Revolution of Therapy in Acute Lymphoblastic Leukemia - Episode 6

Revolutionizing the Treatment of Ph+ ALL with TKIs


Mark R. Litzow, MD: I was struck by a comment that you made about, you see an older patient, and we actually hope now that they may be Philadelphia chromosome [Ph] or BCR-ABL positive. That’s a real sea change from the way we used to think about these patients. So I want to talk a little bit about that because the tyrosine kinase inhibitors [TKIs] that Bijal mentioned earlier—imatinib, dasatinib, nilotinib, bosutinib, and now ponatinib—have really revolutionized the treatment of Philadelphia chromosome-positive ALL, and are turning that from a very poor prognosis subset of ALL into a good prognosis. And I think there’s some, I’ll say controversy, in our field about can we actually move away from chemotherapy, maybe not completely but to a much lower level than we had before, because we’ve got such a powerful agent to use in these patients. Bijal, what would you say about that controversy?

Bijal D. Shah, MD: I’m not willing to move away from chemotherapy altogether unless I have to. I still try to bring in a little bit of vincristine, perhaps even a little bit of cytarabine or methotrexate, for my patients, when I can. That said, the TKIs are extraordinarily powerful. And referencing the European data, dasatinib and steroid alone, it was an 8-week course of the dasatinib. It wasn’t a planned dasatinib until progression. The median survival on that trial I recall was close 2 years. And so I don’t think we know yet whether we can give up the chemotherapy. Personally, I’m a little bit nervous about it because I want to try and maximize what I can get from the TKI.

A harder question you didn’t ask me is which TKI? And I also can’t answer that. I’ve been sticking with dasatinib mainly because of the blood-brain barrier penetration. I think that the data with ponatinib are very provocative, and we’ll see how that data evolve over time in frontline ALL. Again, the question being, is it better to do dasatinib then ponatinib, will you get more mileage? Or is it better to start with ponatinib upfront and you can anticipate something even better because perhaps you’re not selecting for something, you’re simply treating the resistance before it emerges, or clones before they emerge with resistance?

Mark R. Litzow, MD: Or could you start with ponatinib and then switch? So you get away from the long-term use of ponatinib and the risk of vascular toxicity.

Bijal D. Shah, MD: It’s a great question, again, right now I’m not using ponatinib upfront. I still want to see the long-term follow-up data, and then I’ll give you a much more educated answer. I think that dasatinib is fairly well tolerated both on high-dose protocols and low-dose protocols, and that’s been our go-to because of the CNS [central nervous system] penetration issues.

The next question though, given what Jae and his group demonstrated, are we ready for blinatumomab and TKI combinations, and if you had done that same trial again in the elderly Ph-positive population?

Jae Park, MD: So I do, in that patient population, or even in maybe younger patients in the future too, I do agree with Mark, I think we’re likely going to get away with less chemotherapy. How [much] less is the question; completely or how little. I think the Ph-positive ALL is the most changing…. And then there’s a lack of a standard, so to speak, or a very clear sense of what we will do if a patient [is Ph] minus when we get them, or even T-[cell] ALL frontline regimens, when we get Ph-positive, what inductions to use, what consolidation to do, and whether we should transplant. [Those are] whole other questions.

But for the blinatumomab question, I think there’s a role, and I think we’re ready … at least during the consolidation regimen, and maybe perhaps an induction too. These patients do very well with a TKI dasatinib plus steroid alone. The majority may not go into complete molecular remission with this induction approach, and I think this is where blinatumomab TKI combination comes in useful to get into MRD [minimal residual disease]-negative and to continue the regimen for consolidation. And then there’s a difficult question, what to do after that, transplant? Maintenance? Which maintenance type of regimen comes in? But I think having the blinatumomab is quite useful, and that’s what I’m using, blinatumomab in the older Ph-positive patients as a consolidation, with the less intense induction regimens, getting into CR [complete response] with an MRD-positive or negative or close to. And then using blinatumomab as consolidation with a TKI, then having that decision of what to do, which I think there’s no really good prospective data to guide us in that.

Bijal D. Shah, MD: I was going to say, that sounds very remissive of a cooperative group trial.

Anthony S. Stein, MD: There is a cooperative group trial that looked at patients over the age of 65 for Ph-negative, which you already alluded to. Where they got blinatumomab followed by POMP [Purinethol/vincristine/methotrexate/prednisone]. And then for the patients who are Ph-positive, those patients were treated with dasatinib, steroids, followed by blinatumomab, and those results, I don’t think that’s part of the trial. Another trial is being completed. It’s close to accrual, they’re just waiting for further follow-up to hopefully present that data.

Bijal D. Shah, MD: Did they continue the TKI during the blinatumomab phase?

Anthony S. Stein, MD: No, I think there you got dasatinib plus steroids, and then patients went on to TKI.

Jae Park, MD: I think there’s another question, how long to continue the TKI. Definitely during the consolidation, during the maintenance too. In the typical maintenance, it was 2 years, over.… I think there’s a variable practice going beyond 2 years, at 5 years, and some of us are hesitant to stop it altogether because we’re worried about these patients. But TKIs are being continued usually with the consolidation. But another question with these novel therapies is can any of the TKIs can interfere with activity of the other with the blinatumomab. Is there a better partner of the TKI? Is dasatinib better than ponatinib, or nilotinib, or imatinib? So I think there are some questions that need to be addressed and answered through this type of clinical trial to see what is the impact of this type of TKI on the T-cell activity when you combine at least with blinatumomab.

Mark R. Litzow, MD: In younger patients we are proposing a trial randomizing patients to hyper-CVAD [cyclophosphamide/vincristine/doxorubicin/dexamethasone] plus dasatinib or ponatinib, investigator can choose, versus blinatumomab and dasatinib or ponatinib. We’ll have to see if that gets approved and moves forward.

Jae Park, MD: I think it will be a very good study to look at. I mean there’s a real-life decision. I think that when I see patients after the initial induction, it’s typical the decision is should I do hyper-CVAD plus TKI consolidation, exactly what you’re asking, or the blinatumomab consolidation? I think it will be good to get prospective data to address the question.

Bijal D. Shah, MD: That will be a fantastic trial. And fantastic for me because, again, we’re now talking about integration of novel agents as frontline therapy for young adults. And, again, we need trials to prove all of this, but [this is] where I hope we ultimately move so we can get away from some of the very intensive therapeutic approaches that we’ve been giving.

Transcript Edited for Clarity