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.

Figures

Figure 1

CONSORT diagrams of clinical trial CALGB 10001 and companion Leukemia Tissue Bank protocol CALGB 9665.

Figure 2

Summary of q-PCR results showing the time point at which the resistant clone was first detected in each of the 13 patients with a kinase domain mutation present at relapse.

Figure 3

Prevalence of deletions in IKZF1, CDKN2A/B, and PAX5 in available pre-treatment samples (n=28).

Figure 4

A) DFS and B) OS stratified by BCR-ABL1 fusion transcript. C) DFS and D) OS stratified by presence of IKZF1 deletion and BCR-ABL1 fusion transcript. E) DFS and F) OS stratified by WBC count at diagnosis.