TY - JOUR
T1 - Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy
AU - Verma, Dushyant
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
PY - 2010/6/1
Y1 - 2010/6/1
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.
KW - Chronic myeloid leukemia
KW - Clonal evolution
KW - Clonal expression
KW - Dasatinib
KW - Nilotinib
UR - http://www.scopus.com/inward/record.url?scp=77952845388&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952845388&partnerID=8YFLogxK
U2 - 10.1002/cncr.25015
DO - 10.1002/cncr.25015
M3 - Article
C2 - 20499401
AN - SCOPUS:77952845388
SN - 0008-543X
VL - 116
SP - 2673
EP - 2681
JO - Cancer
JF - Cancer
IS - 11
ER -