BCR-ABL1 TKIs in Relapsed/Refractory CML - Episode 8

Early Intervention With Ponatinib in Treatment of CML

June 24, 2019

Harry Erba, MD, PhD:In what circumstance would you think about using ponatinib even earlier?

Jorge Cortes, MD:One area where we have very little data with other drugs, and I think that ponatinib to me is probably the best option, is in the second line, where your first line is a second-generation TKI [tyrosine kinase inhibitor]. If your first-line drug is imatinib, should we have data with dasatinib, nilotinib, and bosutinib, since they work well in a number of patients? It may be possible that ponatinib works better than those, but still, they work well enough that you can go there… But if the first-line is dasatinib and nilotinib, or bosutinib, if it’s for resistance, they’re equals. Yes, you will find some patients who respond, but I think that the 1 drug that stands out in terms of efficacy is ponatinib.

Unfortunately, as these second-line studies were being initiated, this issue of arterial occlusive events came up. These studies were interrupted and really have never restarted again. We were starting a study like that. After 5 patients, I had to stop the study. Of those 5 patients, all those continue having a deep molecular response, and they’re doing fine. But it’s only 5 patients. I think that’s another circumstance where the consideration of an early use of ponatinib deserves attention.

Harry Erba, MD, PhD:Yeah. I agree. If you have not used imatinib, they’re on second generation, and they have secondary resistance. You can do a mutational profile, but only 50% of the patients will have mutation. And then out of those 50%, how many do you think the mutational profile will actually inform you to move from nilotinib to dasatinib, or dasatinib to nilotinib?

Jorge Cortes, MD:Oh, of the ones who had mutation, which is already half, 10% maybe.

Harry Erba, MD, PhD:Yeah, a very low percentage.

Jorge Cortes, MD:Yeah.

Harry Erba, MD, PhD:OK, so ponatinib there. I know we’re not talking about ALL [acute lymphoblastic leukemia], but you know acute leukemias are what you and I do quite a bit of the day.

Jorge Cortes, MD:Yes.

Harry Erba, MD, PhD:The University of Texas MD Anderson Cancer Center generally has some interesting information about the use of ponatinib in Ph-positive [Philadelphia chromosome—positive] ALL, outside theT315Imutation. Do you want to tell us about that?

Jorge Cortes, MD:Yeah. The data there—and of course we’re here, we’re talking about combination with standard chemotherapy—is very good. Of course with chemotherapy, a response rate is almost 90%, but the durability is not there. We have made a lot of improvement going from chemotherapy to chemotherapy plus imatinib, to chemotherapy plus dasatinib. But with ponatinib, we are getting to in excess of 50% to 60% of patients with durable remissions and a long-term survival, something that was completely unexpected and completely unimaginable.

You know, we’re starting to debate now whether you should transplant these patients. In the old days nobody would question that transplant was the way to go. That could still be argued, but at least there’s a debate now because you are seeing these very high rates of durable remissions and an overall survival. I think that this shows that ponatinib is very good, and certainly in that setting on a more advanced disease, in the blast phase, in the Philadelphia-positive ALL, it is absolutely the best drug.

Harry Erba, MD, PhD:Allotransplant. We still do transplants on patients. Is there a role for it? Let’s talk specifically about CML, chronic phase, theT315Imutations developed. Is ponatinib just a bridge to transplant, or could it be considered definitive therapy?

Jorge Cortes, MD:In my opinion, it’s a definitive treatment. The responses, as we mentioned, are high and durable. We actually did an analysis in which we compared the data from the PACE trial with the registry from the European bone marrow transplants.

This is specifically for the patients withT315I. What that analysis showed us is that the survival in the chronic phase was better for the patients who were treated with ponatinib than for the patients who received a transplant. In the accelerated phase, it was the same. The survival was the same. You could argue, “Then why do the transplants if you can choose to take ponatinib and take the pill?” You could say, “Well, it’s because of the risk of arterial occlusive events.” Well, then you have the risk of graft-versus-host disease. They both have risks that we can manage and all that, but there are those risks.

In the blast phase, sure, a transplant is better. I would still use ponatinib to get the patients to at least some hematologic—ideally cytogenetic—response, and then transplant them. But certainly, in the chronic phase, I think it’s definitive treatment.

Transcript edited for clarity.