Impact of Npm1, Flt3, and Ras Mutations on the Outcomes of Elderly Patients with Acute Myeloid Leukemia,

The prognosis of pts with acute myeloid leukemia (AML) can be stratified according to performance status, age, and cytogenetics. Patients with cytogenetically normal AML (CN-AML), have an intermediate prognosis but can be further stratified according to the presence of mutations in the NPM1 (NPM1-MUT, better prognosis), FLT3 (FLT3-MUT: internal tandem duplication [FLT3-ITD] or point mutations at D835, poor prognosis) and RAS genes (RAS-MUT: poor prognosis). Patients with CN-AML NPM1-MUT/FLT3-WT have the best overall survival (OS) rates of those with CN-AML. The impact of such genetic stratification in elderly pts with AML, particularly amongst those receiving epigenetic therapy has not been well established.

We analyzed the outcomes of patients over the age of 60 years with AML (AML>60) receiving standard chemotherapy (n=779) or epigenetic therapy (n=130, i.e. azacitidine or decitabine with or without histone deacetylase inhibitors) at our institution between 2000 and 2010. Of the 130 pts receiving epigenetic therapy, 78 received decitabine-based therapy and 52 azacitidine-based therapy. Of the 779 pts receiving chemotherapy, 74% received AI (ara-C 1.5g/m²x3d and idarubicin 12mg/m²x3d) or AI-based chemotherapy. Baseline characteristics for pts treated with chemotherapy vs epigenetic were: median age (69 vs 72 yrs; p=0.000039), performance status 0–2 (n=124; 95% vs 95%, p=0.8), WBC (5.7×10⁹/dL vs 3.2×10⁹/dL; p=0.00004), Hg (8.2g/dL vs 8.7g/dL; p=0.0004), platelets (49×10⁹/dL vs 55×10⁹/dL; p=0.1), BM blasts (43% vs 35%; p=0.0001), PB blasts (14 vs 6.5; p=0.0006), poor cytogenetics (25% vs 32%; p=0.13).

The CR rates for pts treated with chemotherapy and epigenetic therapy were 47% and 28%, respectively (p=0.0001). The overall response rate (ORR) for both groups (CR+CRp) was 53% and 29% (p=0.0001). However, the median OS of pts treated with chemotherapy or epigenetic therapy was not significantly different (7.6mo vs 6.9mo, p=0.13). NPM1 and FLT3 mutational status was available in 256 (33%) and 667 (85%), respectively. The mutational frequencies for NPM1 (43/256) and FLT3 (85/667) were 17% and 13%, respectively, both of which markedly lower than those reported in younger AML counterparts (∼50% and ∼35%, respectively). Forty-three pts carried NPM1 mutations (3 treated with epigenetic therapy and 40 with chemotherapy) and 85 carried FLT3 mutations (12 treated with epigenetic therapy and 73 with chemotherapy). No differences in OS were observed between FLT3-MUT and FLT3-WT pts treated with epigenetic therapy (n=12 & n=104; p=0.92) and those treated with chemotherapy (n=73 & n=478; p=0.56). Similar results were observed for NPM1-MUT vs NPM1-WT with epigenetic therapy (n=3 & n=35; p=0.2) and chemotherapy (n=40 & n=178; p=0.16), and for those with RAS-MUT vs RAS-WT with epigenetic therapy (n=4 & n=101; p=0.08) and chemotherapy (n=42 & n=355; p=0.55). Next we combined NPM1 and FLT3 mutational status to predict OS (Table 1). No pts with NPM1-MUT/FLT3-MUT AML were treated with epigenetic therapy and therefore no comparisons were made with their counterparts treated with chemotherapy. Pts with NPM1-MUT/FLT3-WT (p=0.006) and those with NPM1-WT/FLT3-WT (p=0.021) AML appeared to achieve higher CR rates when treated with chemotherapy than with epigenetic therapy. However, only pts with NPM1-WT/FLT3-WT (p=0.037) appeared to benefit from chemotherapy over epigenetic therapy regarding OS.

At variance with reported data in younger pts with AML, NPM1, FLT3, and RAS mutational status does not appear to predict outcomes among pts with AML>60. Mutational frequencies of NPM1 and FLT3 are significantly lower compared to those reported in younger pts. Pts with NPM1-WT/FLT3-WT AML may benefit from chemotherapeutic approaches.

No relevant conflicts of interest to declare.