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Dr Elias Jabbour: Third-line Ponatinib “Optimal” for Patients With CML-CP Without T3151 Mutation

Video

Third-line ponatinib is the optimal treatment option for patients with chronic myeloid leukemia in chronic phase (CML-CP) without T3151 mutation, said Elias Jabbour, MD, professor of medicine, Department of Leukemia, MD Anderson Cancer Center.

According to an abstract presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, third-line ponatinib therapy is the optimal treatment option for patients with chronic myeloid leukemia in chronic phase (CML-CP) without T3151 mutation who did not respond to 2 prior tyrosine kinase inhibitors (TKI). Elias Jabbour, MD, professor of medicine in the department of leukemia, MD Anderson Cancer Center, explains how the propensity score analysis used modeling to come to this finding.

Transcript

How did your propensity score analysis allow you to use modeling to compare patients receiving ponatinib for third-line treatment of chronic phase CML with those receiving a second-generation TKI?

The outcome of the CML patient has changed drastically and patients in frontline can do so well. However, with increase of prevalence, patients living longer and longer, we've seen resistance happening about 5% per year. In the second line, there are several options available and that is standard. In a third-line therapy, we do not know what is the best sequence. A physician can switch from one second-generation TKI to another, or they move to ponatinib or dasatinib. So this sequence is not known.

We know ponatinib is very effective in CML. In fact, it does suppress the mutations, and in studies done it has shown great outcome. That being said, the drug was associated with vascular events as a side effect, and therefore people were worried about that, and rightly so.

After that, there was a trial called OPTIC where the investigators adjusted the dose of ponatinib based on efficacy. It means if you respond, we can reduce the dose, and by doing so, we improve on safety. And the study has shown that by doing so, we preserve the efficacy while improving on a safety profile. Therefore, we aimed in the study to compare and assert line, the use of second gen TKI because it's hard to get a randomized trial done, and to see which strategy is better. This was the aim.

Of course, it's a retrospective review. So we went back to our database at MD Anderson and we worked with Takeda to get the cases from the OPTIC and PACE trials where we need to compare between ponatinib and a second-gen TKI. Then we performed what is called propensity score matching. That means we match patients. We tried to get as close as possible for patients to each other in order to be able to compare efficacy, because otherwise you'll be biased. And people may say, "Well, this drug did better because the population in here are not as aggressive as other population. To minimize the bias, we did what's called propensity score matching between 2 populations. We look for responses, how deep responses can go, we look for PFS [progression-free survival] and survival.

First of all, we look at the characteristics of about 350 patients. We excluded T3151 mutation because these are resistant to secondary TKI. When we compared these 2 group of patients, we noticed that those who received ponatinib had more risk factor for cardiovascular events. And we know these TKIs can have a side effect, angina, stroke, and others.

Despite that, we've seen more patients with risk factor for vascular events on ponatinib group. And we've seen as well that those who received ponatinib did so because of more aggressive disease—they have more disease at the baseline, compared to patients who received second gen TKI....Then, in order to minimize the difference, we did the matching, and then we went from 350 to almost 296 patients in each cohort. Then, we minimized the differences when it comes to risk factors. But despite the best matching with it, those who are on ponatinib had the high disease burden still. We define it by more than 10% BCR:ABL1 transcript, or more than 1% compared to the population who received second-gen TKI.

Then we look at the responses. Those received ponatinib had deeper responses compared to patients who received second gen TKI. And that has been shown already. It's a confirmation of what was reported before in a meta analysis. But what's new in our study is, not only that patients do respond, but patients live longer. We did what they called the PFS and survival, and we've shown that patients who received ponatinib had a better survival. That means, for certain doctors, they will say, "Well, ponatinib is not the best drug, I'm going to use another safer drug, correct? And if I don't do well, I can go to ponatinib." Such a strategy can compromise survival. Therefore, the message from our presentation was do not waste time. If you get to the third-line, go for ponatinib because it's linked for a better survival. And to confirm these findings, we did the multivariate analysis, and in the multivariate analysis we showed that ponatinib was the only factor favorably associated with survival benefit, and that is the main message from the study.

Now then we said maybe there's some group of patients who are intolerant. Let's focus on a group with a disease, real disease, we define them among experts in CML as above 1%, PCR. We did repeat the analysis for this group of patients, and in this analysis, we've shown that the difference is more substantial in favor of ponatinib. Better outcome, better responses, and better outcome. Therefore, in conclusion, our study is confirming that ponatinib is superior to second gen TKI rotation in a third-line therapy with deeper responses, better PFS, better survival, and that is more substantiated in patients with a high tumor burden. Therefore, I think the message is so clear that ponatinib is the most optimal strategy to be considered in a third-line setting.

This transcript has been lightly edited for clarity.

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