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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)689-695
Number of pages7
JournalInternational Journal of Hematology
Volume107
Issue number6
DOIs
StatePublished - Jun 1 2018
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Mutation
Blast Crisis
Cytogenetics
Protein-Tyrosine Kinases
Codon
Cohort Studies
Survival
Therapeutics

Keywords

  • Chronic myeloid leukemia
  • Mutation
  • Resistance

ASJC Scopus subject areas

  • Hematology

Cite this

Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR–ABL kinase domain mutations. / Naqvi, Kiran; Cortes, Jorge E.; Luthra, Raja; O’Brien, Susan; Wierda, William; Borthakur, Gautam; Kadia, Tapan; Garcia-Manero, Guillermo; Ravandi, Farhad; Rios, Mary Beth; Dellasala, Sara; Pierce, Sherry; Jabbour, Elias; Patel, Keyur; Kantarjian, Hagop.

In: International Journal of Hematology, Vol. 107, No. 6, 01.06.2018, p. 689-695.

Research output: Contribution to journalArticle

Naqvi, K, Cortes, JE, Luthra, R, O’Brien, S, Wierda, W, Borthakur, G, Kadia, T, Garcia-Manero, G, Ravandi, F, Rios, MB, Dellasala, S, Pierce, S, Jabbour, E, Patel, K & Kantarjian, H 2018, 'Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR–ABL kinase domain mutations', International Journal of Hematology, vol. 107, no. 6, pp. 689-695. https://doi.org/10.1007/s12185-018-2422-6
Naqvi, Kiran ; Cortes, Jorge E. ; Luthra, Raja ; O’Brien, Susan ; Wierda, William ; Borthakur, Gautam ; Kadia, Tapan ; Garcia-Manero, Guillermo ; Ravandi, Farhad ; Rios, Mary Beth ; Dellasala, Sara ; Pierce, Sherry ; Jabbour, Elias ; Patel, Keyur ; Kantarjian, Hagop. / Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR–ABL kinase domain mutations. In: International Journal of Hematology. 2018 ; Vol. 107, No. 6. pp. 689-695.
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T1 - Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR–ABL kinase domain mutations

AU - Naqvi, Kiran

AU - Cortes, Jorge E.

AU - Luthra, Raja

AU - O’Brien, Susan

AU - Wierda, William

AU - Borthakur, Gautam

AU - Kadia, Tapan

AU - Garcia-Manero, Guillermo

AU - Ravandi, Farhad

AU - Rios, Mary Beth

AU - Dellasala, Sara

AU - Pierce, Sherry

AU - Jabbour, Elias

AU - Patel, Keyur

AU - Kantarjian, Hagop

PY - 2018/6/1

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N2 - 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.

AB - 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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KW - Resistance

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