Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial

Abstract

PurposeBosutinib is a potent dual SRC/ABL kinase inhibitor approved for adults with Philadelphia chromosome–positive chronic myeloid leukemia (CML) resistant and /or intolerant to prior therapy. We assessed the efficacy and safety of bosutinib versus imatinib for first-line treatment of chronic-phase CML.MethodsIn this ongoing, multinational, phase III study, 536 patients with newly diagnosed chronic-phase CML were randomly assigned 1:1 to receive 400 mg of bosutinib once daily (n = 268) or imatinib (n = 268). Per protocol, efficacy was assessed in patients who were Philadelphia chromosome–positive with typical (e13a2/e14a2) transcripts (bosutinib, n = 246; imatinib, n = 241). Patients with Philadelphia chromosome–negative–/BCR-ABL1–positive status and those with unknown Philadelphia chromosome status and/or atypical BCR-ABL1 transcript type were excluded from this population.ResultsThe major molecular response (MMR) rate at 12 months (primary end point) was significantly higher with bosutinib versus imatinib (47.2% v 36.9%, respectively; P = .02), as was complete cytogenetic response (CCyR) rate by 12 months (77.2% v 66.4%, respectively; P = .0075). Cumulative incidence was favorable with bosutinib (MMR: hazard ratio, 1.34; P = .0173; CCyR: hazard ratio, 1.38; P < .001), with earlier response times. Four patients (1.6%) receiving bosutinib and six patients (2.5%) receiving imatinib experienced disease progression to accelerated/blast phase. Among treated patients, 22.0% of patients receiving bosutinib and 26.8% of patients receiving imatinib discontinued treatment, most commonly for drug-related toxicity (12.7% and 8.7%, respectively). Grade ≥ 3 diarrhea (7.8% v 0.8%) and increased ALT (19.0% v 1.5%) and AST (9.7% v 1.9%) levels were more common with bosutinib. Cardiac and vascular toxicities were uncommon.ConclusionPatients who received bosutinib had significantly higher rates of MMR and CCyR and achieved responses faster than those who received imatinib. Consistent with the known safety profile, GI events and transaminase elevations were more common with bosutinib. Results indicate bosutinib may be an effective first-line treatment for chronic-phase CML.

BCR‐ABL1 transcript levels at 4 weeks have prognostic significance for time‐specific responses and for predicting survival in chronic‐phase chronic myeloid leukemia patients treated with various tyrosine kinase inhibitors

“…Of 128 patients administered frontline 2G TKIs, 91% and 83% achieved EMR at 3 and 6 months, respectively. In this study, EMR rates were comparable with those of DASISION, ENESTnd, RERISE, and BFORE studies, indicating the use of homogeneous approaches in terms of molecular analysis and study population. Interestingly, the optimal cutoffs for higher CCyR, MMR, and EFS were similar (approximately 40%), which was albeit as a VEMR.…”

“…Three‐month EMR was previously predicted to be achieved in 50%‐71% of imatinib‐treated new CP patients and in 75%‐91% of frontline 2G TKI‐treated patients. In addition, 6‐month EMR ( BCR‐ABL1 transcript level ≤1%) was predicted to be achieved in 49%‐58% of imatinib‐treated patients and in 69%‐82% of 2G TKI‐treated patients …”

Early results of lower dose dasatinib (50 mg daily) as frontline therapy for newly diagnosed chronic‐phase chronic myeloid leukemia

“…The long‐term impact of low‐dose dasatinib as initial therapy for CML will require a longer follow‐up. However, the results reported here appear to be encouraging in comparison with those achieved with other second‐generation TKIs …”

Tyrosine kinase inhibitor interruptions, discontinuations and switching in patients with chronic‐phase chronic myeloid leukemia in routine clinical practice: SIMPLICITY

“…[6][7][8][9][10] Therefore, second generation (2G) TKIs, which can effectively salvage these imatinib patients, are preferred. [14][15][16] Complementary to the wealth of clinical trial data supporting the efficacy and safety of imatinib, dasatinib, and nilotinib, [15][16][17][18][19] observational studies contribute further insights to inform clinical decision making. [11][12][13] Dasatinib, nilotinib, and bosutinib are associated with higher and faster rates of cytogenetic and molecular response as well as reduced rates of progression when compared with imatinib at 400 mg in the first-line setting, although an impact on survival has not been seen to date.…”