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. Deletion of der(9) is powerful prognostic indicator associated with an 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 deletions of der(9).

Methods: We tested the prognostic impact of the deletions of der(9) in 323 patients with CML treated at our institution with the 2nd generation tyrosine kinase inhibitors (TKIs) nilotinib (n=144) or dasatinib (n=179). The presence of deletions of der(9) was investigated by FISH analysis using the LSI-BCR/ABL-(ES) probe (Vysis, Downers Grove, IL) in 244 patients. The median age was 55 years (range, 15–83) and the median follow-up was 18 months (range, 1–44). The primary endpoints evaluated were survival, complete hematologic response (CHR) and cytogenetic responses.

Results: Twenty-eight (12%) patients were found to have del der(9) and 216 an intact der(9). Among patients with deletions, 16 were in chronic phase (CP), 8 in accelerated phase (AP), and 4 in blast phase (BP) at the start of nilotinib or dasatinib therapy. In the group of patients without deletions, 112 were in CP, 54 in AP and 50 in blastic phase (BP). Overall, 222 (91%) of 244 patients were assessable for response. There was no significant difference between patients with or without deletions regarding the rate of CHR, major (MCyR) or complete (CCyR) cytogenetic responses, and event-free (EFS), and overall (OS) survival at 12 months for the total population.

CML Phasedeletion der(9) [No. Patients]CCyR (%)pEFS (12 months)pOS (12 months)p
 No (112) 72 84 0.2 97 0.01 
Chronic Yes (16) 73  78  92  
 Not Done (30)       
 No (54) 31 0.7 54 0.22 69 0.62 
Accelerated Yes (8) 38  75  88  
 Not Done (27)       
 No (50) 24 0.56 30 0.56 
Blastic Yes (4) 25  25  25  
 Not Done (22)       
CML Phasedeletion der(9) [No. Patients]CCyR (%)pEFS (12 months)pOS (12 months)p
 No (112) 72 84 0.2 97 0.01 
Chronic Yes (16) 73  78  92  
 Not Done (30)       
 No (54) 31 0.7 54 0.22 69 0.62 
Accelerated Yes (8) 38  75  88  
 Not Done (27)       
 No (50) 24 0.56 30 0.56 
Blastic Yes (4) 25  25  25  
 Not Done (22)       

Among pts in CP there was no difference in response rate or EFS, but pts without del der(9) had an improved OS at 12 months compared with those carrying der(9) (97% vs 92%; p=0.01). There appears to be no significant difference between pts treated with nilotinib and those treated with dasatinib.

Conclusion: Our results suggest that although the outcome of patients with CML treated in AP or BP with either nilotinib or dasatinib does not differ regardless of their deletion status, those in CP carrying del der(9) deletions may have a worse overall survival than their counterparts without deletions. This is in contrast to what has been reported with imatinib therapy. The reason for this difference is unclear.

Author notes

Disclosure:Research Funding: Dr. Cortes and Dr. Kantarjian receive grant support from Bristol Myers-Squibb and Novartis.