Abstract

Abstract 2297

Background:

BCR-ABL kinase domain mutations occur in 30%-90% of patients (pts) who develop resistance to imatinib. A recent analysis reported that 48% of pts with imatinib resistance or suboptimal response had a baseline mutation at the start of dasatinib therapy (Müller 2009). After 2 years of follow-up, dasatinib treatment of imatinib-resistant pts resulted in notable response rates (complete cytogenetic response [CCyR]: 43% vs 47%) and promising progression-free survival (PFS, 70% vs 80%) in pts with or without baseline mutations, respectively. However, some pts present with two or more co-existing mutations in one or more clones. The outcome of these pts after dasatinib therapy has not been described in detail.

Methods:

This is a retrospective analysis of pts with CML in chronic phase (CML-CP) receiving dasatinib who were imatinib resistant or intolerant and who had >1 BCR-ABL mutation at baseline. Pts with CML-CP from the phase 3 dose optimization trial (-034) and phase 2 START-C (-013) and START-R (-017; dasatinib only population) studies were evaluated. Since the frequency of >1 mutation was expected to be lower than the rates reported for the presence of any mutation, the inclusion of all 3 studies provided a larger population to determine pt responses and outcomes. A 2-year database was used for all 3 studies. Mutations were detected by conventional Sanger sequencing (sensitivity 10%-20%) after nested RT-PCR amplification of the BCR-ABL transcript. BCR-ABL polymorphisms were excluded from analysis. 1150 pts were included in the analysis: -034 (n=662), -013 (n=387), and -017 (n=101). Similar baseline characteristics among those analyzed included: median age (51-55 years), male (47%-53%), median duration of CML (54-64 months [mos]), prior imatinib therapy lasting >3 years (41%-53%) and prior response rates to imatinib (complete hematologic response [82%-92%], major cytogenetic response [MCyR, 28%-42%], and CCyR [15%-21%]). Only the rate of imatinib intolerance differed among the 3 trials: 26% for -034 and -013, whereas imatinib-intolerant pts were not eligible for the -017 study.

Results:

Of 1150 pts analyzed, baseline mutation data were available for 1043 dasatinib-treated pts (Table); 641 (61%) had no baseline mutation (202 intolerant) and 402 (39%) had a baseline mutation (18 intolerant). Of those with mutations, 70 (17%) had >1 mutation (4 intolerant) and 16 (4%) had >2 mutations. The TKI-resistant T315I mutation occurred in 21/402 (5%) and 5/70 (7%) of those with 1 or >1 mutation, respectively–with G250E also occurring in 2 of those 5 pts. The 24-mo response rates for pts with >1 mutation at baseline were lower than the rates in those who had only 1 mutation, or no mutations at baseline for MCyR (52.2% vs 56.4% vs 65%) and CCyR (36% vs 45% vs 56%). The 24-mo PFS rates on dasatinib for those with >1, 1, and no mutation were 57%, 73%, and 83%, respectively. While pts who achieved CCyR at 12 mos had excellent 2-year PFS, regardless of whether they had no, 1, or >1 mutation, pts who achieved partial cytogenetic response (PCyR) or less than PCyR at 12 mos had lower 2-year PFS if they carried >1 mutation compared to those with no or 1 mutation. The 2-year overall survival (OS) rates were 93.5% for those without a mutation and similar for those with 1 or >1 mutation (89%).

Conclusion:

Dasatinib shows considerable efficacy in pts with or without baseline BCR-ABL mutations. However, pts with baseline mutations tended to have lower rates of response and PFS compared with those without mutations at baseline. In addition, the presence of >1 mutation compared with the presence of only 1 mutation yielded the lowest rates of response and PFS.

 Best response by 24 mos     
Total (N=1150) MCyRa CCyRa PFS at 24 mosb Landmark analysis of PFS at 24 mos by response at 12 mosa,b,c OS at 24 mosb,d 
Pts without baseline mutation, N=641 410/633 (64.8) 354/633 (55.9) 83.2% CCyR 96.5% 93.5% 
    PCyR 94.3%  
    Other 75.1%  
Pts w/baseline mutation, N=402 222/399 (55.6) 172/399 (43.1) 70.2% CCyR 93.4% 88.6% 
    PCyR 86.6%  
    Other 72.6%  
Pts w/1 baseline mutation, N=332 186/330 (56.4) 147/330 (44.6) 72.9% CCyR 92.3% 88.6% 
    PCyR 88.1%  
    Other 79.5%  
Pts w/>1 baseline mutation, N=70 36/69 (52.2) 25/69 (36.2) 57.4% CCyR 100% 88.9% 
    PCyR 75%  
    Other 41.7%  
 Best response by 24 mos     
Total (N=1150) MCyRa CCyRa PFS at 24 mosb Landmark analysis of PFS at 24 mos by response at 12 mosa,b,c OS at 24 mosb,d 
Pts without baseline mutation, N=641 410/633 (64.8) 354/633 (55.9) 83.2% CCyR 96.5% 93.5% 
    PCyR 94.3%  
    Other 75.1%  
Pts w/baseline mutation, N=402 222/399 (55.6) 172/399 (43.1) 70.2% CCyR 93.4% 88.6% 
    PCyR 86.6%  
    Other 72.6%  
Pts w/1 baseline mutation, N=332 186/330 (56.4) 147/330 (44.6) 72.9% CCyR 92.3% 88.6% 
    PCyR 88.1%  
    Other 79.5%  
Pts w/>1 baseline mutation, N=70 36/69 (52.2) 25/69 (36.2) 57.4% CCyR 100% 88.9% 
    PCyR 75%  
    Other 41.7%  
a

Ph-negative pts from -034 have been excluded.

b

K-M analyses.

c

Only pts with CyR assessment available at 12 mos (±1.5 mos) are included.

d

Treated pts; Survival data from -017 not available; analysis restricted to -013 and -034.

Disclosures:

Quintás-Cardama: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Kantarjian: Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; Novartis: Consultancy, Research Funding. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Schiffer: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Cellgenix: Consultancy. le Coutre: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Saglio: Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Guilhot: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Hochhaus: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bahceci: Bristol-Myers Squibb: Employment. Lambert: Bristol-Myers Squibb: Employment. Cortes: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding.

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Author notes

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Asterisk with author names denotes non-ASH members.