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 yet been systematically assessed to date in patients treated with 2ndTKIs such as dasatinib, nilotinib and bosutinib. 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 453 pts with CML treated with 2nd TKIs either after imatinib failure (n=299; 124 pts treated with dasatinib, 116 pts treated with nilotinib, and 59 pts treated with bosutinib) or as frontline therapy (n=154; 76 pts treated with dasatinib, and 78 pts treated with nilotinib) between June 2003 and August 2010. After a median follow-up of 37 months (range, 12–67 months), 41 pts (9%) 35 in chronic phase, 2 accelerated phase, and 4 in blast phase) receiving dasatinib (n=11), nilotinib (n=21) or bosutinib (n=9) developed 72 chromosomal abnormalities in Ph-negative metaphases. 32 (44%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of the 2nd TKI to appearance of abnormalities was 8 months (range, 2 – 57 months). The most common cytogenetic abnormalities were: –Y (n=7, 10%), trisomy 8 (n=6, 8%), and del20q (n=5, 7%). Excluding loss of chromosome Y abnormalities and abnormalities observed in only one metaphase, the incidence was 4%. At the time abnormalities were detected, 33 pts were in major cytogenetic response (complete in 26) and 8 in minor cytogenetic response. In all but 14 pts, these events have been transient and disappeared after a median of 3 months (range, 1 – 42 months). In14 pts (+8 n=3, -Y n=3, and del20q n=2), they persisted for a median of 10+ months (range, 3+-60+ months). One pt on dasatinib developed refractory anemia with ringed sideroblasts (associated with trisomy 8); she had CML for 16 years, failed prior therapy with interferon, imatinib, and nilotinib, and achieved a complete cytogenetic response on dasatinib for 24 months, lost her response, progressed and died of multiple organ failure. None of the other pts had any features of myelodysplasia. At the last follow-up, all but 7 pts are alive: 29 in major cytogenetic response (complete in 24), 1 in minor cytogenetic response, and 4 alive with disease. Causes of death included stem cell transplant related morbidities (n=2), multisystem organ failure related to sepsis (n=2), and unknown causes (n=3). We conclude that cytogenetic abnormalities occur in Ph-negative cells in a small fraction of pts (9%; 4% if loss of Y and abnormalities in one metaphase are excluded) treated with the 2nd TKIs. These are frequently transient and usually have no clinical significance, but in rare instances they could signal the emergence of a new malignant clone.
Jabbour:Novartis: Honoraria; BMS: Honoraria. Kadia:Novartis: Consultancy. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.