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

BCR-ABL kinase inhibitors dasatinib, nilotinib and imatinib have become the therapeutic mainstay for patients (pts) with CML-CP. It has been suggested that baseline comorbid conditions be considered in choosing BCR-ABL inhibitors as second-line treatment for pts with CML post-imatinib failure. Cardiovascular (CV) disease is an important comorbid condition in some pts with CML-CP (median age, ∼ 60 years) and can play a critical role in treatment decisions. The DASISION trial is a large Phase 3 study comparing dasatinib with imatinib as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of dasatinib after a minimum of 12 months (mos) of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260-70). We assessed if baseline CV conditions impacted the efficacy and safety of these agents when used as initial treatment for CML-CP.

Five hundred nineteen pts with newly diagnosed CML-CP (median disease duration of 1 mo) were randomized to either dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed in pts with CV conditions and in those without. Pts with myocardial infarction (MI) within 6 mos, uncontrolled angina within 3 mos, congestive heart failure (CHF) within 3 mos, congenital prolonged QT syndrome, QTc interval of > 450 msec or ventricular arrhythmias were excluded. Pts with CV conditions including hypertension, MI > 6 mos prior to the start of treatment, uncontrolled angina > 3 mos prior to the start of treatment, CHF > 3 mos prior to the start of treatment, unstable angina (UA), left ventricular (LV) dysfunction, coronary artery disease (CAD), peripheral artery disease (PAD), transient ischemic attack (TIA), stroke and QTc interval of ≤ 450 msec were not excluded.

Across the 2 treatment arms, there were 85 pts (16%) with ≥ 1 baseline CV condition, 42 of whom had ≥ 2. Of the 85 pts, 69 (35 dasatinib; 34 imatinib) reported having baseline hypertension and 16 (8 dasatinib; 8 imatinib) reported other baseline CV conditions (some pts reported more than 1 CV condition) including LV dysfunction (n = 6), CAD (including clinically documented CAD, prior MI and unstable angina; n = 15), PAD (n = 11), and cerebral artery disease (including prior stroke and TIA, n = 8). The distribution of CV conditions was balanced across the 2 treatment arms. Safety profiles of dasatinib and imatinib in pts with baseline CV conditions were generally similar to those in pts without (Table). Notably, fluid retention including superficial edema and pleural effusion appeared to have occurred more frequently in pts with baseline CV conditions compared to those without. Pleural effusions were all grade 1 or 2, and manageable by dose interruption and/or reduction. In both arms, the 12-mo rates of CCyR and MMR in pts with baseline CV comorbidities were similar to the corresponding rates in pts without (Table). Safety and efficacy profiles of pts with hypertension and pts with CV conditions other than hypertension were also generally similar to those in pts without any CV condition.

Although fluid retention and cardiac AEs were more common in patients with any baseline 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.

Saglio: Brostol-Myers Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani: Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Shah: Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees.