Management of Adverse Events Associated with Dasatinib during Early Periods of Therapy in the Treatment of Chronic Myeloid Leukemia -a Clinical Report of Daria-01 Study

Abstract Background: Dasatinib is a novel kinase inhibitor of BCR-ABL and SRC family kinases that has shown promising anti-leukemic activity against chronic myeloid leukemia (CML). However, some patients experience treatment-related toxicity shortly after initiating dasatinib administration and are managed by drug interruption and/or dose reduction (altered treatment) which can limit the potential benefits of treatment. Methods: To determine the factors that influence compliance and the efficacy of dasatinib therapy, we conducted a phase 2 study of mid-term compliance and the effectiveness of dasatinib therapy in patients with chronic phase CML (CML-CP) (DARIA-01 Study). Treatment was administered until disease progression or intolerable toxicity, as determined by the treating physician. Dasatinib at 100 mg once daily was initially administrated. Dose interruption or reduction to 50 mg once daily was allowed after grade 2 or worse nonhematologic toxicity or grade 3 or worse hematologic toxicity. Trough plasma concentrations of dasatinib (Cmin) at steady state were assessed at 28 days of therapy. Results: In April 2014, 32 CML-CP patients were enrolled in the study, which included at least 6 months of follow-up. The median age was 53 years (range, 20–86). Twenty-four (75.0%) were previously untreated patients with CML-CP, and the remaining eight (25.0%) were switched from other tyrosine kinase inhibitors (imatinib, five patients; nilotinib, three patients) because of intolerance or resistance to these drugs. During the initial 28 days, 28 patients continued with 100 mg/day treatment, and four received doses of 50 mg/day. The incidence of altered treatment was 25% during the initial 3 months and 34% during the initial 6 months from dasatinib administration. Four patients who experienced dose reduction during the initial 3 months continued with 50 mg/day treatment thereafter at their request. Except one who experienced gastro-intestinal bleeding, all patients could continue dasatinib therapy. Age (>60 years) and Cmin divided by the given dasatinib dose (Cmin/D) were significantly correlated with a higher incidence of altered treatment during the initial 3 months (p = 0.0095) (p = 0.0083). Twenty-five (78%) patients achieved complete cytogenetic response (CCyR), and 13 (40%) achieved major molecular response at 6 months. The incidence of pleural effusion during the initial 28 days was significantly correlated with Cmin/D (p = 0.032) but was not related to the molecular response rate at 6 months (40% vs. 41%, p = 0.98). Conclusion: Current data demonstrate that patients treated with dasatinib who displayed a high Cmin/D (>1.0) value at day 28 and/or who were aged 60 and over were at a high risk for altered treatment during the early periods of therapy. Patients who experienced pleural effusion could be well managed by dose reduction and/or temporal interruption of dasatinib and could still achieve the preferable molecular response rate. Individualizing therapy by incorporating a pharmacokinetic assay would improve compliance and the efficacy of dasatinib therapy, particularly for elderly patients. Disclosures Morita:Bristol: Honoraria.