In chronic myeloid leukemia (CML), the progress from chronic phase (CP) to advanced disease with accelerated phase (AP) or blast phase (BP) is frequently accompanied or preceded by cytogenetic evolution within the Philadelphia-positive (Phþ) clones: although in CP additional chromosomal alterations are identified in o5% of patients only, their frequency increases to 30% in AP and up to 80% in patients with BP. 1 This phenomenon is believed to reflect the genetic instability of CML. 1 It was clearly shown that the additional chromosomal alterations follow nonrandom patterns: 2 The ‘major route changes’ comprise alterations such as trisomy 8, isochromosome i (17q) or an extra Philadelphia chromosome. Diverse numerical abnormalities (for example, monosomy 7 or trisomy 21) and the t (3; 21)(q26; q22) have been identified as ‘minor route changes.’These specific chromosomal alterations are associated with diverse prognostic profiles: although alterations such as the t (3; 21) are indicative of an adverse prognosis and rapid progression to BP, othersFfor example, trisomy 8Fare less unfavorable. Corresponding to the pre-imatinib era, the Phþ clonal cytogenetic evolution was still identified to worsen prognosis in patients receiving imatinib, 3 although good responses to imatinib were still possible. 4 In a cohort of 141 patients having received treatment with imatinib for CP following interferon failure, O’Dwyer et al. 5 described a 50% relapse risk in patients with clonal evolution in contrast to 3% in those without evidence of this phenomenon. Thus, the clinical impact of Ph þ clonal evolution in patients receiving imatinib has been investigated in several studies. However, whether the introduction of tyrosine kinase inhibitors (TKIs) has induced changes in these cytogenetic patterns, remains to be clarified, as all respective studies were performed before the introduction of imatinib. 2 We here compared two subgroups:(1) 245 CML patients with evidence of Ph þ clonal evolution all investigated in the Munich Leukemia Laboratory (MLL) in the period 2005–2009 under treatment with TKIs and (2) 500 CML patients who had been published in the Mitelman Database before the year 2000 (for example, before the introduction of imatinib)(http://cgap. nci. nih. gov/Chromosomes/Mitelman).

The 245 patients from our cohort were retrospectively selected for this study because of the detection of additional cytogenetic abnormalities in the Phþ clones at diagnosis of CML or during the course of disease. There were 172 males and 73 females (median age, 60.7 years; range, 17.9–90.3) with different stages of CML. Bone marrow (or, in occasional cases, peripheral blood) samples were sent for diagnostic workup to the MLL between August 2005 and June 2009. Patients received treatment with imatinib or with the second-generation TKIs dasatinib and nilotinib. In 91 patients, additional cytogenetic abnormalities in the Phþ clone were identified at diagnosis of the CML, whereas 154 patients acquired them during the course of disease during treatment with TKIs. The phase of CML was known in 134 patients: 93 patients had CP, 13