Clinical Significance of Loss of Chromosome Y (−Y) in Patients with Chronic Myeloid Leukemia (CML): Is It Clonal Evolution?.

Clonal evolution (CE), in chronic myeloid leukemia (CML), is characterized by the appearance of additional cytogenetic abnormalities in Philadelphia-positive (Ph+)-cells and is considered a criterion of accelerated phase (AP). Loss of chromosome Y (−Y) frequently occurs in male individuals with aging and has been generally not considered a clinically significant abnormality in hematologic malignancy. In CML it is most frequently not considered an abnormality representing CE assuming it lacks the prognostic implications of other abnormalities in this setting. We thus investigated the frequency and prognostic significance among 352 patients with CML in chronic phase (CP) treated with imatinib mesylate at our institution. −Y was detected along with Ph+ in 7 patients (2%): 3 at the time of diagnosis and 4 during the course of therapy, after a median of 47 months (range, 9–130 months) from diagnosis. Median age was 56 years (range, 40–75 years). Three patients had received prior interferon. Best response to imatinib was complete cytogenetic response in 2 patients (29%), partial in 1 (14%), minor in 2 and complete hematologic response in 2. All but one patient have lost their response after a median of 26 months (range, 2–55 months). In only one patient, −Y was transient and disappeared after 3 months. This patient is in ongoing molecular remission. Of the 6 patients who failed imatinib, 3 patients also failed subsequent therapies (nilotinib, dastinib, and chemotherapy, respectively) and 2 of them subsequently died of progressive disease. The other 3 patients responded to salvage therapy (combination of farnesyl transferase inhibitors and imatinib, homoharingtonine, and chemotherapy), and one of them is in molecular remission following allogeneic stem cell transplantation. The median overall survival from the appearance of the −Y has not been reached. We conclude that CE involving −Y abnormality is uncommon in patients with CML treated with imatinib but it may be associated with poor outcome and should be considered as a manifestation of clonal evolution.