Abstract

Dasatinib (SPRYCEL®) is the most potent BCR-ABL inhibitor and is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Previous studies have demonstrated the efficacy and safety of dasatinib 70 mg BID for patients with CML-AP who are intolerant or resistant to imatinib. In the phase III CA180-035 study, patients with CML-AP, blast phase CML, or Ph+ ALL were randomized to dasatinib 140 mg QD or 70 mg BID. The primary trial objective was to compare major hematologic response (MaHR) rates between the two schedules. Secondary objectives included a comparison of major cytogenetic response (MCyR) rates, time to and duration of responses, progression-free survival (PFS), overall survival (OS), and safety profiles between the two schedules. Previous analyses from this study have demonstrated that QD treatment is associated with equivalent efficacy and less frequent key adverse events (AEs) compared with BID treatment. Here, 2-year results from the subgroup with CML-AP (n=317) recruited from 97 international sites are reported. Among patients randomized to QD (n=158) or BID (n=159) treatment with dasatinib, rates of MaHR and MCyR were similar (MaHR: 66% vs 68%; MCyR: 39% vs 43%, respectively; Table). Excluding patients that were BCR-ABL positive, Ph negative (n=3), rates of MCyR were nearly identical. Most MaHRs were achieved within 4 months of therapy and most MCyRs were achieved within 6 months. Based on Kaplan-Meier analyses, an estimated 65% vs 60% of patients had maintained a durable MaHR in QD and BID groups, respectively, at 24 months. Estimated PFS rates were 51% vs 55% and OS rates were 63% vs 72%, respectively. Although dasatinib was generally well tolerated with both dose schedules, QD treatment was associated with an improved safety profile compared with BID treatment. Only small increases in AE rates were observed compared with 1-year data. Cytopenias were the most common AEs and for QD vs BID treatment, rates of grade 3/4 events were 59% vs 69% for neutropenia and 64% vs 67% for thrombocytopenia. Fewer drug-related fluid retention events (including pleural effusion, superficial edema, and peripheral edema) were reported in the QD (34%) vs BID (48%) group. In particular, significantly fewer patients experienced a pleural effusion with QD vs BID treatment (p<0.001, all grades). No grade 4 pleural effusions occurred. Pleural effusions were manageable and led to treatment discontinuation in only 5% (QD) and 9% (BID) of patients. Grade 3/4 nonhematologic AEs were reported in less than 7% of all QD and BID patients and included dyspnea (3% vs 7%) and diarrhea (3% in both groups). Median durations of dasatinib therapy were 15 months (QD) and 12 months (BID), and median values of mean daily doses were 138 mg and 110 mg, respectively. Fewer dose reductions (38% vs 50%) and interruptions (64% vs 74%) occurred in the QD group. At the time of analysis, 34% of the QD group and 35% of the BID group remained on study, with a median duration of therapy of 23 months in both groups. Overall, extended follow-up from the CA180-035 study confirms earlier findings and demonstrates that in patients with CML-AP with imatinib resistance or intolerance, dasatinib 140 mg QD has equivalent efficacy to dasatinib 70 mg BID but with an improved safety profile. Similar durable responses were observed with both schedules.

Table

 Patients (%) 
 QD (n=158) BID (n=159) 
MaHR 66 68 
MCyR 39 43 
MCyR (excluding BCR-ABL+ Ph−, n=3) 38 43 
24-month PFS 51 55 
24-month OS 63 72 
Neutropenia, grade 3/4 59 69 
Thrombocytopenia, grade 3/4 64 67 
Pleural effusion (drug-related)   
All grades 20 39 
Grade 3 
Interruption 38 50 
Reduction 64 74 
 Patients (%) 
 QD (n=158) BID (n=159) 
MaHR 66 68 
MCyR 39 43 
MCyR (excluding BCR-ABL+ Ph−, n=3) 38 43 
24-month PFS 51 55 
24-month OS 63 72 
Neutropenia, grade 3/4 59 69 
Thrombocytopenia, grade 3/4 64 67 
Pleural effusion (drug-related)   
All grades 20 39 
Grade 3 
Interruption 38 50 
Reduction 64 74 

Disclosures: Kantarjian:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Kim:Wyeth Company: Research Funding; Bristol-Myers Squibb: Research Funding; IL-Yang Company: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. DiPersio:Genzyme: Honoraria. Bradley-Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment.

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