Genotypic and clinical heterogeneity within NCCN favorable-risk acute myeloid leukemia

Abstract

The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KIT^wt); and AML with normal cytogenetics and mutations in NPM1 (NPM1^mut); or biallelic mutations in CEBPA (CEBPA^mut/mut), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them. Patients with NPM1^mut AML were significantly older than those in the other groups. Targeted next-generation sequencing on DNA from peripheral blood or bone marrow revealed significantly more mutations in NPM1^mut AML than the other favorable-risk diseases, especially in genes related to DNA splicing and methylation. CEBPA^mut/mut AMLs exhibited more mutations in transcription-related genes. Patients with NPM1^mut AML and CEBPA^mut/mut AML show significantly reduced overall survival in comparison with CBF-KIT^wt AML. These findings emphasize that favorable-risk AML patients have divergent outcomes and that differences in clinical and genotypic characteristics should be considered in their evaluation and management.

Keywords: Acute myeloid leukemia; Core binding factor; Favorable risk; Molecular diagnostics.

Figure 1. Distribution of mutated genes in favorable-risk AML

Each column represents an individual case of AML. The dark blocks indicate the genes mutated in the case. The lines are organized by functional category: A. Splicing; B. Methylation; C. Chromatin; D. Receptor/Kinase; E. RAS-related; F. Transcription. Only the genes that were mutated in these cases are shown. t-CBF, core binding factor translocation.

Figure 2. Survival Curves

Each panel shows a Kaplan-Meier survival curve comparing NPM1^mut AML (solid lines), CBF-KIT^wt AML (dashed lines), and CEBPA^mut/mut AML (dotted lines). A. Overall survival (OS) of all patients. B. OS for all patients that received induction chemotherapy (N=27 for NPM1^mut AML; N=21 for CBF-KIT^wt AML; N=5 for CEBPA^mut/mut AML). C. OS for NPM1^mut patients by age. D. OS for NPM1^mut patients that received induction chemotherapy by age. E. Relapse-free survival of patients who achieved complete remission (N=23 for NPM1^mut AML; N=21 for CBF-KIT^wt AML; N=5 for CEBPA^mut/mut AML). F. OS of relapsed patients measured from the date of relapse (N=10 for NPM1^mut AML; N=5 for CBF-KIT^wt AML; N=3 for CEBPA^mut/mut AML).