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.
OBJECTIVE
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.


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.


CONCLUSIONS
We conclude that routine mutation screening of patients who appear to be responding to imatinib may identify those at high risk of disease progression.
Khorashad
Jamshid S
JS
Department of Haematology, Hammersmith Hospitals Trust, Imperial College London, Du Cane Rd, London W12 0NN, United Kingdom.
de Lavallade
Hugues
H
Apperley
Jane F
JF
Milojkovic
Dragana
D
Reid
Alistair G
AG
Bua
Marco
M
Szydlo
Richard
R
Olavarria
Eduardo
E
Kaeda
Jaspal
J
Goldman
John M
JM
Marin
David
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010770:Phosphotransferases / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use; D017434:Protein Structure, Tertiary / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D010770:Phosphotransferases