Justin M. Watts, MD
Based on advances in the understanding of the disease biology of acute myeloid leukemia (AML), numerous drugs have entered the treatment paradigm, resulting in better outcomes for particularly hard-to-treat patients, said Justin M. Watts, MD.
“Several new drug approvals have really changed the treatment landscape of AML in a way that we have never seen before and are really offering a lot of promising advances in terms of remission rates and even in overall survival (OS) for our patients,” said Watts, “including both those with newly diagnosed disease and those who have relapsed and whom we are still trying to get to allogeneic transplantation.”
In just the last 2 years, FLT3 inhibitors such as midostaurin (Rydapt) and gilteritinib (Xospata) have received regulatory approval, along with IDH1/2 inhibitors, such as enasidenib (Idhifa) and ivosidenib (Tibsovo). Venetoclax (Venclexta)-based combinations have also emerged, along with CPX-351 (Vyxeos), gemtuzumab ozogamicin (Mylotarg), and the hedgehog inhibitor glasdegib (Daurismo).
In an interview with OncLive®
during the 2019 State of the Science Summit™ on Hematologic Malignancies, Watts, an assistant professor of medicine at the Sylvester Comprehensive Cancer Center, University of Miami Health System, shed light on these promising agents and their impact in the space, discussed remaining challenges, and expressed his hope for an era where most patients with AML will be cured.
OncLive®: What are the recently approved agents in AML and where they fit in the treatment paradigm?
: In younger patients with AML, who traditionally do better than those who are older, we are using these new agents—mostly in combination with induction chemotherapy, or, in some cases, as single agents in relapsed disease. There is gilteritinib if a patient has a FLT3
mutation, or the IDH1/2 inhibitors if they have an IDH1/2
Midostaurin is the first FDA-approved FLT3 inhibitor and that's used in combination with 7+3 induction chemotherapy and consolidation therapy. That leads to an overall survival benefit; it's modest but very real. The [combination] is well tolerated and that is our standard of care if the patient has a FLT3
mutation, they’re being treated with upfront therapy, and if they’re younger than age 60.
Gilteritinib was more recently approved as a single agent for patients with relapsed/refractory FLT3
-mutated AML based on an estimated 20% response rate in those patients. OS data comparing it with salvage chemotherapy are still pending.
In terms of the IDH1/2 inhibitors, there are enasidenib and ivosidenib. Both are FDA approved now for patients with those mutations with relapsed/refractory AML, based on response rates of around 20%, complete remissions (CRs), other responders with less complete but partial remissions, and many patients with prolonged periods of stable disease and so on. There are also several reports of patients who have had very long responses with those drugs as well. Those drugs have all been approved based on response rates, except for midostaurin. However, for some of them, we are still waiting for survival data or for those studies to be completed.
Venetoclax is another new exciting drug that has been approved, but for a different indication—not for relapsed disease, and it's not for a FLT3
mutation. It's approved for use in combination with azacitidine or decitabine in the frontline setting. That [regimen] was approved based on a very impressive 60% CR rate reported in a phase II study compared with about a 20% rate of azacitidine or decitabine alone. Venetoclax is also being studied in a variety of combinations for several indications given its suppressive activity; however, this activity seems to be far greatest in patients with treatment-naïve disease, regardless of setting.
Lastly, CPX-351 is the only other agent that has [improved] OS with randomized phase III data behind it. It’s also approved for patients [as a frontline treatment], but this is a much more intensive therapy. Venetoclax does increase adverse events (AEs) compared with azacitidine or decitabine alone, but CPX-351 is quite intensive chemotherapy. It is approved based on a survival benefit in a very difficult-to-treat population of older adults with secondary type AML, meaning they had a prior myelodysplastic syndrome or therapy-related AML. There was a fairly significant OS benefit, equating to a 31% decrease in the risk of death in those who received CPX-351 versus standard 7+3. Also, higher remission rates were observed and so on.