Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl 
fusion protein with deregulated tyrosine kinase activity that is required for 
maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl, 
induces major cytogenetic remission (MCR) or complete cytogenetic remission 
(CCR) in the majority of patients with CML in first chronic phase. However, 
thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR 
demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of 
which were clinically associated with a myelodysplastic syndrome (MDS). Further 
analysis identified previous exposure to cytarabine and idarubicin as 
significant risk factors for the subsequent occurrence of abnormalities in 
Philadelphia chromosome-negative (Ph-) cells. To investigate if cytogenetically 
normal but clonal hematopoiesis might be present in other patients in 
cytogenetic remission, we studied X-chromosome inactivation as a marker of 
clonality by polymerase chain reaction analysis of the human androgen receptor 
(HUMARA). We find that imatinib restores a polyclonal pattern in most patients 
in CCR and MCR. Nonetheless, our results are consistent with the notion that 
targeted therapy of CML with imatinib favors the manifestation of Ph- clonal 
disorders in some patients. They indicate that patients on imatinib should be 
followed with conventional cytogenetics, even after induction of CCR.