Allo-HSCT vs consolidation chemotherapy in younger patients with intermediate-risk AML

The optimal selection of patients with acute myeloid leukemia (AML) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an area of research that continues to evolve.¹ For patients with favorable-risk AML who achieve first complete remission (CR), there is a clear benefit associated with high-dose cytarabine-based consolidation chemotherapy, whereas patients with high-risk AML with adequate performance status and a suitable donor are candidates for allo-HSCT.

However, while allo-HSCT may be associated with lower rates of relapse in patients with intermediate-risk AML, there is an increased risk of transplant-related mortality. Moreover, at present, there is no agreed optimal treatment strategy for patients classified as intermediate risk; therefore, there is a need to explore the most beneficial therapy for this patient group.¹

Here, we summarize the key points from the ETAL-1 trial by Bornhäuser et al.¹ published in JAMA Oncology, evaluating allo-HSCT versus standard consolidation chemotherapy in patients with intermediate-risk AML.

Study design and patient characteristics

This was a phase III, prospective, randomized controlled trial (NCT01246752) conducted across 16 centers in Germany from 2011–2018. Eligible patients were aged 18–60 years with intermediate-risk AML in first CR or CR with incomplete hematological recovery, with a human leukocyte antigen-matched sibling or unrelated donor available. Patients were randomized 1:1 either to allo-HSCT or consolidation chemotherapy group according to:

• Age (18–40 years vs 41–60 years),
• NPM1 and CEBPA variant status
• Donor type (unrelated vs related)

In the consolidation chemotherapy group, patients who experienced hematologic or molecular relapse could subsequently receive allo-HSCT.

The primary endpoint was overall survival (OS). Secondary endpoints included disease-free survival (DFS), cumulative incidence of relapse (CIR), treatment-related mortality, and quality of life measured according to the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and safety.

In total, 76 patients were randomized to receive allo-HSCT and 67 patients to consolidation chemotherapy (Table 1).

Table 1. Patient characteristics*

Key points

Survival outcomes

• The 2-year OS rate was similar between the two groups (Figure 1).
• The 2-year DFS rate was higher in the allo-HSCT group compared with the consolidation chemotherapy group (Figure 1).

Figure 1. Survival outcomes by treatment group*

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; DFS, disease-free survival; OS, overall survival.
*Data from Bornhäuser, et al.¹

• Predefined subgroup analysis revealed that patients in the allo-HSCT group with non-favorable-risk AML, compatible unrelated donors, aged ≤40 years and >40 years, or who were male, had improved DFS compared with those in the consolidation chemotherapy group (Figure 2).
• Similar OS was also observed between the treatment groups (Figure 2).

Figure 2. The A OS and B DFS outcomes in patients treated with allo-HSCT versus consolidation chemotherapy by subgroup* 

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; DFS, disease-free survival; ELN, European Leukemia Network; HLA, human leukocyte antigen; HR, hazard ratio; OS, overall survival; UD, unrelated donor.
*Adapted from Bornhäuser, et al.¹

• Post hoc analysis of patients with intermediate-risk AML showed:
  • No OS advantage in the allo-HSCT group compared with the consolidation chemotherapy group at 2 years (76% vs 83%, respectively).
  • 2-year DFS rates were higher in the allo-HSCT group than the consolidation chemotherapy group (70% vs 39%; p = 0.02).

Non-relapse mortality, relapse incidence, and safety

• Allo-HSCT was associated with higher rates of 2-year non-relapse mortality but lower 2-year CIR compared with consolidation chemotherapy (Figure 3).

Figure 3. 2-year NRM and CIR by treatment group* 

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; CIR, cumulative incidences of relapse; NRM, non-relapse mortality.
*Data from Bornhäuser, et al.¹

• All 41 patients in the consolidation chemotherapy group who relapsed received allo-HSCT either directly (n = 20) or after salvage therapy (n = 21).
• Incidences of serious adverse events were similar between the allo-HSCT group (74%) and the consolidation chemotherapy group (74%).

Quality of life outcomes

• The SF-36 scales were similar between the treatment groups.
• Patients in the allo-HSCT group had a shorter median duration of in-hospital stay (median, 42.5 days; interquartile range, 31.0–62.0) than patients in the consolidation chemotherapy group (median, 106.0 days; interquartile range, 72.0–143.0; p < 0.001).

Conclusion

While allo-HSCT was associated with improved DFS, this did not translate to an OS benefit in patients aged <60 years with intermediate-risk AML. Patients in the consolidation chemotherapy group who already had suitable donors identified were able to receive allo-HSCT either directly or after salvage therapy. Given the results of this study, younger patients with intermediate-risk AML may benefit from consolidation chemotherapy with measurable residual disease monitoring to detect early signs of potential relapse in patients for whom allo-HSCT may be beneficial. Further studies that apply longitudinal monitoring of measurable residual disease to optimize the timing of allo-HSCT for patients are warranted.