Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: An evolving treatment paradigm

Elias Jabbour, Hagop Kantarjian, Jorge Cortes

Research output: Contribution to journalReview article

Abstract

Although imatinib remains the gold standard for first-line treatment of chronic myeloid leukemia (CML), increasing recognition of imatinib resistance and intolerance has led to the development of additional tyrosine kinase inhibitors (TKIs), which have demonstrated effectiveness as salvage therapies or alternative first-line treatments. Although additional options represent progress, the availability of 3 second-generation TKIs (dasatinib, nilotinib, and bosutinib) and 1 third-generation TKI (ponatinib) has added complexity to the treatment paradigm for CML, particularly CML in the chronic phase. Two second-generation agents (dasatinib and nilotinib) are approved for use as first-line and subsequent therapy. Thus, the appropriate sequencing of TKIs is a frequent quandary, and is incompletely addressed in clinical guidelines. Here, we review studies that might guide selection of a second- or third-generation TKI after failure of TKI therapy in patients with chronic-phase CML. These studies evaluate prognostic factors such as first-line cytogenetic response and BCR-ABL1 mutation status, which might help physicians identify patients who are likely to respond to second-generation TKIs, and those for whom ponatinib or an investigational agent might be more appropriate. We summarize evidence to date that suggests that use of a second-generation TKI as third-line therapy confers limited value in most CML patients, and we also explore the utility of current event-free survival versus traditional outcomes to predict long-term benefits of sequential TKI use. Finally, we present 3 case studies to illustrate how prognostic factors and other considerations (eg, tolerability) can be used to individualize subsequent therapy in cases of TKI resistance or intolerance.

Original languageEnglish (US)
Pages (from-to)323-334
Number of pages12
JournalClinical Lymphoma, Myeloma and Leukemia
Volume15
Issue number6
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

Fingerprint

Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein-Tyrosine Kinases
Leukemia, Myeloid, Chronic Phase
Therapeutics
Salvage Therapy
Cytogenetics
Disease-Free Survival
Guidelines
Physicians
Mutation

Keywords

  • BCR-ABL1
  • Outcome
  • Prognosis
  • Resistance
  • Response

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia : An evolving treatment paradigm. / Jabbour, Elias; Kantarjian, Hagop; Cortes, Jorge.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 15, No. 6, 01.06.2015, p. 323-334.

Research output: Contribution to journalReview article

@article{0becf25396934d6b85af8c2e2f144853,
title = "Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: An evolving treatment paradigm",
abstract = "Although imatinib remains the gold standard for first-line treatment of chronic myeloid leukemia (CML), increasing recognition of imatinib resistance and intolerance has led to the development of additional tyrosine kinase inhibitors (TKIs), which have demonstrated effectiveness as salvage therapies or alternative first-line treatments. Although additional options represent progress, the availability of 3 second-generation TKIs (dasatinib, nilotinib, and bosutinib) and 1 third-generation TKI (ponatinib) has added complexity to the treatment paradigm for CML, particularly CML in the chronic phase. Two second-generation agents (dasatinib and nilotinib) are approved for use as first-line and subsequent therapy. Thus, the appropriate sequencing of TKIs is a frequent quandary, and is incompletely addressed in clinical guidelines. Here, we review studies that might guide selection of a second- or third-generation TKI after failure of TKI therapy in patients with chronic-phase CML. These studies evaluate prognostic factors such as first-line cytogenetic response and BCR-ABL1 mutation status, which might help physicians identify patients who are likely to respond to second-generation TKIs, and those for whom ponatinib or an investigational agent might be more appropriate. We summarize evidence to date that suggests that use of a second-generation TKI as third-line therapy confers limited value in most CML patients, and we also explore the utility of current event-free survival versus traditional outcomes to predict long-term benefits of sequential TKI use. Finally, we present 3 case studies to illustrate how prognostic factors and other considerations (eg, tolerability) can be used to individualize subsequent therapy in cases of TKI resistance or intolerance.",
keywords = "BCR-ABL1, Outcome, Prognosis, Resistance, Response",
author = "Elias Jabbour and Hagop Kantarjian and Jorge Cortes",
year = "2015",
month = "6",
day = "1",
doi = "10.1016/j.clml.2015.03.006",
language = "English (US)",
volume = "15",
pages = "323--334",
journal = "Clinical Lymphoma, Myeloma and Leukemia",
issn = "2152-2650",
publisher = "Cancer Media Group",
number = "6",

}

TY - JOUR

T1 - Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

T2 - An evolving treatment paradigm

AU - Jabbour, Elias

AU - Kantarjian, Hagop

AU - Cortes, Jorge

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Although imatinib remains the gold standard for first-line treatment of chronic myeloid leukemia (CML), increasing recognition of imatinib resistance and intolerance has led to the development of additional tyrosine kinase inhibitors (TKIs), which have demonstrated effectiveness as salvage therapies or alternative first-line treatments. Although additional options represent progress, the availability of 3 second-generation TKIs (dasatinib, nilotinib, and bosutinib) and 1 third-generation TKI (ponatinib) has added complexity to the treatment paradigm for CML, particularly CML in the chronic phase. Two second-generation agents (dasatinib and nilotinib) are approved for use as first-line and subsequent therapy. Thus, the appropriate sequencing of TKIs is a frequent quandary, and is incompletely addressed in clinical guidelines. Here, we review studies that might guide selection of a second- or third-generation TKI after failure of TKI therapy in patients with chronic-phase CML. These studies evaluate prognostic factors such as first-line cytogenetic response and BCR-ABL1 mutation status, which might help physicians identify patients who are likely to respond to second-generation TKIs, and those for whom ponatinib or an investigational agent might be more appropriate. We summarize evidence to date that suggests that use of a second-generation TKI as third-line therapy confers limited value in most CML patients, and we also explore the utility of current event-free survival versus traditional outcomes to predict long-term benefits of sequential TKI use. Finally, we present 3 case studies to illustrate how prognostic factors and other considerations (eg, tolerability) can be used to individualize subsequent therapy in cases of TKI resistance or intolerance.

AB - Although imatinib remains the gold standard for first-line treatment of chronic myeloid leukemia (CML), increasing recognition of imatinib resistance and intolerance has led to the development of additional tyrosine kinase inhibitors (TKIs), which have demonstrated effectiveness as salvage therapies or alternative first-line treatments. Although additional options represent progress, the availability of 3 second-generation TKIs (dasatinib, nilotinib, and bosutinib) and 1 third-generation TKI (ponatinib) has added complexity to the treatment paradigm for CML, particularly CML in the chronic phase. Two second-generation agents (dasatinib and nilotinib) are approved for use as first-line and subsequent therapy. Thus, the appropriate sequencing of TKIs is a frequent quandary, and is incompletely addressed in clinical guidelines. Here, we review studies that might guide selection of a second- or third-generation TKI after failure of TKI therapy in patients with chronic-phase CML. These studies evaluate prognostic factors such as first-line cytogenetic response and BCR-ABL1 mutation status, which might help physicians identify patients who are likely to respond to second-generation TKIs, and those for whom ponatinib or an investigational agent might be more appropriate. We summarize evidence to date that suggests that use of a second-generation TKI as third-line therapy confers limited value in most CML patients, and we also explore the utility of current event-free survival versus traditional outcomes to predict long-term benefits of sequential TKI use. Finally, we present 3 case studies to illustrate how prognostic factors and other considerations (eg, tolerability) can be used to individualize subsequent therapy in cases of TKI resistance or intolerance.

KW - BCR-ABL1

KW - Outcome

KW - Prognosis

KW - Resistance

KW - Response

UR - http://www.scopus.com/inward/record.url?scp=84931569737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931569737&partnerID=8YFLogxK

U2 - 10.1016/j.clml.2015.03.006

DO - 10.1016/j.clml.2015.03.006

M3 - Review article

C2 - 25971713

AN - SCOPUS:84931569737

VL - 15

SP - 323

EP - 334

JO - Clinical Lymphoma, Myeloma and Leukemia

JF - Clinical Lymphoma, Myeloma and Leukemia

SN - 2152-2650

IS - 6

ER -