A BCR-ABL1-Like Gene Expression Profile Confers a Poor Prognosis In Patients with High-Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report From Children9s Oncology Group (COG) AALL0232

Abstract 743 We have previously identified a subset of National Cancer Institute (NCI)-HR B-cell precursor (BCP) ALL patients with a gene expression profile similar to that of BCR-ABL1 ALL (BCR-ABL1-like ALL (Mullighan, N Engl J Med 2009; den Boer, Lancet Oncology 2009; Harvey, Blood, 2010, and unpublished data) and poor outcome on the COG P9906 trial, which was limited to a selected subset of HR BCP ALL patients. These cases are BCR-ABL1-negative but commonly have deletion or mutation of IKZF1. Up to half of these cases harbor rearrangements, deletions and/or mutations activating cytokine receptors and tyrosine kinase signaling (e.g. CRLF2 and activating JAK1/2 mutations), although the kinase-activating mutations in many cases remain unknown. In this analysis, we have assessed the prognostic significance of this BCR-ABL1-like signature in an unselected cohort of BCR-ABL1 negative BCP ALL patients consecutively enrolled on COG AALL0232. This phase 3 trial utilized a 2×2 factorial design comparing dexamethasone (DEX) versus prednisone (PRED) during induction, and high dose methotrexate (HD-MTX) versus Capizzi methotrexate (C-MTX) during interim maintenance 1 (IM-1). We recently reported improved event free survival (EFS) for patients receiving HD-MTX versus C-MTX (Larsen, J Clin Oncol 29: 6s, 2011) and for DEX versus PRED among patients Event-free survival (EFS) for BCR-ABL1-like cases was inferior to that of non-BCR-ABL1-like cases, irrespective of the clustering algorithm used to identify them, with 5-yr EFS rates of 63.1±7.2% vs. 84.9±2.0% (p We next examined variables that contributed to outcome in patients who displayed the BCR-ABL1-like signature, identified either by ROSE or PAM. Older (≥ 10 years) BCR-ABL1-like patients were significantly more likely to have an initial white blood count greater than 100,000/ul (ROSE: p 100,000/ul at diagnosis (HR 1.62, p=0.047), and hypodiploidy (HR 3.0, p=0.034). In summary, the BCR-ABL1-like gene expression profile identified a subset of unselected BCP ALL patients using two different clustering algorithms that was strongly associated with a high rate of treatment failure, even with the best available therapy recently identified in COG AALL0232. The prognostic significance of these gene signatures was also independent of other known risk factors. Ongoing work to determine the genetic and biochemical landscape that contribute to this phenotype will hopefully yield new approaches to treatment for these BCR-ABL1-like patients in order to improve outcome. Disclosures: Borowitz: BD Biosciences: Research Funding. Wood: BD Biosciences: Research Funding. Hunger: Bristol-Myers Squibb: Membership on an entity9s Board of Directors or advisory committees, Speaker9s children own stock in BMS.