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

During first-line BCR-ABL inhibitor therapy for CML-CP, concomitant medication use is associated with worse adherence to CML therapy, which may detrimentally affect efficacy (St Charles, ASH 2009; Marin, J Clin Oncol 2010). Medications may include adjuvants to anti-CML therapy or treatments for comorbid conditions. Depending on posology, the number of medications may affect BCR-ABL inhibitor efficacy and safety. Dasatinib is a BCR-ABL inhibitor 325-fold more potent than imatinib at inhibiting BCR-ABL in vitro and is taken once daily (QD) at any time of day with or without food. Medications that prolong QTc, or increase or decrease dasatinib levels (CYP3A4 substrates/inhibitors/inducers, PPIs and H₂ antagonists) should be avoided. In the phase 3 DASISION trial, first-line dasatinib 100 mg QD had superior efficacy vs imatinib 400 mg QD in pts with newly diagnosed CML-CP, including significantly higher complete cytogenetic response (CCyR) and major molecular response (MMR) rates. Here, efficacy and safety of dasatinib (and imatinib) by number and type of baseline medications were analyzed.

519 pts with newly diagnosed CML-CP were randomized to dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260) arms. Exclusion criteria included prior interferon or systemic anti-CML therapy (except anagrelide, hydroxyurea, or ≤28 days of imatinib), and baseline pleural effusion, cardiovascular disease, or bleeding disorder unrelated to CML. Efficacy and safety were assessed using rates of CCyR/MMR or drug-related adverse events (AE), respectively. Baseline medications were defined as any additional medication taken prior to initiating study therapy, as reported by individual investigators.

189/259 pts (73%) in the dasatinib arm and 194/260 pts (75%) in the imatinib arm were receiving ≥1 baseline medication (median 2, range 1–7). Medications taken by ≥5% of pts were prophylactic allopurinol therapy for tumor lysis syndrome (51%); alimentary tract or metabolism therapies, eg, antacids or PPIs (33%: omeprazole 6%, famotidine <1%); nervous system therapies, eg, NSAIDs or other analgesics (22%); cardiovascular therapies, eg, calcium channel blockers, loop diuretics, β blockers, and ACE inhibitors (21%); agents for blood or blood-forming organs, eg, folic acid or statins (15%); systemic antibiotics/antifungals/vaccines (7%); and respiratory system therapies, eg, antihistamines or inhaled steroids (7%). 12-month CCyR and MMR rates were unaffected by the number of baseline medications. Pts in the dasatinib arm receiving 0, 1–3, or ≥4 medications (27%, 56%, and 17%, respectively) had CCyR rates of 79%, 85%, and 87% and MMR rates of 43%, 49%, and 42%, respectively. Pts in the imatinib arm receiving 0, 1–3, or ≥4 medications had CCyR rates of 76%, 70%, and 71% and MMR rates of 35%, 26%, and 23%, respectively. In pts receiving baseline medications, safety was similar irrespective of the number received. Respective grade 3/4 thrombocytopenia rates for pts receiving 0, 1–3, or ≥4 medications were 28%, 17%, and 13% in the dasatinib arm and 9%, 9%, and 17% in the imatinib arm; grade 3/4 neutropenia rates were 29%, 13%, and 31% in the dasatinib arm and 31%, 18%, and 11% in the imatinib arm. Nonhematologic AEs of any grade occurring in ≥10% of pts receiving dasatinib and 0, 1–3, or ≥4 medications, respectively, were diarrhea in 17% vs 19% vs 13% (13% vs 19% vs 17% with imatinib), nausea/vomiting in 12% vs 9% vs 18% (25% vs 23% vs 23% with imatinib), arthralgia/myalgia in 12% vs 10% vs 11% (28% vs 13% vs 14% with imatinib), rash in 6% vs 12% vs 18% (19% vs 16% vs 20% with imatinib), fluid retention in 9% vs 23% vs 24% (41% vs 44% vs 37% with imatinib), pleural effusion in 1% vs 13% vs 13% (0% with imatinib) and superficial edema in 7% vs 8% vs 16% (25% vs 41% vs 31% with imatinib). Efficacy and safety patterns were generally comparable in pts receiving various baseline medication categories. Additional analyses of on-study medication characteristics and effects on efficacy or safety will be presented.

Although occurrence of pleural effusion and fluid retention appeared higher in patients receiving ≥1 medication with dasatinib, overall, the number of medications administered at baseline in the DASISION trial did not appear to affect efficacy or safety of dasatinib (or imatinib) in pts with newly diagnosed CML-CP.

Guilhot: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: This abstract discusses the use of first-line dasatininb in CML-CP. Kantarjian: Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Wyeth: Research Funding. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Hochhaus: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bradley-Garelik: Bristol-Myers Squibb: Employment. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Cortes: Bristol-Myers Squibb: Research Funding.