Survival Outcomes for Patients (Pts) with Chronic Myeloid Leukemia (CML) with Clonal Evolution (CE) Treated with 2nd Generation Tyrosine Kinase Inhibitors (TKI) after Imatinib Failure.

Abstract

Background: CE has been considered a criterion for accelerated phase (AP) CML, particularly when it appears during the course of therapy, when it is associated with a poor prognosis. CE may involve a variety of chromosomal abnormalities and may signal resistance to imatinib. The 2nd generation TKI (2nd TKI) dasatinib and nilotinib are effective in patients with AP after failure to imatinib, including those with CE. However, it is unclear whether different chromosomal abnormalities constituting CE may have the same outcome after therapy with 2nd TKI.Methods: We analyzed the outcome after 2nd TKI therapy of 61 pts with CML with CE who had failed prior imatinib therapy.Results: The median age was 55 years (range 23–76); the median follow-up after start of 2nd TKI was 18.9 months (mo) (range 5.3–39.3), and median CML duration 67.9 mo (0.4–206.6). Thirty-five pts had CE alone and 26 had CE with other AP features. At the time of this report 59 patients are evaluable for response: 30 treated with dasatinib and 29 with nilotinib. The accompanying table summarizes the findings.Conclusion: CE constitutes a heterogeneous entity with variable outcome with 2nd TKI. Regardless of the percentage of metaphases with CE, those with trisomy 8 or with abnormalities in chromosome 17 may have the worse outcome. In all cases, the presence of other features of AP further worsens the outcome. The molecular events behind this worse outcome and potential therapeutic approaches directed at them need to be defined.Characteristics (n=59)CCyR n/no. evaluable(%)pEFS % (12mo)pOS % (12mop% Cellls with CE<163/12(25)627716-354/10(40)606836-999/15(60)73801007/22(32)0.24600.96780.85Other AP featuresNo18/34(53)8089Yes5/25(20)0.0240<0.001600.005Double Ph+No9/28(32)5569Yes14/31(45)0.42710.93840.72Trisomy 8No21/49(43)7284Yes2/10(20)0.2920<0.00140<0.001Chr 17 AbnormalitiesNo19/45(42)7483Yes4/14(29)0.53290.003560.02Other TranslocationsNo20/42(48)6175Yes3/17(18)0.04690.71820.81Other abnormalitiesNo15/37(41)6281Yes8/22(36)0.79650.45700.93CCyR: Complete Cytogenetic Response, EFS: Event Free Survival, OS: Overall Survival, Chr: Chromosome, Ph+: Philadelphia chromosome positive, n: number of patients