-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2884 Molecular Dissection of Normal Karyotype Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster III
Hematology Disease Topics & Pathways:
Technology and Procedures, cytogenetics, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Jacob Shreve, BS, MD, MS1, Manja Meggendorfer, PhD2, Sudipto Mukherjee, MD, PhD, MPH3, Wencke Walter, PhD4*, Stephan Hutter, PhD4*, Ahed Makhoul, MD5*, Nathan Radakovich, BA6, Hassan Awada, MD7, Yihong Guan, PhD7*, Teodora Kuzmanovic, BA8*, Jaroslaw P. Maciejewski, MD, PhD8, Claudia Haferlach, MD9, Mikkael A. Sekeres, MD, MS10, Torsten Haferlach, MD11 and Aziz Nazha, MD12

1Cleveland Clinic, Granger, IN
2MLL Munich Leukemia Laboratory, Munich, Bavaria, Germany
3Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
4MLL Munich Leukemia Laboratory, Munich, Germany
5Taussig Cancer Institute, Cleveland Clinic, Leukemia Program, Department of Hematology and Medical Oncology, Cleveland, OH
6Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Bellingham, WA
7Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
8Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
9MLL Munich Leukemia Laboratory, Inning am Ammersee, Germany
10Leukemia Program, Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
11MLL Munchner Leukamie Labor Gmbh, Munchen, Germany
12Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Quantitative Health Sciences, Avon Lake, OH


Conventional cytogenetics remain one of the most important prognostic factors in acute myeloid leukemia (AML), though 50-60% of patients (pts) have normal karyotype (NK), conventionally classified as intermediate-risk, and have very heterogeneous outcomes. A fraction of mutations such as NPM1, FLT3-ITD, and CEBPa can improve risk stratification for some pts but underestimate the molecular complexity and interactions between these genes and others.


Genomic and clinical data of 2,793 primary AML (pAML) pts were analyzed. A panel of 35 genes that are commonly mutated in AML and myeloid malignancies and have shown to impact OS was included. Correlation of each mutation with others and their impact on OS were evaluated. OS was calculated from the date of diagnosis to date of death or last follow-up.


Of 2,793 pts with pAML, 1,352 (48%) had NK and were included in the final analysis. The median age was 55 years (range, 18-93). The median number of mutations/sample was 3 (range, 0-7). The most commonly mutated genes were: NPM1 (49%), DNMT3A (37%), FLT3-ITD (24%), CEBPa (19%), TET2 (17%), IDH2 (17%), and RUNX1 (15%). In univariate Cox regression analysis, mutations in NPM1 (HR 0.81, p=0.008), and CEBPa (single mutant, HR 0.8, double mutant, HR 0.69, p<0.001, respectively) were associated with longer OS, while mutations in DNMT3a (HR 1.26, p=0.003), FLT3-ITD (HR 1.49, p<0.001), TET2 (HR 1.26, p=0.02), RUNX1 (HR 1.36, p=0.003), SRSF2 (HR 1.58, p<0.001), IDH1 (HR 1.29, p<0.001), and ASXL1 (HR 1.89, p<0.001) were associated with shorter OS. The median OS for pts with 0-2 mutations/sample was 59.3m, compared to 34.1m for pts with 3-4 mutations, and 16.1m for pts with > 5 mutations (p<0.001).

A total of 67% of pts had NPM1, DNMT3A, and FLT3-ITD mutated alone or in combination with each other. The median OS for pts with NMP1Mut/DNMT3AWT/FLT3-ITDWT was 99.1 months(m), NMP1Mut/DNMT3AMut/FLT3-ITDWT 54.8m, NMP1Mut/DNMT3AWT/FLT3-ITDMut 42.3m, NMP1Mut/DNMT3AMut/FLT3-ITDMut 13.4m, NMP1WT/DNMT3AMut/FLT3-ITDMut 13.1m, and NMP1WT/DNMT3AWT/FLT3-ITDWT (triple negative) 32.7m, Figure 1. Based on the median OS of each combination, we divided our pt cohort into favorable, intermediate-1, intermediate-2, and unfavorable categories with median OS of 174.9 m (95%CI 79.4-Not reached), 54.8 m (95%CI 28.7-Not reached), 29.2 m (95%CI 22.8-49.6), and 13.8 m (95%CI 12.2-16.1), respectively, p < .001), Figure 1.


We propose a simplified and robust approach to risk stratify AML pts with NK based on the mutational status of NPM1, DNMT3A, FLT3-ITD (alone or in combination with each other), CEBPa, and the number of mutations/sample.

Disclosures: Mukherjee: Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria. Maciejewski: Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Sekeres: Pfizer: Consultancy; Takeda/Millenium: Consultancy; BMS: Consultancy. Nazha: Jazz: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee.

*signifies non-member of ASH