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Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR–ABL kinase domain mutations

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Abstract

Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR–ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP). 9/14 CP patients responded to treatment (best response complete hematologic response—CHR-4; complete cytogenetic response—CCyR-1; major molecular response—MMR-4); only 4/12 AP patients (CHR 3; MMR 1) and 7/22 BP patients responded (CCyR 2; MMR 2; partial cytogenetic response—PCyR-3). After a median follow-up of 65 months from mutation detection, 36 patients (75%) died: 9/14 (64%) in CP, 9/12 (75%) in AP, and 18/22 (82%) in BP (p = 0.003); median overall survival was 12 months. Patients with E255K/V mutation have a poor prognosis, regardless of the stage of the disease at detection.

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Acknowledgements

Dr. Cortes has received research support from Ariad, BMS, Novartis, Pfizer, and Teva. Dr. Cortes is consultant for Ariad, Novartis, BMS, and Pfizer.

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Authors and Affiliations

  1. Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Kiran Naqvi, Jorge E. Cortes, Raja Luthra, Susan O’Brien, William Wierda, Gautam Borthakur, Tapan Kadia, Guillermo Garcia-Manero, Farhad Ravandi, Mary Beth Rios, Sara Dellasala, Sherry Pierce, Elias Jabbour, Keyur Patel & Hagop Kantarjian

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  1. Kiran Naqvi
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  2. Jorge E. Cortes
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  3. Raja Luthra
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  4. Susan O’Brien
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  6. Gautam Borthakur
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  8. Guillermo Garcia-Manero
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  11. Sara Dellasala
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  13. Elias Jabbour
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  14. Keyur Patel
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  15. Hagop Kantarjian
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Correspondence to Jorge E. Cortes.

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Naqvi, K., Cortes, J.E., Luthra, R. et al. Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR–ABL kinase domain mutations. Int J Hematol 107, 689–695 (2018). https://doi.org/10.1007/s12185-018-2422-6

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  • DOI: https://doi.org/10.1007/s12185-018-2422-6

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