Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors

Dan Jones, Deborah Thomas, C. Cameron Yin, Susan O'Brien, Jorge E. Cortes, Elias Jabbour, Megan Breeden, Francis J. Giles, Weiqiang Zhao, Hagop M. Kantarjian

Research output: Contribution to journalArticle

Abstract

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 lymphoblastic leukemia (ALL) are less well studied. METHODS. The authors assessed KD mutations in patients with recurrent Phpositive 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.

Original languageEnglish (US)
Pages (from-to)985-994
Number of pages10
JournalCancer
Volume113
Issue number5
DOIs
StatePublished - Sep 1 2008
Externally publishedYes

Fingerprint

Philadelphia Chromosome
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Point Mutation
Phosphotransferases
Mutation
Therapeutics
Codon
Recurrence
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms
Clone Cells

Keywords

  • Biologic selection
  • Chronic myeloid leukemia
  • Kinase inhibitor
  • Lymphoid leukemia
  • Therapy resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors. / 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.

In: Cancer, Vol. 113, No. 5, 01.09.2008, p. 985-994.

Research output: Contribution to journalArticle

Jones, D, Thomas, D, Yin, CC, O'Brien, S, Cortes, JE, Jabbour, E, Breeden, M, Giles, FJ, Zhao, W & Kantarjian, HM 2008, 'Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors', Cancer, vol. 113, no. 5, pp. 985-994. https://doi.org/10.1002/cncr.23666
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. / Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors. In: Cancer. 2008 ; Vol. 113, No. 5. pp. 985-994.
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abstract = "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 lymphoblastic leukemia (ALL) are less well studied. METHODS. The authors assessed KD mutations in patients with recurrent Phpositive 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.",
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T1 - Kinase domain point mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia emerge after therapy with BCR-ABL kinase inhibitors

AU - Jones, Dan

AU - Thomas, Deborah

AU - Yin, C. Cameron

AU - O'Brien, Susan

AU - Cortes, Jorge E.

AU - Jabbour, Elias

AU - Breeden, Megan

AU - Giles, Francis J.

AU - Zhao, Weiqiang

AU - Kantarjian, Hagop M.

PY - 2008/9/1

Y1 - 2008/9/1

N2 - 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 lymphoblastic leukemia (ALL) are less well studied. METHODS. The authors assessed KD mutations in patients with recurrent Phpositive 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.

AB - 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 lymphoblastic leukemia (ALL) are less well studied. METHODS. The authors assessed KD mutations in patients with recurrent Phpositive 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.

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KW - Chronic myeloid leukemia

KW - Kinase inhibitor

KW - Lymphoid leukemia

KW - Therapy resistance

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DO - 10.1002/cncr.23666

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