Lower overall survival in ELN favorable-risk AML with DNA-MR mutations

The 2017 European LeukemiaNet (ELN) recommendations separate patients with acute myeloid leukemia (AML) into three risk groups (favorable, intermediate, and adverse) based on significant chromosomal aberrations and gene mutations. However, some studies have suggested that prognosis may vary within the favorable group depending on mutations that are not included in the ELN risk criteria, such as DNA methylation mutations in regulatory regions (DNA-MR) of genes such as DNMT3A, IDH1, IDH2, and TET2. James Yu and colleagues have evaluated the impact of DNA-MR mutations on the outcomes of patients within the 2017 ELN favorable-risk group from a single-center study.¹

Results of this study were presented as an oral abstract at the 2021 Transplantation & Cellular Therapy (TCT) Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR) by James Yu and are summarized below.

Study design and patient characteristics¹

All adult patients with AML who underwent intensive induction at the AdventHealth Orlando Hospital, Orlando, US, in 2017–2020 were reviewed. Those with acute promyelocytic leukemia or therapy-related AML were excluded from the analysis, while those with de novo AML or myelodysplastic syndrome-related AML were included. Next generation sequencing was carried out on the 124 remaining patients, using a target panel of 53 AML-related genes, including the DNA-MR genes of TET2, DNMT3A, IDH1, IDH2, and SETBP1. Patients were defined as positive for DNA-MR gene mutations if at least one of these genes were mutated.

Patients were classified into four groups:

1. ELN favorable with DNA-MR gene mutations (n = 18)
2. ELN favorable without DNA-MR gene mutations (n = 23)
3. ELN intermediate (n = 40)
4. ELN adverse (n = 43)

Patient characteristics can be seen in Table 1.

Table 1. Patient characteristics*

BM, bone marrow; Hb, hemoglobin; HSCT, hematopoietic stem cell transplantation; PB, peripheral blood; PLT, platelet; WBC, white blood cell. *Data from Yu et al.1
Characteristic	N = 124
Median age, years	61.5
Female, %	39.5
Median WBC count, 103/µL	9.7
Median PLT count, 103/µL	53.0
Median Hb level, g/dL	8.0
Median BM blast, %	51.0
Median PB blast, %	42.0
Karyotype abnormality               No, %               Yes (at least 1), %	54.8 45.2
HSCT, %	45.2

Overall survival and relapse-free survival were analyzed between the four groups using a two-tailed log-rank test, with a 5% significance level.

Results

The median follow-up of all patients was 57.3 weeks.

Incidence of DNA-MR gene mutations¹

• DNA-MR gene mutations occurred in 43.9% of patients in the ELN favorable-risk group and were less common in the intermediate and adverse groups (32.5% and 18.6%, respectively).
  • A breakdown of the type of DNA-MR gene mutations in the favorable risk group can be seen in Figure 1. Mutations in the DNMT3A gene were the most common, occurring in 22% of patients.

*Data from Yu et al.¹

Overall survival¹

The median overall survival was significantly decreased in patients in the ELN favorable-risk group with DNA-MR gene mutations compared to those without, or those in the ELN intermediate group; but was similar to that of patients in the ELN adverse group (Table 2).

Table 2. Median overall survival*

Bold type indicates statistical significance. ELN, European LeukemiaNet; DNA-MR, deoxyribose nucleic acid methylation regulatory gene mutations; OS, overall survival. *Data from Yu et al.1
Group	Median OS, days	p-value (comparison with Group 1)
1 (ELN favorable with DNA-MR)	299
2 (ELN favorable without DNA-MR)	NR	0.0002
3 (ELN intermediate)	987	0.0159
4 (ELN adverse)	422	0.9641

Relapse-free survival¹

Relapse-free survival was significantly decreased in patients in the ELN favorable-risk group with DNA-MR gene mutations compared to those without (Table 3).

Table 3. Median relapse-free survival*

Bold type indicates statistical significance. ELN, European LeukemiaNet; DNA-MR, deoxyribose nucleic acid methylation regulatory gene mutations; RSF, relapse-free survival. *Data from Yu et al.1
Group	Median RFS, days	p-value (comparison with Group 1)
1 (ELN favorable with DNA-MR)	511
2 (ELN favorable without DNA-MR)	NR	0.0141
3 (ELN intermediate)	494	0.9436
4 (ELN adverse)	305	0.5826

Co-occurrence of DNA-MR gene mutations with genetic abnormalities in the ELN favorable group¹

• DNA-MR gene mutations co-occurred with NPM1 mutations in 94% of patients in Group 1 (ELN favorable with DNA-MR mutations)
• Only one patient (5.5%) had a DNA-MR gene mutation that co-occurred with CBFB-MyH1
• DNA-MR mutations were not found to co-occur with RUNX1-RUNX1T1 or CEBPA-biallelic mutations in this cohort

Conclusion

DNA-MR gene mutations are common in patients with AML who are deemed to have favorable-risk status by the 2017 ELN criteria. They were associated with a less favorable prognosis in terms of both overall and progression-free survival compared with patients without these mutations. Moreover, these outcomes were similar to those of patients who are deemed as intermediate- or adverse-risk by the 2017 ELN criteria.

As DNA-MR gene mutations often co-occurred with NPM1 mutations, the authors suggest that perhaps this group of patients should have a different management regimen, for example, by being offered a hematopoietic stem cell transplantation in order to improve prognosis.

Limitations to the study include the relatively small sample size and that the prognostic effect of each individual type of DNA-MR gene mutation was not taken into account. Furthermore, the effects of AML treatments that effect DNA methylation, such as azacitidine or other demethylation agents, were also not analyzed as part of this study. Therefore, further studies in a larger population are required to confirm these results.