Prognostic implications of NPM1 co-mutation in FLT3-TKD-mutated AML: A retrospective study

FMS-like tyrosine kinase 3 (FLT3) inhibitors have improved the outcomes in patients with FLT3-internal tandem duplication-mutated (FLT3-ITD^mut) acute myeloid leukemia (AML). In contrast, the effects of FLT3-tyrosine kinase domain mutations (FLT3-TKD^mut) in AML remain inadequately understood. 

The characteristics and outcomes of patients with FLT3-TKD^mut AML, including their responses to intensive chemotherapy (IC) or low-intensity therapy (LIT), and the prognostic impact of NPM1 co-mutations, were assessed in a retrospective cohort study. Results were published by Arora et al. in Cancer.

The study consisted of an FLT3-TKD^mut cohort (n = 124) and an NPM1^mut/FLT3-TKD wild-type (FLT3-TKD^wt) cohort (n = 126). In the FLT3-TKD^mut cohort, 54 patients received IC, while 70 patients received LIT. In the NPM1^mut/FLT3-TKD^wt cohort, 46 patients received IC, while 80 patients received LIT. Responses were assessed using the International Working Group criteria.

Key learnings

In the FLT3-TKD^mutIC cohort, the CRc and 3-year OS rates were 81% and 56%, respectively. Patients with NPM1^mut vs NPM1^wt had a higher 3-year OS (74% vs 40%; HR, 0.4; p = 0.03) and 3-year EFS (65% vs 42%; HR, 0.4; p = 0.046).

In patients with NPM1^wt vs those with an NPM1 mutation in the IC cohort, allo-HSCT showed improved 3-year OS (89% vs 30%; p = 0.02). In the LIT cohort, allo-HSCT showed improved 3-year OS in patients with NPM1^wt vs NMP1^mut AML (75% vs 27%; p = 0.1). 

The CRc and 3-year OS rates were 63% and 23%, respectively, in the FLT3-TKD^mut LIT cohort. Patients with NPM1^mut vs NPM1^wt showed a higher 3-year OS (32% vs 16%; p = 0.04).  

NPM1 co-mutations are commonly harbored in patients with FLT3-TKD^mut AML, with key prognostic implications. A lack of NPM1 co-mutations is associated with poor response rates and outcomes, and allo-HSCT should be strongly considered for patients in first remission.