The randomised Phase 3 DASISION trial of the BCR-ABL kinase inhibitor dasatinib (Sprycel, Bristol-Myers Squibb) has been shown to achieve significantly higher rates of complete cytogenetic response (CCgR) and major molecular response (MMR) than imatinib as first-line treatment in patients with previously untreated chronic myeloid leukaemia in the chronic phase (CML-CP), which has been shown to be maintained for up to 18 months.1,2
Safety analysis has found that, although occurrence of pleural effusion and fluid retention appeared higher in these patients receiving ≥1 medication with dasatinib, overall, the number of medications administered at baseline did not appear to affect efficacy or safety of dasatinib (or imatinib).3 In addition, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids.4 The occurrence of pleural effusion and management interventions was shown not to negatively affect the achievement of CCgR or MMR.4 These findings are in line with data reported previously for second-line dasatinib in CML patients resistant or intolerant to imatinib.5 Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated anti-tumour activity of dasatinib.
Although fluid retention and cardiac adverse events (AEs) were more common in patients with any baseline cardiovascular (CV) condition, overall these data show no substantial impact of baseline CV conditions on the general safety and efficacy of dasatinib or imatinib as initial treatment for CML-CP.6
The significant adverse events observed with dasatinib, including fluid retention, pleural effusions and Grade 3-4 cytopenias, may be driven by the level of the residual dosage of dasatinib (Cmin). An optimisation study, OPTIM, based on the monitoring of dasatinib plasma levels (Cmin and Cmax) in patients with CML-CP newly diagnosed and treated with dasatinib as front line therapy, found that pharmacokinetic parameters of dasatinib were different in aged patients.7 A trend was observed between Cmax and responses and also between Cmin and fluid retention or pleural effusion.
2. N Shah, H Kantarjian, A Hochhaus et al. Dasatinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) In the DASISION Trial: 18-Month Follow-up. Abstract 206 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
3. F Guilhot, H Kantarjian, N Shah et al. Dasatinib (Versus Imatinib) In Patients (Pts) with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of Safety and Efficacy by Use of Baseline Medications In the DASISION Trial. Abstract 2295 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
4. K Porkka, M Baccarani, A Hochhaus et al. Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial. Abstract 2282 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
6. G Saglio, A Hochhaus, J Cortes et al. Safety and Efficacy of Dasatinib Versus Imatinib by Baseline Cardiovascular Comorbidity In Patients with Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of the DASISION Trial. Abstract 2286 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.
7. P Rousselot, S Boucher, G Etienne et al. Pharmacokinetics of Dasatinib as a First Line Therapy In Newly Diagnosed CML Patients (OPTIM dasatinib trial): Correlation with Safety and Response. Abstract 3432 presented at 52nd ASH, Orlando, FL, December 4-7, 2010.