Abstract

Recent data for patients with chronic-phase (CP) CML indicate that development of resistance or intolerance to imatinib and treatment intervention following progression to advanced-phase disease are both associated with poor clinical outcome (with 3-year survival rates of 72% for chronic-phase disease, 30% for accelerated-phase CML, and 7% for blast-phase CML) (

Kantarjian et al.
Cancer
2007
;
109
:
1556
–60
). Results also demonstrate that intervention with a second-generation tyrosine kinase inhibitor is more effective for individuals with chronic-phase CML than for those with advanced-phase disease. Of note, development of hematologic resistance (loss of a complete hematologic response [CHR]) was identified as an independent prognostic factor with a 3-year survival rate of 57% (compared with 92% for patients who experienced cytogenetic resistance [loss of a major cytogenetic response (MCyR)]). The objective of the current data analysis was to assess whether the development of hematologic resistance to imatinib would be a predictor of poor response to dasatinib (SPRYCEL®) relative to the development of cytogenetic resistance. Data from three Phase-II/III dasatinib clinical studies (CA180–013 [70 mg BID], CA180–017 [70 mg BID], and CA180–034 [100mg QD, 50 mg BID, 140 mg QD, 70 mg BID]) in patients with CP CML with resistance to prior imatinib were evaluated. Consistent with our earlier findings, significantly higher complete cytogenetic response (CCyR) rates were reported for patients who had developed secondary or acquried cytogenetic resistance to prior imatinib than for those with hematologic resistance. The improved rates of CCyR in patients with cytogenetic resistance to imatinib were associated with prolongation of progression-free survival compared to patients with hematologic resistance, thereby confirming the importance of early intervention in the event of imatinib resistance and the significance of achieving CCyR with dasatinib.

Loss of MCyRLoss of CHR
Nn%Nn%
n = number of patients with [1] complete cytogenetic response or [2] progression 
Complete cytogenetic response [1] 
CA180–013 47 34 72 71 27 38 
CA180–017 19 12 63 22 23 
CA180–034       
    100 mg QD 28 21 75 14 14 
    50 mg BID 17 11 65 12 25 
    140 mg QD 18 50 16 50 
    70 mg BID 23 19 83 12 17 
Progression-free survival at 1 year [2] 
CA180–013 47 95 71 15 84 
CA180–017 19 94 22 85 
CA180–034       
    100 mg QD 28 96 14 93 
    50 mg BID 17 100 12 58 
    140 mg QD 18 87 16 93 
    70 mg BID 23 95 12 69 
Loss of MCyRLoss of CHR
Nn%Nn%
n = number of patients with [1] complete cytogenetic response or [2] progression 
Complete cytogenetic response [1] 
CA180–013 47 34 72 71 27 38 
CA180–017 19 12 63 22 23 
CA180–034       
    100 mg QD 28 21 75 14 14 
    50 mg BID 17 11 65 12 25 
    140 mg QD 18 50 16 50 
    70 mg BID 23 19 83 12 17 
Progression-free survival at 1 year [2] 
CA180–013 47 95 71 15 84 
CA180–017 19 94 22 85 
CA180–034       
    100 mg QD 28 96 14 93 
    50 mg BID 17 100 12 58 
    140 mg QD 18 87 16 93 
    70 mg BID 23 95 12 69 

These results confirm previous observations and

  1. emphasize the importance of close monitoring of treatment response to imatinib, and

  2. argue for early intervention in case of imatinib resistance.

Late intervention, ie waiting for patients to lose a hematologic response, appears to significantly diminish the effectiveness of dasatinib.

Author notes

Disclosure:Employment: David Liu - Bristol-Myers Squibb; Tai-Tsang Chen - Bristol-Myers Squibb. Ownership Interests:; David Liu - Bristol-Myers Squibb; Tai-Tsang Chen - Bristol-Myers Squibb. Research Funding: Hagop Kantarjian - Bristol-Myers Squibb and Novartis; Jorge Cortes - Bristol-Myers Squibb; Susan O’Brien - Bristol-Myers Squibb.