Abstract

Background: Submicroscopic deletions of the derivative chromosome 9 [Del der(9)] mapping to regions adjacent to the translocation breakpoints occur in 9% to 15% of patients with CML. Del der(9) is a powerful prognostic indicator associated with unfavorable prognosis in patients treated with interferon-alpha (IFN-α)-based therapies. Imatinib is currently the standard treatment for patients with CML and it appears to overcome the adverse prognostic impact imparted by Del der(9).

Methods: We investigated the prognostic impact of Del der(9) in 353 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=161) or dasatinib (n=192). The presence of Del der(9) prior to 2nd generation TKIs was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 245 patients. The median age was 53 years (range, 15–83) and the median follow-up was 24 months (range, 1–53). The primary endpoints evaluated were complete hematologic response (CHR), cytogenetic response, and survival.

Results: Twenty-eight (11%) patients carried Del der(9) and 217 an intact der(9). Among patients with deletions, 22 were in chronic phase (CP), 4 in accelerated phase (AP), and 2 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 122 were in CP, 55 in AP and 40 in BP. Overall, 229 (93%) patients were assessable for response after a median of 25 months (range, 1–53) of therapy. The outcome by CML phase is shown in Table 1.

CML phase Deletion der(9) No. CCyR (%) p EFS (12 mo) p OS (12 mo) p 
 No 122 79 0.77 86 0.05 97 0.04 
CP Yes 22 75  60  78  
 Not done 46       
 No 55 36 1.0 37 0.47 60 0.95 
AP Yes 25  67  75  
 Not done 27       
 No 40 19 1.0 0.85 35 0.39 
BP Yes    
 Not done 35       
CML phase Deletion der(9) No. CCyR (%) p EFS (12 mo) p OS (12 mo) p 
 No 122 79 0.77 86 0.05 97 0.04 
CP Yes 22 75  60  78  
 Not done 46       
 No 55 36 1.0 37 0.47 60 0.95 
AP Yes 25  67  75  
 Not done 27       
 No 40 19 1.0 0.85 35 0.39 
BP Yes    
 Not done 35       

There was no difference in response rates among patients in CP, but those without Del der(9) had an improved EFS and OS at 24 months compared with those carrying Del der(9) (EFS: 86% vs 60%, p=0.05; OS: 97% vs 78%; p=0.04). Notably, whereas a trend towards worse EFS (p=0.05) and OS (p=0.12) was observed in patients in CP with Del der(9) treated with nilotinib, these outcomes were not significantly affected by Del der(9) in patients receiving dasatinib (EFS: p=0.47; OS: p=0.76).

Conclusion: Our results suggest that, in contrast to what has been reported with imatinib therapy, patients with CML-CP carrying Del der(9) who failed imatinib may have a worse survival than their counterparts without deletions after treatment with 2nd generation TKI. This deleterious effect is more apparent among patients treated with nilotinib than among those receiving dasatinib.

Disclosures: Kantarjian:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. O’Brien:Bristol Myers-Squibb: Research Funding. Cortes:Bristol Myers Squibb: Research Funding; Novartis: Research Funding.

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