All-oral chemotherapy regimen tolerable and efficacious for newly diagnosed acute myeloid leukemia

1. In this phase 1-2 trial involving patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy, an all-oral regimen of decitabine–cedazuridine plus venetoclax was well tolerated without higher-grade toxic effects.

2. In the phase 2b segment, a complete response was achieved in nearly half of patients who received the intervention.

Evidence Rating Level: 2 (Good)

Study Rundown: For patients with newly diagnosed acute myeloid leukemia (AML) who are poor candidates for intensive induction chemotherapy, venetoclax plus a parenteral hypomethylating agent is standard lower-intensity therapy. However, the need for repeated parenteral treatment visits remains burdensome. Oral decitabine–cedazuridine has been found to yield pharmacokinetic exposure comparable to intravenous decitabine, raising the possibility of a fully oral venetoclax-based regimen. This phase 1-2, open-label, multicenter trial evaluated oral decitabine–cedazuridine plus oral venetoclax in patients with newly diagnosed AML who were 75 years of age or older or otherwise ineligible for intensive chemotherapy. Overall, the regimen showed no drug–drug interaction and had encouraging activity in the pivotal phase 2b cohort, with complete response in nearly half of patients and median overall survival beyond 1 year. Toxicity was driven mainly by myelosuppression, but later schedule adjustments appeared to reduce post-remission adverse events. The generalizability of these findings was limited by the nonrandomized design, lack of a direct comparator, and absence of formal quality-of-life assessment. Nonetheless, these results suggest that an all-oral venetoclax-based approach may be a feasible alternative for selected older or unfit patients with newly diagnosed AML.

Click to read the study in NEJM.

Relevant Reading: Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia

In-Depth [prospective cohort]: This open-label, multicenter, nonrandomized trial enrolled 189 patients across 34 centers in the United States, Canada, and Spain, including 30 patients in phase 1, 58 in phase 2a, and 101 in the pivotal phase 2b cohort. Eligible patients had newly diagnosed AML, were 75 years of age or older or had coexisting conditions precluding intensive chemotherapy, and received oral decitabine–cedazuridine on days 1 through 5 plus oral venetoclax after a ramp-up. In phase 2b, schedule shortening was allowed after bone marrow blast clearance to mitigate prolonged cytopenias. Of patients in phase 2b, 81% qualified on the basis of age of at least 75 years, and 24% had adverse cytogenetics. In phase 2b, complete response occurred in 47% of patients (95% confidence interval [CI], 36 to 57), and complete response or complete response with incomplete hematologic recovery occurred in 63% (95% CI, 53 to 73). Among patients with complete response, 75% (95% CI, 57 to 87) maintained response at 12 months. Median overall survival was 15.5 months (95% CI, 7.6 to not estimable). While p-values were not reported due to the lack of a direct comparator group, the prespecified phase 2b efficacy criterion was met because the lower bound of the 95% CI for complete response exceeded the historical threshold of 17.9%. The safety profile of the regimen was generally as anticipated, with adverse events of any grade in 99% of patients, serious adverse events in 84%, and treatment-related adverse events of grade 3 or higher in 72%. The most common treatment-related grade 3 or higher adverse events were anemia (30%), neutropenia (26%), febrile neutropenia (25%), platelet count decrease (25%), and thrombocytopenia (20%). Mortality was 3% at 30 days and 10% at 60 days. Among responding patients, serious adverse events declined from 62% to 28% by cycle 4, while febrile neutropenia declined from 39% to 14%, supporting the dose-modification strategy used in later cycles.

Image: PD

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