Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative Metaphases Appearing during Novel Tyrosine Kinase Inhibitors (NTKI) Therapy in Patients (pts) with Chronic Myeloid Leukemia (CML) after Imatinib-Failure.

The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized in pts with CML. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. This phenomenon has not been yet systematically assessed to date in patients treated with NTKIs such as dasatinib and nilotinib. By definition, this phenomenon is evaluable only among pts who achieve at least a minor cytogenetic response. We assessed the frequency and the significance of this event among 107 pts with CML after imatinib failure receiving dasatinib (=70) or nilotinib (n=37) therapy between June 2003 and March 2006. After a median follow-up of 13 months (range, 3–32 months), 12 pts (11%) (chronic phase n=6, accelerated phase n=6) receiving dasatinib (n=6) or nilotinib (n=6), developed 21 chromosomal abnormalities in Ph-negative metaphases. Ten (48%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of the NTKI to appearance of abnormalities was 7 months (range, 0–15 months). The most common cytogenetic abnormalities were: trisomy 8 (n=3, 14%) and del 20q (n=3, 14%). Excluding loss of chromosome Y abnormalities and abnormalities observed in only one metaphase, the incidence was 5%. At the time, abnormalities were detected, 8 pts were in major cytogenetic response (complete in 6) and 4 in minor cytogenetic response. In all but 4 pts these events have been transient and disappeared after a median of 4 months (range, 3–9 months). In 4 pts (+8 n=2, −Y n=1, and add1q, del10q, and del20q n=1), they persisted for a median of 5+ months (range, 3+ – 9+ months). One pt on dastinib developed refractory anemia with ringed sideroblasts (associated with trisomy 8); he had CML for 16 years, failed prior therapy with interferon, imatinib, and nilotinib, and achieved a complete cytogenetic response on dasatinib; none of the other pts has any feature of myelodysplasia. At the last follow-up, all pts are alive: 2 pts lost their response; one of them underwent allogeneic stem cell transplantation and achieved a major molecular remission. The other 10 pts remained in major cytogenetic response (complete in 8). We conclude that cytogenetic abnormalities occur in Ph-negative cells in a small fraction of patients (11%; 5% if loss of Y and abnormalities in one metaphase excluded) treated with the NTKIs. These are frequently transient and usually have no clinical significance, but in rare instances they could signal the emergence of a new malignant clone.