TY - JOUR
T1 - Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL)
T2 - molecular analysis of CALGB (Alliance) 10001 and 9665
AU - DeBoer, Rebecca
AU - Koval, Gregory
AU - Mulkey, Flora
AU - Wetzler, Meir
AU - Devine, Steven
AU - Marcucci, Guido
AU - Stone, Richard M.
AU - Larson, Richard A.
AU - Bloomfield, Clara D.
AU - Geyer, Susan
AU - Mullighan, Charles G.
AU - Stock, Wendy
N1 - Publisher Copyright:
© 2016 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2016/10/2
Y1 - 2016/10/2
N2 - 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.
AB - 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.
KW - Drug resistance
KW - lymphoid leukemia
KW - prognostication
KW - transcription factor changes
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U2 - 10.3109/10428194.2016.1144881
DO - 10.3109/10428194.2016.1144881
M3 - Article
C2 - 26892479
AN - SCOPUS:84958751941
SN - 1042-8194
VL - 57
SP - 2298
EP - 2306
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 10
ER -