TKIS IN CML : The appearance of abnormal clones in Ph- cells

Introduction. Tyrosine kinase inhibitors (TKIs) have changed the approach to the management of chronic myeloid leukemia (CML). Imatinib and dasatinib are potent TKIs to which most patients (pts) show a major (MCR) or complete cytogenetic response (CCR). There have been reports of clonal changes in the Ph- cells of CML pts treated with TKIs, the most common of which are trisomy chr.8 and monosomy chr.7. Materials and Methods Before and during TKI treatment, cytogenetic and FISH analyses using a dual fusion double colour probe were made of 101 pts (84 treated with imatinib, and 17 with dasatinib) diagnosed as having CML between 1999 and 2008. Results. Eight pts developed a total of nine chromosomal abnormalities, six of which occurred during imatinib and three during dasatinib treatment (Table). The (20q) deletions in the pts on imatinib were observed 43 and 54 months after starting therapy, 7 and 42 months after they had achieved CCR; the -y anomalies were observed 27 and 31 months after starting therapy, 24 and 25 months after CCR. The -y anomaly in the patient treated with dasatinib developed developed 45 months after starting therapy, six months after CCR. It is worth noting that one of the two pts with trisomy chr.8 in MCR on imatinib subsequently developed trisomy chr.9 (20 months after switching to dasatinib, 11 months after CCR): the trisomy chr.8 is still present. All of the abnormalities arising during MCR and not CCR are trisomy chr.8.Conclusions. All of the pts are still in MCR/CCR and no clinical progression or myelodisplastic disease has been documented during follow-up. Whether the TKIs played a role in the occurrence of the abnormalities remains to be determined as they could be related to CML clonal instability and/or drug effects. The prognostic implications need to be verified in a larger CML group over a longer follow-up.