https://www.onclive.com/peer-exchange/acute-myeloid-leukemia/emerging-therapeutic-approaches-in-acute-myeloid-leukemia?sp=
Emerging Therapeutic Approaches in AML

Panelists:Rafael Bejar MD, PhD, UCSD Moores Cancer Center; Elias Jabbour, MD, MD Anderson Cancer Center; Rami S. Komrokji, MD, Moffitt Cancer Center; Ruben A. Mesa, MD, FACP, Mayo Clinic Cancer Center



Transcript:

Ruben A. Mesa, MD, FACP:
It’s a great segue, because I think we identified that this is a very tough group of patients. As I try to instruct my fellows on acute leukemia, I really try to take the words ‘good risk’ out of their lexicon. I think sometimes it can be confusing for patients. I think it can be a bit misleading. As I look at AML, it’s really a question of poor risk or horrible risk. When you really look at the comparison to other illnesses, it’s a very, very serious illness for which we clearly have made great strides. But it’s still a very catastrophic illness, and patients are very fortunate if they’re able to overcome their disease. So, clearly, the focus is strongly on new therapies: how can we impact them further? Elias, you brought up the issue of ABT-199 as one promising agent. Let’s have a bit of a discussion around some of the promising agents in this space. Why don’t you tell us a little bit about that one and where that might play a role?

Elias Jabbour, MD: There’s plenty of new drugs, a plethora of new agents. Pick and choose, and do the combination you want. Just to remind everybody that the FDA has not approved any drug in the last 20 years for AML, except for Mylotarg (gemtuzumab ozogamicin) that was withdrawn from the market. So we really need treatment for these patients. There are plenty of agents. Among them you mentioned venetoclax or ABT-199. It induces MRD-negativity in CLL. In AML, it’s a BCL-2 inhibitor, anti-apoptotic, and all these paths are being targeted. The drug was used as a single agent. Adding ABT-199 to decitabine, it’s really a good combination. You can induce responses, a 70% response rate and higher in an unfit patient, newly diagnosed. It’s better than decitabine alone, by the way. We induce MRD-negativity.

I’m not sure about duration of response. We don’t have the data yet, and the data are not so mature. But at least we can have a good response, achieve a deeper response, and go for transplant. If we’re going to go for transplant, send the best population you have for transplantation if they are fit. If not, at least have a good response and maintain it. I may go for induction with combination and move over to a maintenance program with decitabine. We’re seeing new data coming from the oral formulation of azacitidine, for example. That is about ABT-199. It’s being explored in AML, soon in ALL and in CLL, among others.

We had the vosaroxin, which is a topoisomerase inhibitor. There was a randomized study presented last year at the ASH, by Farhad Ravandi, where patients in [the] relapsed setting were randomized to either high-dose ara-C or high-dose ara-C and vosaroxin. The primary endpoint was not met, although as a preset design, patients who did not go for transplantation who are elderly, most of them, did have a survival improvement. The drug is not approved. It may get an approval in Europe, but we’re using this drug for MPN/MDS patients transforming into AML, unfit for chemotherapy in combination with decitabine.

There was a presentation at the ASH meeting combining decitabine and vosaroxin. The drug can cause severe mucositis, can have some complications. The lower dose, 70 mg/m2, is better than the higher dose. It’s still unknown whether it’s better than decitabine alone or not. You know when you do the phase II, you get so excited. You go for a phase III study, you get disappointed, or sometimes you can have 10 days improvement or a month’s improvement. It’s not enough in leukemia, but in pancreatic cancer, it can get you a Nobel Prize.

There are other interesting compounds being presented at the ASH meeting: IDH2 inhibitors, IDH1, IDH2. They’re being used as a single agent in these patients—although the allele level doesn’t change with therapy—but they go into response, late responses. Single-agent monotherapy? I don’t think it’s enough, but at least we have a good signal to go for a combination and, hopefully later on, a randomized trial. The sorafenib FLT3 inhibitors are a family present to stay. We use sorafenib off-label because it’s not approved for AML, but we will have the first drug hopefully approved as a FLT3 inhibitor.

We had the Mylotarg in the past. We have new antibodies, different than the Mylotarg, being assessed for CD33 expression. Rami mentioned the CD123, as well, an antibody by Johnson & Johnson and others. They have drugs, as well as monoclonals, being assessed. Spliceosome modulators, as well. We have a plethora of drugs, the IDAs. As Rafael mentioned, let’s have the good personalized medicine. Let’s use the drug where really we can induce a response. Because if it’s given to everybody, than we get neutral results and nobody know what’s going on.

Ruben A. Mesa, MD, FACP: There’s whole different avenues of investigation which really are quite exciting. I was looking at the breakdown of the different oral sessions for therapy for AML, of which there are multiple. Now, one potential avenue is being discussed in another plenary abstract by Omar Abdel-Wahab’s group from Memorial around the spliceosome and whether that can be leveraged or targeted some way in myeloid mutations. Rafael, why don’t you walk us through a little bit in terms of the spliceosome and a little bit about how those observations may be something we might be able to leverage in the future?

Rafael Bejar MD, PhD: So what people discovered clinically was that these splicing factors are often mutated in myeloid malignancies, and including some cases of AML, as well. What we know is that these splicing factor mutations only affect one gene. We never really see two splicing factor genes mutated together, and one of the reasons that might be is because these two hits aren’t tolerated. It suggests that further disruption of the spliceosome might actually not be something that the cells can tolerate; it might cause cell death.

So, in the abstract that you mentioned, the investigators generated a mouse model where the mouse carries the mutation that we see in patients and then treated those mice with an inhibitor of the spliceosome. And what they found was that the cells that carry that mutation were selectively sensitive to that agent, whereas the normal hematopoietic cells that don’t have any preexisting abnormalities of the spliceosome could tolerate the treatment. So we may actually have a therapeutic window to treat with a splicing inhibitor, a type of drug that we typically don’t think of as an antineoplastic or a cancer drug.
                                                                                                                                                                                                                                                                                                              
Transcript Edited for Clarity
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