The prognostic impact of copy number alterations in pediatric AML patients

In pediatric Acute Myeloid Leukemia (AML) patients, chromosomal instability is often a feature which can lead to disease relapse after therapy and thus novel prognostic markers are required to further improve risk stratification.

In an article published ahead of print in Blood on 14^th April 2017, Marijiana Vujkovic from The Children’s Hospital of Philadelphia, Philadelphia and colleagues, investigated Copy Number Alterations (CNAs), somatic changes to chromosome structure that result in gain or loss in copies of sections of DNA,  and its prognostic significance in pediatric patients with de novo AML.

In this study, samples from 446 patients with de novo AML enrolled on Children’s Oncology Group (COG) trials (CCG-2961 [NCT00003790], AAML-03P1 [NCT00070174] and AAML-0531 [NCT01407757] were genotyped.

The key results were:

• Average somatically acquired CNAs in patient samples; 1.14
• Mean somatically acquired CNAs in patients in favorable-, standard- and poor-risk groups were 1.1, 1.3 and 0.8 respectively
• Novel reoccurring gains and losses in 1p26.3, 2q37.1 and 10p12.31 were identified 
• Decreased 3-year Overall Survival (OS) was associated with CNAs presence; HR = 1.7, P = 0.005
• Presence of CNAs were associated with inferior 3-year Event Free survival (EFS) and increased risk of relapse from the end of induction; HR = 1.4, P = 0.029 and HR = 1.4, P = 0.043 respectively
• In a subgroup analysis, CNA presence was significantly associated with decreased OS and EFS in only standard-risk patients

In summary, this is the first study to show an association between CNA presence and treatment outcomes in pediatric AML patients. Additionally, the presence of CNAs is significantly associated with survival in standard-risk pediatric AML patients.

Abstract

Childhood acute myeloid leukemia (AML) is frequently characterized by chromosomal instability. Approximately 50% of patients have disease relapse, and novel prognostic markers are needed to improve risk stratification. We performed genome-wide genotyping in 446 pediatric patients with de novo AML enrolled on Children's Oncology Group (COG) studies, AAML0531 (NCT01407757), AAML03P1 (NCT00070174), and CCG2961 (NCT00003790). Affymetrix and Illumina Omni 2.5 platforms were used to evaluate copy number alterations (CNAs) and determine their associations with treatment outcome. Data from Affymetrix and Illumina studies were jointly analyzed with ASCAT and GISTIC software. An average of 1.14 somatically acquired CNAs per patient were observed. Novel reoccurring altered genomic regions were identified, and the presence of CNAs was found to be associated with decreased 3-year overall survival (OS), event-free survival (EFS), and relapse risk from the end of induction I (HR 1.7, 95%CI 1.2–2.4, HR 1.4, 95%CI 1.0–1.8, and HR 1.4, 95%CI 1.0–2.0, respectively). Analyses by risk group demonstrated decreased OS and EFS in the standard risk group only (HR 1.9, 95%CI 1.1–3.3, and HR 1.7, 95%CI 1.1–2.6, respectively). Further studies are required to test the prognostic significant of CNA presence in disease relapse in AML ptients.