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
N1 - Funding Information:
Dr Jabbour has received honoraria from ARIAD Pharmaceuticals, Inc, Pfizer, Bristol-Myers Squibb, Novartis, and Teva, unrelated to the submitted work; Dr Kantarjian has received research grants from Novartis , Bristol-Myers Squibb , Pfizer , and ARIAD Pharmaceuticals, Inc , unrelated to the submitted work; Dr Cortes reports grants and personal fees for consulting from ARIAD Pharmaceuticals, Inc, Bristol-Myers Squibb, Novartis, Pfizer, and Teva, unrelated to the submitted work.
Publisher Copyright:
© 2015 Elsevier Inc.
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
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U2 - 10.1016/j.clml.2015.03.006
DO - 10.1016/j.clml.2015.03.006
M3 - Review article
C2 - 25971713
AN - SCOPUS:84931569737
SN - 2152-2650
VL - 15
SP - 323
EP - 334
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - 6
ER -