Naval Daver, MD
A wealth of new drugs and novel combinations has significantly improved 5-year overall survival (OS) rates for elderly patients with acute myeloid leukemia (AML); however, the remaining challenge for research involves determining where these emerging strategies best fit in with traditional therapies, according to Naval G. Daver, MD.
In addition to standard chemotherapy options, IDH1/2 inhibitors, such as ivosidenib (Tibsovo); FLT3 inhibitors, such as quizartinib; antibody–drug conjugates, such as gemtuzumab ozogamicin (Mylotarg); and more have emerged in the space.
“We are seeing the field heading toward a nonchemotherapy or low-chemotherapy backbone,” said Daver, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “For the first time now, there is a lot of excitement about developing low-intensity regimens with targeted therapy, immunotherapy, and venetoclax [Venclexta].”
In an interview with OncLive®
during the 23rd Annual
International Congress on Hematologic Malignancies,®
Daver discussed the recent advances made in AML, stressed the importance of minimal residual disease (MRD) testing, and highlighted where research in the field is heading in order to achieve a higher cure rate.
OncLive®: What are the current treatment options for patients with AML?
: There are now many treatment options for patients with AML. It has been a fantastic last 2 years, with 8 drugs approved and a couple of drugs also under FDA review. [These developments have] dramatically shifted the landscape of AML. Historically, we selected treatment based on the fitness and age of the patient. Therefore, if patients were considered fit enough to receive high-dose chemotherapy, they were given induction with the 7 + 3 regimen or the 7 + 3 “light” regimen. Those who were not considered fit enough because of their age or performance status were given low-intensity therapy. Although we were able to cure about 50% of younger patients, only about 15% to 20% of older patients were cured.
Now, with the advent of several targeted therapies, such as IDH inhibitors, we are seeing response rates of 30% to 40% as single agents. We do not think their ideal use is in the relapsed setting, because we are seeing that the use of combinations in the frontline setting with chemotherapy is leading to higher responses. The survival seems to be better [with that approach], as well.
Similarly, with other targeted agents, such as quizartinib and gilteritinib (Xospata)—both of which are very active—we see that these drugs give us about a 50% response rate in patients with FLT3
mutations who fail frontline chemotherapy. A recent randomized study showed that the use of quizartinib as a single-agent oral therapy gave us double the response rates seen with triplet chemotherapy. We also saw an improvement in OS. Even though these are pills and intuitively, we may think they will not be that powerful, we essentially doubled responses. That is where the field is moving—so that we can use these agents not in the salvage setting but incorporate them [up front], where the curative potential is greater. We have studies now combining [FLT3 inhibitors] with induction chemotherapy.
Another agent that is probably the most important breakthrough we have had in AML is a drug called venetoclax, which is a BCL-2 inhibitor. The study that was done in elderly patients with AML combined standard treatment with azacitidine alone versus azacitidine with venetoclax. That study, at this time, is ongoing in a phase III format. What we are seeing is that the combination of azacitidine and venetoclax gave us a response rate of 72%, which is 3 times higher than what has been seen with azacitidine alone. The median OS was 17 months—double that of standard therapy.
We are very excited about this because for the first time in our elderly patients with AML, we are now looking at 5-year predictive survivals of about 40%; historically, this was about 15%. This is just the beginning, because once we establish azacitidine plus venetoclax as the standard of care, the next step is going to be figuring out how to improve on that further. Can you add the FLT3 inhibitors if the patient has FLT3
mutations? Could you add IDH1/2 inhibitors? Can we add immunotherapies? We are starting several trials looking at this at The University of Texas MD Anderson Cancer Center.