General AML

Allogeneic hematopoietic cell transplantation versus chemotherapy consolidation in acute myeloid leukemia (AML)

AML patients are generally older, more frail and unable to tolerate intensive chemotherapy. Despite initial complete remission (CR), they have worse outcomes due to frequent disease relapse, occurring often within first 12–18 months. The optimal consolidation treatment regimen for these patients has not yet been determined. Celalettin Ustun from Rush University, Chicago, US and colleagues published results of a retrospective study in Leukemia, comparing outcomes for older patients receiving allogenic hematopoietic cell transplantation (allo-HSCT) with chemotherapy (CT) consolidation.1  

Patient characteristics
  • Patients 60–75 years old in first complete remission (CR1); allo-HSCT n= 431 and CT n= 211 (with median age of 64.2 and 67.9 years respectively; P < 0.001)
  • Higher white blood cells (WBC) and incidence of secondary AML in the allo-HSCT
  • Favourable cytogenetics and FLT3 mutations were more frequent in the CT arm than in the allo-HSCT arm (11% vs 1.7%; P < 0.001, and 57% vs 18%, respectively)
  • All CT patients received prior consolidation therapy vs 60% of allo-HSCT
  • Median follow-up for allo-HSCT arm was 56.9 months (95% CI, 2–96.3) and for CT arm 53.1 (95% CI, 8.6–84.5)
  • Primary endpoint of the study was overall survival (OS) and secondary endpoints included complete remission rate (CR), disease-free survival (DFS), progression-free survival (PFS), and adverse effects.
Results
  • CT consolidation improved outcomes in the initial 9 months of the therapy, thereafter patients receiving allo-HSCT had a much lower hazard ratio (Table 1)
  • OS at 5-year point was higher with allo-HSCT (28.6%, 95% CI, 24.4–33.6) than CT (13.8%, 95% CI, 9.2–20.7)
  • DFS was 23.7% (19.9-28.3%) for allo-HSCT and 11.1% (7–17.6%) for CT
  • Conditioning intensity, age, and Karnofsky performance status (KPS) had no impact on patient outcome
  • Umbilical cord blood (UCB) grafts were associated with higher treatment-related mortality (TRM), and lower OS (Table 2)

Table 1. Significant findings from the multivariate analysis.

Variables

TRM

Relapse

DFS

OS

HR (95% CI)

P value

HR (95% CI)

P value

HR (95% CI)

P value

HR (95% CI)         

P value

Therapy

 

0.0003*

 

0.0002*

 

<0.0001

 

<0.0001

Before 9 months

CT

1

 

1

 

1

 

1

 

Allo-HSCT

2.81 (1.53­–5.16)

0.001

1.04 (0.73–1.48)

0.82

1.38 (1.03–1.87)

0.03

1.52 (1.07–2.17)

0.02

After 9 months

CT

1

 

1

 

1

 

1

 

Allo-HSCT

0.74 (0.45–1.2)

0.22

0.42 (0.29–0.61)

<0.0001

0.52 (0.39–0.70)

<0.0001

0.53 (0.40–0.70)

<0.0001

Cytogenetic risk group

 

0.52

 

<0.0001

 

<0.0001

 

<0.0001

Favourable/

intermediate

1

 

1

 

1

 

1

 

Poor

1.23 (0.87–1.74)

0.25

2.12 (1.65–2.73)

<0.0001

1.74 (1.42–2.13)

<0.0001

1.74 (1.41–2.14)

<0.0001

Missing

1.03 (0.6–1.77)

0.91

1.32 (0.93–1.89)

0.12

1.20 (0.09–1.62)

0.22

1.13 (0.83–1.54)

0.43

TRM treatment-related mortality, DFS disease-free survival, OS overall survival, HR hazard ratio

Table 2. Multivariate analysis within the allo-HSCT group.

Variables

TRM

Relapse

DFS

OS

HR (95% CI)

P value

HR (95% CI)

P value

HR (95% CI)

P value

HR (95% CI)       

P value

Conditioning intensity

 

 

 

 

 

 

 

 

MAC

1

 

1

 

1

 

1

 

NMA/RIC

0.99 (0.65­–1.51)

0.95

1.39 (0.93–2.08

0.11

1.19 (0.89–1.59)

0.24

1.14(0.85–1.54)

0.39

Donor type

 

0.0004

 

0.07

 

0.0003

 

<0.0001

HLA-identical sibling

1

 

1

 

1

 

1

 

HLA partially MURD/

MMURD

1.47 (0.75–2.88)

0.26

0.70 (0.38–1.26)

0.23

0.94 (0.61–1.46)

0.79

1.05 (0.66–1.65)

0.85

HLA-well matched URD

1.23 (0.74–2.04)

0.42

0.73 (0.5–1.06)

0.1

0.88 (0.66–1.20)

0.44

0.97 (0.71–1.33)

0.85

UCB

2.69 (1.59–4.55)

0.0002

1.18 (0.77–1.80)

0.45

1.65 (1.19–2.28)

0.003

1.87 (1.34–2.60)

0.0002

TRM treatment-related mortality, DFS disease-free survival, OS overall survival, HR hazard ratio, MAC myeloablative conditioning, NMA nonmyeloablative, RIC reduced-intensity conditioning, MURD matched unrelated donor, MMURD mismatched unrelated donor, UCB umbilical cord blood

Conclusions

The study indicates improved long-term survival and reduced relapse risk in older patients with AML in CR1 on allo-HSCT therapy, especially in higher-risk populations. However, allo-HSCT was associated with higher early risk from TRM and may not suitable for patients with comorbidities. The large number of patients from multiple centres included in the analysis, especially inclusion of older patients, availability of cytogenetic data, and the long follow-up were the key strengths of the study. Also, the allo-HSCT cohort with different donor types and conditioning regiments representing broad clinical practice further strengthen the data.

The study limitations included a lack of data on; molecular profiling, minimal residual disease, comorbidities and geriatric assessment. Additionally, the CT cohort of the study may not have reflected the general population of older AML patients due to stringent selection criteria used.

References
  1. Ustun C. et al. Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study. Leukemia. 2019 May 9. DOI: 10.1038/s41375-019-0477x.
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