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2002 Validation of the High-Risk Prognostic Score Defined By the Presence of Mutations in NRAS or TP53 in a Cohort of 497 Patients with Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Clinically relevant
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Rosa Ayala, MD, PhD1*, Pau Montesinos, MD, PhD2,3*, Eva Barragán, PhD4,5,6*, Joaquin Martinez-Lopez, MD7,8,9,10*, Miguel A. Sanz5,11,12, Yanira Ruiz-Heredia13*, Santiago Barrio14*, Juan Manuel de la Rosa13*, Inmaculada Rapado15*, Pilar Martinez, MD16*, Rafael Colmenares17*, Maria Pozas17*, Xabier Gutierrez17*, María Luz Morales18* and Noemí Álvarez Sánchez-Redondo, PhD13*

1Hematology Department, Hospital Universitario 12 de Octubre,, Madrid, Spain
2CIBERONC, Instituto Carlos III, Madrid, Spain
3Hospital Universitari i Politècnic La Fe, Valencia, Spain
4Servicio de Hematología. Hospital La Fe, Valencia, Spain, Valencia, Spain
5CIBERONC, Madrid, Spain
6Hematology Department, Hospital Universitario La Fe de Valencia,, Valencia, Spain
7Hematology and hemotherapy department, Hospital Universitario 12 De Octubre, Madrid, Spain
8Hospital Universitario 12 de Octubre (H12O), Centro Nacional de Investigaciones Oncológicas (CNIO)-H12O and Universidad Complutense de Madrid, Madrid, Spain
9Hospital 12 de Octubre, H12O-CNIO, Haematological Malignancies Clinical Research Unit, Universidad Complutense, CIBERONC, Madrid, Spain
10H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research Center, Madrid, Spain
11Hematology Department, University and Polytechnic Hospital La Fe, Valencia, Spain
12Department of Medicine, University of Valencia, Valencia, Spain
13Department of Translational Hematology, Research Institute Hospital 12 de Octubre (i+12) Hematological Tumors Clinical Research Unit H12O-CNIO, Madrid, Spain, Madrid, Spain
14Hospital 12 De Octubre, CIBERONC, Madrid, ESP
15Department of Hematology, Hospital Universitario 12 de Octubre, CNIO, Madrid, Spain
16Haematology department, 12 Octubre Hospital, Madrid, Spain
17) Department of Translational Hematology, Hematology Service, Hospital 12 de Octubre, Madrid, Spain, Madrid, Spain
18Department of Translational Hematology, Research Institute Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, Madrid, Spain


Older AML patients have a different mutational landscape compared to younger patients. The prognostic classification of AML proposed by the European Leukemia Net (2017) is based on the presence of mutations in FLT3 (ITD), NPM1, CEBPA, RUNX1, ASXL1 and TP53. However, our group has identified a high-risk prognostic score in older patients with AML, who are undergoing treatment with azacitidine or low-dose cytarabine plus fludarabine, which predict a shorter survival.


Validation of the previously identified high-risk prognostic score, defined by the presence of mutations in NRAS or TP53, in 3 cohorts of patients with AML who have been studied by NGS with a custom panel in the healthcare practice (Cohort 1: Intensive treatment; cohort 2: Hypomethylating agents and cohort 3: low-dose cytarabine)


The study was conducted on a series of 535 patients diagnosed with AML (mean age 67). Patients evaluated for OS and RFS were 497 cases: intensive treatment (schemes 3+7 or similar; n=238), hypomethylating agents (azacitidine, decitabine; n=113) and treated with low-dose cytarabine (n=146). 38 patients on supportive therapy were excluded.

Mutational profile was identified at diagnosis by NGS technique (Ion Torrent System), using a custom panel of 41 genes involved in myeloid pathologies: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, DNMT3A, EPAS1, EPOR, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KDM6A, KIT, KMT2A, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PRPF40B, RAD21, RUNX1, SETBP1, SF3A1, SF3B1, SH2B3, SMC1A, SRSF2, STAG2, TET2, THPO, TP53, U2AF1, VHL, WT1 y ZRSR2.

The mean OS and RFS were compared by means of Kaplan-Meier curves using the log-rank test. The bioinformatics analysis was performed with the SPSS software.


The median SG and RFS of this series was 10.8 months and 6.9 months respectively.

The mutational profile in older patients was different from that analyzed in younger patients. We observed greater presence of mutations in NPM1 in younger patients (34.4 vs 18.6%, p=0.04), while in older than 65 years were identified more mutations in ASXL1 (3.9 vs 16.6%, p<0.01) or RUNX1 (8.6 vs 18.4%, p=0.005). No differences were observed in TP53, NRAS, TET2, DNMT3A and FLT3-ITD. However, we detected differences in VAF distribution of variants with lower VAF in younger patients in NPM1 (0.9 vs 5%, p=0.001), RUNX1 (4.1 vs 9.1%, p=0.003), ASXL1 (1.5 vs 8.2%, p<0.001) and TP53 (5.9 vs 14%, p<0.001)

The median OS for intensively treated patients with a low-risk prognostic score was 49.1 months (17.56, 80.60) vs. 18.9 (14.98, 22.79) for high-risk patients (p=0.015). The median RFS was 45.2 months (5.2; 85.14) for low-risk patients vs. 42.1 (18.35; 65.92) for high-risk patients (p=0.167).

The median OS for low-risk patients treated with hypomethylating agents was 13.2 months (9.02, 17.47) vs. 4.8 (1.6, 7.9) for patients with a high-risk score (p=0.002). The median RFS was 9.9 months (7.4, 12.3) for low-risk patients vs. 14.9 (10.1, 19.8) for high-risk patients (p=0.682).

The median OS for patients treated with low-dose cytarabine was 8.4 months (4.9, 12.1) for low risk vs. 3.1 (1.22, 4.94) for high risk (p<0.001). The median RFS was 6.8 months (5.28, 8.42) for low-risk patients vs. 3.7 (2.75, 4.66) for those with a high-risk score (p=0.008).


We have confirm that exist differences in the mutational profile between older and younger AML patients and these differences have implications in the definition of risk of these patients. The prognostic score defined by the presence of mutations in the TP53 and NRAS genes, has been validated as an adverse prognostic factor across the three treatment groups studied (intensive treatment, hypomethylating agents and low-dose cytarabine) for OS, and this score no predict risk of relapse in the cohorts with intensive and hypomethylating treatments at difference to the low-dose cytarabine cohort.

ML.M. enjoys a research grant from the Spanish Society of Hematology and Hemotherapy. This work has been financed thanks to the aid PI16/01225 and PI19/01518, from the Instituto de Salud Carlos III (Ministerio de Economía, Industria y Competitividad) and co-financed by the European Development Fund.

Disclosures: Montesinos: Astellas, Novartis, Janssen: Speakers Bureau; Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding. Martinez-Lopez: Incyte: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; BMS: Consultancy, Research Funding. Sanz: Teva, Daiichi-Sankyo, Orsenix, AbbVie, Novartis, and Pfizer: Other: Consulting or Advisory Role.

*signifies non-member of ASH