Induction Strategies for Philadelphia-Positive ALL

Transcript:

Mark R. Litzow, MD: Jae, tell us a little bit about how we approach the classic Philadelphia [Ph] chromosome positive or BCR-ABL positive ALL [acute lymphoblastic leukemia] with induction therapy and factors to take into account.

Jae Park, MD: I wouldn’t say there’s one standard approach for these patients, you can actually say that about adult ALL patients. There’s no single induction. Unlike the pediatric setting, where there’s a very set regimen for these patients, defined by representing risk factors, for patients with Philadelphia chromosome positive ALL, I think here are a couple of different approaches that one can take. One approach is the TKI (tyrosine kinase inhibitor), whether it it’s imatinib, dasatinib, or ponatinib, which for some of these patients could be the first-line therapy as a backbone. For induction therapy, there are now a good number of the data using a TKI plus a steroid, either prednisone or dexamethasone in combination, for a 90-day induction time.

These tend to be older patients who are less likely to tolerate intense multiagent chemotherapy, so they could be at the high level of potential induction mortality. So, minimizing exposure to myelosuppressive induction chemotherapy is one way to really significantly reduce induction complications in mortality for those patients.

If you use that approach with a steroid plus TKI, at the end of induction—again, depending on the regimen, it’s usually around 90 days or so—you do need some type of a consolidation therapy and it may depend on the fitness of some of the patients. So I think typically for us, if someone is treated with consolidation, for some of these patients it could involve TKI plus chemotherapy such as hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] or mini hyper-CVD [cyclophosphamide and dexamethasone at 50% dose reduction, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m² × 4 doses] or some agreeable version of multiagent chemotherapy. Or, the TKI plus blinatumomab if they are MRD [minimal residual disease] positive. That could be another approach that can be taken as well.

I think there are now increasing data from the Italian studies and other studies as well using dasatinib and blinatumomab as a frontline therapy. Studies such as those are showing very good results when blinatumomab, in combination with TKI, are used for induction and consolidation, some of the patients with less toxicities than traditional chemotherapy.

There’s another approach of using again a TKI plus steroid. The other approach will be going on for younger, fit patients with Philadelphia chromosome positive ALL. But those patients are getting either dasatinib or ponatinib with hyper-CVAD combinations, so I do see that there’s another common regimen that people have used, and we have used ourselves as well. So, those typical combinations use a hyper-CVAD backbone of 8 cycles and again, a TKI is being added.

And there is a little bit more toxicity associated with it, certainly for older patients. But again, for younger fit patients, I think there could be options. So either of those approaches I think are very reasonable to take, depending on the fitness of the patients and the comfort level of the physician treating those patients. But there are no randomized trials showing that one approach would be better. I think toxicity-wise, it is less than with a less intensive approach.

And then following that, there’s still a remaining question: Should we be transplanting, doing allotransplant for these patients, especially when they achieve a good MRD negative or a molecular remission with undetectable BCR-ABL transcript? And we used to be transplanting a lot more patients with Ph-positive ALL, but now with these better agents such as the TKIs and perhaps blinatumomab, if they are treated very early and achieve a good, very deep response, should all these patients be undergoing transplant or just continue with this type of consolidation maintenance therapy?

There are high-risk features I think that we’re beginning to learn for those patients who are not meeting those landmarks, such as the MRD-positive patients at the end of induction or certainly after consolidation. Those are proven to be high-risk patients, and for those patients, we are thinking of allotransplant for sure. But, again, for the responding patients I think that remains to be answered.

Mark R. Litzow, MD: We’re actually going to be initiating a cooperative group clinical trial next year, randomizing patients to TKI plus blinatumomab versus TKI plus hyper-CVAD to get at the answer that you were mentioning there. I think the big question is whether to transplant those patients or not. And I think you’ve moved away from transplanting patients with Philadelphia-positive ALL if they have a good response to initial therapy.

Rachel E. Rau, MD: The data suggest that most patients will do quite well with chemotherapy and TKI alone. That being said, there’s still about a 30% relapse rate among those patients. However, they’re highly salvageable. And therefore, I almost feel like the best risk strategy to identify in those who need transplant is actually relapse. I think we’ve saved a lot of kids from an unnecessary transplant, especially given that they seem to be exquisitely salvageable and you can get them to transplant and, therefore, I think that’s the better way to identify who needs a transplant.

Transcript Edited for Clarity