Comparison of First-Line Treatments in Chronic Myeloid Leukemia
In the phase III BFORE trial reported in the Journal of Clinical Oncology by Cortes et al, the SRC/ABL kinase inhibitor bosutinib (Bosulif) improved response rates vs imatinib in first-line treatment of patients with Philadelphia chromosome (Ph)-positive chronic phase chronic myeloid leukemia (CML) with typical BCR-ABL1 transcript types. Bosutinib is already approved for the treatment of adults with Ph-positive resistant CML or who are intolerant to prior therapy.
Study Details
In the ongoing open-label trial, 536 patients with newly diagnosed Ph-positive CML from 151 sites in 26 countries were randomized between July 2014 and August 2015 to receive 400 mg once daily of bosutinib (n = 268) or imatinib (n = 268). Randomization was stratified by Sokal risk group and geographic region.
The primary endpoint was major molecular response at 12 months in the modified intent-to-treat population, with the primary analysis including only patients with typical BCR-ABL1 transcript types (e13a2 or e14a2); this population consisted of 246 patients in the bosutinib group and 241 patients in the imatinib group. Patients with Ph-negative/BCR-ABL1–positive status and those with unknown Ph status or atypical BCR-ABL1 transcript types were excluded from the primary analysis. At data cutoff, all patients had a minimum follow-up of 12 months. The study is ongoing and is expected to last approximately 5 years per patient.
For the bosutinib vs imatinib groups in the modified intent-to-treat population: the median age was 52 vs 53 years (19% vs 17% ≥ 65 years); 58% vs 56% were male; 78% vs 77% were white and 12% vs 12% were Asian; prior hydroxyurea or anagrelide had been received by 53% vs 55%; the median duration from diagnosis was 23 vs 26 days; Sokal risk group was low for 38% vs 39%, intermediate for 41% vs 39%, and high for 21% vs 21%; Eastern Cooperative Oncology Group performance status was 0 (71% vs 71%) or 1 in all patients; 5.7% vs 3.3% had extramedullary disease; and 11.4% vs 12.0% had a history of cardiac disease and 6.1% vs 6.6% had a history of cardiac procedures.
Major Molecular Response Rates
The major molecular response rate at 12 months was 47.2% in the bosutinib group vs 36.9% in the imatinib group (odds ratio [OR] = 1.55, P = .02), and the complete cytogenetic response rate at 12 months was 77.2% vs 66.4% (OR = 1.74, P = .0075). Major molecular response rates were higher in the bosutinib group at 3 months (4.1% vs 1.7%), 6 months (35.0% vs 18.3%), and 9 months (42.3% vs 29.5%); the cumulative incidence function of major molecular response was higher with bosutinib (hazard ratio [HR] = 1.34, P = .0173), indicating a shorter time to response with bosutinib.
The cumulative incidence function for complete cytogenetic response was also greater in the bosutinib group (HR = 1.38, P < .001). Major molecular response rates at 12 months were 34.0% vs 16.7% among patients with high Sokal risk scores, 44.9% vs 39.1% among those with intermediate scores, and 58.1% vs 46.3% among those with low scores. Dose escalation due to suboptimal response occurred in 17.2% vs 27.5% of patients. In the total patient population, major molecular response rates at 12 months were 46.6% vs 36.2% (OR = 1.57, P = .0126). Disease progression to blast phase occurred in 1.6% vs 2.5% of patients. Overall survival at 12 months was 99.6% vs 97.9%.
Adverse Events
The most common adverse events of any grade were diarrhea (70%), nausea (35%), thrombocytopenia (35%), increased alanine transaminase (ALT) (31%), and increased aspartate transaminase (AST; 23%) in the bosutinib group and nausea (39%), diarrhea (34%), muscle spasms (26%), and neutropenia (21%) in the imatinib group. Grade ≥ 3 adverse events occurred in 56% vs 43% of patients, with the most common (> 10% of patients) being ALT increase (19%) and thrombocytopenia (14%) in the bosutinib group and neutropenia (12%) in the imatinib group. Cardiac events occurred in 5.2% vs 5.3% of patients, and peripheral vascular events occurred in 1.5% vs 1.1%.
Adverse events led to dose interruptions in 56% vs 36% of patients, dose reductions in 35% vs 17%, and treatment discontinuation in 14% vs 11%. The most common causes of discontinuation in the bosutinib group were ALT increase (4.9%) and AST increase (2.2%).
The investigators concluded: “Patients who received bosutinib had significantly higher rates of [major molecular response] and [complete cytogenetic response] and achieved responses faster than those who received imatinib. Consistent with the known safety profile, [gastrointestinal events and transaminase elevations were more common with bosutinib. Results indicate bosutinib may be an effective first-line treatment for chronic-phase CML.”
The study was supported by Avillion under a collaborative development agreement with Pfizer and by grants from the National Cancer Institute.
Jorge E. Cortes, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
