iwAL 2024 | Novel treatments & combinations in AML: mechanisms of resistance to venetoclax & approaching R/R disease

Richard Stone:

Hi. My name is Richard Stone from Dana-Farber Cancer Institute in Boston, Massachusetts. I have the honor, along with Marina Konopleva, of chairing this very exciting session, which dealt with venetoclax and azacitidine resistance in AML, which is a vexing clinical problem.

We had the fortune of hearing from two wonderful investigators, Doctors Konopleva and Cluzeau, who’ll introduce themselves in a second, who took us from the preclinical data to the clinical data we have available today. So let’s hear from Marina and Thomas.

Marina Konopleva:

Hi. I’m Marina Konopleva. I’m at Montefiore/Einstein Cancer Center in Bronx, New York. Been working on venetoclax resistance for quite some time.

Thomas Cluzeau:

Hi. I am Thomas Cluzeau from Nice University Hospital in France.

Richard Stone:

Dr. Konopleva, could you summarize some of the key reasons why patients become resistant to venetoclax based on your groundbreaking research?

Marina Konopleva:

Oh, thank you, Rich. So I think, as you said, that this is a big clinical problem because majority of the older patients unfit for chemotherapy are now being treated with this regimen. So combination of clinical data and our preclinical research identified several key mechanisms of resistance to ven-based therapies.

Ones that are emerging fairly quickly are mutations in signaling genes, such as FLT3, PTPN11, KRAS and NRAS. The way that works is they upregulate the antiapoptotic family members that are not targeted by venetoclax. So the way we think to deal with those is potentially use the signaling inhibitors that has been shown beneficial in combination with FLT3 inhibitors. There are some newer multi-kinase inhibitors that can affect RAS signaling or MAP-kinase signaling, and we are hopeful to get into AML trials of RAS, actual direct RAS inhibitors.

For the second, more difficult, I would say, mechanism of resistance, emergence of TP53 mutations or pre-existence of those mutations. So these mutations disable apoptotic cascade. They inhibit BAX activation, and this is a major mechanism of acquired and pre-existing resistance to venetoclax. Unfortunately, so far, the clinical data do not support any valuable combination in that setting. However, we think that perhaps working on downstream of P53, such as activating BAX directly could be beneficial, but this is a long way to go. We’re also working on the role of another antiapoptotic family member such as BCL-XL, and a combination of BCL-XL inhibitors with BCL2 inhibitors in this setting.

Finally, I showed the recent data from the VIALE-A study long-term follow-up looking at the mechanism of genomic resistance in patients who stayed on the study for more than two years and subsequently progressed. That’s where we showed that there were no BCL2 mutations detected. However, again, mutations in BAX were shown in 17% of patients who progressed on the study.

With that said, the mutation load for those was quite low, and they had additional mutations in the background. So what we think is that perhaps this contributes to the emergence of resistance, but they may not be the only mechanism why patients are progressing. That’s something that we are trying to understand by using single-cell sequencing and the modeling of these mutations in the laboratory.

Richard Stone:

Excellent. Thomas, you reviewed a number of strategies, clinical strategies for dealing with patients who progress after azacitidine and venetoclax, or perhaps just progress from other agents. Can you review the key ongoing clinical data?

Thomas Cluzeau:

Yeah. During my presentation, so I listed all clinical trials in relapsed/refractory setting using azacitidine plus venetoclax plus another drug.

As you know, first we need to do a molecular characterization. So I discussed for the FLT3-mutated patients, so the combination was azacitidine plus venetoclax plus gilteritinib. So the results are really interesting in term of response, but unfortunately, the median overall survival is only around six months. So this is a good combination with safety, but with a decrease of the dose of the gilteritinib at 80 milligrams per day, but the duration of response is a little bit short.

For the IDH1 and IDH2-mutated patients, we could combine azacitidine plus venetoclax plus ivosidenib (for the IDH1) and enasidenib for IDH2. There was two interesting studies showing a high level of response rate and a good duration of response using the combination.

There is one with azacitidine plus venetoclax plus IDH inhibitor, and another one with an oral treatment with ASTX727 plus venetoclax plus IDH inhibitor. Of course, the duration of response are better if there was no use of venetoclax before the relapse.

After, we discussed about KMT2A rearrangement in NPM1 patients and we have some data about azacitidine plus venetoclax plus bleximenib, and we have for the moment a really high level of response in KMT2A rearrangement patients, but also in NPM1-mutated patients.

For the other patients, I discussed two clinical trials. So one using IMGN632. This is a conjugated antibody against CD123, and the results seem to be really promising. We discussed also a publication about azacitidine plus venetoclax plus pevonedistat, but only with a few patients, but with some interesting results.

So the conclusion is that the azacitidine plus venetoclax could be a backbone at relapse, and we could maybe add some drug when, at relapse, when the patient is refractory, maybe we could discuss other design of clinical trials when there is a positive minimal residual disease persistence under azacitidine plus venetoclax.

Richard Stone:

Yeah. Picking up on that point, I’d like to ask you both the following question. As many patients have received azacitidine or chemotherapy plus venetoclax and then relapse, and we know that the duration of life after failure of azacitidine and venetoclax is measured in just several months, does it make sense to go back to using azacitidine and venetoclax? Or should we just be using these single agents as single agents, rather than subjecting the patient to more myelotoxicity? Marina?

Marina Konopleva:

Yeah, I think we discussed that a little bit at the session, but I think that venetoclax would still play a role, even in the setting of venetoclax resistance, because the data show that the blasts are refracted, they are still partially BCL2-dependent. So if you use another agent that will, let’s say, deplete MCL1 or reduce the signaling, then BCL2 inhibition will still help. So I would argue for using like a doublet, but I think there’s no role for azacitidine in that setting.

Richard Stone:

Thomas?

Thomas Cluzeau:

Yeah, I totally agree. Venetoclax, yes. And azacitidine, maybe not.

Richard Stone:

Right. So we’re maybe move from triplets to doublets-

Marina Konopleva:

Right

Thomas Cluzeau:

Yeah.

Richard Stone:

… with wonderful results. With some of the relapsed/refractory patients with the triplets involving a specific inhibitor, maybe it would’ve been just as good with venetoclax plus the specific inhibitor.

Marina Konopleva:

Right, right.

Richard Stone:

Okay. Well, this has been really a fascinating discussion and gives me at least some hope that we’ll have new agents based on rational mechanisms of actions to use for our patients with advanced AML. So thank you very much.