Dasatinib 140 Mg Once Daily (QD) Demonstrates Equivalent Efficacy and Improved Safety Compared with 70 Mg Twice Daily (BID) in Patients with Chronic Myeloid Leukemia in Blast Phase (CML-BP): 2-Year Data from CA180-035

Abstract CML-BP has a poor prognosis and is refractory to most therapies. Dasatinib (SPRYCEL®), the most potent BCR-ABL inhibitor, is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL. Dasatinib also inhibits important tyrosine kinases (eg, SRC family kinases) that may play a role in imatinib resistance and disease progression. Previous studies have demonstrated the efficacy and safety of dasatinib 70 mg BID for patients with imatinib-resistant or -intolerant CML-BP, leading to its approval in this patient group. CA180-035 is an open-label phase III study comparing dasatinib dosing at 70 mg BID vs 140 mg QD in patients with advanced CML (accelerated phase or BP) or Ph+ ALL who are resistant or intolerant to imatinib. The primary trial objective was to compare major hematologic response (MaHR) rates with QD or BID dosing. The main secondary objectives were to compare major cytogenetic response (MCyR) rates, time to and duration of response, progression-free survival (PFS), overall survival (OS), and safety profiles between the two schedules. Preliminary 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 149 patients with myeloid BP (MBP) CML (75 QD and 74 BID) and 61 patients with lymphoid BP (LBP) CML (33 QD and 28 BID) are reported. Following dasatinib treatment, durable MaHRs and MCyRs were achieved by patients in both the MBP and LBP groups, and extended PFS and OS were observed in a proportion of patients (Table). Excluding patients that were BCR-ABL positive, Ph negative (n=10), rates of MCyR were comparable. Dasatinib was generally well tolerated, and with both schedules, cytopenias were the most commonly reported AEs. Grade 3/4 treatment-related nonhematologic AEs were infrequent with both schedules, with diarrhea, nausea, headache most commonly reported and each occurring in <7% of each group. In the LBP group, fewer drug-related fluid retention AEs of any grade, including pleural effusions, occurred with QD vs BID dosing. Only one grade 4 pleural effusion occurred (MBP QD group). For both patient populations, fewer QD-treated patients required dose reductions for toxicity. In the MBP group, median durations of dasatinib therapy were 3.3 months (QD) and 3.1 months (BID) and in the LBP group, these were 3.4 months (QD) and 3.6 months (BID). Median average daily doses with QD vs BID dosing were 140 mg vs 138 mg (MBP) and 140 mg vs 123 mg (LBP). Overall, extended follow-up from the CA180-035 study supports preliminary findings and demonstrates the equivalent efficacy of dasatinib 140 mg QD and 70 mg BID in patients with imatinib-resistant or -intolerant CML-BP. QD treatment may be associated with improved tolerability, particularly in the LBP group. Durable responses were observed with both schedules in this high-risk population. Table CML-MBP (n=149) CML-LBP (n=61) 140 mg QD (n=75) 70 mg BID (n=74) 140 mg QDm (n=33) 70 mg BID (n=28) MaHR, n (%) 21 (28) 21 (28) 14 (42) 9 (32) Median duration of MaHR (months) 8 9 5 8 MCyR, n (%) 21 (28) 22 (30) 17 (52) 13 (46) MCyR (excluding BCR-ABL+ Ph−, n=10) (%) 25 28 50 40 Median duration of MCyR (months) 7 10 4 8 24-month PFS (%) 11 18 NA NA 24-month OS (%) 24 28 21 16 Grade 3/4 neutropenia (%) 79 74 79 86 Grade 3/4 thrombocytopenia (%) 81 80 85 86 Fluid retention, any grade (%) 34 31 21 39 Pleural effusion, any grade (%) 20 18 21 36 Pleural effusion, grade 3–4 (%) 5 5 6 4 Pericardial effusion, any grade (%) 0 4 0 7 Discontinuation for drug toxicity n (%) 7 (10) 16 (22) 5 (15) 1 (4)