Background: Achieving a cytogenetic (CG) response or a molecular response after imatinib therapy has been associated with improved event-free (EFS) and transformation-free survival (TFS). It is unclear whether achieving these responses earlier confers an advantage. A recent update of the IRIS trial suggests that achieving a major CG response (MCyR) at 12, 18 or 24 months (mo) confers a similar TFS advantage. Another report (

J Clin Oncol 2006;24:454
) suggests that achieving a complete CG response (CCyR) at 12 or 24 mo confers equal prognosis to patients. Although some patients may indeed improve their response with continued therapy, a pt not in CCyR faces the competing possibilities of eventually achieving a CCyR vs progressing.

Methods: We analyzed the risks of improving the CG response vs progressing for pts not in CCyR at different times to determine whether early responses confer an advantage. 258 pts with CML CP treated with IM were analyzed. Progression was defined as transformation to AP or BP, loss of CHR or major CG response, or a doubling of the white cell count to more than 20x109/L.

Results: After 3 mo of IM therapy, 77 (74%) of 104 assessable pts for CG response had a CCyR whereas 17 (16%) progressed. These differences were consistently significant at 6 and 12 mo (p=0.04) (Table 1).

We then analyzed the long term risk of progression vs the probability of achieving CCyR according to the molecular response at different time points (Table 2).

Patients with Bcr-Abl/Abl transcript levels >1–10 after 3 mo of therapy had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with ≤1. However, they have a significantly higher risk of eventual progression that is more similar to that of pts with values of >10. The risk of progression increases to 23% if transcript levels >10 at 6 mo.

Conclusion: These results suggest that while the risk of progression may be similar for pts who achieve a CCyR regardless of the time at which that is attained, those who fail to obtain a CCyR within the first 12 mo of IM therapy have higher rates of disease progression. This risk is discernible as early as 3 mo into IM therapy and may provide a rationale for therapies that induce higher rates of early molecular response (e.g. high-dose imatinib, new tyrosine kinase inhibitors).

Table 1
Time on imatinibNo. not in CCyRNo. with eventual outcome with continued therapy (%)
CCyRProgressionp value
3 months 104 77 (74) 17 (16)  
6 months 47 28 (60) 12 (26) 0.04 
12 months 26 16 (62) 8 (31)  
Time on imatinibNo. not in CCyRNo. with eventual outcome with continued therapy (%)
CCyRProgressionp value
3 months 104 77 (74) 17 (16)  
6 months 47 28 (60) 12 (26) 0.04 
12 months 26 16 (62) 8 (31)  
View Large

Table 2
% Probability
Months%Bcr-Abl/AblNo.CCyRProgressionp value
 ≤ 1 87 98 2  
3 > 1–10 76 92 11 0.04 
 > 10 30 67 13  
 ≤ 1 140 99 4  
6 > 1–10 34 91 9 0.005 
 > 10 13 62 23  
% Probability
Months%Bcr-Abl/AblNo.CCyRProgressionp value
 ≤ 1 87 98 2  
3 > 1–10 76 92 11 0.04 
 > 10 30 67 13  
 ≤ 1 140 99 4  
6 > 1–10 34 91 9 0.005 
 > 10 13 62 23  
View Large

Topics:
brachial plexus neuritis, imatinib mesylate, leukemia, myelocytic, chronic, bcr-abl tyrosine kinase, disease progression, iris trial, protein-tyrosine kinase inhibitor, leukocytes

Disclosure: No relevant conflicts of interest to declare.

Author notes

*

Corresponding author

2006, The American Society of Hematology
2006
Sign in via your Institution