The bela trial: Bosutinib versus imatinib in patients with chronic phase chronic myeloid leukemia; 18-month follow-up

Background. Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor with minimal inhibitory activity against PDGFR or c-kit. Aim. The phase 3 BELA study compared bosutinib with imatinib in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic phase chronic myeloid leukemia (CP CML). Methods. Patients (N = 502) with Ph+ CP CML stratified by Sokal score and region were randomized to oral bosutinib 500 mg/day (n = 250) or imatinib 400 mg/day (n = 252). Study design and endpoints have been described (Gambacorti, ASH 2010). Safety analyses included all treated patients; efficacy analyses included all randomized patients (intent-to-treat [ITT] population). Results.Median treatment duration was 16.6 months for bosutinib and 16.8 months for imatinib; 69% and 78% of patients, respectively, were still receiving therapy. Common treatment-emergent adverse events (TEAEs; ≥20% of patients) observed with bosutinib and imatinib, respectively, were diarrhea (68%, 22%), vomiting (31%, 14%), nausea (31%, 35%), rash (21%, 16%), and muscle cramps (4%, 20%). Pleural effusions were seen in 3% of bosutinib patients (no imatinib patients). Grade ≥3 TEAEs (≥2% of patients) seen with bosutinib were diarrhea (10%), vomiting (3%), pneumonia (3%), and dyspnea (2%). Median cumulative duration of diarrhea was 33 days for bosutinib and 17 days for imatinib. Grade ≥3 laboratory abnormalities (≥10% of patients) with bosutinib and imatinib, respectively, were elevated alanine aminotransferase (23%, 3%), thrombocytopenia (14%, 14%), elevated aspartate aminotransferase (11%, 3%), neutropenia (9%, 21%), and hypophosphatemia (4%, 17%). Twenty-two percent of bosutinib patients and 6% of imatinib patients discontinued due to AEs. Deaths occurred in 4 (1.6%) bosutinib patients and 12 (4.8%) imatinib patients; overall, 81% of these died from disease progression, with CML-unrelated deaths reported for only 1 bosutinib patient and 2 imatinib patients. In efficacy analyses, complete cytogenetic response (CCyR) rates for bosutinib and imatinib, respectively, at 1 year were 70% and 68% for the ITT population, and 78% and 68% for the evaluable population (P = 0.026). Cumulative CCyR rates by 1 year were 79% (bosutinib) and 75% (imatinib). Major molecular response (MMR) rates at 1 year were higher for bosutinib versus imatinib (39% vs 26%; P = 0.002), as were cumulative MMR rates by 1 year (47% vs 32%; P <0.001). Time to CCyR and MMR were significantly shorter with bosutinib (P <0.001 for both). Transformation to accelerated/blast phase occurred in 4 (2%) patients on bosutinib and 10 (4%) patients on imatinib (P = 0.053). Treatment failures were reduced in the bosutinib group compared with the imatinib group (3% vs 10%; P <0.001). Event-free survival rates were similar between groups (92% for bosutinib and 90% for imatinib). Summary/Conclusions. Safety and efficacy were consistent with previously reported results. Bosutinib had a distinct and acceptable toxicity profile. Bosutinib showed a significantly higher MMR rate at 1 year, significantly faster times to CCyR and MMR, and a borderline significantly lower transformation rate versus imatinib. In conclusion, bosutinib may provide a new therapeutic option in patients with newly diagnosed Ph+ CP CML. Data for the 18- month follow-up will be presented.