TY - JOUR
T1 - Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression
AU - Khorashad, Jamshid S.
AU - De Lavallade, Hugues
AU - Apperley, Jane F.
AU - Milojkovic, Dragana
AU - Reid, Alistair G.
AU - Bua, Marco
AU - Szydlo, Richard
AU - Olavarria, Eduardo
AU - Kaeda, Jaspal
AU - Goldman, John M.
AU - Marin, David
PY - 2008/10/10
Y1 - 2008/10/10
N2 - Purpose: Kinase domain (KD) mutations in the BCR-ABL gene are associated with resistance to imatinib in chronic myeloid leukemia (CML) but their incidence and prognostic significance in chronic phase (CP) patients without resistance are unclear. Patients and Methods: We analyzed outcome for 319 patients with CML-CP who were treated with imatinib; 171 were in early CP (ECP) and 148 were in late CP (LCP). Patients were screened routinely for mutations using direct sequencing regardless of response status. The 5-year cumulative incidence of mutations was 6.6% for ECP and 17% for LCP patients. Results: Of the 319 patients, 214 (67%) achieved complete cytogenetic responses (CCyR). The identification of a mutation without other evidence of imatinib resistance was highly predictive for loss of CCyR (RR, 3.8; P = .005) and for progression to advanced phase (RR, 2.3; P = .01), though the intervals from first identification to loss of CCyR and disease progression were relatively long (median, 21 and 16 months, respectively). Mutations in the P-loop (excluding residue 244) were associated with a higher risk of progression than mutations elsewhere. Conclusion: We conclude that routine mutation screening of patients who appear to be responding to imatinib may identify those at high risk of disease progression.
AB - Purpose: Kinase domain (KD) mutations in the BCR-ABL gene are associated with resistance to imatinib in chronic myeloid leukemia (CML) but their incidence and prognostic significance in chronic phase (CP) patients without resistance are unclear. Patients and Methods: We analyzed outcome for 319 patients with CML-CP who were treated with imatinib; 171 were in early CP (ECP) and 148 were in late CP (LCP). Patients were screened routinely for mutations using direct sequencing regardless of response status. The 5-year cumulative incidence of mutations was 6.6% for ECP and 17% for LCP patients. Results: Of the 319 patients, 214 (67%) achieved complete cytogenetic responses (CCyR). The identification of a mutation without other evidence of imatinib resistance was highly predictive for loss of CCyR (RR, 3.8; P = .005) and for progression to advanced phase (RR, 2.3; P = .01), though the intervals from first identification to loss of CCyR and disease progression were relatively long (median, 21 and 16 months, respectively). Mutations in the P-loop (excluding residue 244) were associated with a higher risk of progression than mutations elsewhere. Conclusion: We conclude that routine mutation screening of patients who appear to be responding to imatinib may identify those at high risk of disease progression.
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U2 - 10.1200/JCO.2008.16.9953
DO - 10.1200/JCO.2008.16.9953
M3 - Article
C2 - 18645191
AN - SCOPUS:54349089682
SN - 0732-183X
VL - 26
SP - 4806
EP - 4813
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 29
ER -