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2023-04-05T09:29:57.000Z

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

Apr 5, 2023
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Learning objective: After reading this article, learners will be able to discuss clinical factors of relevance when considering allo-HSCT in patients with intermediate-risk AML.

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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*

Characteristics, % (unless otherwise stated)

Allo-HSCT
(n = 76)

Consolidation chemotherapy
(n = 67)

Median age (range), years

50.5 (19.0–60.0)

51.0 (24.0–60.0)

Age group

 

 

               18–40 years

21

16

               41–60 years

79

84

CEBPA status

 

 

               Biallelic variant

5

1

NPM1 status/FLT3-ITD status

 

 

               Variant/variant

17

20

               Variant/wild-type

25

22

               Wild-type/variant

7

5

               Wild-type/wild-type

51

53

               Missing

9

4

ELN 2017 category

 

 

               Favorable

32

28

               Intermediate

66

69

               Adverse

2

3

Available donor

 

 

               Matched sibling

24

34

               Matched unrelated (10/10)

67

52

               Mismatched unrelated (9/10)

9

13

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; ELN, European Leukemia Network; ITD, internal tandem duplication.
*Adapted from Bornhäuser, et al.1

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.

  1. Bornhäuser M, Schliemann C, Schetelig J, et al. Allogeneic hematopoietic cell transplantation vs standard consolidation chemotherapy in patients with intermediate-risk acute myeloid leukemia: a randomized clinical trial. JAMA Oncol. Online ahead of print. DOI: 10.1001/jamaoncol.2022.7605

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