Comprehensive Age-Stratified Impact of NPM1 Mutation in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) with NPM1 mutation (MT) in the absence of FLT3-ITD is a favorable prognostic risk group in various stratification schemes, including the recently published machine learning-based, clinical-feature agnostic analysis of AML mutations (Awada et al., Blood 2021). However, prior large clinical trials based large registry data (Ostronoff et al., JCO 2015) observed that the positive prognostic impact of NPM1^MT is not general as it does not seem to extend to elderly patients above 65 ys. in contrast to prior smaller studies. In this group, a formal, extensive analysis has not been performed on patients treated outside clinical trials.

AML cohort from Karmanos Cancer Institute (n=52) was enhanced by a publicly available metanalytic cohort consisting of various sub-studies (Awada et al., Blood 2021) to a total of 2,165 AML patients to identify and validate the age-stratified analyses of the impact of NPM1^MT in AML. Only patients whose NPM1 mutation status was available were included in the study. Baseline clinical and molecular characteristics were noted. Chi-square test was used to study various parameters as described, and Kaplan Meir curves were used for survival analyses.

In total, 25% (533/2,165) of the patients carried NPM1^MT. Male: Female ratio was 0.92. NPM1^MT was enriched in primary (p) AML compared to NPM1^WT [94 vs. 74%, p=0.0001], whereas there were less secondary (s) AML in NPM1^MT compared to NPM1^WT [6 vs. 26%, p=0.0001]. NPM1^MT was less associated with abnormal karyotype versus NPM1^WT [16 vs. 63%, p<0.0001]. Median variant allele frequency (VAF) in evaluable patients was 38% [range, 5-60%], and all mutations were canonical frameshift. Median overall survival (OS) was significantly better in NPM1^MT compared to NPM1^WT patients [24 vs. 17.5 mo., p=0.003]. When grouped by FLT3-ITD mutational status, NPM1^MT patients had a better OS compared to NPM1^WT in FLT3-ITD^NEG group [29 vs. 17 mo., p=0.00045]. Whereas there was no difference in OS in the FLT3-ITD^POS group [15 vs. 21 mo., p=0.461]. NPM1^MT patients with pAML had a better OS compared to NPM1^MT patients with sAML [31 vs 9.6 mo., p=0.001].

When stratified by age groups, NPM1^MT/FLT3-ITD^NEG patients had a significantly higher OS than NPM1^WT/FLT3-ITD^NEG patients in the 55-65 year age group (75 vs. 20 mo., p=0.002). After splitting this group, the OS benefit was preserved in the 55-60 (58.5 vs. 16 mo., p=0.041) and 60-65 year group (mOS not estimable vs. 21 mo., p =0.011). There was no difference in OS for NPM1^MT/FLT3-ITD^NEG vs. NPM1^WT/FLT3-ITD^NEG patients in the age groups <55 years (not estimable vs. 155 mo. p=0.066), 65-75 years (13 vs. 13.1 mo., p=0.46), and >75 years (3.3 vs. 5.2 mo., p=0.32). NPM1^MT patients with lesser co-occurring mutations had a greater OS [≤3 vs. >3 total mutations, 51 vs. 18 mo., p=0.046]. The median age was 60.5 years compared to 66.4 years in the two populations, respectively (p=0.001). The most common associated mutations in <65 vs. >65 year with NPM1^MT were DNMT3A (38% vs. 43%, p=0.27), IDH2 (23% vs. 25%, p=0.61), TET2 (13% vs. 27%, p=0.0001), FLT3-ITD (21% vs. 16%, p=0.16), IDH1 (19% vs. 15%, p=0.25), NRAS (13% vs. 7%, p=0.03), SRSF2 (5% vs. 15%, p=0.0002), WT1 (10% vs. 4%, p=0.01), PTPN11 (5% vs. 8%, p=0.18), CEBPA (5% vs. 6%, p=0.63), and ASXL1 (1% vs 7%, p=0.0006). In comparing dominant vs. non-dominant NPM1^MT, OS was not different in NPM1^MT/FLT3-ITD^NEG patients [46.5 vs. 21 mo. P=0.42); however, there was a trend towards better survival in the NPM1^MT/FLT3-ITD^POS group [OS not estimable vs. 22 mo., p=0.06 resp.].

In sum, extensive analysis of the age-stratified impact of NPM1^MT in AML revealed intricate details of prognostic groups. We validated the prior findings of the not favorable impact of NPM1^MT in older (>65 ys.) AML patients. We also found no difference in the frequently associated negatively impacting (such as FLT3) mutations. Since this dataset broadly represents patients treated outside clinical trials, it underscores whether they were undertreated or truly ineligible for intensive induction therapy. If the former is true, older NPM1^MT AML should be stringently selected for aggressive therapeutic or targeted interventions, which could enhance their survival in this otherwise positive prognostic group. Our ongoing analysis, to be presented at the ASH meeting, will determine whether the less intense therapy may be the culprit and identify any subgroup that would respond better.

Balasubramanian:Kura Oncology: Research Funding.