Abstract 1128

Poster Board I-150

Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population.

Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months.

At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance.

The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1.

Conclusions

DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR.

Table 1:

Best response to DAS and clinical outcome

Baseline CharacteristicsCCyR
MMR2 yr PFS2 yr OS
Maintained/Achieved response
CCyR on IM and at start of DAS (n=30)  90* 53.3%† 96.2% 100% 
CCyR on IM but not at start of DAS (n=49)  83.7%* 75.5%† 97.4% 97.7% 
No CCyR on IM or at start of DAS (n=171) IM 3 12 mo (n=62) 50%* 35.5%† 78.2% 96.2% 
 IM < 12 mo (n=109) 77.1%* 61.5%† 91.7% 96.8% 
Hematologic intolerance to IM (n=46)  43.5% 28.3% 67.9% 88.4% 
Non-hematologic intolerance to IM (n=228)  78.9% 60.1% 94.4% 98.1% 
Baseline CharacteristicsCCyR
MMR2 yr PFS2 yr OS
Maintained/Achieved response
CCyR on IM and at start of DAS (n=30)  90* 53.3%† 96.2% 100% 
CCyR on IM but not at start of DAS (n=49)  83.7%* 75.5%† 97.4% 97.7% 
No CCyR on IM or at start of DAS (n=171) IM 3 12 mo (n=62) 50%* 35.5%† 78.2% 96.2% 
 IM < 12 mo (n=109) 77.1%* 61.5%† 91.7% 96.8% 
Hematologic intolerance to IM (n=46)  43.5% 28.3% 67.9% 88.4% 
Non-hematologic intolerance to IM (n=228)  78.9% 60.1% 94.4% 98.1% 
*

p< 0.001 CCyR between groups with different prior IM CCyR status

†

p< 0.001 MMR between groups with different prior IM CCyR status

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Disclosures

Khoury:BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

Topics:
dasatinib, imatinib mesylate, leukemia, myelocytic, chronic, hematotoxicity, measles-mumps-rubella vaccine, toxic effect, protein-tyrosine kinase inhibitor, follow-up, leukemia, myeloid, chronic-phase, treatment outcome

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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