Gene mutation-based treatment decision tools can identify elderly AML patients who benefit from intensive treatment

The main incidence of acute myeloid leukemia (AML) is elderly patients ≥60 years of age
.

Although the survival rate of young AML patients has been significantly improved in recent years, the survival rate of elderly AML patients has not changed significantly
.

The current standard treatment for elderly AML patients with younger or better physical status is still intensive chemotherapy, and some patients can be treated with sequential allogeneic hematopoietic stem cell transplantation (Allo-HSCT)
.

Genetic changes are a key prognostic factor for AML patients receiving intensive treatment.
However, due to the differences in the genomic characteristics of elderly AML patients with young AML patients, related studies mainly explore the prognostic value of genetic changes in young AML patients
.

Although some recent studies have explored the prognostic value of a wider range of reproducible genetic abnormalities in the elderly AML population, the results of related studies have not yet been able to guide the treatment decisions of elderly AML patients
.

In order to better design and carry out randomized studies of intensive treatment and lower-intensity treatment suitable for elderly AML patients, it is necessary to develop specific treatment decision-making tools to determine which part of the elderly AML patients can benefit from the treatment of the "7+3" regimen.

.

Research methods Prospective, multi-center, ALFA1200 study enrolled AML patients who were ≥60 years old and received intensive chemotherapy with the "7+3" regimen
.

The researchers designed a reproducible classification system based on the sequencing results of the patients' 37 genes.
The elderly AML patients included in the study were divided into groups to distinguish the patients who benefited from the "7+3" regimen
.

In addition, the researchers re-verified the classification system in 3 other independent cohorts
.

Research Results The ALFA1200 study included 509 patients from September 2012 to June 2016, of which 471 (92%) patients had genetic testing samples and data
.

The median age of the patients included in the study was 68 years old, 82.
8% of the patients had newly diagnosed AML, the median white blood cell count was 5.
3×109/L, 80.
7% of the patients had bone marrow blasts ≥30%, and 72.
4% of the patients were in the first or second stage.
Complete remission (CR) or CR without recovery of platelets (CRp) was achieved after one course of treatment
.

At a median follow-up of 44.
8 months, the median recurrence-free survival (RFS) and overall survival (OS) of AML patients were 14.
8 months and 21.
2 months, respectively
.

 In the study, 84 patients were stratified by cytogenetic risk as poor prognosis, 339 patients had a moderate prognosis, 13 patients had a good prognosis, and 35 patients were not tested for cytogenetics
.

The gene mutations and overall survival (OS) of patients in different groups are different
.

 The sequencing results of 37 genes of patients in the study showed that the most common mutations were DNTM3A mutation (28.
7%), NPM1 mutation (27.
0%), TET2 mutation (21.
0%) and FLT3-ITD mutation (18.
7%)
.

Univariate analysis showed that NPM1 mutation, IDH2-R140 mutation and DNMT3A mutation were associated with higher CR/CRp rate after 1-2 courses of treatment (P<0.
05), while TET2 mutation, NRAS mutation, RUNX1 mutation, ASXL1 mutation, SETBP1 mutation and ETV6 mutation were associated with a lower CR/CRp rate (P<0.
05) after 1-2 courses of treatment
.

Multivariate analysis showed that among 387 non-cytogenetic patients with poor prognosis, NPM1 mutation was associated with prolonged OS (HR: 0.
57, P=0.
0004), while FLT3-ITD had low (HR: 1.
85, P=0.
0005) or high Gene ratio (HR: 3.
51, P＜10-4), DNMT3A mutation (HR: 1.
86, P＜10-4), NRAS mutation (HR: 1.
54, P=0.
019), ASXL1 mutation (HR: 1.
89, P= 0.
0003) is related to OS shortening
.

Among 84 patients with poor cytogenetic prognosis, TP53 mutation (HR: 2.
49, P=0.
0003) and KRAS mutation (HR: 3.
60, P=0.
001) were independent poor prognostic factors for OS
.

 The researchers combined the mutations of 7 genes (NPM1, FLT3-ITD, DNMT3A, ASXL1, NRAS, KRAS, TP53) and cytogenetic risk stratification to develop an ALFA treatment decision tool for elderly AML patients.
This decision tool will Elderly AML patients are divided into three groups: cytogenetic risk is not poor prognosis or NPM1 mutation, FLT3-ITD low allele ratio, DNMT3A mutation, ASXL1 mutation, NRAS mutation contains no more than 1 item, or NPM1, FLT3-ITD Patients with wild type, DNMT3A, ASXL1, and NRAS are in the "go-go" group; patients with a poor cytogenetic risk prognosis, and KRAS mutations or TP53 mutations at the same time are in the "no-go" group; other patients are in the "slow-" group.
go” group
.

According to the above grouping pattern, 39.
1% of the patients in the study were in the "go-go" group, and the 2-year OS rate was 66.
1%; 7.
6% of the patients were in the "no-go" group, and the 2-year OS rate was 2.
8%; 53.
3% Of the patients were in the "slow-go" group, and the 2-year OS rate was 39.
1% (P<10-5)
.

In the three independent cohorts, 31.
2%-37.
7% and 11.
2%-13.
5% of patients were classified into the "go-go" group and the "no-go" group, respectively.
There were significant statistical differences in RFS and OS among patients in different groups
.

Research conclusions ALFA treatment decision-making tool is a simple and effective prognostic model, which can be used to predict the benefit of AML patients ≥60 years old who receive "7+3" regimen intensive chemotherapy
.

Reference: Raphael Itzykson, Elise Fournier, Céline Berthon,et al.
Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy.
Blood.
2021 Aug 19;138(7):507-519.
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