Gabriel Mannis, MD
After a 40-year treatment paradigm with little to no change, 2017 saw 4 regulatory approvals in the field of acute myeloid leukemia (AML).
The FDA approvals of gemtuzumab ozogamicin (Mylotarg), CPX-351 (Vyxeos), midostaurin (Rydapt), and enasidenib (Idhifa) are among the exciting therapeutic advancements for the treatment of patients with AML.
Additionally, venetoclax (Venclexta) is showing promise in combination with cytarabine, based on results from a phase I/II trial. In this study, the combination achieved complete responses (CRs) in two-thirds of the patients. The combination led to CR or CR with incomplete blood count recovery (CR) in 38 of 61 patients (62%) treated with the recommended dose of venetoclax. One additional patient had a partial response. In the subgroup of patients with intermediate-risk disease status, the combination resulted in a CR of 76%.
In an interview during the 2017 OncLive®
State of the Science SummitTM
on Hematologic Malignancies, Gabriel Mannis, MD, an assistant professor of hematology and blood and marrow transplantation, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discussed novel therapies shifting the treatment paradigm for patients with AML.
OncLive: Please provide an overview of your presentation on novel therapies in AML.
The treatment of AML has essentially been the same for the last 40 years since the development of 7+3 chemotherapy. Over the past 30 years, the main improvements that have been attempted have been various additions or modifications to 7+3. Over 4 decades, none have been shown to improve outcomes for patients with AML.
In the last 40 years, there has only been one drug that has been FDA approved for the treatment of patients with AML and it was taken off the market shortly after it was approved. There is a lot of excitement in the field and we expect that, within the next year, there may be 1 or 2 more drugs approved. The treatment paradigm for AML has really changed dramatically over the last 6 to 9 months.
Of those 4 FDA-approved drugs, 1 is the FLT3 inhibitor midostaurin, which was approved in combination with 7+3 for patients with FLT3
mutations. CPX-351 was approved, which combines cytarabine and daunorubicin. In patients with secondary AML or de novo AML with myelodysplasia-related changes, CPX-351 was shown to improve overall survival, which was almost doubled for patients receiving CPX-351 compared with 7+3 chemotherapy.
For patients with secondary AML or therapy-related AML, CPX-351 is the new standard of care for fit patients who are able to undergo intensive chemotherapy. Patients like it because it has the added benefit that they do not lose their hair and it is much less toxic than standard 7+3 chemotherapy. The main downside is it concentrates in the bone marrow; therefore, the time to recovery is longer—causing patients to stay in the hospital longer than needed otherwise.
There is also an IDH inhibitor that is showing promise. One of the steps forward regarding drug development for AML is that we are realizing that not all AML cases are the same. Every patient has a unique form of AML and by understanding the molecular heterogeneity, we are able to target their AML in a personalized fashion. IDH
mutations are present in somewhere between 6% to 13% of patients. There are IDH1
mutations. The IDH2 inhibitor enasidenib was approved earlier this year in the setting of relapsed/refractory AML. It showed a 20% CR rate and a 40% overall response rate. It is well tolerated so that even older and frailer patients can receive it.
We participated in the phase I study at UCSF investigating the IDH1 inhibitor ivosidenib. It seems that the regimen will be FDA approved in early 2018.
Finally, of the 4 FDA-approved drugs, gemtuzumab ozogamicin (Mylotarg) was initially approved over a decade ago and was taken off the market. It has now been reapproved by the FDA after further studies show that a lower dose improves OS when added to 7+3 chemotherapy. The groups who benefitted were those with favorable- and intermediate-risk AML. While it benefitted patients of all ages, it is likely to be used in favorable-risk patients with AML in combination with 7+3 chemotherapy.
Reflecting on the 2017 ASH Annual Meeting, what were some exciting abstracts in AML?
One of the exciting things from the meeting was the emerging data about venetoclax (Venclexta) in AML. Venetoclax was FDA approved for the treatment of relapsed/refractory CLL, but it is being studied in combination with both hypomethylating agents and cytarabine for the treatment of elderly patients who are not fit for intensive chemotherapy. Those patients now are likely to get single-agent hypomethylating treatments or low-dose cytarabine with response rates of 20% to 30%.