Triplets With Azacitidine/Venetoclax Aim to Improve Responses in AML

Courtney D. DiNardo, MD, MSCE

Although the combination of azacitidine (Vidaza) and venetoclax (Venclexta) has become a standard-of-care regimen in the treatment of patients with acute myeloid leukemia (AML), triplet therapies built off this backbone could improve outcomes and address unmet needs for subsets of patients, according to Courtney D. DiNardo, MD, MSCE.

“Azacitidine plus venetoclax is a fantastic treatment for AML. We have more patients responding than ever before and survival is better. However, we don't want to stop there; it's not a curative regimen that's good enough for everyone. We want to consider adding [agents to create] triplets on that [backbone],” said DiNardo, who presented on triplet therapies in AML at the 2023 SOHO Annual Meeting.

In an interview with OncLive^®, DiNardo discussed ongoing investigations of triplet regimens with an azacitidine/venetoclax backbone for the treatment of patients AML, highlighted the unmet needs that remain in older and high-risk subgroups within this patient population, and expanded on the importance of considering the toxicity profiles when studying triplet regimens. DiNardo is an associate professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center and an associate member at The University of Texas Graduate School of Biomedical Sciences in Houston.

OncLive: What has the combination of azacitidine and venetoclax meant for the AML treatment paradigm?

DiNardo: Azacitidine [plus] venetoclax is the current, new standard of care for older patients with AML, which is the majority of patients with AML. [The combination] has revolutionized our treatment of AML and has led approximately] two-thirds of patients achieving responses such as complete remission and remission with complete count recovery. This has extended survival to approximately 15 months, so this is much better than [past] survival that was consistently under a year. However, this is still not good enough. We don't want to have the story end there, which is why we're talking about moving beyond just azacitidine and venetoclax.

What unmet needs are novel triplet therapies aiming to address?

The most important thing is that azacitidine and venetoclax is not a curative regimen on its own. [Approximately] two-thirds of patients will respond, and that's fantastic, but [that means] one-third of patients don’t [respond]. Therefore, we want to have better options for capturing an initial response in those patients.

Of those who do respond, unfortunately, patients will relapse eventually—some sooner than others. Some of those unmet needs [are in] patients who tend to relapse earlier, [such as] patients with p53 mutations and signaling mutations, including FLT3. Those are populations with a particular need.

Could you highlight some of the azacitidine and venetoclax–based triplet regimens currently under investigation?

I started [my presentation] with a conversation of triplets including FLT3 inhibitors. Patients with FLT3-ITD–mutated AML tend to be in that group of patients who don't respond as well or as long as others [to azacitidine plus venetoclax]. Therefore, there's an unmet need there. It makes sense for [patients with] for FLT3-ITD mutations to add a FLT3 inhibitor to the azacitidine/venetoclax backbone. We did see [in a phase 1/2 trial (NCT04140487) of the combination of azacitidine, venetoclax, and gilteritinib (Xospata)] that responses tended to be better. However, one question [surrounds] tolerability. Can we make this a safe thing to do for our older patients with AML? I believe the answer is yes, but we have to modify the dosing a little bit.

I also talked about the role of potentially adding a purine analog, such as cladribine or fludarabine, for patients with a more monocytic phenotype, [who] often have some signaling mutations as well. There are some data there. I also spoke about adding an IDH inhibitor. Although patients [with IDH mutations] are not the ones who do the worst with azacitidine and venetoclax, this is not a curative regimen. Can we do better? Can add an IDH1 or IDH2 inhibitor [to improve outcomes] for those targeted subsets?

For triplets using the azacitidine/venetoclax backbone, are there any toxicity concerns when adding a third agent to the regimen?

Azacitidine/venetoclax is a myelosuppressive regimen compared with azacitidine alone. When adding in something else, you want to ensure that you're not compounding myelosuppression. That is the [the most important] thing when it comes to the adverse effect [AE] profile and the things to be monitoring.

We'll often do shorter venetoclax durations. we will do earlier bone marrows [assessments] around day 14 to see if they've cleared their leukemia and shorten the venetoclax duration that way. Sometimes with the synergistic activity of venetoclax with targeted therapy, such as a FLT3 inhibitor, you need lower doses of the FLT3 inhibitor. That is also something that we're paying attention to, and we're evaluating in ongoing trials.

How could the investigation of triplet regimens affect the AML treatment landscape?

Thus far in our early clinical trial data, [triplets with the azacitidine/venetoclax backbone] have led to improved, deeper remissions. The hope is that this will continue to carry forward, but with a focus on managing the AE profile and toxicity. This includes the management of myelosuppression and ensuring that we identify the right combinations and the right duration of venetoclax to make sure that these therapies are well tolerated and patients are deriving benefit.

Beyond triplets, is there any other ongoing research in AML that you're intrigued by?

There are a lot of exciting things going on in AML. I would say that the next class of therapy that's got the AML community the most excited would be menin inhibitors. We are excited about those and the ongoing trial data. From my perspective, I love the genomics of AML and targeted therapies. Therefore, I believe that some of our updated sequencing opportunities, as well as identifying mutations and tracking minimal residual disease, are key next steps and an important avenue for us.

Hopefully, the world of immuno-oncology is going to hit the myeloid space. We're still working there, but there are a lot of exciting new things happening.

Reference

DiNardo C. Triplet regimens in AML: beyond azacytidine plus venetoclax. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.