AML Research Centers Around the Optimization of Available Combinations

Improving the understanding of available combinations, decreasing toxicities, and progressing toward fixed-duration regimens represent essential focuses of acute myeloid leukemia (AML) research, according to Uma Borate, MBBS, MS.

In an exclusive interview with OncLive^®, Borate discussed data from the phase 1b/2 Beat AML master clinical trial (NCT03013998); as well as the trial’s OPTI-AML substudy and its recently reported findings for 14- vs 28-day dosing schedules of azacitidine (Vidaza) plus venetoclax (Venclexta).¹ Borate also discussed where she feels the AML field needs focus future efforts to catch up to other blood cancer treatment paradigms, along with upcoming clinical trials she has her eye on.

Data from the OPTI-AML showed that patients on a 28-day schedule with the regimen for 2 cycles (n = 83) experienced a complete response (CR) rate of 49.4% (95% CI, 38.2%-60.6%) vs 43% (95% CI, 32.4%-54.2%) in patients who received the regimen on 14-day schedules (n = 86). These efficacy data ultimately did not meet criteria to show noninferiority for the shorter regimen.

Borate is a physician and professor of hematology in the Department of Internal Medicine at The Ohio State University Comprehensive Cancer Center—James in Columbus.

OncLive: What is the Beat AML master clinical trial? Why is it important for AML, and what is its ultimate goal?

Borate: The Beat AML master clinical trial launched 10 years ago, and the goal of this study was to take patients with AML who were 60 or older, which is a majority of these patients, and understand the totality of their leukemia in terms of all the different genetic changes or genomic mutations that make up their disease and then match them to targeted therapies that would help control and hopefully treat and cure their disease the best compared to standard chemotherapy.

The [OPTI-AML] study did that very successfully and showed that it was okay to wait for a week or so before we could get all the information back about a patient's genetics from their leukemia and then assign the most appropriate therapy for patients. Since then, what has happened that pertains to the OPTI-AML trial is that we've had this amazing progress in the treatment of AML in older patients, where we treat patients with hypomethylating agents and venetoclax. [Azacitidine plus venetoclax] came into force in 2018 and was fully approved in 2020, and since then, a lot of our older AML trials have evolved to include this combination. Thus, OPTI-AML is a natural evolution of what the master clinical trial was designed to do.

What was the rationale behind OPTI-AML? What is the history of azacitidine and venetoclax dosing schedules in AML?

The genesis of this trial came after 2018 when we had this amazing, relevant advance for older patients with AML where treating them with a combination of a hypomethylating agent, azacitidine plus a BCL2 inhibitor, venetoclax, extended survival significantly for up to almost 14 months to 15 months in these patients. The way these drugs were given together, specifically venetoclax, is for 28 days for the first cycle, then a bone marrow biopsy is done, and if the patient's leukemia is in good control, you wait for the counts to come up, and then you do the same thing again for 28 days.

Over the last 5-plus years since this [schedule] has been used widely, in the AML community. In community practices, it's been recognized that doing these 28-day cycles for 2 months in a row can be toxic to patients if they continue to have really low blood counts and be pan-cytopenic for prolonged periods of time. [These toxicities] in turn make them susceptible to infections, some of which can be fatal, lead to hospitalizations, or [lead to] prolonged infections like fungal infections. There's a lot of interest in the community in shortening the duration of venetoclax, and there have been several retrospective studies looking at 7, 14, and 21 days of venetoclax and whether they provide the same amount of efficacy as the entire 28 days for the first 2 cycles.

However, we never had any prospective data on [these schedules]. [Therefore], we designed the OPTI-AML trial to address the question: Can we randomly assign patients with AML who are 60 or older of any genomic makeup, all genomic subtypes were included, to either 28 days for 2 cycles or 14 days for 2 cycles? [We chose] 2 cycles because more than 80% of patients get a response in these 2 cycles, they're important to get good disease control initially. The primary end point of the study looked at if patients achieve a CR at a prespecified statistical rate with the 14- vs 28-day schedule.

What efficacy data was shown for different dosing schedules of azacitidine and venetoclax in AML? How effective was each schedule with patients harboring mutations?

We just had the complete OPTI-AML results come out in Blood, and bottom line is: The 14-day schedule was not the same in terms of CR rates to the 28-day schedule. The study was designed as a noninferiority study, and what we showed was that the 14-day schedule did not meet the noninferiority statistical end point compared to the 28-day schedule, CR rates with the 28-day schedule were actually higher. CR rates for the 28-day schedule were close to 47% compared with 43% with the 14-day schedule.

On the flip side of that, there was hope or hypothesized by all of us, including the AML community, that giving less than would at least help with toxicities, cytopenias, shorter stays in the hospital, fewer fatal infections, and maybe even fewer people dying early of their complications. [These improvements in toxicities] were not shown to be the case. The same number of people on both arms ended up with low blood counts and needing to be in the hospital. The rate at which patient counts recovered was actually the same in both arms, thus, reducing the venetoclax by 14 days did not mitigate what we know to be common toxicities with the 28 days.

The CR rates for the primary end point did not meet noninferiority; however, because the confidence interval of these two numbers was large, it is hard to conclude if one was better than the other. We cannot say for sure that [these schedules] are the same. We also did show that for certain genomic subtypes like NPM1 and IDH2, the 28-day arm seemed to get more of those patients into a CR compared with the 14-day arm.

However, a huge caveat [is that] these are very small subsets. The study was not powered for this in totality, in both arms we only had 10 NPM1-mutated patients, we don’t make some sweeping conclusions based on small subsets, but [these data] are hypothesis-generating and provocative. [For patients with NPM1 mutations] who do really well, we definitely don't want to undertreat for any reason. The AML community really needs to focus on looking at specific genomic subsets of AML and really determining how much venetoclax is appropriate for those subsets. If we took out patients with NPM1 and IDH2 mutations and looked at everybody else, patients did the same in terms of CR rates with both schedules. There's clearly a subset of patients with AML who are older who might be just fine with less than 28 days for 2 cycles, but our study was not powered to look at specific subsets; it was an all-comers population.

Why is it important to optimize currently available treatments in AML? Where should the AML field focus future research?

We all want novel breakthroughs; we all want the next best thing that can cure your disease. The reality is, for a lot of our older patients, the treatments that we currently have are treatments that are prohibitive for them because of toxicities. If we keep giving [patients who are older] treatments that are proved to be toxic, they're going to spend a lot of the time they have left in our clinics and our hospitals and without good quality of life. [Therefore,] it’s just as important to optimize the dosing and toxicities of existing treatments for our older patients with AML as it is to have new, amazing, and curative breakthroughs, that’s why this question of what is the right dose of a currently approved therapy to reduce toxicities and maintain efficacy is so important. Along those lines, I would take it a step further and ask: Even if we do get the right dose of venetoclax, these therapies are meant to be given forever, for a subset of patients with AML that are older that are not going to go to curative stem cell transplant, can we do time limited therapies?

This has been explored in chronic lymphocytic leukemia and many other blood cancers. Can we do the same in AML?. Can we give [treatment] to patients for 12, 16, or 18 months, and then stop, follow their disease or minimal residual disease and see what happens, instead of continuing to expose them to therapy for years? [Fixed duration regimens are] probably somewhere the next frontier that would be really good to look at.

A phase 1 trial [NCT03013998] that we've talked about extensively was led by Joshua Zeidner, MD, and has already been published in the Journal of Clinical Oncology… [this trial] will give more information about the three-drug combination of azacitidine, venetoclax, plus revumenib [Revuforj] for our older patients who have NPM1 or KMT2-mutations.² This is really novel because you're adding a third drug to this backbone, and we really want to understand the effectiveness, but also the toxicities of this triplet regimen. [This trial is] something to watch for.

References

1. Borate UM, Huang Y, Lin TL, et al. OPTI-AML: prospective comparison of 28 vs.14 days of venetoclax induction with azacitidine in older adults with AML. Blood. doi:10.1182/blood.2026034611
2. Zeidner J, Lin T, Welkie R, et al. Azacitidine, venetoclax, and revumenib for newly diagnosed NPM1-mutated or KMT2A-rearranged AML. J Clin Oncol. 2025;43:2606-2615. doi:10.1200/JCO-25-00914