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Kinase domain point mutations in Philadelphia chromosome‐positive acute lymphoblastic leukemia emerge after therapy with BCR‐ABL kinase inhibitors
Author(s) -
Jones Dan,
Thomas Deborah,
Yin C. Cameron,
O'Brien Susan,
Cortes Jorge E.,
Jabbour Elias,
Breeden Megan,
Giles Francis J.,
Zhao Weiqiang,
Kantarjian Hagop M.
Publication year - 2008
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.23666
Subject(s) - dasatinib , medicine , imatinib , philadelphia chromosome , point mutation , myeloid leukemia , abl , mutation , leukemia , acute lymphocytic leukemia , cancer research , oncology , gastroenterology , lymphoblastic leukemia , genetics , tyrosine kinase , gene , biology , chromosomal translocation , receptor
BACKGROUND. BCR‐ABL kinase domain (KD) mutations are detected in approximately 45% of patients with imatinib‐resistant chronic myeloid leukemia. Patterns of KD mutations in Philadelphia chromosome (Ph)‐positive acute lympho‐ blastic leukemia (ALL) are less well studied. METHODS. The authors assessed KD mutations in patients with recurrent Ph‐positive ALL after treatments that included 1 or more kinase inhibitors (n = 24 patients) or no prior kinase inhibitor (KI) therapy (n = 12 patients). RESULTS. ABL KD mutations were detected by direct sequencing in 15 of 17 patients (88%) who had recurrent Ph‐positive ALL and received prior imatinib (n = 16) or dasatinib (n = 1) treatment and in 6 of 7 patients (86%) who had resistant/recurrent tumors treated with ≥2 KIs compared with 0 of 12 patients with recurrent Ph‐positive ALL who never received KIs. A restricted set of mutations was observed, mostly Y253H and T315I, and were detected on average 10 months after KI initiation, and mutations were not detected in the initial tumor samples before KI therapy in 12 patients who were assessed. Using a more sensitive pyrosequencing method, mutations were not detected at codons 315 and 253 in the diagnostic samples from those 12 patients or in 30 patients with Ph‐positive ALL who never developed recurrent disease. CONCLUSIONS. ABL KD mutations, especially at codons 315 and 253, emerged at the time of disease recurrence in the vast majority of patients who had Ph‐positive ALL and received maintenance KI therapy. Thus, the authors concluded that ongoing KI exposure may alter the patterns of recurrence and favor the outgrowth of clones with KI‐resistant mutations. Cancer 2008. © 2008 American Cancer Society.