Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up.

Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML. ClinicalTrials.gov Identifier: NCT00261846.

Gambacorti-Passerini C ，Brümmendorf TH ，Kim DW ，Turkina AG ，Masszi T ，Assouline S ，Durrant S ，Kantarjian HM ，Khoury HJ ，Zaritskey A ，Shen ZX ，Jin J ，Vellenga E ，Pasquini R ，Mathews V ，Cervantes F ，Besson N ，Turnbull K ，Leip E ，Kelly V ，Cortes JE ... -  《-》

Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib.

Cortes JE ，Kantarjian HM ，Brümmendorf TH ，Kim DW ，Turkina AG ，Shen ZX ，Pasquini R ，Khoury HJ ，Arkin S ，Volkert A ，Besson N ，Abbas R ，Wang J ，Leip E ，Gambacorti-Passerini C ... -  《-》

Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial.

Bosutinib is an oral, dual SRC/ABL1 tyrosine kinase inhibitor for resistant/intolerant chronic myeloid leukaemia (CML). We assessed the efficacy and safety of bosutinib 500 mg/d (n = 250) versus imatinib 400 mg/d (n = 252) after >24 months from accrual completion in newly diagnosed chronic phase (CP)-CML (Bosutinib Efficacy and Safety in Newly Diagnosed CML trial [BELA]). Cumulative complete cytogenetic response (CCyR) rates by 24 months were similar (bosutinib, 79%; imatinib, 80%); cumulative major molecular response (MMR) rates were 59% for bosutinib and 49% for imatinib. Responses were durable; 151/197 vs. 172/204 and 125/153 vs. 117/131 responders remained on treatment and maintained CCyR and MMR, respectively. Since the 12-month primary analysis, no new accelerated-/blast-phase transformations occurred with bosutinib; four occurred with imatinib. Early response (BCR-ABL1/ABL1 ≤ 10%, 3 months) was associated with better CCyR and MMR rates by 12 and 24 months (both arms). Gastrointestinal events and liver function test elevations were more common, and neutropenia, musculoskeletal events and oedema were less common with bosutinib. Discontinuations due to adverse events were more common with bosutinib versus imatinib (most commonly alanine aminotransferase elevation: 4% vs. <1%); most occurred within the first 12 months. Cardiovascular adverse events were similar in both arms. Bosutinib continues to demonstrate good efficacy and manageable tolerability in newly diagnosed CP-CML patients.

Brümmendorf TH ，Cortes JE ，de Souza CA ，Guilhot F ，Duvillié L ，Pavlov D ，Gogat K ，Countouriotis AM ，Gambacorti-Passerini C ... -  《-》

Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors.

Kantarjian HM ，Cortes JE ，Kim DW ，Khoury HJ ，Brümmendorf TH ，Porkka K ，Martinelli G ，Durrant S ，Leip E ，Kelly V ，Turnbull K ，Besson N ，Gambacorti-Passerini C ... -  《-》

Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study.

Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6-96.3) and 25.6 (0.2-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3-5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.

Gambacorti-Passerini C ，Cortes JE ，Lipton JH ，Kantarjian HM ，Kim DW ，Schafhausen P ，Crescenzo R ，Bardy-Bouxin N ，Shapiro M ，Noonan K ，Leip E ，DeAnnuntis L ，Brümmendorf TH ，Khoury HJ ... -  《-》