Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy

Dushyant Verma, Hagop Kantarjian, Jianqin Shan, Susan O'Brien, Zeev Estrov, Guillermo Garcia-Manero, Charles Koller, Gautam Borthakur, Jorge Cortes

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. METHODS: The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. RESULTS: Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. CONCLUSIONS: Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined.

Original languageEnglish (US)
Pages (from-to)2673-2681
Number of pages9
JournalCancer
Volume116
Issue number11
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

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Clonal Evolution
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein-Tyrosine Kinases
Survival
Cytogenetics
Therapeutics
Survival Rate
Metaphase
Disease-Free Survival
Philadelphia Chromosome
Chromosomes, Human, Pair 17
Splenomegaly
Hemoglobins
Multivariate Analysis
Drug Therapy

Keywords

  • Chronic myeloid leukemia
  • Clonal evolution
  • Clonal expression
  • Dasatinib
  • Nilotinib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. / Verma, Dushyant; Kantarjian, Hagop; Shan, Jianqin; O'Brien, Susan; Estrov, Zeev; Garcia-Manero, Guillermo; Koller, Charles; Borthakur, Gautam; Cortes, Jorge.

In: Cancer, Vol. 116, No. 11, 01.06.2010, p. 2673-2681.

Research output: Contribution to journalArticle

Verma, D, Kantarjian, H, Shan, J, O'Brien, S, Estrov, Z, Garcia-Manero, G, Koller, C, Borthakur, G & Cortes, J 2010, 'Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy', Cancer, vol. 116, no. 11, pp. 2673-2681. https://doi.org/10.1002/cncr.25015
Verma, Dushyant ; Kantarjian, Hagop ; Shan, Jianqin ; O'Brien, Susan ; Estrov, Zeev ; Garcia-Manero, Guillermo ; Koller, Charles ; Borthakur, Gautam ; Cortes, Jorge. / Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy. In: Cancer. 2010 ; Vol. 116, No. 11. pp. 2673-2681.
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AU - Kantarjian, Hagop

AU - Shan, Jianqin

AU - O'Brien, Susan

AU - Estrov, Zeev

AU - Garcia-Manero, Guillermo

AU - Koller, Charles

AU - Borthakur, Gautam

AU - Cortes, Jorge

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N2 - BACKGROUND: Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. METHODS: The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. RESULTS: Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. CONCLUSIONS: Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined.

AB - BACKGROUND: Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known. METHODS: The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy. RESULTS: Ninety-five patients were in chronic phase, 30 had clonal evolution, 28 were in accelerated phase (AP), and 24 were in AP plus clonal evolution. Major cytogenetic response rates were 58%, 54%, 28%, and 13%; 2-year overall survival (OS) rates were 86%, 73%, 68%, and 33%; and 2-year event-free survival (EFS) rates were 69%, 67%, 31%, and 8%, respectively. The hematologic and cytogenetic response rates, OS, and EFS were no different between patients in chronic phase with clonal evolution and patients with chronic phase and no clonal evolution. However, clonal evolution had a significant adverse impact when associated with other features of AP. On multivariate analysis, clonal evolution had no independently significant effect on achieving major cytogenetic response on the second generation tyrosine kinase inhibitors. The factors predicting increasing major cytogenetic response to second generation tyrosine kinase inhibitors were prior achievement of major cytogenetic response with imatinib, higher hemoglobin levels, no splenomegaly, lower percentage of Philadelphia chromosome-positive metaphases, and no prior chemotherapy. CONCLUSIONS: Clonal evolution constitutes a heterogeneous entity with variable outcome with second generation tyrosine kinase inhibitors, with trisomy 8, chromosome 17, and complex abnormalities having the worst outcome, regardless of the number of metaphases involved. The molecular events behind these abnormalities and potential therapeutic approaches directed at them need to be defined.

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KW - Nilotinib

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