Cytogenetic Clonal Evolution in Chronic Myeloid Leukemia during Imatinib Mesylate Treatment.

Cytogenetic clonal evolution (CE) - the presence of cytogenetic abnormalities in addition to the Ph chromosome in chronic myeloid leukemia (Ph+ CML) is a known poor prognostic factor associated with disease progression. Occurence of additional cytogenetic abnormalities in both Ph positive and Ph negative mitoses was also described in imatinib treated CML patients and was associated with occuring therapy resistance. The long - term significance is so far poorly understood. Objective. To monitor cytogenetic abnormalities in chronic phase CML patients on imatinib treatment, following long-term interferon alfa (IFN) or hydroxyurea treatment. To compare the haematological disease progression in patients with or without cytogenetic evolution

Patients and methods: Cytogenetic evolution was analyzed in 57 patients (median age 56, range 18–73) treated with imatinib in chronic phase, following interferon resistance or intolerance. The duration of IFN application was 22 months (range 3 – 46 months), duration of imatinib treatment was 16 months (range 6 – 55 months). Cytogenetic abnormalities were detected by conventional cytogenetics - caryotype analysis and fluorescence in situ hybridisation (FISH).

Results: Complete cytogenetic remission was accomplished in 55 of 57 pts (96%) on imatinib, significant or complete cytogenetic response was observed in 36 of 57 patients (66%). Cytogenetic evolution was observed in 11 patients (19%) treated with imatinib: in the Ph+ clone (9 cases) and in the Ph− clone (2 cases). Median duration of imatinib treatment before the CE identification was 16 months (range 7–36 months). The most common additional abnormality was trisomy 8 (8 pts), second Ph chromosome (4 pts), and del (17) (4 pts). In 5 cases we observed the simultaneous occurence of two different cytogenetic abnormalities. Haematological progression was observed in 7 of 11 patients (63%) following 2 – 22 months imatinib treatment (median 9 months). 5 pts (46%) exited. Six patients live 8–22 months from the detection of cytogenetic evolution. Secondary malignancy was diagnosed in 1 patient. In the group of patients without cytogenetic evolution haematological progression was observed only in 9 of 46 (19.5%) cases, 4 patients died (14.3%).

Conclusion: The role of IM concerning the cytogenetic evolution occurence in CML patients is not so far clear, the suppression of the Ph+ clone could enhance the proliferation of resistant ones. In our group of patients CE was documented in 11 patients (19%), in both Ph+ and Ph− cells. Significantly higher was the risk of haematological progression. CML patients treated with imatinib should be regularly monitored with conventional cytogenetic techniques, not only to follow the decrease in the proportion of Ph-positive cells, but also to look for new especially Ph-negative clonal chromosomal abnormalities.

A longer follow-up time and systematic monitoring of cytogenetics is needed to establish the prognostic impact of clonal evolution in CML patients treated with imatinib.