Abstract 1723: IKZF1/CDKN2A co-deletion predicts shorter survival in adult B-ALL
Authors: Patel Shiven , Mason Clinton C. , Glenn Martha J. , Paxton Christian N. , South Sara T. , Cessna Melissa H. , Asch Julie , Cobain Erin F. , Bixby Dale L. , Smith Lauren B. , Schiffman Joshua D. , Miles Rodney R. 
Published: August 2015

Abstract
B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL. Prognostic biomarkers are needed for better risk-stratification and therapy selection. Microarray-based genome-wide profiling studies in pediatric patients have revealed recurrent abnormalities in B-cell development and cell cycle regulation. IKZF1 alterations convey a negative prognostic impact in pediatric B-ALL, but their significance is not well characterized in adult B-ALL. CDKN2A alterations have also been associated with a poorer prognosis in adult Ph+ ALL, possibly by mediating resistance to targeted therapy. The copy number landscape of adult B-ALL has not been fully assessed, and given its inferior prognosis, may be distinct from its pediatric counterpart. We identified 70 adult B-ALL patients (median age 45 years, range 18-83) from 1998-2013 at three institutions. DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) diagnostic bone marrow clots and assessed with the OncoScan FFPE Express genome-wide single nucleotide polymorphism (SNP) assay (Affymetrix). Copy number alteration (CNA) analysis was performed using Nexus Software V7 (Biodiscovery) and in-house coding. The most frequent CNAs called by the software were manually verified for probe evidence. Clinical data available on this cohort included age, gender, hematologic laboratory values at presentation, CSF involvement, receipt of allogeneic transplant, cytogenetic profile, presence of t(9;22), event-free survival (EFS), and overall survival (OS). Estimated median survival time of the entire adult B-ALL patient cohort was 29 months. Recurrent deletions in the diagnostic samples were noted at several loci, including CDKN2A (47%), IKZF1 (40%), PAX5 (24%), BTG1 (17%), and BTLA (14%). Recurrent gains were identified at the following loci: ERG (30%), ETS2 (21%), MYB (20%), UBASH3B (20%), PRKCH (19%), CDK6 (17%), and ETV6 (16%). No individual CNA heralded a significant prognostic impact in the entire cohort or in subgroup analyses stratified by presence of t(9;22) for either EFS or OS, though this could be due to our relatively smaller sample size in contrast to pediatric studies that have observed a prognostic impact at some of these loci. However, the combination of both CDK2NA and IKZF1 deletions (26%) correlated with a significantly worse overall survival than having only one or neither of these deletions (both vs CDKN2A only: p = 0.028, both vs IKZF1 only: p = 0.027, both vs neither deleted: p = 0.048). Age was the only other covariate significant in univariate analyses for OS, yet IKZF1/CDKN2A co-deletion remained significant in multivariate analysis adjusting for age. Adult B-ALL demonstrates frequent CDKN2A deletions, IKZF1 deletions, and CDKN2A/IKZF1 co-deletions. To our knowledge, the negative prognostic impact of the CDKN2A/IKZF1 co-deletion is a novel finding in adult B-ALL and requires further validation in larger cohorts.
Citation Format: Shiven Patel, Clinton C. Mason, Martha J. Glenn, Christian N. Paxton, Sara T. South, Melissa H. Cessna, Julie Asch, Erin F. Cobain, Dale L. Bixby, Lauren B. Smith, Joshua D. Schiffman, Rodney R. Miles. IKZF1/CDKN2A co-deletion predicts shorter survival in adult B-ALL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1723. doi:10.1158/1538-7445.AM2015-1723