All-oral regimen approved for older patients with AML who are ineligible for intensive chemotherapy

Abstract

The US Food and Drug Administration has approved an oral combination of the decitabine–cedazuridine hypomethylating agent (HMA) in tablet form with venetoclax for adults aged 75 years or older with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy.¹

“HMAs together with venetoclax is the current standard for older, unfit patients with AML, but now we are trying to make that treatment simpler,” says Hagop M. Kantarjian, MD, a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “Currently, when we use an HMA, it is either azacitidine given subcutaneously or intravenously daily for 7 days or decitabine given intravenously daily for 5 days. This becomes cumbersome to patients, particularly after they are in remission.”

The new all-oral combination was approved based on the results of the phase 1/2 ASCERTAIN-V trial.² All patients received 35 mg of decitabine and 100 mg of cedazuridine on Days 1–5 and 400 mg of venetoclax daily in 28-day cycles after the initial ramp-up in Cycle 1 to reduce tumor lysis syndrome. During phase 2b of the trial, decreased duration of decitabine and cedazuridine was allowed based on documented bone marrow blast clearance.

During phase 2b, 47% of patients achieved a complete response (CR), and 63% achieved a CR or CR with incomplete hematologic recovery. Among those patients who achieved a CR, 80% were still responding at 6 months, and 75% were still responding at 12 months. The median overall survival was 15.5 months.

There were no drug-drug interactions observed. During phase 2b, the most common adverse events of grade 3 or higher were anemia (30%), neutropenia (26%), and febrile neutropenia (25%).

“Traditionally, during induction, we end up admitting patients for inpatient therapy so that if there are complications, we can manage them appropriately and quickly to reduce mortality,” says Dr Kantarjian. With this regimen, the mortality rate was 3% at 30 days and 10% at 60 days. “This combination of oral decitabine with venetoclax allows us to do all the treatment as an outpatient, possibly even during induction if patients are monitored closely.”

Additionally, instead of patients coming to the clinic 7 days every month, this new regimen means that patients can come only 1 day a month, Dr Kantarjian says. However, there may be some concern about the potential cost of the oral medications.

“However, if you factor in the cost of the IV medications, cost of hospitalization, cost of clinic visits, that may even out,” Dr Kantarjian says. “Someone needs to do an analysis of the price of the drugs versus the potential benefits of all-oral therapy.”

The next steps will be to look at bringing this all-oral approach to targeted therapies, such as FLT3, IDH1, or menin inhibitors, in the form of “triplet regimens” for older patients and then perhaps also for young or fit patients with AML, Dr Kantarjian says.