Blood: Effect of NPM1 and FLT3 mutations on prognosis in patients with AML treated with oral azacitidine

Multiple cytogenetic and molecular abnormalities have been implicated
in the pathogenesis of acute myeloid leukemia (AML).
The most common gene mutations in AML patients are variations in the ribosphine 1 (NPM1) and fms-associated tyrosine kinase 3 (FLT3) genes, both of which have been shown to be associated with
treatment outcomes and survival.

The QUAZAR AML-001 trial is a randomized, placebo-controlled, phase 3 study evaluating oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia who achieve the first remission after intensive chemotherapy (IC) and who are not candidates for hematopoietic stem cell transplantation
.

Patients were randomized 1:1 to Oral-AZA (300 mg) or placebo for a 28-day course of treatment
.
The researchers assessed recurrence-free survival (RFS) and overall survival (OS) in subgroups of patients defined by NPM1 and FLT3 mutation status at the time of AML diagnosis, and whether survival outcomes in these subgroups were affected
by post-IC measurable residual disease (MRD).

Overall, 469 (99.
4%) of the 472 randomized patients had evaluable mutation data; At the time of diagnosis of AML, 137 (29.
2%) carried NPM1 mutations, 66 (14.
1%) carried FLT3 mutations (with internal tandem replication [ITD] or/and tyrosine kinase domain mutations [TKDmut]), and 30 (6.
4%) carried NPM1 mutations and FLT3-ITD variants
.

OS and RFS of two groups of patients with NPM1 mutations

In patients with NPM1 mutations, OS and RFS were improved by 37 percent and 45 percent
, respectively, in the Oral-AZA group compared to the placebo group.
Patients with NPM1 mutations received Oral-AZA had significantly longer median overall survival, regardless of the presence or absence of MRD after IC (no MRD: 48.
6 vs 31.
4 months; With MRD: 46.
1 vs 10.
0 months).

OS and RFS of two groups of patients with FLT3 mutations

In patients with FLT3 mutations, OS and RFS in the Oral-AZA group improved by 37 percent and 49 percent
, respectively, compared to the placebo group.
The median OS was 28.
2 months and 16.
2 months in the Oral-AZA group and placebo group with FLT3 mutation but without MRD, respectively, and 24.
0 months and 8.
0 months in patients with FLT3 mutation and MRD, respectively.

In summary, oral azacitidine significantly improved the survival outcomes of patients with acute myeloid leukemia who achieved the first remission after intensive chemotherapy, regardless of NPM1/FLT3 mutation status, cellular risk, and MRD status after intensive chemotherapy
.

Original source:

Hartmut D?hner, et al.
Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine.
Blood (2022) 140 (15): 1674–1685.
https://doi.
org/10.
1182/blood.
2022016293