Academic Background

Acute Myeloid Leukemia (AML) is a malignant blood disorder, with the core of its treatment being induction chemotherapy, typically involving a combination of cytarabine and anthracyclines (such as daunorubicin). Although this treatment regimen has been in use since the 1980s, questions regarding the optimal dose of daunorubicin and the efficacy of single versus double induction remain unresolved. The original dose of daunorubicin was 45 mg/m², but subsequent studies showed that a dose of 90 mg/m² significantly improved remission rates and survival. However, the 60 mg/m² dose has been widely used in clinical practice for decades, making the comparison between 60 mg/m² and 90 mg/m² the next logical question to address. Additionally, whether a second induction is necessary for patients who respond well to the first induction remains an unanswered question.

Source of the Paper

This paper was co-authored by Christoph Röllig and multiple scholars from Germany, the Czech Republic, and other countries, published on September 16, 2024, in the Journal of Clinical Oncology. The study was conducted by the Study Alliance Leukemia and aimed to compare the efficacy of 60 mg/m² versus 90 mg/m² daunorubicin in the first induction therapy through a randomized controlled trial, as well as to explore the advantages and disadvantages of single versus double induction.

Research Process

Patient Selection and Grouping

The study enrolled 864 newly diagnosed AML patients aged 18 to 65, excluding those with acute promyelocytic leukemia. Patients were randomly assigned to receive either 60 mg/m² or 90 mg/m² daunorubicin in combination with cytarabine. On day 15 after the first induction, patient response was assessed via bone marrow cytology or histology. Patients with bone marrow blasts below 5% were defined as “good early responders” and entered the second part of the study, where they were randomized to receive either a second induction or no further induction.

Treatment Protocol

The study was divided into two parts. In the first part, patients were randomized to receive either 60 mg/m² or 90 mg/m² daunorubicin. In the second part, good early responders were randomized to receive a second induction or no further induction. The dose of daunorubicin in the second induction was adjusted based on the first induction dose to ensure the total cumulative dose did not exceed the safety threshold.

Data Analysis

The primary endpoints of the study were the proportion of patients with bone marrow blasts below 5% on day 15 after the first induction and the complete remission (CR) rate at the end of induction. Statistical analysis was performed using R software, with the primary analysis based on the intent-to-treat (ITT) principle.

Main Results

Comparison of Daunorubicin Doses

In the first randomization, the proportions of good early responders in the 60 mg/m² and 90 mg/m² daunorubicin groups were 44% and 48%, respectively, with no significant difference (p=0.983). The composite complete remission (CRc) rates at the end of induction were 90% and 89%, respectively, while the 3-year relapse-free survival (RFS) rates were 54% and 50%, and the 3-year overall survival (OS) rates were 65% and 58%, respectively, with no significant differences.

Comparison of Single vs. Double Induction

Among the 389 good early responders, the CRc rates for single and double induction were 87% and 85%, respectively, while the 3-year RFS rates were 51% and 60%, and the 3-year OS rates were 76% and 75%, respectively, with no significant differences.

Conclusion

The study demonstrated that in the context of classical 7+3 induction therapy, 90 mg/m² daunorubicin once daily does not significantly improve early response rates, remission rates, or survival compared to 60 mg/m² once daily. For patients with a good early response after the first induction, a second induction has only a limited impact on relapse-free survival and does not result in an overall survival benefit.

Highlights of the Study

1. Clarity on Dose Selection: The study confirmed that 60 mg/m² daunorubicin once daily has similar efficacy to 90 mg/m² in induction therapy, with comparable safety.
2. Necessity of Double Induction: For patients with a good response after the first induction, a second induction did not significantly improve long-term survival, suggesting that it can be omitted to reduce adverse effects.
3. Large-Scale Randomized Controlled Trial: This study, through a large-scale randomized controlled trial, provided strong evidence to support the induction therapy regimen for AML.

Significance of the Study

This study offers important clinical guidance for AML induction therapy, supporting the use of 60 mg/m² daunorubicin as the standard dose and suggesting that a second induction can be omitted for patients with a good response to the first induction, thereby reducing treatment-related adverse effects. This finding not only has scientific value but also provides important practical references for clinical practice.

Other Valuable Information

The study also mentioned that future research should focus on treatment intensification or de-escalation based on minimal residual disease (MRD) to tailor treatment to individual disease biology. Additionally, with the approval of novel targeted agents, future treatment protocols may be further optimized.