BCR-ABL1 TKIs in Relapsed/Refractory CML - Episode 7

Role of Ponatinib in Treatment of R/R CML

June 24, 2019

Harry Erba, MD, PhD:Let’s move on and focus now on ponatinib, and where does it have a role in the treatment of relapsed-refractory CML [chronic myeloid leukemia]?

Jorge Cortes, MD:Ponatinib is very effective. The response rates in the third-line—well, actually it was third or beyond—line of therapy, that PACE trial, 60% of patients had received at least 2 TKIs [tyrosine kinase inhibitors], and 90% had received at least 3 TKIs. Yet the weight of major cytogenetic response in the chronic phase was over 65% in these patient populations. It is incredibly effective if you put that in the context. Most of these were actually complete cytogenetic responses, so this is about 50% to 55% of the responses. If you put it in the context of, for example, the second generation—dasatinib, nilotinib, or bosutinib—only after imatinib failure, those studies showed a complete cytogenetic response of only 40%. Which we value, but it tells you how ponatinib was incredibly effective. So definitely, it’s a patient that has had at least 2 prior TKIs. Ponatinib is very effective in that setting. Of the drugs that we have available, I think it’s the most effective. Not to mention, of course, theT315I. That’s the only drug that works. So that no matter how many prior lines of therapy, if I haveT315I, ponatinib is the way to go.

Harry Erba, MD, PhD:It was interesting in the results of the PACE study that you published, the response rate in theT315Ipopulation seemed to be a little bit higher than just in the relapsed-refractory setting.

Jorge Cortes, MD:That is correct. That was the group that had the highest response rate. Some of that had to do with the fact that they had fewer prior therapies, because once they developed that, there was nothing else to give them. But it also reflects that high sensitivity of the high efficacy of ponatinib against theT315I.

Harry Erba, MD, PhD:Recently you’ve given us an update from PACE, a 5-year update. Are patients being able to stay on ponatinib and stay in response?

Jorge Cortes, MD:Yeah, absolutely, and that’s very important. These responses are durable. It’s not just the transient response and they come up with something else. These patients have been the patients who achieved the major cytogenetic response, or that was a primarily endpoint, but then we have many patients who have a high percentage—it’s almost 50% of patients with major molecular response—and they’ve also been able to maintain their major molecular response. Certainly, the patients can maintain their responses for the long term. These results that you’re talking about, it’s a 5-year follow-up. So they are durable responses.

Harry Erba, MD, PhD:You’ve had a lot of experience with ponatinib. We’ve been made to be quite concerned about the toxicity of ponatinib. What has your experience been like?

Jorge Cortes, MD:That’s where we started recognizing the risk of arterial occlusive events. We didn’t recognize it early enough. Only as PACE was starting to finish enrollment and the data started coming up, we realized that there were a significant number of patients who developed these events—either cardiovascular, cerebral vascular, or peripheral arterial. And there’s no question that it has…

I believe that a good part of that is the drug. And we can talk about the mechanisms and why that happens, but some of that—that’s a lesson for any of these other drugs—is that we were not paying as much attention as we should have to managing their diabetes, their cholesterol, and their hypertension. If you look at the curves of the blood pressure during the management of these patients on ponatinib, blood pressures were way high, and they remained high, which means evidently we were not doing a good job at controlling the blood pressure.

I don’t think we would have eliminated the risk by controlling these risks better. But if we had done a better job, I think that we would have decreased the risk of developing these events in at least some patients. That’s a lesson to learn now, but that makes it more important that the patient is not just a PCR [polymerase chain reaction]. You need to monitor everything else and manage that well. With that, I think that we can use ponatinib more. For a while, this was a big scare, and people were not using ponatinib at all. No, I think it’s a good drug. We should use it when it’s indicated, but we need to use it properly.

Transcript edited for clarity.