Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia


  • T.D. Kim
  • S. Tuerkmen
  • M. Schwarz
  • G. Koca
  • H. Nogai
  • C. Bommer
  • B. Doerken
  • P. Daniel
  • P. le Coutre


  • Haematologica


  • Haematologica 95 (4): 582-588


  • Background Additional chromosomal aberrations (ACA) in Philadelphia chromosome-positive (Ph-positive) chronic myeloid leukemia (CML) are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain (KD) are probably the most common mechanisms of imatinib resistance. DESIGN AND METHODS: We assessed the influence of ACA and BCR-ABL KD mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect ACA and sequencing of the BCR-ABL KD was performed to detect point mutations. RESULTS: Among 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase (CP), accelerated phase (AP) and blast crisis (BC), respectively, 19 (36%) had ACA and 20 (38%) had BCR-ABL kinase domain mutations. All patients without ACA had a superior overall survival (89%) than patients with ACA (54%) at 2 years (p=0.0025). In CP, overall survival at 2 years was 100 and 62 % (p=0.0024) for patients without or with ACA, respectively. BCR-ABL KD were associated with lower remission rates to nilotinib with a major cytogenetic remission in 9 of 20 (45%) patients as compared to 26 of 33 (79%) in patients without mutations (p<0.05). However, overall survival was not affected by BCR-ABL KD mutations. Conclusions Whereas BCR-ABL KD mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of ACA may reflect genetic instability and therefore intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overal survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with CML under tyrosine kinase inhibito therapy.