10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial

Abstract

Background: Venetoclax with hypomethylating agents is a new standard of care for newly diagnosed (ND) patients with acute myeloid leukemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine which has shown promising results in high-risk AML in phase 2 trials. We hypothesized that venetoclax with 10-day decitabine may be effective in ND and relapsed/refractory (R/R) AML, particularly for high-risk subgroups. Methods: This phase II study enrolled 168 patients with ND AML older than 60 years, secondary AML (sAML), and R/R AML. Patients were required to have an ECOG performance status of 3 or less, WBC less than 10×109/L, and adequate end-organ function. Ineligibility for intensive chemotherapy was based on the treating physicians’ assessment. Patients with favorable-risk cytogenetics, e.g., t(15;17) or core-binding factor AML, or prior BCL2-inhibitor therapy were excluded. Patients received decitabine 20mg/m2 IV for 10-days with oral venetoclax 400mg daily (DEC10-VEN) for induction, followed by decitabine 5-days with venetoclax for consolidation. The primary efficacy endpoint was overall response rate (ORR). The trial was registered on Clinicaltrials.gov, number NCT03404193 and continues to accrue patients. Findings: Between January 19, 2018 and December 16, 2019, we enrolled 70 patients; (42%) had ND AML, 15 patients (9%) had untreated sAML, 28 patients (17%) had treated sAML, and 55 patients (33%) had R/R AML. The median age was 71 years (IQR, 65–76) and 30% patients had ECOG performance status of 2 or higher. The ORR among all patients was 74% (95% CI 67, 80) and in disease subgroups were: ND AML, 89% (95% CI 79, 94); untreated sAML, 80% (95% CI 55, 93); treated sAML, 61% (95% CI 42, 76); and R/R AML, 62% (95% CI 49, 74). The most common treatment-emergent adverse events included infections with grade 3/4 neutropenia (n=84, 50%) and febrile neutropenia (n=49, 29%). There were six grade 5 adverse events including five infections with therapy-related grade 3/4 neutropenia, and one case of renal failure unrelated to study regimen. Interpretation: DEC10-VEN is safe and has high activity in ND AML and molecularly defined R/R AML subsets. Funding: NIH/NCI R01CA235622