Catherine Lai, MD, MPH

The treatment landscape for acute myeloid leukemia (AML) has changed dramatically over the past 3 years, and of all the options that have become available, venetoclax (Venclexta) has had the most significant impact in the management of patients with newly diagnosed disease who are older or ineligible for intensive chemotherapy, according to Catherine Lai, MD, MPH.

“The response rates with this agent can be similar to some of our induction chemotherapy regimens; however, the toxicity profile is significantly different,” noted Lai, who added that the combination of the agent with the hypomethylating agent azacitidine led to a 34% reduction in the risk of death when compared with azacitidine alone in the phase 3 VIALE-A trial.

Results presented during the 2020 European Hematology Association Congress showed that at a median follow-up of 20.5 months, the median OS was 14.7 months with the combination versus 9.6 months with azacitidine alone (HR, 0.66; 95% CI, 0.52-0.85; P <.001); this translated to a 34% reduction in the risk of death.

The complete remission (CR) rate was significantly higher with the combination, at 36.7% versus 17.9% with azacitidine alone (P <.001). The composite CR was also higher with venetoclax/azacitidine versus azacitidine alone, at 66.4% versus 28.3%, respectively (P <.001).

“We now have several new therapies in AML; some are very exciting and have shown excellent responses. Some have less efficacy and we must consider the toxicity profiles to determine whether their use is in the patient’s favor,” explained Lai. “In clinically stable patients, it's important to wait for all mutation test results to return prior to making any treatment decisions. When patients relapse, we must then repeat the mutation testing. Lastly, we must be mindful of the combinations we are giving along with [plans for] sequencing; the goal is to maximize the patient’s duration as well as quality of life.”

In an interview with OncLive^®during the 2020 Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Lai, the director of Leukemia at MedStar Georgetown University Hospital’s Lombardi Comprehensive Cancer Center, discussed the significance of venetoclax in the AML treatment paradigm, the data from the VIALE-A trial, and remaining challenges faced in practice.

OncLive^®: What has been the impact of venetoclax in AML?

Lai: The treatment landscape for AML has changed dramatically in the past 3 years. Prior to this, we were mostly using a variation of traditional cytotoxic chemotherapies. Since 2017, 8 new FDA approvals have entered into our armamentarium. Some of the most commonly used combinations consist of venetoclax with a hypomethylating agent, as well as targeted agents, such as FLT3, IDH1 and IDH2 inhibitors.

Of all the drugs that have been recently approved, venetoclax has had the greatest impact on how we treat our patients with newly diagnosed disease who are older or unfit for intensive chemotherapy.

Moreover, this agent allows for patients to be treated in the outpatient setting, which is important, especially since these patients are older and at risk for infection. This is particularly important in light of the coronavirus disease 2019 pandemic.

Could you provide some background on the VIALE-A trial?

VIALE-A is a randomized, phase 3 study comparing ventoclax plus azacitidine to azacitidine alone that followed the initial single arm trial of ventoclax plus a hypomethylating agent. Although the use of venetoclax with a hypomethylating agenthas been FDA approved, [that decision] was based on [data from] a non-randomized study. It’s important to have subsequent phase 3 data to prove efficacy.

Results from this study showed that the response rates do, in fact, hold [true] to the initial data that were presented. When you compare the 2 arms, a significant difference was observed between those in the venetoclax/azacitidine arm and those who received azacitidine alone. The CR rates were about 37% in the venetoclax/azacitidine arm compared with approximately 18% in the azacitidine-alone arm.

The composite CR rate was approximately 66% in the combination arm compared with 28% in the monotherapy arm. Notably, the median time to first response was 1 month, thus, we are seeing responses early on. It's important to do bone marrow biopsies after the first cycle of therapy to determine timing of subsequent cycles.

Furthermore, the trial showed that the duration of response [with the combination] was longer by approximately 4 months. It was very helpful that this study looked at rates of transfusion independence.

Investigators evaluated the rate of red blood cell transfusion independence and it was discovered that this occurred in about 60% of patients on the combination arm compared with about 35% of patients on the monotherapy arm. For those who aren't achieving remission but can still achieve transfusion independence, I believe that is an important end point to look at. Especially for older patients, it’s important to try to maximize their quality of life.

What does the safety profile of this combination look like?

With the combination, we are seeing prolonged cytopenias and as aresult, patients are at increased risk of fungal infections. Depending on type of anti-fungal prophylaxis used, dose modifications to venetoclax may be needed.

This is certainly a subtle nuance of the combination; oncologists who treat many leukemia patients are aware of this, because we see these patients every day. However, this is a great opportunity for local oncologists to learn how to use this combination by co-managing patients with their academic specialists.

You also mentioned that advances have been made for patients with IDH1/2 mutations. Could you expand on these new developments?

IDH1/2 mutations are not common in AML but there are 2 targeted agents: ivosidenib (Tibsovo) for IDH1-mutated disease and enasidenib for IDH2-mutated disease. In general, it's important to ensure that we're getting next-generation sequencing panels on all patients as well as cytogenetics and FISH so that we can really understand the heterogeneity of the AML.

Recent data presented at ASH 2019 showed no change in OS based on time to treatment. For patients who are clinically stable, it’s important to ensure that we're waiting for mutation results to return prior to making any treatment decisions.

The VIALE-A data and the initial phase I/II study evaluated venetoclax in combination with a hypomethylating agent in a subset of patients who presented with different mutations. They specifically looked at those with FLT3, IDH1, IDH2, and p53 mutations.

Patients with IDH1 and IDH2 mutations had a significant response and did very well with the combination. I think it is important to think about how to optimize sequencing of treatment. Although many new combinations work very well, it’s important to remember that most [patients] will eventually relapse.

In your own practice, how do you choose among the available therapies?

We need to speak with our patients about their overall goals for treatment. Many new options have emerged, and this is overwhelming to patients. We should ask questions, such as whether they have a life event coming up or day to day goals, and then we can work backward to figure out the best course of therapy. Fitness is also important in AML, physiologic age plays a bigger role than chronologic age. In older patients who are ‘fit’, I tend to treat them more intensively because that can sometimes translate into a longer OS. I also look at their mutation profile since this can determine treatment options and help predict response to therapy.

Are there any unmet needs in this space?

There's an unmet clinical need in patients who have p53 mutations because these patients tend to be insensitive to traditional cytotoxic chemotherapy. We must seek better therapies for these patients with the goal of a sustained complete remission that will allow patients the opportunity to move onto allogeneic BMT. Two agents currently being studied in p53-mutated disease are APR-246 and magrolimab. Both appear to have very promising activity.

What challenges remain with regard to sequencing?

The main issue is that we don't know what the best sequence is yet with regard to these newer agents. We also don’t know whether combinations of novel drugs (e.g.- triplets) are superior to doublets or cetain targeted single agents because there's a risk-benefit profile in terms of toxicity. For example, if you're combining 3 drugs in the up-front setting, there's likely to be more toxicity. However, there is potential for an earlier CR or MRD-negativity, which may translate into a longer OS and hopefully better quality of life. We do not know whether giving all 3 drugs up front is the same as giving 2 drugs followed by 1 drug, or 1 drug followed by 2 drugs will have equal efficacy. We need additional clinical trials to answer these questions.

Reference

DiNardo C, Jonas B, Pullarkat V, et al. A randomized, double-blind, placebo-controlled study of venetoclax with azacitidine vs azacitidine in treatment-naïve patients with acute myeloid leukemia ineligible for intensives therapy-VIALE-A. Presented at: EHA25 Virtual; June 11-21, 2020; Virtual. Abstract LB2601. https://bit.ly/2FHmIvc.