Evolution in Acute Myeloid Leukemia Induction Strategies

Transcript:Ruben A. Mesa, MD, FACP: We clearly are seeing at this ASH meeting a tremendous amount of interest in one of the plenary abstracts regarding the addition of a FLT3 inhibitor to patients who are FLT3 mutated, along with 7+3 chemotherapy. There’s other abstracts looking at adding sorafenib. There is a lot of interest in adding other components, specifically on the induction side. What are your thoughts around the evolution of that? Are we at a point now where that should be viewed as a new standard?

Elias Jabbour, MD: In the FLT3/ITD patient, adding PKC412 (midostaurin) to chemotherapy improved the response rate and overall survival. In our hospital, when we went retrospective with all historical data, in patients with FLT3/ITD mutation, giving FLT3 inhibitors has improved overall survival of these patients. Now, these are not randomized trials; it’s a trend in phase II studies, but you compare them in a similar patient population. They are improving survival.

The Germans have reported this trial where they added a FLT3 inhibitor (sorafenib is a FLT3 inhibitor among other kinase inhibitors) that clearly showed improvement in outcome across the board, regardless of the FLT3 status. The question is, in 2015, should we implement adding kinase inhibitors across the board for everybody? I don’t know the answer for that. However, I can tell you that at my institution, the tendency is to add sorafenib across the board.

Rafael Bejar MD, PhD: Regardless of mutational status?

Elias Jabbour, MD: Correct.

Rafael Bejar MD, PhD: Interesting.

Rami Komrokji, MD: I want to start by saying it is very exciting to have a plenary session with a study that shows survival advantage in AML. We’ve been waiting a long time for a new treatment that improves the outcome, and I think the impact of this treatment in this population that carry the mutation, from this study, is going to be important. And I think it will change the standard of care. So, in that defined population that the study had with the FLT3 inhibitor, I think that will change the standard.

I agree with Eli that I think the FLT3-mutated patients, clinically we see a benefit for them. The studies sometimes were not selected for FLT3-positive patients, but there are other things we are looking at to improve the outcomes. Some of the simple things that have been the subject of research for a long time include adding third-agent chemotherapy. There have been studies done in Europe, for example, looking at a cladribine addition to anthracycline plus cytarabine. In their studies, there was a survival advantage. This had not been adopted or used much on our side.

There are data about gemtuzumab. It was available, and it was a drug approved at one point for relapsed/refectory AML. In younger patients, adding it to the backbone of intensive chemotherapy could be a thing. Now we’re talking again about the FLT3 becoming a standard of care. So there’s exciting opportunities here to improve the outcome. I’m really very excited about the drug that shows a survival advantage in younger AML patients. We’ve not had that for a while.

Elias Jabbour, MD: I’ll add something very important. Just to finish with cladribine. We presented at the ASH meeting adding clofarabine to idarubicin and ara-C. There was a study published in the Journal of Clinical Oncology from Poland where they added cladribine to 7+3 that showed improvement in overall survival. So, in young patients who can tolerate chemotherapy, adding clofarabine to idarubicin/ara-C has shown a better event-free survival in younger patients who can tolerate chemotherapy compared to doublet.

Now, one thing we always think when we treat elderly or young patients: what is your early mortality rate at four weeks and eight weeks? And the significant progress made, at least we may ignore it or underestimate it, is supportive care. In patients who are 50 and older, by doing optimal supportive care—like induction in a laminar air flow room, antifungal therapy, antibiotics—we were able to reduce mortality by 10% at induction, which is great. We haven’t done chemotherapy yet or the prognostic features. But having good supportive care for these patients is crucial. In MDS patients, they die from infection more than acute myeloid leukemia transformation. So it’s crucial to have great supportive care and a great team in order to minimize this and then implement it.

Ruben A. Mesa, MD, FACP: I think it is so true. We can really focus on the long term in terms of who’s going to be the donor for the transplant in the high-risk patient, and in the second week, they’re in the ICU with a life-threatening infection. That could be a key part.

Rami Komrokji, MD: To your point, we actually have a poster at this ASH trying to look at the short-term mortality with induction chemotherapies. You clearly see increased mortality in patients above age of 70. Your group had published about predictors like serum creatinine, but we were thinking to create that and to see if we can move the intensive chemotherapy down the road as an outpatient regimen to try to identify patients that would be at lower risk of mortality that can be moved out. But in patients above 70, we still see around 10% to 15% mortality, and most of those are actually infection.

Transcript Edited for Clarity