Venetoclax/HMA Approach Revolutionizes Care for Certain Subsets of AML

The combination of the BCL-2 inhibitor venetoclax (Venclexta) with the hypomethylating agent azacitidine has transformed the management of certain subsets of patients with acute myeloid leukemia (AML), according to Kira Gritsman, MD, PhD.

Results from the phase 3 VIALE-A trial (NCT029935233) showed an improvement in overall survival (OS) with venetoclax/azacitidine versus azacitidine alone in treatment-naïve patients who were ineligible for intensive chemotherapy, at 14.7 months versus 9.6 months, respectively (HR, 0.66; 95% CI, 0.52-0.85; P <.001). Moreover, the incidence of complete remission proved to be higher with the venetoclax combination compared with azacitidine alone, at 36.7% versus 17.9%, respectively (P <.001).

Based on these data, and findings from the phase 3 VIALE-C trial (NCT03069352), in October 2020, the FDA granted a regular approval to the BCL-2 inhibitor for use in combination with azacitidine, decitabine, or low-dose cytarabine for patients with newly diagnosed AML who were aged 75 years or older or who had comorbidities precluding intensive induction chemotherapy.

“This is really going to revolutionize care, particularly for elderly patients with AML [in terms of] up-front therapy; [it will] also [be important for] patients who may be younger but have medical contraindications to chemotherapy,” noted Gritsman.

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on Hematologic Malignancies, Gritsman, an associate professor in the Departments of Medicine (Oncology) and Cell Biology at Albert Einstein College of Medicine, further discussed the significance of the VIALE-A trial examining venetoclax plus azacitidine in older patients with AML and the emergence of minimal residual disease (MRD) as an important end point in clinical trials.

OncLive^®: What are some of the new goals of the novel therapeutic approaches that are being explored in AML?

Gritsman: Several new agents have been approved in recent years and include small molecule inhibitors that target specific genetic subgroups. Although that ongoing effort is very important, a more recent development is focused on the idea that there may be non-genetic mechanisms of resistance or relapse. It might be difficult to cure AML by targeting specific mutations, because even if you've identified a subset of patients who have those mutations, they may have multiple clones that have different subsets of mutations. As such, the mutations that then arise at relapse may not be targeted by that drug.

A couple of strategies are being explored to target non-genetic resistance; these include targeting epigenetic mechanisms and using the immune system to eliminate AML cells, as is being done in solid tumors. Another very big [goal of] current novel therapies is to eliminate MRD, which has been associated with poor prognosis and relapse. MRD is becoming a very important end point in clinical trials.

One such approach is examining venetoclax in combination with a HMA, as was examined in the VIALE-A study. Could you speak to the clinical significance of this research?

VIALE-A was recently published in the New England Journal of Medicine [and results led to] the full FDA approval for the venetoclax and HMA combination. This study [enrolled] patients who were ineligible for standard chemotherapy, either due to age or a medical reason. [Patients] also could not have received a prior HMA, nor could they have good cytogenetics, which included acute promyelocytic leukemia.

Patients were randomized 2:1 to either venetoclax with azacitidine, or azacitidine with placebo. The results were quite impressive, with a significant overall survival benefit. The most interesting aspect of this trial is that responses [were observed] in multiple genetic subgroups of AML. The study wasn't fully powered to look at differences between genetic subtypes, but [investigators] did see significant responses in many subgroups, including TP53-mutated disease, which is a very poor prognostic category of AML.

You mentioned that MRD has become an important end point in clinical trials, and this was evaluated in VIALE-A. What was learned with regard to this?

Investigators did look at MRD as a secondary end point. In the venetoclax/azacitidine arm, one-quarter of the patients who achieved a complete response [CR] or CR with incomplete hematologic recovery were MRD negative; this [subset] experienced very prolonged survival. I believe 74% of [these] patients had a 24-month survival, which is quite significant considering that this is primarily an elderly patient population.

How do you foresee these data impacting the AML paradigm?

In the past, we really didn't have many aggressive options to offer these patients who had a significant response rate. Now, we can offer them this therapy. [However, this approach] is not completely non-toxic; a significant rate of serious adverse effects [were observed], including febrile neutropenia. Still, fewer overall toxicities [were observed with venetoclax/azacitidine] than [is typically observed with] 7+3 chemotherapy.

We now have this therapeutic option to offer these patients and it is actually becoming a new backbone for many new clinical trials investigating new agents for this type of patient population. [In these trials,] the new drug can be tested in combination with venetoclax and HMA versus venetoclax and HMA alone [because] this is really going to become the standard of care for this patient population.

What we can't say, however, is whether this would be an effective option for patients with good-risk cytogenetics, who may not be candidates for chemotherapy; that patient population was not eligible for this trial.

Are further subgroup analyses planned? What questions still need to be answered?

I'm sure there will be a push to analyze response to this treatment in different subgroups and try to understand which may be more or less sensitive [to this approach]. Even in this study where they didn't have a high number of patients in each subgroup, a very high rate of response [was observed] in patients with IDH mutations, for example. A response [was noted] in patients with TP53 mutations, but that was still a bit lower. However, you can't really compare between them in a statistically-powered fashion. That will be an important area of investigation, and also to identify potential subgroups that may not benefit [from this approach].

Are there any other emerging approaches under exploration that you want to highlight?

One major area is targeting and trying to activate p53 function. There have been a couple of different approaches that have been tested. One [approach] that is currently in the clinic that's promising is a drug called APR-246, which actually causes a structural change in the conformation of p53. [This] makes it active and allows it to activate as transcriptional targets. There are also multiple other treatments being tested that affect epigenetic regulation, including, for example, LSD1 inhibitors.

There are other inhibitors that specifically target epigenetic regulators. Many of them actually are catalytic inhibitors of enzymes. These are enzymes either affect writers or readers of epigenetic code. It's a different approach to AML treatment.

Reference

1. 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