Venetoclax Spearheads Myriad of AML Advances

Jacqueline S. Garcia, MD

One of the most exciting advances made in the acute myeloid leukemia (AML) paradigm has been the addition of venetoclax (Venclexta), said Jacqueline S. Garcia, MD, as the agent has been shown to have high response rates with durable remissions.

“What was really striking is, venetoclax, which is an oral BH3 mimetic that targets the antiapoptotic protein called BCL-2, looks to be modestly active as a single agent, but very active when used in combination with active AML drugs, such as cytarabine, or hypomethylating agents like azacitidine or decitabine,” said Garcia, a physician at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School.

Venetoclax received accelerated approval from the FDA in November 2018 for use in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of patients with newly diagnosed AML, ≥75 years of age, who have comorbidities that preclude the use of intensive induction chemotherapy.

The regulatory decision was based on data from two early-phase trials: M14-358 and M14-387. In the M14-358 trial, treatment with venetoclax plus azacitidine resulted in a 37% complete remission (CR) rate and a 24% CR with partial hematological recovery (CRh) rate. Furthermore, the combination of venetoclax and decitabine showed CR and CRh rates of 54% and 7.7%, respectively. The M14-387 trial evaluating the combination of venetoclax and low-dose cytarabine (LDAC) led to CR and CRh rates of 21%.

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Garcia highlighted key progress made in AML and remaining questions with maintenance strategies.

OncLive: How would you describe the current AML treatment paradigm?

Garcia: Treatment in AML has changed over the last 18 months due to a bevy of new drugs that have received approval. When we think about AML, [treatment] depends on the age of the patient and what their mutation profile looks like. For the most part, for patients who are able to receive intensive chemotherapies, we're still using standard induction chemotherapy or maybe the liposomal formulation called CPX-351 (Vyxeos). This is based on the recent approval for therapy-related AML or AML with myelodysplastic-related changes due to the survival benefit seen there.

For patients who are older, or those who are not eligible for this type of intensive regimen, a new treatment that is available, which has been exciting and promising that recently received accelerated approval is venetoclax plus hypomethylating agents, which include decitabine or azacitidine. It has also been approved for use in combination with low-dose cytarabine. We're still waiting for survival data.

Could you discuss the impact of the venetoclax approval? How does this agent impact the space?

Much of the excitement that has been generated in the field in the last 6 months was the venetoclax approval. In cancer cells, we know that antiapoptotic proteins like BCL-2, MCL1, or even Bcl-XL, could be expressed to different degrees. And, what we've learned about cancers is that there's a balance that exists between these antiapoptotic or proapoptotic proteins. Apoptosis means initiation of cell death; cancer cells can't die unless chemotherapeutic drugs can initiate that [death]. What’s striking is that when venetoclax works, it causes binding directly to BCL-2, which is an antiapoptotic protein, which then releases it from proapoptotic factors, which can then [allow it to] initiate cell death.

We've learned through the chronic lymphocytic leukemia cohorts, there was a ton of activity, which led to the approval. Fortunately, when using the combination in patients with AML, we've also seen striking activity with response rate, which is as high as 70% in particular in patients with non-favorable chromosomes or cytogenetics. This has been promising.

What's also notable is that the durability of the remission is close to 1 year for most patients, but for those who were treated at the dose that led to the FDA approval, the median duration of remission and survival has not yet been met, suggesting to us that there could be patients who can benefit from therapy long-term. They also noticed that there was good depth of response for patients who were able to have minimal residual disease (MRD) negativity at certain time points. Because of that negativity, they were able to predict patients who would have longer durations of remissions. That has been exciting to us, as it suggests that not only is the drug effective, but [it induces] durable and deep [responses].

[In terms of] our older patients with AML, we have been lacking in that arena. Now, for the first time, there are more patients that we can probably transplant that we never thought that we could and there are more therapies available that we didn't think could be entertained. It has been promising and very exciting. A phase III study, which is currently ongoing, will confirm the survival benefit with venetoclax plus azacitidine.

What promising chemotherapy regimens are currently under investigation?

On an investigational level, we recently had an approval for patients with therapy-related or secondary AML or AML with myelodysplastic-related changes with CPX-351. Other approaches that are currently under investigation and look to be very promising, includes standard induction chemotherapy plus FLT3 inhibitors. The data [of 7 + 3] in combination with crenolanib looks very good, showing a very high complete remission rate—well over 80%—and it also looks to be quite tolerable. The combination of 7 + 3 with IDH1/2 inhibitors is also very exciting.

Those data were also presented at the 2018 ASH Annual Meeting. Essentially, when we use the same backbone, we've been able to add active selective targeted therapies; but then again, that only provides therapies for about one-third of the patients who present. As such, we need a lot more therapies available. There are ongoing studies that have just begun. [Some are] looking at midostaurin (Rydapt) in patients with FLT3 wild-type disease. Since it's a [less-targeted] first-generation kinase, there may be additional patients who benefit [from that approach]. [Results from the] RATIFY trial, led to the FDA approval of midostaurin for FLT3-mutated AML. As midostaurin, similar to sorafenib (Nexavar), and other drugs that we've used in AML are active, we are looking to see whether or not patients with FLT3 wild-type disease might benefit, too. There are also some smaller investigational studies looking to combine venetoclax with upfront therapies or MDM2 inhibitors so there's a lot more to come.

What maintenance options are available for those who are not candidates for transplant?

Quite frankly, it still is not quite clear what to do with maintenance therapies. Maintenance therapy suggests that someone is already in a deep remission. We’ve been very fortunate to have more therapies that can get patients into deep remissions, but how long can patients stay in remission? Our tools for measuring MRD or measurable genetic or cytogenetic disease are still undergoing evolution, and we are still trying to integrate them into current practice. It's not like how it is in acute lymphoblastic leukemia, where MRD assessment is standard of care and it's very clear at what time points patients should be tested. In AML, it's still something that we're trying to figure out.

However, we have a lot of tools available, including [multiparameter flow] cytometry and deep genetic testing, whether or not its qPCR or next-generation sequencing or digital droplet platforms. We have the tools available, and much of the data so far look like persistent MRD does portend poor outcome or increased risk of relapse compared with those who don't have those features. However, it still remains unclear what time points to check.

There have been a few subsets of AML where the data has been clearer, primarily because the data are more mature and our technique for how we evaluate the disease was also more thought out. That [data] include patients with core-binding factor leukemia or those who have a NPM1 mutation. In terms of maintenance therapies now, because we don't know how to fully measure MRD in terms of what time points yet, it makes the question [of maintenance a] hard [one].

There was a recent clinical trial that used azacitidine to try to reduce relapse, and what was notable was that although disease-free survival was increased, overall survival was not met. It's still not clear what the role of azacitidine is. Furthermore, in that particular clinical trial, MRD was not presented, so we don't know what those data look like yet. If you pick out the highest-risk patients, you might be able to select patients who would be most likely to benefit, and spare those who otherwise wouldn't need it, of any additional toxicity.

In terms of the post-transplant patients, there has been much more mature maintenance studies that are ongoing or have been published. [That research] includes the use of drugs like FLT3 inhibitors. There are investigational therapies with IDH inhibitors, and there have been many published studies with hypomethylating agents. More recently, there was a large study that The University of Texas MD Anderson Cancer Center led with low-dose azacitidine, and it looked to be a negative study. There was still a high risk of relapse that did not look like it was reduced with the implementation of this good therapy, suggesting that we need to do a better job with these patients in terms of offering them more effective therapies in the maintenance setting.

It remains unclear what to do with maintenance right now, and it definitely deserves a lot of attention since we're starting to get more patients into remission. Everyone can still go to transplantation depending on their fitness. Donor availability is less of an option nowadays, now that we have many alternative options available. However, because of age and comorbidities, it does make us think—what else we can do for patients without causing them further harm?

FDA Prescribing Information for Venetoclax. Accessed April 26, 2019. rxabbvie.com/pdf/venclexta.pdf.