want to see that that’s not the case with those patients. They may have certain implications. As the patient responds, they usually appear early. If by 12 months, 18 months, they haven’t developed that, it’s not that it’s not going to happen. But it’s very low yield, so I continue monitoring only by PCR.

We talked earlier about the patient whose PCR is negative from the beginning. Well, the best you can do then is the FISH [fluorescence in situ hybridization] test. It’s more sensitive than cytogenetics. That’s why you do it at the beginning. You want to make sure that your FISH really captures that, and then you can follow your patient with FISH. Sure, you don’t get information about major molecular response and all that, but that’s what you can do for that patient. Again, we already talked about that. If they have a complete cytogenetic response, their survival is going to be good. If a patient develops resistance, then I do the full assessment, and then it’s important to check for mutations in addition to that. A patient who is having a good response, even if they’re lagging behind a little bit, I don’t check for mutations. It has no value.

Harry Erba, MD, PhD:I follow a very similar plan. The only place in which we might differ maybe a little bit is if a patient has a complete cytogenetic remission by peripheral blood analysis. I don’t feel as obligated to do that follow up marrow looking for the Ph-negative clone because I don’t know what to do with that data, actually. But, I understand why we would differ on that 1.

Jorge Cortes, MD:Yeah, and that’s an important point. We don’t really know exactly what to do with those patients. I do it because I want to know, but certainly there’s no clear indication what the strategy is to address that.

Transcript edited for clarity.