For more than four decades, the combination of cytarabine and daunorubicin, known as 7+3, has anchored induction therapy for medically fit patients with newly diagnosed acute myeloid leukemia (AML). Venetoclax-based combinations were originally established for patients considered unable to tolerate intensive chemotherapy.

Recent randomized studies suggest that some fit patients achieve better leukemia control with less toxicity, shorter hospitalization and a greater chance of reaching stem cell transplantation. This challenges the assumption that intensive chemotherapy must work better in patients able to receive it.

Why 7+3 Has Lasted

7+3 has endured because it reliably induces remission, and decades of experience have established how to combine it with consolidation and allogeneic stem cell transplantation. Its limitations are equally familiar. Patients may spend several weeks in hospital with profound cytopenias, infections and bleeding complications, and relapse remains common after successful induction, especially in adverse-risk AML.

In 2002, the expression “SAB,” meaning “same as before,” was used to describe the slow evolution of AML induction. Outcomes were improving, but much of the progress came from better supportive care, antimicrobial treatment and transplantation practices. Higher daunorubicin doses, gemtuzumab ozogamicin and FLT3 inhibitors each improved outcomes in selected subgroups, and CPX-351 improved survival in older patients with secondary or therapy-related AML, which shows that AML does not respond to induction as one disease.

Venetoclax Entered the Debate

Venetoclax entered AML treatment through a different population. VIALE-A showed azacitidine-venetoclax outperformed azacitidine alone on response and overall survival in patients unfit for intensive chemotherapy, and venetoclax has since paired well with low-dose cytarabine too, confirming BCL2 inhibition as a legitimate backbone.

Later experience showed that responses could be rapid and deep, including measurable residual disease negativity in some patients, and that treatment could often begin without the extended inpatient induction associated with 7+3.

Randomized Comparisons

Earlier comparisons of venetoclax-based therapy and intensive chemotherapy relied heavily on historical controls or nonrandomized cohorts, making interpretation difficult.

In a phase 2b study from China of 188 adults aged 18-59 years, venetoclax plus decitabine was compared directly with idarubicin and cytarabine. The venetoclax combination met the noninferiority criterion and produced a higher composite complete remission rate, approximately 89% vs 79%. Patients required less transfusion support and had fewer severe infectious complications, including pneumonia, febrile neutropenia and sepsis. Adverse-risk patients appeared to benefit more from the venetoclax combination, and core-binding-factor AML, especially RUNX1::RUNX1T1-positive disease, favored intensive chemotherapy.

Another randomized study, NCT06066242, compared azacitidine plus venetoclax, conventional intensive induction and a hybrid intensive/venetoclax approach in adults aged 60-75 years. Early event-free and overall survival were similar across groups, with a possible advantage for azacitidine plus venetoclax in adverse-risk disease. Early follow-up, low transplantation rates and intensive consolidation after remission in some patients limit interpretation. Both studies showed that reducing induction intensity does not necessarily compromise leukemia control, and neither established a survival advantage over intensive chemotherapy.

PARADIGM

PARADIGM enrolled 172 adults with newly diagnosed AML who were considered eligible for intensive chemotherapy at nine US academic centers. Patients received azacitidine plus venetoclax or conventional induction with 7+3 or CPX-351. Median age was 64 years, and 72% had adverse-risk AML by European LeukemiaNet 2022 criteria.

At a median follow-up of 21.9 months, median event-free survival was 14.5 months with azacitidine plus venetoclax and 6.2 months with intensive chemotherapy, a hazard ratio of 0.57. Overall response rates were 88% and 62%, and composite complete remission rates were approximately 78% and 53%. Conventional complete remission rates were closer, at 56% and 49%, so part of the composite advantage came from remissions with incomplete hematologic recovery.

The trial was not powered to show an overall survival advantage. Median overall survival was 21.5 months with azacitidine plus venetoclax and 18.0 months with intensive chemotherapy, a difference that was not statistically significant. Given the phase 2 sample size, the enrichment for adverse-risk AML and the exclusion of important molecular groups, larger studies are needed before the findings can support a broad change in standard treatment.

Toxicity and Hospital Time

Grade 3 or higher infections occurred in 28% of patients receiving azacitidine plus venetoclax and 41% of those receiving intensive chemotherapy. Severe hemorrhagic events occurred in 2% and 12%.

The difference in hospital use was larger. During the first 30 days after randomization, patients on the venetoclax combination spent an average of 12.5 days in hospital, compared with 27.3 days with intensive chemotherapy. Over the first six months, mean inpatient time was 39.3 versus 58.5 days. Weeks in hospital during induction can affect physical function, nutritional status, independence and employment, and add to the caregiver burden.

Access to Transplantation

Sixty percent of patients receiving azacitidine plus venetoclax proceeded to allogeneic transplantation, compared with 40% of those receiving intensive chemotherapy.

For many patients with adverse-risk AML, transplantation offers the best established chance of long-term disease control, so induction has to achieve remission while preserving the organ function and performance status needed for the procedure. A patient who reaches remission but develops severe infectious or organ complications, or whose consolidation is delayed, may lose the opportunity to be transplanted.

PARADIGM did not randomize patients to transplantation, and differences in postremission decisions, response or clinical recovery could contribute to the observed rates. The study also cannot show whether patients transplanted after azacitidine plus venetoclax have the same relapse risk as those transplanted after intensive chemotherapy.

Which AML Subtypes Still Favor Intensive Induction?

The evidence does not support abandoning 7+3 across AML. PARADIGM excluded patients with core-binding-factor fusions, FLT3 mutations, and NPM1-mutated AML under age 60. Core-binding-factor AML does best with intensive cytarabine-based induction, consistent with the RUNX1::RUNX1T1 result in the Chinese study. Favorable-risk NPM1- or CEBPA-mutated AML can also respond durably to intensive chemotherapy with consolidation guided by molecular response.

In FLT3-mutated AML, adding a FLT3 inhibitor to intensive chemotherapy has improved survival. Triplet regimens combining a FLT3 inhibitor with aza-ven have shown encouraging results, but randomized evidence is needed before they can replace intensive induction.

Adverse-risk AML is where the PARADIGM results are most relevant. Conventional chemotherapy often produces short-lived responses, transplantation is frequently needed for durable control, and aza-ven may be an effective induction option for selected patients. TP53-mutated and MECOM-rearranged leukemia remain difficult to treat, and the favorable results in the broader adverse-risk group cannot be assumed to apply to them.

Intermediate-risk AML may be the hardest group in which to choose an induction strategy. Some patients achieve long-term remission with chemotherapy-based consolidation, and others have enough relapse risk to benefit from transplantation. The decision rests on molecular risk, donor availability, treatment response and MRD results.

Measurable Residual Disease

Randomized studies show that venetoclax-based combinations can achieve MRD-negative responses in patients eligible for intensive chemotherapy. Whether these remissions protect against relapse as durably is unknown. Patients can reach transplantation with similar MRD results after different induction regimens, and their outcomes then depend on residual resistant clones, conditioning intensity, donor immune effects and maintenance therapy.

Trials in Molecular Subgroups

Upcoming trials focus on genetic subgroups, where intensive regimens are the established comparator. VINCENT compares azacitidine plus venetoclax with intensive chemotherapy incorporating gemtuzumab ozogamicin in NPM1-mutated, FLT3-wild-type AML. VICTOR tests venetoclax plus low-dose cytarabine against an intensive chemotherapy-based approach in older patients with similar molecular features, with particular attention to molecular disease control.

QUIZZICAL pits quizartinib combined with azacitidine and venetoclax against quizartinib-containing intensive induction in FLT3-ITD-mutated AML. These trials may show where venetoclax-based treatment can replace conventional induction, particularly in the molecular subgroups excluded from PARADIGM.