Characterization of Ph-negative abnormal clones emerging during imatinib therapy

BACKGROUND: Imatinib is a tyrosine kinase-specific inhibitor widely used for the treatment of chronic myeloid leukemia (CML). Studies reported the occurrence of additional cytogenetic abnormalities in the Philadelphia chromosome (Ph)-negative cell population emerging after treatment-induced suppression of the Ph-positive clone. These abnormalities were described in a relatively high proportion of patients treated with imatinib compared with the anecdotal reports of similar cases in patients treated with other drugs. However, the origin of these abnormalities as well as their biological and clinical significance are unknown. METHODS: The study involved 13 cases of patients diagnosed with CML carrying cytogenetic abnormalities in their Ph-negative cell population after imatinib treatment. The presence of the markers within the CD34+ stem cell compartment and the cell culture growth were analyzed and patients were followed over time. RESULTS: CD34+ cells express the cytogenetic markers present in Ph- cells, suggesting a possible involvement of the stem cell population. Cultured cells showed normal growth in all but 1 patient. No growth advantage was demonstrated for the Ph-negative or the Ph-positive clone after cell culture. CONCLUSIONS: After follow-up of up to 49 months, none of the patients had evolved to myelodysplasia or acute leukemia. Hypothesis regarding the biological and clinical significance of these abnormalities are formulated.