Oral Decitabine and Cedazuridine Plus Venetoclax Shows Efficacy, Safety for Older or Unfit Patients With AML

Decitabine and cedazuridine (ASTX727), an oral formulation of decitabine which is able to accomplish equivalent area-under-curve exposure to intravenous decitabine, plus venetoclax demonstrated efficacy as a fully oral regimen and was found to be safe for most older or unfit patients with acute myeloid leukemia (AML), according to a recent phase 2 study.

“Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukemia who are ineligible for intensive chemotherapy,” explained Alexandre Bazinet, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas, and coauthors.

This ongoing study enrolled patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. These patients 75 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 to3, or major comorbidities, or were patients with relapsed/refractory (R/R) AML. Being aged 18 years or older and having an ECOG performance status of 2 or less were requirements for the R/R disease treatment cohort, without any limits in the number of previous lines of therapy.

Treatment consisted of ASTX727 (cedazuridine 100 mg and decitabine 35 mg) orally for 5 days and venetoclax 400 mg orally for 21 to 28 days, in 28-day cycles. The primary outcome was the overall response rate (ORR) of ASTX727 plus venetoclax. Living patients who didn’t complete the first cycle were not evaluable for response. The data cutoff for the analysis for this study was Sept 22, 2023. Between March 16, 2021, and Sept 18, 2023, 62 patients were enrolled (49 frontline and 13 R/R) with a median age of 78 years (interquartile range [IQR] 73 to 82). The median follow-up time was 18.3 months (IQR 8.8 to 23.3). The ORR was found to be 30 (64%) of 47 patients (95% CI, 49 to 77) in the frontline cohort and 6 (46%) of 13 patients (19 to 75) in the R/R cohort.

Safety was assessed among all patients who started treatment, and the most common grade 3 or worse treatment-emergent adverse events were found to be febrile neutropenia in 11 (18%) of 62 patients, pneumonia in 8 (13%), respiratory failure in 5 (8%), bacteraemia in 4 (6%), and sepsis in 4 (6%). Study authors noted that 3 deaths occurred in patients in remission (1 sepsis, 1 gastrointestinal hemorrhage, and 1 respiratory failure) and were potentially treatment-related. 

In conclusion, “ASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukemia,” concluded Bazinet and colleagues.

“Our findings should be confirmed in larger multicentric studies,” they added.

Source:

Bazinet A, Garcia-Manero G, Short N, et al. Oral decitabine and cedazuridine plus venetoclax for older or unfit patients with acute myeloid leukaemia: a phase 2 study. Lancet Haematol. Published online March 4, 2024. doi:10.1016/S2352-3026(24)00033-4