Dasatinib 140 Mg Once Daily (QD) Has Equivalent Efficacy and Improved Safety Compared with 70 Mg Twice Daily (BID) in Patients with Imatinib-Resistant or -Intolerant Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): 2-Year Data from CA180- 035

Patients with ALL who have the Ph chromosome rearrangement and the resulting BCR-ABL oncogene represent 20–40% of cases of adult ALL and have an adverse prognosis. Even with current standard therapies, which comprise aggressive multi-agent chemotherapy, imatinib, and allogeneic stem cell transplant, there is a high risk of relapse. Dasatinib (SPRYCEL^®) is a potent BCR-ABL inhibitor, and has 325-fold greater potency than imatinib against unmutated BCR-ABL in vitro. Dasatinib is also active against SRCfamily kinases, which may have a role in Ph+ ALL pathogenesis. Following a phase II trial, dasatinib was approved for the treatment of imatinib-resistant or -intolerant Ph+ ALL. CA180-035 is a randomized, phase III, open-label trial comparing dasatinib 140 mg QD with 70 mg BID in patients with advanced CML (accelerated or blast phase) or Ph+ ALL. The primary trial objective was to compare the major hematologic response (MaHR) rates of QD and BID dosing schedules. Secondary objectives included comparison of major cytogenetic response (MCyR) rates, time to and duration of response, progressionfree 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, results are reported in 84 patients with Ph+ ALL randomized to QD (n=40) or BID (n=44) schedules with a minimum of 2 years of follow-up. MaHR rates were similar with dasatinib administered QD (38%) or BID (32%), and all MaHRs were achieved within 4 months. Of the 15 patients (QD) and 14 patients (BID) who achieved a MaHR, median durations were 4.6 and 11.5 months, respectively. A MCyR was achieved by 70% (QD) and 52% (BID) of patients, with median durations of 4.1 and 4.4 months, respectively. Excluding patients that were BCR-ABL positive, Ph negative (n=11), rates of MCyR were nearly identical (QD 69% vs BID 51%). Estimated 24-month rates of OS were similar in QD and BID groups (11% vs 20%; hazard ratio 1.26, 95% CI 0.78–2.04). Dasatinib was generally well tolerated. The most common grade 3/4 nonhematologic AEs in both groups included diarrhea (5% in both groups) and nausea (QD 3% vs BID 5%). Fewer patients experienced a pleural effusion when dasatinib was administered QD (all grades, 18%; grade 3–5, 5%) vs BID (all grades, 32%; grade 3–5, 14%). The incidence of grade 3/4 cytopenia was similar in both groups, including neutropenia (QD 67% vs BID 72%) and thrombocytopenia (QD 72% vs BID 61%). Fewer patients required dose reductions for toxicity with QD (10%) vs BID (23%) treatment. Median durations of dasatinib therapy were 3.4 months in the QD group and 2.5 months in the BID group, although these were longer in patients who achieved a MaHR (4.6 and 5.9 months, respectively). Median average daily doses were 140 mg (QD) and 138 mg (BID). At last follow-up, most patients had discontinued therapy, with disease progression (QD 70% vs BID 75%) the most common cause. In conclusion, findings from the CA180-035 trial in patients with Ph+ ALL are consistent with previous data and demonstrate that dasatinib is associated with durable treatment responses in a proportion of patients with a poor prognosis who are resistant or intolerant to imatinib. Compared with the approved BID dosing schedule, dasatinib administered as a once-daily dose has equivalent efficacy, provides greater convenience, and may have improved safety in this patient group.