Prognostic impact of FLT3-ITD and CEBPA mutations in cytogenetically normal AML

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) have varied clinical outcomes, and advances in molecular analysis in recent years have highlighted genetic diversity among these patients. Treatment strategies for CN-AML continue to be debated, particularly the suitability of hematopoietic stem cell transplantation (HSCT), and a better understanding of clinical outcomes according to mutational status may help guide treatment decisions.

In a study published in the Journal of Cancer Research and Clinical Oncology, Hong Wang and colleagues evaluated the prognostic impact of AML-related gene mutations in patients with CN-AML and the effect of these molecular markers and MRD status on outcomes after HSCT.¹ Here, we are pleased to provide a summary of their results.

Study design

Included in the retrospective analysis were 428 patients with CN-AML who achieved complete remission after induction therapy and had complete cytogenetic and molecular data.

The prognostic value of six AML-related gene mutations were evaluated: NPM1, CEBPA, FLT3-ITD, FLT3-TKD, DNMT3A, and C-KIT. Measurable residual disease (MRD) was assessed by multiparameter flow cytometry and/or PCR (polymerase chain reaction). Study endpoints were overall survival (OS) and disease-free survival (DFS).

Patient characteristics

Study patients had a median age of 43 years (range, 16–73) and most (72.9%) received an induction regimen comprising either idarubicin (8–12 mg/m²) or daunorubicin (60–90 mg/m²) on Days 1–3 and cytarabine (100 mg/m²) on Days 1–7. Consolidation therapy was intermediate/high-dose cytarabine-based chemotherapy (50.5%) or HSCT (49.5%).

Overall, 65.9% of patients had ≥1 gene mutation, 40.2% of whom had a mutation in a single gene, 18.2% had mutations in two genes, and 7.5% had mutations in ≥3 genes. The frequency of each gene mutation is shown in Figure 1.

*Data from Wang et al.¹

Risk factors affecting survival

The risk factors significantly associated with DFS and/or OS in univariate and multivariate analyses are shown in Table 1.

Table 1. Risk factors affecting DFS and OS*

chemo., chemotherapy; DFS, disease-free survival; HB, hemoglobin; HR, hazard ratio; HSCT, hematopoietic stem cell transplantation; mut, mutant; OS, overall survival; wt, wild type; y, years. P values in bold are statistically significant. *Data from Wang et al.1
Variable	DFS			OS
	3-year DFS, %	Uni-variate p value	Multi-variate HR, p value	Median OS, months	Uni-variate p value	Multi-variate HR, p value
Age (≥60 y vs <60 y)	39 vs 72	0.013	1.87 0.047	41.3 vs 79.2	0.029	1.43 0.200
HB (<100 g/L vs ≥100 g/L)	68 vs 70	0.526	—	60.7 vs 101.4	0.039	1.50 0.064
CEBPA (mut vs wt)	81 vs 65	0.013	0.55 0.044	— vs 60.7	< 0.001	0.32 0.001
FLT3-ITD (mut vs wt)	59 vs 71	0.001	2.07 0.001	36.9 vs 79.2	0.001	1.70 0.009
DNMT3A (mut vs wt)	55 vs 71	0.023	1.49 0.142	44.3 vs 79.2	0.242	—
Consolidation therapy (HSCT vs chemo.)	75 vs 63	0.042	0.71 0.124	79.2 vs 39.0	< 0.001	0.40 < 0.001

In the multivariate analysis:

• FLT3-ITD^mut was an independent prognostic factor for inferior DFS and OS;
• CEBPA^mut was an independent prognostic factor for favorable DFS and OS; and
• HSCT consolidation therapy was independently associated with favorable OS but did not reach statistical significance for favorable DFS.

In a sub-analysis of patients receiving HSCT consolidation therapy (n = 212), FLT3-ITD^mut and MRD before transplantation were each associated with worse 3-year DFS (p = 0.021 and p < 0.001, respectively) and median OS (p = 0.023 and p < 0.001, respectively); however, MRD before transplantation was the only risk factor to be independently associated with poor DFS (p < 0.001) and OS (p < 0.001) after multivariate analysis.

The prognostic effect of combined gene mutations

Patients with CEBPA^mut/FLT3-ITD^wt had a favorable prognosis, with 3-year DFS and OS rates of 84% and 90%, respectively. In contrast, patients with CEBPA^wt/FLT3-ITD^mut had a poor prognosis, with a 3‑year OS rate of just 44%. Patients with CEBPA^wt/FLT3-ITD^wt and patients with CEBPA^mut/FLT3-ITD^mut had intermediate prognoses that were comparable between the two groups.

Similarly, patients with NPM1^wt/FLT3-ITD^mut had a poor prognosis, with a median OS of just 32.5 months.

The prognostic effect of HSCT according to genetic risk group

Although HSCT consolidation therapy did not improve outcomes for patients with favorable genetics (low risk), it significantly improved outcomes for patients with intermediate or adverse genetics (standard/high risk), with superior median OS (p < 0.001) and DFS (p = 0.044) for standard/high risk transplant recipients compared with those who had not received a transplant.

Summary

Molecular analysis revealed an association between FLT3-ITD and CEBPA mutations and either poor or favorable prognoses, respectively, for patients with CN-AML. Combined CEBPA^wt/FLT3-ITD^mut status confers particularly poor OS. Consolidation with HSCT significantly improves the prognosis of patients with intermediate/adverse genetics, and MRD before transplantation is an independent predictor of outcome for HSCT recipients.