Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665

Abstract

Recent studies have identified oncogenic lesions in Philadelphia chromosome-positive (Ph+)  acute lymphoblastic leukemia (ALL) and ABL1 kinase mutations that confer resistance to tyrosine kinase inhibitors. We sought to determine the prevalence and clinical impact of these lesions in patients on CALGB 10001, a previously reported Phase II study of imatinib, chemotherapy, and hematopoietic cell transplant in adult Ph + ALL. Of the 58 enrolled, 22 relapsed. By direct sequencing, an ABL1 kinase mutation known to induce imatinib resistance was present at relapse in 13 of 20. Using quantitative PCR assays, the mutations were detectable at diagnosis or early during treatment in most (62%) relapsed patients. Aberrations in IKZF1, CDKN2A/B, and PAX5 were assessed in 28 samples using SNP arrays and genomic DNA sequencing. Of these, 22 (79%) had IKZF1 deletion. The combination of IKZF1 deletion and p210 BCR-ABL1 (p < 0.0001), high white blood cell count (p = 0.021), and minimal residual disease (p = 0.013) were associated with worse disease-free survival.

Keywords:

• Drug resistance
• lymphoid leukemia
• prognostication
• transcription factor changes

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.3109/10428194.2016.1144881.

This work was supported by U10CA180821 and U10CA180882 (Alliance for Clinical Trials); CA: 1-U10-CA180835-01 (WS); U10CA180861, CA140158 CA016058-40, U24CA196171-01 (CDB); NCI RC4 CA156329, St Jude Cancer Support Grant P30 CA021765, the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital (CM); Dr Mullighan was supported by a Pew Scholar in the Biomedical Sciences and by a St. Baldrick's Foundation Scholar award. We would also like to acknowledge Jing Ma, Pathology, St. Jude Research Hospital and the Clinical Applications of Core Technology Laboratory of the Hartwell Center for Bioinformatics and Biotechnology at St. Jude Children's Research Hospital.