The chronic myeloid leukemia (CML) is characterized by the presence of t(9;22)(q34;q11) that results in chimerization of BCR and ABL genes on the rearranged chromosome 22 or Philadelphia chromosome (Ph). Imatinib has been established as the first line of therapy for CML; in case of Imatinib failure or resistance, other second or third generation tyrosine kinase inhibitors (TKIs) are considered. However, acquisition of additional clonal abnormalities (ACAs) interferes in management of CML. We described a complex scenario of cytogenetic remission, relapse, response to TKIs and behavior of ACAs in a case of CML. Conventional G-banding and FISH cytogenetics, and quantitative PCR studies were conducted in the bone marrow for diagnosis and follow up (FU) of the changes of BCR-ABL gene and ACAs at different time intervals. Ph- chromosome disappeared within 6 months of Imatinib therapy, and re-appeared within a year. Subsequent change of TKI to dasatinib eliminated the Ph+ clone, but established an ACA with trisomy 8 (+8). Further change to Nilotinib, eliminated +8 clone, but re-emergence of Ph+ clone occurred with an ACA with monosomy 7 (-7). Reinstate of Dasatinib eliminated Ph+ and -7 clones, but with gradual reappearance of Ph+ and +8 clones. The patient discontinued FU, though participated in a long term examination. The complexity of ACAs and Ph+ clones needs frequent monitoring with changes of TKI and technologies.