Abstract

Abstract 2285

Non-standard doses of dasatinib sustain cytogenetic response in chronic myeloid leukemia (CML) patients

Introduction:

Dasatinib (Sprycel; Bristol Myers Squibb, New York, NY, USA), a second-generation tyrosine kinase inhibitor (TKI), is effective for treating patients with chronic myeloid leukemia (CML) as a first or second line drug. The standard doses are 100mg per day for chronic phase (CP), 140mg per day for accelerate phase (AP) or blast phase (BP). Up to 73% patients require dose reductions and 25% have to suspend therapy permanently due to intolerance. We analysed factors that may influence the outcomes of patients who received low-doses of dasatinib after failure or intolerance to other TKIs. Since most of our patients were not eligible for allogeneic SCT and other second-generation TKI was not available in our hospital, off-label doses of dasatinib were occasionally used.

Methods:

We reviewed the records of 74 patients treated with dasatinib in our hospital from November 2005 until July 2010 with CML all phases, 27 patients required dose reductions for intolerance. All patients had previously received imatinib (Gleevec; Novartis, Basel, Switzerland) and four patients had also been treated with nilotinib (Tasigna; Novartis). In general, dose interruptions were done in patients with grade 3 or 4 hematological or non-hematological toxicity. The severity and the duration of the adverse events were considered for dose reduction. Criteria for CML phases and response were previously reported by Baccarani et al1.

Results:

Five patients already had complete cytogenetic response (CCyR) before starting dasatinib and sustained it with non-standard doses with median daily dose of 63mg (50-71mg); four of them also maintained (n=3) or achieved (n=1) major molecular response (MMR). The remaining 22 patients, who had no cytogenetic response with a prior TKI, were analysed (Table 1). With low-dose dasatinib, 4 patients (18%) achieved CCyR and MMR, one (5%) had a major cytogenetic response; 17 patients (77%) had no cytogenetic response to dasatinib.

Discussion:

Dose reductions are frequent among patients on dasatinib therapy, but dose intensity is not associated with failure-free survival and does not impact response2. Our analysis also showed that dose intensity as well as disease phase was not significant to achieve response. Patients resistant to first-line TKI had a higher chance to not achieve CCyR submitted to a lower dose regimen, but in those with CCyR when low-dose regimen was initiated, response was maintained. In conclusion, non-standard doses of dasatinib may be effective to sustain CCyR in patients intolerant to this TKI, and at the same time is ineffective for patients who developed resistance to first-line TKI.

References:

1-Baccarani M, Cortes J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.J Clin Oncol. 2009 Dec 10;27(35):6041-51.

2-Santos FPS, Kantarjian H, et al. Br J Haematol. 2010 Aug;150(3):303-12.Br J Haematol. 2010 Aug;150(3):303-12.

Table 1:

Response to non-standard dose of dasatinib

Clinical FeatureCCyR and MCyR N=7No response N=17P value
Age (years) 59 (34–71) 60 (24–82)  
Male/Female 4/1 10/7  
CP 3 (60%) 7 (41%) 0.62 
AP or BP 2 (40%) 10 (59%)  
Prior therapy 0 (0%) 5 (29%) 0.28 
Interferon + TKI 5 (100%) 12 (71%)  
TKI only    
Median duration of dasatinib suspension (days) 28 (0–77) 30 (0–222) 0.61 
Median daily dose (mg) 47 (28–50) 39 (27–77) 0.60 
CP 70 (65–76) 41 (23–96) 0.20 
AP 47 (28–54) 48 (23–96) ns 
Dose intensity (%)* 47 (19–57) 47 (21–96) ns 
Dose intensity first 6 months on dasatinib (%) 14 (7–15) 9 (1–17) 0.08 
Treatment with low-dose dasatinib (months)    
Progression, or failure to therapy# 0 (0%) 6 (35%) – 
  3 deaths  
Switch therapy for: 2 (43%) 16 (94%) 0.02 
Resistance to prior TKI 3 (57%) 1 (6%)  
Intolerance to prior TKI    
Mutation – 7 (41%): F359V (2), F317L (2), T315I, F482S, E450G  
Clinical FeatureCCyR and MCyR N=7No response N=17P value
Age (years) 59 (34–71) 60 (24–82)  
Male/Female 4/1 10/7  
CP 3 (60%) 7 (41%) 0.62 
AP or BP 2 (40%) 10 (59%)  
Prior therapy 0 (0%) 5 (29%) 0.28 
Interferon + TKI 5 (100%) 12 (71%)  
TKI only    
Median duration of dasatinib suspension (days) 28 (0–77) 30 (0–222) 0.61 
Median daily dose (mg) 47 (28–50) 39 (27–77) 0.60 
CP 70 (65–76) 41 (23–96) 0.20 
AP 47 (28–54) 48 (23–96) ns 
Dose intensity (%)* 47 (19–57) 47 (21–96) ns 
Dose intensity first 6 months on dasatinib (%) 14 (7–15) 9 (1–17) 0.08 
Treatment with low-dose dasatinib (months)    
Progression, or failure to therapy# 0 (0%) 6 (35%) – 
  3 deaths  
Switch therapy for: 2 (43%) 16 (94%) 0.02 
Resistance to prior TKI 3 (57%) 1 (6%)  
Intolerance to prior TKI    
Mutation – 7 (41%): F359V (2), F317L (2), T315I, F482S, E450G  

#progression to AP or BP, loss of hematological or cytogenetic response, no hematological response after 3 months on dasatinib.

*

adapted from Santos FPS et al2

Disclosures:

Off Label Use: Dasatinib was used for patients with chronic myeloid leukemia on lower doses (off-label) due to toxicity. No other tyrosine kinase inhibitor was available to switch therapy and patients did not have matched donor for transplant.

Author notes

*

Asterisk with author names denotes non-ASH members.