What is the treatment approach for Acute Myeloid Leukemia (AML) as investigated in the AML96 trial?

AML96 Trial: Treatment Approach for Acute Myeloid Leukemia

The AML96 trial demonstrated that post-remission treatment for AML should be risk-stratified based on patient and disease characteristics, with allogeneic stem cell transplantation benefiting favorable-risk patients and autologous transplantation showing superior outcomes for intermediate-risk patients. 1

Overview of the AML96 Trial

The AML96 trial was a multicenter study that enrolled 909 patients with AML, including:

• 586 patients aged 15-60 years who achieved complete remission after double induction therapy
• Median age of 67 years for the elderly cohort (range 61-87 years)
• Exclusion of patients with t(8;21) translocation

Key Treatment Components

1. Induction Therapy:

   • Standard cytarabine-based induction with anthracycline 2, 3
   • Double induction approach to achieve complete remission

2. Post-Remission Treatment (PRT):

   • Priority-based and risk-adapted allocation to:
     • Allogeneic stem cell transplantation
     • Autologous stem cell transplantation
     • High-dose cytarabine consolidation chemotherapy

Risk Stratification in AML96

The trial developed a prognostic model (PRT score) based on five independent factors 1:

• Age
• Percentage of CD34-positive blasts
• FLT3-ITD mutant-to-wild-type ratio
• Cytogenetic risk
• De novo vs. secondary AML

This model stratified patients into three risk groups with significantly different survival outcomes:

• Favorable risk: 3-year survival 68%
• Intermediate risk: 3-year survival 49%
• Unfavorable risk: 3-year survival 20%

Treatment Outcomes by Risk Group

Favorable Risk Group

• Allogeneic HSCT showed superior outcomes (82% survival)
• Compared to autologous HSCT (66%) and chemotherapy (55%)

Intermediate Risk Group

• Autologous HSCT demonstrated best outcomes (62% survival)
• Compared to allogeneic HSCT (44%) and chemotherapy (41%)

Unfavorable Risk Group

• Overall poor outcomes regardless of treatment approach
• 3-year survival of only 20%

Elderly AML Patients in AML96

For patients >60 years (n=909), the trial showed 4:

• Complete remission rate of 50%
• 5-year overall survival of only 9.7%
• Development of a risk score for elderly patients based on:
  • Karyotype
  • Age
  • NPM1 mutation status
  • White blood cell count
  • Lactate dehydrogenase
  • CD34 expression

Current NCCN Recommendations Based on Similar Principles

The NCCN guidelines incorporate similar risk-stratification principles 2:

1. Favorable-risk cytogenetics/molecular markers:

   • High-dose cytarabine consolidation without transplant

2. Intermediate-risk cytogenetics:

   • Consider allogeneic HSCT with HLA-identical sibling
   • Autologous HSCT may be beneficial based on AML96 findings

3. Poor-risk features:

   • Allogeneic HSCT recommended, even with unrelated matched donor

Important Considerations and Pitfalls

• Timing is critical: Early identification of transplant candidates during induction is essential 5
• Age considerations: Patients <60 years generally have better transplant outcomes 5
• Comorbidities: Pre-existing conditions significantly impact treatment tolerance 2
• Novel agents: The treatment landscape has evolved since AML96 with targeted therapies for specific mutations (FLT3, IDH1/2) 6, 7
• Venetoclax combinations: For older/unfit patients, venetoclax with hypomethylating agents has become standard 2, 8

Conclusion

The AML96 trial provided valuable insights into risk-stratified post-remission treatment for AML, demonstrating that allogeneic HSCT benefits favorable-risk patients while autologous HSCT may be optimal for intermediate-risk patients. This risk-adapted approach continues to inform modern AML treatment strategies, though the landscape has evolved with the addition of targeted therapies and novel combinations.