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Defining Ponatinib's Role in Ph-Positive ALL

Panelists: Mark R. Litzow, MD, Mayo Clinic; Ryan D. Cassaday, MD, University of Washington School of Medicine; Aaron C. Logan, MD, PhD, University of California San Francisco Medical Sciences Building; Bijal D. Shah, MD, Moffitt Cancer Center; Anthony S. Stein, MD, Hematologic Malignancies and Stem Cell Transplantation Institute
Published: Tuesday, Feb 13, 2018



Transcript: 

Bijal D. Shah, MD: Based on the data, would you move to ponatinib front-line?

Anthony S. Stein, MD: Based on Martinelli’s data, and the data from University of Texas MD Anderson Cancer Center using hyper-CVAD plus ponatinib, I would consider changing from dasatinib to ponatinib. My only concern is as we treat more patients with ponatinib, are we going to get more vascular complications? I think one way of overcoming that is to start with 45 mg and then, after 1 cycle, bring the dose down to 30 mg and 15 mg, not keeping patients at 45 mg continuously.

Bijal D. Shah, MD: My big concern is what to do after the ponatinib. That continues to be my concern. I’m one of those stalwarts. I’m still using dasatinib, or Sprycel, and hyper-CVAD induction. I try to get as much mileage as I can out of a second generation TKI. If I fail to achieve a good molecular endpoint with my TKI in preparation for allotransplant, that’s when I’ll consider moving to ponatinib almost as a bridge to try and get them there. But I’ve just been concerned that I may use up my options. The initial data with ponatinib—and again, it was a combination of patients with CML blast phase and some ALL in the New England Journal of Medicine paper—was a median remission duration up around 6 to 9 months, if I recall. And that bears clinically with what I’ve seen in most of my patients. I don’t want to use it up. I’m still just very apprehensive about taking that risk.

Ryan D. Cassaday, MD: I agree, Bijal. I take the same sort of approach. I also agree with your point, Anthony, about the low intensity strategies for these patients that we’re trying to get into the deepest remission possible. At least in my practice—and you can certainly disagree with me if you see differently—the patient who is diagnosed with ALL and is truly unfit for intense chemotherapy is generally pretty infrequent. This is a disease of younger people. While Ph-positive disease is relatively more common in older patients, I don’t really see too many patients who I don’t think I could give some form of chemotherapy to.

And I think the other practical implication about trying to use ponatinib in the frontline setting is the fact that it’s only approved for relapsed/refractory ALL. While the studies that are ongoing may be able to change how we’re able to prescribe it, right now there may be some challenges outside the context of a clinical trial, unless a patient wants to pay for it out-of-pocket.

Aaron C. Logan, MD, PhD: I would say that although I used to agree with your sentiment about saving the ponatinib in case patients fail a second generation TKI, I’m now reluctant to pull that punch because I think we have options for relapsed/refractory, even Ph-positive, ALL with some of the newer agents that have activity in that disease. You may not necessarily need to rely on the ponatinib to get them back in remission. I think that you have one shot on goal to get your newly diagnosed patient with ALL into the best remission and to minimize the complications that they’ll have from therapy. So, at this point, I think my opinion is that whenever it’s permissible with the payer, I’d love to have the ponatinib up front and get that best response.

Bijal D. Shah, MD: No one around the table said imatinib.

Mark R. Litzow, MD: That’s an interesting point. I think we don’t know for sure whether dasatinib or even ponatinib is truly better. Certainly, my standard has been to use dasatinib. Another quick question before we switch over to Ph-negative disease is, when would you do a mutation analysis for BCR-ABL? Do you do it at diagnosis or when they start to fail therapy?

Ryan D. Cassaday, MD: I typically reserve that for a time after a recurrence or a persistence of disease. It’s not something that I’m routinely doing at the time of diagnosis.

Aaron C. Logan, MD, PhD: And usually, you have to have more than very low MRD levels of disease in order to do an ABL kinase domain mutational analysis. It’s unusual at a very relapse that you’re going to have the opportunity to do that.

Mark R. Litzow, MD: This is the last thing I’ll mention for Ph-positive ALL. There’s an interesting abstract at this meeting, the ASH meeting, of combining inotuzumab with bosutinib. It’s sort of a novel combination. This is in relapsed/refractory patients, and what they saw anticipated a nice response rate. We’ve got a lot of options for Ph-positive ALL these days, and it has really been very encouraging to see.

Transcript Edited for Clarity 

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Transcript: 

Bijal D. Shah, MD: Based on the data, would you move to ponatinib front-line?

Anthony S. Stein, MD: Based on Martinelli’s data, and the data from University of Texas MD Anderson Cancer Center using hyper-CVAD plus ponatinib, I would consider changing from dasatinib to ponatinib. My only concern is as we treat more patients with ponatinib, are we going to get more vascular complications? I think one way of overcoming that is to start with 45 mg and then, after 1 cycle, bring the dose down to 30 mg and 15 mg, not keeping patients at 45 mg continuously.

Bijal D. Shah, MD: My big concern is what to do after the ponatinib. That continues to be my concern. I’m one of those stalwarts. I’m still using dasatinib, or Sprycel, and hyper-CVAD induction. I try to get as much mileage as I can out of a second generation TKI. If I fail to achieve a good molecular endpoint with my TKI in preparation for allotransplant, that’s when I’ll consider moving to ponatinib almost as a bridge to try and get them there. But I’ve just been concerned that I may use up my options. The initial data with ponatinib—and again, it was a combination of patients with CML blast phase and some ALL in the New England Journal of Medicine paper—was a median remission duration up around 6 to 9 months, if I recall. And that bears clinically with what I’ve seen in most of my patients. I don’t want to use it up. I’m still just very apprehensive about taking that risk.

Ryan D. Cassaday, MD: I agree, Bijal. I take the same sort of approach. I also agree with your point, Anthony, about the low intensity strategies for these patients that we’re trying to get into the deepest remission possible. At least in my practice—and you can certainly disagree with me if you see differently—the patient who is diagnosed with ALL and is truly unfit for intense chemotherapy is generally pretty infrequent. This is a disease of younger people. While Ph-positive disease is relatively more common in older patients, I don’t really see too many patients who I don’t think I could give some form of chemotherapy to.

And I think the other practical implication about trying to use ponatinib in the frontline setting is the fact that it’s only approved for relapsed/refractory ALL. While the studies that are ongoing may be able to change how we’re able to prescribe it, right now there may be some challenges outside the context of a clinical trial, unless a patient wants to pay for it out-of-pocket.

Aaron C. Logan, MD, PhD: I would say that although I used to agree with your sentiment about saving the ponatinib in case patients fail a second generation TKI, I’m now reluctant to pull that punch because I think we have options for relapsed/refractory, even Ph-positive, ALL with some of the newer agents that have activity in that disease. You may not necessarily need to rely on the ponatinib to get them back in remission. I think that you have one shot on goal to get your newly diagnosed patient with ALL into the best remission and to minimize the complications that they’ll have from therapy. So, at this point, I think my opinion is that whenever it’s permissible with the payer, I’d love to have the ponatinib up front and get that best response.

Bijal D. Shah, MD: No one around the table said imatinib.

Mark R. Litzow, MD: That’s an interesting point. I think we don’t know for sure whether dasatinib or even ponatinib is truly better. Certainly, my standard has been to use dasatinib. Another quick question before we switch over to Ph-negative disease is, when would you do a mutation analysis for BCR-ABL? Do you do it at diagnosis or when they start to fail therapy?

Ryan D. Cassaday, MD: I typically reserve that for a time after a recurrence or a persistence of disease. It’s not something that I’m routinely doing at the time of diagnosis.

Aaron C. Logan, MD, PhD: And usually, you have to have more than very low MRD levels of disease in order to do an ABL kinase domain mutational analysis. It’s unusual at a very relapse that you’re going to have the opportunity to do that.

Mark R. Litzow, MD: This is the last thing I’ll mention for Ph-positive ALL. There’s an interesting abstract at this meeting, the ASH meeting, of combining inotuzumab with bosutinib. It’s sort of a novel combination. This is in relapsed/refractory patients, and what they saw anticipated a nice response rate. We’ve got a lot of options for Ph-positive ALL these days, and it has really been very encouraging to see.

Transcript Edited for Clarity 
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