Azacitidine/Venetoclax Represents New Gold Standard for Older Patients with Treatment-Naïve AML

Brian A. Jonas, MD

Older patients with a median age of 68 years make up the majority of the acute myeloid leukemia (AML) population. The advanced age of these patients makes treating them with standard leukemia therapies quite difficult, which was the justification for seeking a novel strategy.

Beginning with a phase 1b study, the combination of azacitidine and venetoclax (Venclexta) demonstrated the ability to improve outcomes in this difficult to treat AML subgroup. The combination was later moved on to phase 3 in the VIALE-A clinical trial (NCT02993523) and showed encouraging results.

The median overall survival in patients who received azacitidine plus venetoclax was 14.7 months compared with 9.6 months for those who received azacitidine alone, (HR, 0.66; 95% CI, 0.52 to 0.85; P <.001), and the complete remission rate of 36.7% versus 17.9% (P <.001), respectively. Based on these outcomes, the FDA granted approval to azacitidine plus venetoclax or low-dose cytarabine as treatment of adult patients with aged 75 years or older with newly-diagnosed AML or patients who have comorbidities precluding intensive induction chemotherapy.

In an interview with Targeted Oncology following the announcement of the FDA approval of the combination, Brian Jonas, MD, assistant professor of Medicine, UC Davis Comprehensive Cancer Center, provided insight on the VILAE-A study results. He also gave expert advice on how to approach treating older patients with AML in practice.

TARGETED ONCOLOGY: Can you describe the prognosis of older patients with previously untreated AML?

Jonas: This represents a very challenging diagnosis. Anyone that sees a lot of AML patients recognizes this.One of the issues is that the population tends to be older. These patients have a median age of around 68 in the United States. This makes it challenging for many of the patients to tolerate some of the more intense chemotherapy regimens that have been developed in the past. As a result, it can be difficult to get patients into remission, or to have their remissions be durable. Overall, the prognosis has generally been considered poor for this patient population.

TARGETED ONCOLOGY: What was the rationale for combining azacitidine and venetoclax in the earlier phase 1b study?

Jonas: Azacitidine is a drug that’s been in use in patients with AML for some time. It is a so-called hypomethylating agent. It alters the epigenetic landscape of the DNA, and this affects gene expression. There is potentially some anti-leukemic activity in addition to the reprogramming [factor].

In terms of Bcl-2, this has been shown to play a big role in survival in terms of leukemia cell, in particular, leukemia stem cells. It has emerged as an important target in AML. Venetoclax targets Bcl-2 by binding to it and allowing the release of pro-apoptotic proteins that can lead to programmed cell death.

Preclinically, there’s a synergy with venetoclax and azacitidine and the combination seems to impact both the metabolic pathways in the cell as well as synergistic killing of cells. This shows that before the trial was even initiated there was evidence in the laboratory that these drugs work together and could potentially improve outcomes.

TARGETED ONCOLOGY: Can you highlight the key findings from the confirmatory study? What are the implications of these findings?

Jonas: The phase 3 VILAE-A study was a randomized placebo-controlled study comparing AZA/venetoclax to AZA/placebo and the reason that study was initiated was because in the phase 1b study, the outcomes were very impressive. The response rates were also very high, and patients were doing better than 1 would expect with azacitidine. That's what led to the starting of the phase 3 trial.

The phase 3 trial confirmed what we had already been seeing in the phase 1 study, which was the very good outcomes of the combination of azacitidine and venetoclax. In a phase 3 setting that was randomized and placebo-controlled, it was shown that the combination was superior to azacitidine monotherapy and again, this is what we saw in the phase 1 study.

Furthermore, looking at all the various subgroups, there were very similar findings in terms of high response rates in certain molecular subtypes compared to what we saw in the phase 1 study. Overall, it confirmed the security of this combination regimen and over what was historically used and in the setting of these older AML patients, and that was azacitidine monotherapy.

TARGETED ONCOLOGY: What advice would you give to other oncologists about how to manage the toxicities that may arise with this combination?

Jonas: The combination regimen has more effects on the blood counts than the monotherapy, so there are more cytopenias that occur. The other adverse events were well-tolerated. There are some gastrointestinal adverse events that impact some patients, but they are usually low-grade and manageable. The main issue is with cytopenias.

What we have learned over time using this regimen is that there are a number of interventions that can be done to manage the cytopenias and make the regimen something that patients can tolerate. One of those strategies is reducing the number of days of venetoclax in patients who achieved a response. Sometimes, some breaks between cycles are utilized to allow for blood count recovery. There is also a strategy to reduce the azacitidine dose over time. Some people also use growth factors to help support blood counts, and many of us use antimicrobials in a prophylactic setting to help reduce the risk of infection. These are all way to mitigate the blood count abnormalities that we see at a high rate with the combination compared with azacitidine monotherapy.

TARGETED ONCOLOGY: How will this combination changed practice? Beyond the VIALE-A study, what does the future hold for this combination in AML?

Jonas: I’m quite excited about the results of the confirmatory study, and I have been using this regimen. I think most oncologists out there consider this combination to be the standard of care. It has pushed the envelope from where we were before with azacitidine monotherapy.

There’s a lot of education that come into play in terms of managing the cytopenias, which I eluded to before. [Education] will help our colleagues and non-academic centers and private practices to feel comfortable using the regimen.

From a future perspective, one thing that’s intriguing about this is [the questions of] could this now serve as new backbone that for which we can add additional drugs, and can we move forward with novel combinations that built upon this. It is kind of like what we did with the 7 + 3 regimen that was developed in the 1970s. Although good outcomes were shown, we know that it doesn't cure everybody, and they're still patients who don't respond and patients who relapse. There is opportunity down the line to explore those populations.

_Reference:

_{DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020; 383(7):617-629. doi: 10.1056/NEJMoa2012971}