Azacitidine–venetoclax improved event-free survival in induction-eligible AML
1. In this randomized phase 2 trial involving previously untreated adults with acute myeloid leukemia, azacitidine–venetoclax improved event-free survival compared with intensive induction chemotherapy.
2. Azacitidine–venetoclax was also associated with higher response rates, more frequent transition to hematopoietic-cell transplantation, fewer severe infectious and bleeding events, and substantially fewer inpatient days.
Evidence Rating Level: 1 (Excellent)
Study Rundown: For decades, intensive cytarabine- and anthracycline-based induction chemotherapy has been the standard initial treatment for functionally fit patients with AML. However, intensive treatment commonly causes prolonged marrow suppression, resulting in suboptimal long-term outcomes for many patients. Azacitidine–venetoclax became a standard first-line option for patients considered unfit for intensive chemotherapy after prior trials demonstrated favorable efficacy and tolerability, but whether this lower-intensity regimen could replace induction chemotherapy in fit patients remained uncertain. In this multicenter, randomized phase 2 trial, previously untreated adults with AML who were eligible for intensive induction were assigned to azacitidine–venetoclax or standard induction chemotherapy. Azacitidine–venetoclax prolonged event-free survival and produced more overall and composite complete responses. Patients receiving the combination also transitioned to hematopoietic-cell transplantation more frequently and experienced fewer serious infectious and hemorrhagic complications as well as reduced hospitalization. No clear overall-survival advantage was demonstrated, although the trial was not powered to formally assess this outcome. Strengths included randomized allocation, intention-to-treat analysis, multicenter enrollment, and assessment of clinically meaningful outcomes extending beyond remission. Important limitations included the open-label phase 2 design, modest trial size, and exclusion of patients with core-binding-factor fusions or specific gene mutations. Overall, these findings suggest that azacitidine–venetoclax may represent an effective, less resource-intensive frontline alternative to induction chemotherapy for selected patients with AML.
Click to read the study in NEJM
Relevant Reading: Venetoclax and azacitidine for younger acute myeloid leukemia patients independent of fitness for intensive chemotherapy
In-Depth [randomized controlled trial]: This investigator-initiated, open-label, multicenter phase 2 randomized controlled trial enrolled 172 adults with previously untreated AML who were considered eligible for induction chemotherapy. Participants were randomized 1:1 to azacitidine–venetoclax or intensive induction chemotherapy. Patients assigned to azacitidine–venetoclax received azacitidine 75 mg/m² on days 1 through 7 plus venetoclax 400 mg daily in repeating 28-day cycles, with modifications permitted for cytopenias and drug interactions. The induction group received either conventional 7+3 chemotherapy or CPX-351, selected before randomization. At a median follow-up of 21.9 months, median event-free survival was 14.5 months with azacitidine–venetoclax versus 6.2 months with induction chemotherapy (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.39 to 0.84; P=0.002). One-year event-free survival was 53% versus 36%, respectively. Overall response occurred in 88% versus 62% of patients, while composite complete remission occurred in 78% versus 53% of patients. Hematopoietic-cell transplantation was subsequently performed in 60% of the azacitidine–venetoclax group compared with 40% of the induction group. Median overall survival was 21.5 versus 18.0 months, with no apparent between-group difference. Severe infectious adverse events occurred less frequently with azacitidine–venetoclax than with induction chemotherapy, as did severe hemorrhagic events. During the first 30 days, patients receiving azacitidine–venetoclax spent a mean of 12.5 inpatient days compared with 27.3 days in the induction group, and no azacitidine–venetoclax recipients required ICU admission during this period compared with 10% of patients receiving induction chemotherapy. These findings suggest that low-intensity therapy may be a viable treatment option in select fit patients with AML.
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