Abstract 5560: Prognostic effect of co-mutations on patients with NPM1+ acute myeloid leukemia (AML) enrolled in the Connect® Myeloid registry
Authors: Maciejewski Jaroslaw P. , Pollyea Daniel A. , Roboz Gail J. , Seiter Karen , Scott Bart L. , DeGutis Irene S. , Kiselev Pavel , Yu Edward , McBride Ali , Heydendael Willem , Erba Harry P. 
Published: June 2023

Abstract
Introduction: The 2017 World Health Organization classification of myeloid neoplasms and acute myeloid leukemia (AML) recognizes AML with mutated NPM1 as a distinct entity with favorable prognosis. However, as mutations other than NPM1 may further influence disease prognosis, here we assess the prognostic effect of NPM1 co-mutations in patients (pts) with AML enrolled in the Connect® Myeloid Registry (NCT01688011).
Methods: The Registry is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed AML, myelodysplastic syndromes, idiopathic cytopenia of undetermined significance, or myelofibrosis. In this analysis, pts with AML ≥55 years of age were grouped by known NPM1 status (NPM1+ vs NPM1‒). The frequency of gene mutations was analyzed among patients with NPM1+ AML and NPM1‒ AML. Overall survival (OS) was evaluated using the Cox model adjusted for age and mutations in TP53 and RUNX1.
Results: Overall, 123 pts with NPM1+ AML and 360 pts with NPM1‒ AML were included. Most pts were male (NPM1+, 61.5%; NPM1−, 60.7%) and White (NPM1+, 78.0%; NPM1−, 85.6%); median (range) age was 67 (55-87) and 71 (55-97) years for the NPM1+ and NPM1− groups, respectively. After adjusting for age, pts with NPM1+ AML had significantly longer median OS than pts with NPM1‒ AML (26 vs 15 months; HR [95% CI]: 0.58 [0.44-0.76]; P &lt; 0.01; Table). Pts with NPM1+ vs NPM1‒ AML had a lower frequency of certain key mutations such as TP53 (1.6% vs 18.6%) and RUNX1 (0.8% vs 14.8%). The significant survival benefit with NPM1+ vs NPM1‒ initially observed after adjusting for age was not observed after further adjusting for presence of TP53 and RUNX1 mutations (NPM1+ vs NPM1‒; 23 vs 19 months; HR [95% CI]: 0.75 [0.48-1.17]; P = 0.21).
Conclusions: TP53 plus RUNX1 mutation was identified as a pattern of co-mutational burden that were observed less frequently and potentially contributed to the improved OS of pts with NPM1+ AML and poorer OS of pts with NPM1‒ AML.
NPM1+n = 123 NPM1‒n = 210 Overall survival, months Adjusted for age 26.0 15.0 Hazard ratio (95% CI) 0.58 (0.44-0.76) Adjusted for age, TP53, RUNX1 23.0 19.0 Hazard ratio (95% CI) 0.75 (0.48-1.17) Frequency of gene mutations, n (%)TP53 2 (1.6) 39 (18.6) ASXL1 3 (2.4) 37 (17.6) FLT3-ITD 44 (35.8) 36 (17.1) TET2 20 (16.3) 34 (16.2) DNMT3A 29 (23.6) 33 (15.7) IDH2 11 (8.9) 33 (15.7) RUNX1 1 (0.8) 31 (14.8) NRAS/KRAS 11 (8.9) 30 (14.3) IDH1 18 (14.6) 18 (8.6) CEBPA 4 (3.3) 15 (7.1) WT1 5 (4.1) 14 (6.7) FLT3-TKD 18 (14.6) 13 (6.2) PHF6 0 12 (5.7) PTPN11 4 (3.3) 12 (5.7) SF3B1 2 (1.6) 8 (3.8) C-KIT 1 (0.8) 7 (3.3) EZH2 1 (0.8) 4 (1.9) ETV6 0 3 (1.4) MLL-PTD 1 (0.8) 1 (0.5) Other 30 (24.4) 114 (54.3)
Citation Format: Jaroslaw P. Maciejewski, Daniel A. Pollyea, Gail J. Roboz, Karen Seiter, Bart L. Scott, Irene S. DeGutis, Pavel Kiselev, Edward Yu, Ali McBride, Willem Heydendael, Harry P. Erba. Prognostic effect of co-mutations on patients with NPM1+ acute myeloid leukemia (AML) enrolled in the Connect® Myeloid registry. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5560.