Bosutinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia – BELA Trial: 24-Month Follow-up

Abstract

455 Introduction: Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. The phase 3 BELA study compared bosutinib with imatinib in patients (pts) with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). Methods: Pts were randomized 1:1 to open-label oral bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252) and stratified by Sokal score risk group (low, medium, high) and geographical region. The primary efficacy endpoint was complete cytogenetic response (CCyR) at 12 mo in the intent-to-treat population. Key secondary and exploratory efficacy endpoints included major molecular response (MMR) at 12 mo, time to CCyR and MMR, duration of CCyR and MMR, time to and incidence of transformation to accelerated/blast phase (AP/BP) CML, event-free survival (EFS), and overall survival. Safety analyses included all treated pts. Results: The median treatment duration was 19.3 mo for bosutinib and 19.5 mo for imatinib; 67% and 74% of pts, respectively, are still receiving therapy. The primary reason for discontinuation of bosutinib was toxicity (23%), while the primary reason for discontinuation of imatinib was disease progression (13%). Rates of CCyR and MMR are shown in the table. The rate of cumulative CCyR by 18 mo was 79% in both arms, and the cumulative rate of MMR by 18 mo was 55% in the bosutinib arm versus 45% in the imatinib arm. Median time to CCyR was faster for bosutinib versus imatinib (12.7 vs 24.6 wk); median time to MMR was also faster for bosutinib versus imatinib (36.9 vs 72.3 wk). Transformation to AP/BP CML while on treatment occurred in 4 (2%) pts on bosutinib and 13 (5%) pts on imatinib. On-study deaths from any cause occurred in 6 (2%) pts receiving bosutinib versus 13 (5%) pts receiving imatinib, and included 5 (2%) and 9 (4%) pts, respectively, who died due to CML progression. Median on-treatment EFS and overall survival were not yet reached for either arm. At 18 mo, the Kaplan-Meier estimates of EFS were 95% for bosutinib versus 91% for imatinib, and the estimates of overall survival were 99% versus 95%, respectively. Bosutinib was associated with higher incidences compared with imatinib of gastrointestinal events (diarrhea [69% vs 22%, respectively], vomiting [32% vs 14%], pyrexia [18% vs 10%], and abdominal pain [13% vs 7%]). In contrast, bosutinib was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Fewer pts on bosutinib experienced grade 3/4 laboratory abnormalities of neutropenia (11% vs 24% with imatinib), while the incidences of grade 3/4 anemia and thrombocytopenia were similar between treatment arms (8% with anemia and 14% with thrombocytopenia). Grade 3/4 liver function test abnormalities occurred more frequently with bosutinib versus imatinib (increased alanine aminotransferase [23% vs 4%] and aspartate aminotransferase [12% vs 3%]). Although common with bosutinib, gastrointestinal events and liver function test abnormalities were typically transient, managed with dose modifications, and not life threatening. Conclusions: The study did not meet the primary endpoint (CCyR at 12 mo); early discontinuation of bosutinib due to adverse events may have contributed to this observed lack of difference. However, bosutinib did result in a higher rate of MMR at 12 mo, faster times to MMR and CCyR, fewer events of transformation to AP/BP CML, and fewer overall and CML-related deaths compared with imatinib, suggesting superiority of bosutinib in pts with newly diagnosed CP CML. In addition, the 18-mo estimates for both EFS and OS currently favor bosutinib. Bosutinib and imatinib were each associated with acceptable but distinct toxicity profiles. Based on these results, bosutinib may offer a new therapeutic option for pts with newly diagnosed CP CML. Minimum of 24 mo of follow-up will be presented for all pts. Disclosures: Cortes: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Guilhot:CHU de Poitiers: Employment; Pfizer Inc: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria.

Treatments for chronic myeloid leukemia: a qualitative systematic review

“…A single ongoing, open-label, phase 3 RCT (BELA) (502 patients randomized) of bosutinib (500 mg OD) compared with imatinib (400 mg OD) in the first-line setting has been reported with patients followed for up to 24 months. 11 , 12 , 47 Numerically higher CCyR at 1 year (70% versus 68%) and cumulative CCyR rates by 1 year (79% versus 75%) were reported for bosutinib-treated versus imatinib-treated patients, although these differences were not statistically significant. 12 Bosutinib-treated patients reported both significantly higher MMR at 1 year (41% vs 27%, P = 0.002) and a 1-year cumulative MMR rate (47% vs 32%, P < 0.001) compared with imatinib-treated patients.…”

“… 17 , 44 – 46 A single RCT (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia [BELA]) compared bosutinib with imatinib. 11 , 12 , 47 Different doses/administration schedules of imatinib were compared in two trials. 18 , 19 , 48 Different dose regimens of dasatinib were compared in one trial.…”

Tyrosine kinase inhibitors as a first‐line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed‐treatment comparison

“…A total of 365 potentially relevant references were identified by the electronic search, of which a total of six trials, reported in 20 published papers and conference abstracts, met the inclusion criteria and were pooled in meta-analysis. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Figure 1 depicts the results of the search strategy and study selection.…”

“…Both trials had a maximum follow-up period of 5 years. Four publica-tions and abstracts reported on bosutinib versus imatinib in newly diagnosed CML patients, referred to as BELA, [28][29][30][31] with a median reported follow-up period of 19 months; the trial is still ongoing. Two conference abstracts reported on ponatinib versus imatinib in newly diagnosed CML patients, referred to as EPIC 32,33 ; EPIC was terminated early after a median of 3 months and a follow-up time of 5 months, due to the observation of vascular events in long-term follow-up of phase II trial evaluating ponatinib 37 ; therefore, data of this study were not included in the pooled MTC, but a direct comparison was conducted comparing ponatinib to imatinib.…”

Treatment Development of Chronic Myeloid Leukemia

“…Saglio et al report the response of nilotinib was better than imatinib and the higher cytogenetic response rate (CCyR) at 24 months was 87% in nilotinib vs. 77% in imatinib and MMR response rate at 24 months was 71% in nilotinib vs. 44% in imatinib [8]. Cortes et al reported there were no significant difference between the imatinib and bosutinib in CCyR response rate at 12 months study, while the MMR rate at 12 months study was significantly higher with bosutinib better than imatinib (41% vs. 27%; P<0.001) [13].…”