Background: Second generation TKI have shown preclinical activity against most imatinib resistant BCR-ABL KD mutations with the exception of T315I. Clinical efficacy has been demonstrated across all phases of CML after imatinib failure.

Study Aims: We investigated whether in vitro sensitivity of KD mutation correlates with outcome of pts receiving 2nd generation TKI.

Study Groups: We analyzed 169 pts with imatinib failure, who were treated with 2nd generation TKI, for detection of mutations in the entire KD of BCR-ABL. Median age was 50 years (yr) (11–96). They received imatinib for a median of 30 months (mo) (2–70) and were followed for a median of 23 mo (3–38) from the start of therapy with 2nd generation TKI.

Results: After imatinib failure, 81 pts (40 CP, 24 AP, 17 BP) received dasatinib (D) and 88 pts (19 CP, 47 AP, 22 BP) received nilotinib (N). KD mutations were detected prior to TKI switch in 42 pts (52%) treated with D and 45 pts (51%) treated with N. The IC50 values for each drug for in vitro kinase inhibition for each mutation (

O’Hare, Can Res 2005;65:4500
) was used to classify mutations into high sensitive (54), intermediate sensitive (24), and low sensitive (9) to D [IC50 values<2 (27), 2–20 (10), and >1000 nM (5)] (
Hochhaus, JCO 2007;25:362s
) and N [IC50 values<70 (27), 200–450 (14), and >2000 nM (4)]. In 59 CP pts (40 D, 19 N), response was simlar for 31 pts with and 28 without baseline mutation: CHR 77% vs 96% (p=0.054); MCyR 58% vs 68% (p=0.61), CCyR 52% vs 50% (p=0.9), respectively. The 2-yr EFS for pts with and without mutations were 63% and 72%, respectively (p=0.4). Outcome correlated with the mutation IC50 (Table 1). Among 71 AP pts (24 D, 47 N), response was similar for 41 pts with and 30 without baseline mutation: CHR 68% vs 70% (p=0.87); MCyR 63% vs 60% (p=0.96); CCyR 54% vs 47% (p=0.73), respectively. The 2-yr EFS for pts with and without mutation were 33% and 40%, respectively (p=0.41). As in CP, there was a trend for worse outcome for AP pts with intermediate sensitivity mutations (Table 1). In 39 BP pts (17 D, 22 N), response was not different between 15 pts with and 24 pts without baseline mutation: CHR was achieved in 27% vs 42% (p=0.49); MCyR in 20% vs 25% (p=0.9) being CCyR in 13% vs 25% (p=0.45). The 2-yr EFS for pts with and without mutations were 33% vs 29%, respectively (p=0.96).

Conclusions: 2nd generation TKI are capable of inducing hematologic and cyogenetic responses in a significant proportion of imatinib resistant pts across all phases. Outcome depends on the type of mutation, with mutations with predicted intermediate levels of sensitivity having decreased probability of response and EFS, particularly in CP. The correlation with IC50 is less evident in advanced phases suggesting more complex mechanisms of resistance.

Table 1.
percent2-year (%)
PhaseIC50NMCyRCCyREFSOS
EFS=Event-free survival; OS=Overall survival 
CP Low 18 84 74 78 88 
 Intermediate 9 25 25 29 70 
P-value   0.006 0.03 0.007 0.05 
AP Low 29 41 38 39 75 
 Intermediate 8 9 9 20 60 
P-value   0.01 0.07 0.52 0.81 
BP Low 7 29 14 20 14 
 Intermediate 7 14 14 0 14 
P-value   0.46 0.9 0.65 0.34 
percent2-year (%)
PhaseIC50NMCyRCCyREFSOS
EFS=Event-free survival; OS=Overall survival 
CP Low 18 84 74 78 88 
 Intermediate 9 25 25 29 70 
P-value   0.006 0.03 0.007 0.05 
AP Low 29 41 38 39 75 
 Intermediate 8 9 9 20 60 
P-value   0.01 0.07 0.52 0.81 
BP Low 7 29 14 20 14 
 Intermediate 7 14 14 0 14 
P-value   0.46 0.9 0.65 0.34 
View Large

Topics:
bcr-abl tyrosine kinase, brachial plexus neuritis, imatinib mesylate, leukemia, myelocytic, chronic, mutation, phosphotransferases, protein-tyrosine kinase inhibitor, mechlorethamine, dasatinib, nilotinib

Disclosure:Research Funding: Hk and JC received research grants from Novartis oncology and BMS. Membership Information: EJ is a member on Speakers Bureau for Novartis oncology and BMS.

2007, The American Society of Hematology
2007
Sign in via your Institution