Chronic Myeloid Leukemia: Retrospective Analysis of the PACE Study

EP: 1.Team Introductions: CML Experts From UT Southwestern vs. Mayo Clinic

EP: 2.Chronic-Phase CML: The OPTIC Study

EP: 3.Cross Q&A: Ponatinib Dosing in Relapsed/Refractory Chronic-Phase CML

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EP: 4.Chronic Myeloid Leukemia: Retrospective Analysis of the PACE Study

EP: 5.Cross Q&A: Arterial Occlusive Events With Ponatinib in the PACE Trial

EP: 6.Olverembatinib Study in Patients With Heavily Pretreated Chronic Myeloid Leukemia

EP: 7.Cross Q&A: Role of Olverembatinib in Heavily Pretreated CML

EP: 8.Chronic Myeloid Leukemia: Long-Term Follow-up of Low-Dose Dasatinib

EP: 9.Cross Q&A: Real-World Use of Low-Dose Dasatinib in CML

EP: 10.Mayo Clinic and UT Southwestern “Face Off” Over Multiple Myeloma and CML

Transcript:

Judy Schreiber, PhD, RN: We will move on to Dr Mangaonkar’s presentation on the PACE trial.

Abhishek Mangaonkar, MBBS: I’ll discuss this retrospective analysis of arterial occlusive events in the PACE trial[NCT01207440]. This was this was a paper published that did a central adjudication of these events and discussed them in more detail. Dr Begna shared some of his data, but the arterial occlusive events with ponatinib in [the] PACE trial were at a frequency of about 31% in [patients with] chronic phase CML [chronic myeloid leukemia], and about 26% of them qualified as serious adverse events. The PACE trial did not just include chronic phase CML, but it also included Philadelphia chromosome–positive ALL [acute lymphoblastic leukemia] patients, in the overall cohort the frequency of these adverse effects was [approximately] 25% and 20% of them were serious.

Here’s the breakdown of what these events truly were. In chronic phase CML, you can see that the majority of them were cardiovascular events, myocardial infarctions were the predominant sort of AEs [adverse events] and 12% of them were serious. Cerebral vascular strokes were 13% of patients, 10% being serious and also peripheral vascular occlusions. There were about 14% of patients, 11% being severe. You can see that the numbers are a little bit less than the overall cohort, but still quite significant that a sizeable percentage of these patients do develop either cerebrovascular, cardiovascular, peripheral vascular events. There is some point to say that the [with the more] events per year, the more the exposure is, that you could eventually build up on the toxicity so that’s a concern with this drug as well. There were about 5to 6% venous thromboembolic events in the study as well and certainly that is also a concern. [Jorge Cortes, MD, professor and deputy chair, Department of Leukemia, The University of Texas MD Anderson Cancer Center]…looked at these arterial occlusive events by the PACE trial, by an independent adjudication committee…[comprising] a cardiologist and neurologist, and basically there was a central review of these adverse events.

This was the methodology, [in] this case every single AE that was identified or deemed to be a vascular event was reviewed by a central team of 2cardiologists and then if there was agreement between the two, then essentially that case was adjudicated as such. If there was no agreement between the 2cardiologists, then this was reviewed again by another member of the team and [if] there was majority consensus, then it was adjudicated. If not, then again, this was sent back to a panel of clinical specialists. The reason for doing that was because as we all know the grading and attributions can be variable depending on who’s assessing these adverse events and there can be a lot of variability to that. This was a central way of doing it. What they found was the overall incidence of these vascular events was lower when it was assessed by the sort of central committee. Remember the original numbers, there were about 25% patients with arterial occlusive event. With the adjudication, it was lower at around 17%. More than one serious adverse effect was again, lower, [at] 16%. And the treatment related AEs that were associated with the treatment itself was again, lower. It’s also important to note on the right, the exposure to the drug, if you look at 0 to 1, 1 to 2, 2 to 3, 3 to 4, and 4 to 5. Again, all these AEs when they were assessed, they were lower when they were assessed by the adjudication committee. Again, this is a very important slide.

They also looked at the risk factors. What are the other risk factors in the patient, and then try to see which patients actually have more adverse events with ponatinib versus not. As you can see, only 3% of patients without any other cardiovascular risk factors like hypertension, diabetes, smoking, and those factors had arterial occlusive event as opposed to 1to 2risk factors there were 13% patients and 3 or more risk factors there were almost 30% patients that developed this adverse event. Now this is again, the overall survival, this is a retrospective study or sort of evaluation, at least not like study itself, but there was no difference in the overall survival. I think the important point from this is the other cardiovascular risk factors matter a lot to assess the risk for arterial occlusive events and venous occlusive events with ponatinib. In conclusion the independent evaluation of arterial occlusive events with ponatinib revealed a lower incidence of arterial occlusive events and also the serious arterial occlusive events was lower than what was initially reported. The second point is very important and says cardiovascular risk factors should be controlled prior to ponatinib initiation, and that could mean control of blood pressure, control of diabetes, try to get them to quit smoking and these factors can have an impact on their risk overall going forward. Now, often we don’t have time for that, but I try to do that in some of all my patients if I start them on ponatinib.

Judy Schreiber, PhD, RN: Thank you so much.

Transcript edited for clarity.