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

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Genomic Determinants of Prognosis in Patients with Acute Myeloid Leukemia
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, Myeloid Malignancies
Sunday, December 11, 2022: 5:15 PM

Abdul Moiz Khan, MD1, Sushmitha Nanja Reddy, MBBS2*, Mai M M Aly, MD3,4*, Vikram Dhillon, DO2*, Ali Al Sbihi, MD2*, Tariq Kewan, MD4*, Waled Bahaj, MD4, Carmelo Gurnari, MD4,5, Bayan Al-Share, MD6*, Gregory Dyson1*, Valeria Visconte, PhD4 and Suresh Kumar Balasubramanian, MD4,7

1Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI
2Department of Internal Medicine, Wayne State University, Detroit, MI
3Assiut University Hospital, Clinical Hematology Unit, Internal Medicine Department,, Assiut, Egypt
4Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
5Department of Biomedicine and Prevention, Ph.D. in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy
6Monument Health Cancer Care Institute, Rapid City, SD
7Department of Oncology, Wayne State University/ Karmanos Cancer Institute, Detroit, MI

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 NPM1MT 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 NPM1MT 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 NPM1MT. Male: Female ratio was 0.92. NPM1MT was enriched in primary (p) AML compared to NPM1WT [94 vs. 74%, p=0.0001], whereas there were less secondary (s) AML in NPM1MT compared to NPM1WT [6 vs. 26%, p=0.0001]. NPM1MT was less associated with abnormal karyotype versus NPM1WT [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 NPM1MT compared to NPM1WT patients [24 vs. 17.5 mo., p=0.003]. When grouped by FLT3-ITD mutational status, NPM1MT patients had a better OS compared to NPM1WT in FLT3-ITDNEG group [29 vs. 17 mo., p=0.00045]. Whereas there was no difference in OS in the FLT3-ITDPOS group [15 vs. 21 mo., p=0.461]. NPM1MT patients with pAML had a better OS compared to NPM1MT patients with sAML [31 vs 9.6 mo., p=0.001].

When stratified by age groups, NPM1MT/FLT3-ITDNEG patients had a significantly higher OS than NPM1WT/FLT3-ITDNEG 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 NPM1MT/FLT3-ITDNEG vs. NPM1WT/FLT3-ITDNEG 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). NPM1MT 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 NPM1MT 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 NPM1MT, OS was not different in NPM1MT/FLT3-ITDNEG patients [46.5 vs. 21 mo. P=0.42); however, there was a trend towards better survival in the NPM1MT/FLT3-ITDPOS group [OS not estimable vs. 22 mo., p=0.06 resp.].

In sum, extensive analysis of the age-stratified impact of NPM1MT in AML revealed intricate details of prognostic groups. We validated the prior findings of the not favorable impact of NPM1MT 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 NPM1MT 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.

Disclosures: Balasubramanian: Kura Oncology: Research Funding.

*signifies non-member of ASH