Optimizing Real-World Ponatinib Use in Ph+ ALL: Treatment Considerations


Insights on real-world ponatinib treatment strategies and safety in Philadelphia-positive acute lymphoblastic leukemia are provided by Hagop Kantarjian, MD, and Bijal D. Shah, MD, MS.

Bijal D. Shah, MD, MS:
Dr Kantarjian, with all these data in mind, is there a group that you would favor ponatinib in? Or maybe a different question: Is there a group where you feel nervous about giving ponatinib?

Hagop M. Kantarjian, MD: So as you know, our group is biased toward ponatinib-based therapy because early on, when other people were concerned about the ponatinib toxicities, we went all in with the ponatinib-based regimens. So we did hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, methotrexate, cytarabine, and dexamethasone]-ponatinib, that looked very good. And then we moved in 2017 to ponatinib-blinatumomab. We learned a bit the hard way that ponatinib at 45 mg daily can be toxic, so we went down to 30 mg for the induction and then 15 mg and complete molecular response, which is achieved very quickly in most of the patients. And we are happy with the results. Now, we’re still concerned that there are some subsets where we need to look at things more closely…. So, the first thing is not all Philadelphia-positive ALLs [acute lymphoblastic leukemias] are the same. So if you have a patient with … [who] develops CML in the lymphoblastic phase, we think that these patients need a bit more chemotherapy. So we give them the mini CVD, ponatinib, with blinatumomab. If we have a patient with a relapsed Philadelphia-positive ALL because they got frontline therapy [that] did not optimize the TKIs [tyrosine kinase inhibitors] or blinatumomab, then we also give them dose-adjusted hyper-CVAD, ponatinib, with blinatumomab. In those 2 categories, we consider transplant.

The third category where we worry is a patient on ponatinib-blinatumomab who continues to have either PCR [polymerase chain reaction] positivity over 0.1%, but, more importantly, clonoSEQ positive even at the level of 10 in 1 million. And we have seen people who are clonoSEQ positive or clonoSEQ negative, and they are PCR positive. So these patients do not relapse. That’s a unique category of the patients. But in the patients who are PCR negative, if they remain clonoSEQ positive, these are the patients who we worry [about] and then either we modify the treatment or consider an allogeneic stem cell transplantation. The other thing we worry about is with the ponatinib/blinatumomab in the first 60 patients, even though the estimated 4-year survival is over 90%, we saw 2 CNS [central nervous system] relapses. And that’s worrisome because we are not using anymore high-dose Ara-C [cytarabine]–methotrexate. So this is where we increased the … to 16. But we are thinking that if we see more CNS relapses, we may reintroduce a course of high-dose methotrexate–Ara-C just as a form of CNS prophylaxis.

So, Dr Shah, let me ask you this. Now that we have the PhALLCON results out in the open and we are hoping for an FDA approval of ponatinib on that basis, how would that impact your practice and how do you see the approval of ponatinib in terms of the treatment landscape in newly diagnosed Philadelphia-positive ALL?

Bijal D. Shah, MD, MS: Like you, we’ve moved to ponatinib. I think that it would make my life much simpler to not have to…conduct peer-to-peers or…really struggle in terms of the insurer approval for these medications in our ALL patients. But really our go-to for easily 5 years now has been ponatinib. And…we really have been convinced by the data with ponatinib and blinatumomab. So we are commonly using that as our preferred approach for managing our Philadelphia-positive patients, though I recognize that is not yet standard of care. And so…hearing this guidance around intrathecals is very helpful and certainly we’ll continue doing what we can to follow these patients closely. So far, I have to tell you, we’ve been really impressed, really pleased with how well it’s done. I’m still struggling with what to do for [patients with Ikaros-positive mutations]. For now, we are treating them with ponatinib-blinatumomab. I don’t know whether these patients will need a longer course of ponatinib maintenance or maybe indefinite ponatinib, or if there’s something different that we need to do in that particular cohort of patients. But that’s another group that I’m following very closely. On the whole, as ... these data … as impactful as they are, as important as they are, forgetting regulatory approval, for me at this stage, they’re supporting what I’m doing right now in the clinic. And, again, it’s been really nice to see.

I have to tell you, before we were using ponatinib regularly up front…it was very common for me to see these compound mutation problems where I really didn’t have a TKI I could draw from. And so I’m seeing much less of that. That, again, has been really delightful. And I think it’s really changed…my ability to take care of these patients. So that’s…broadly how I think about the PhALLCON data. As I mentioned…the next big question, of course, is going to be ponatinib vs the other TKIs. I don’t know if we’ll ever have a study like that, but thinking about what it means to use ponatinib as opposed to dasatinib, bosutinib, or nilotinib. And, again, I do think that ponatinib is probably the better approach, but that’s something that we’ll have to sort out as we go.

Transcript is AI-generated and edited for clarity and readability.

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