Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial

Abstract

A B S T R A C T PurposeBosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). Patients and MethodsA total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. ResultsThe complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P ϭ .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P Ͻ .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P Ͻ .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. ConclusionThis ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.

Tyrosine kinase inhibitor (TKI) therapy for newly-diagnosed patients with chronic myeloid leukemia: focusing on TKI discontinuation due to adverse events – is better always good?

“…Although many patients with CML in chronic phase (CML-CP) achieve and maintain durable responses under imatinib, some need to be switched to alternative tyrosine kinase inhibitors (TKIs) due to intolerance and/or failure. After being first tested successfully in imatinib-resistant/-intolerant patients, second-generation TKIs (2GTKIs) (nilotinib, dasatinib, and bosutinib) were then utilized in the upfront setting and they were compared with imatinib among patients with CML-CP in three phase III prospective, randomized, companysponsored trials [1][2][3]. Although bosutinib was proven to be efficient among imatinib-resistant or -intolerant cases, it failed to demonstrate superior outcomes over imatinib in the BELA (Bosutinib Efficacy and Safety in Newly Diagnosed CML) trial, in which the primary end point was complete cytogenetic response (CCyR) at 12 months [3].…”

“…After being first tested successfully in imatinib-resistant/-intolerant patients, second-generation TKIs (2GTKIs) (nilotinib, dasatinib, and bosutinib) were then utilized in the upfront setting and they were compared with imatinib among patients with CML-CP in three phase III prospective, randomized, companysponsored trials [1][2][3]. Although bosutinib was proven to be efficient among imatinib-resistant or -intolerant cases, it failed to demonstrate superior outcomes over imatinib in the BELA (Bosutinib Efficacy and Safety in Newly Diagnosed CML) trial, in which the primary end point was complete cytogenetic response (CCyR) at 12 months [3]. Although the rate of major molecular response (MMR) in the bosutinib arm was significantly superior than that of patients receiving imatinib (41% vs. 27%, p < 0.001) as a secondary end point, the primary end point was not different for bosutinib (70%) versus imatinib (68%) (p = 0.601); consequently, bosutinib was not approved as a frontline treatment option for patients with CML-CP since the primary end point was not met [3].…”

Initial treatment for patients with chronic myeloid leukemia

“…8 The results of bosutinib treatment, second-line and first-line, are similar to those of nilotinib and dasatinib, although the differences in comparison with imatinib are less significant, because of the side effect of the drug, mainly diarrhea and increase of aspartate and alanine aminotransferase.…”

“…8 A fifth compound (Ponatinib, Ariad) has been tested in second-line and third-line treatment. 9 Imatinib, first of the class, was introduced more than 10 years ago.…”

Chronic myeloid leukemia: Second‐line drugs of choice

“…At a median follow-up of 30-35 months, MCyR and CCyR was achieved by 59% and 48%, respectively, of patients with chronic phase disease [19]. Bosutinib has also been investigated as a first-line therapy in the phase III BELA trial, with the CCyR rate found to be no different to that of imatinib at 12 months, although superiority of bosutinib in some secondary efficacy endpoints was evident [70,71]. This same study provided the ideal framework to evaluate the safety of bosutinib as it was administered in a controlled way (i.e., vs. imatinib) in over 500 patients followed for a minimum of 5 years.…”