Different Patterns of Cytogenetic Evolution in CML Treated with Imatinib.

In CML the Ph+ cell clone is genetically unstable leading to the acquisition of typical additional abnormalities during accelerated phase and blast crisis in up to 60 to 80 % of pts. Imatinib, by selectively inhibiting bcr-abl tyrosinkinase induces complete cytogenetic remissions in up to 80% of pts. Beneath others, two main mechanisms are responsible for the development of Imatinib-resistance: On the molecular level mutations of the bcr-abl domain and on the cytogenetic level acquisition of additional abnormalities can occur. To investigate the latter phenomenon a cohort of 67 pts treated with Imatinib was karyotyped sequentially. Treatment results were as follows: CCR: 40 (60%), MaCR: 4 (6%), MinCR: 9 (13.4%), NR: 7 (10.5%), cytogenetic progression: 5 (7.5%). Five different patterns of cytogenetic progression under Imatinib were observed. I (occurrence of an additional abnormality): One case with initial t(3;9;22) and additional 17p-/P53 allelic loss 36 after months under Imatinib. II (expansion of an initially present additional abnormality): Initial t(9;22) and a subclone with additional t(2;3), followed by expansion of the sublone with additional t(2;3). III (occurrence of multiple additional, partly atypical abnormalities and expansion of this clone): One case with initial t(9;22) and additional inv(3q), 7q-, +19, +Ph. IV (occurrence of typical additional abnormalities and expansion of the clone with the highest number of abnormalities): Initial t(9;22) and additional +8,+Ph. V (discordant response): Initial t(9:22), subsequent MaCR with parallel occurrence of a clone with additional +8,+8,+Ph and further progression. Of the five cases with cytogenetic progression two pts (I,V) had been treated with Imatinib only, one pt had a combination of Imatinib and IFN (II) and two pts (III, IV) had low-dose AraC before Imatinib. It can be concluded that pretreatment with AraC might have modulated the genetic response to Imatinib possibly leading to genetic evolution via selection of cytogenetically resistant clones in 2/5 cases. In 3/5 cases intrinsic mechanisms must have contributed to Imatinib-resistance. As demonstrated by case V our observations furthermore draw the attention to the underestimated problem of discordant genetic responses only traceable by classical cytogenetics. Thus the therapeutic consequences of these findings have not been clearly defined as yet.