Bosutinib Use Research Articles

PS1176 PRIMARY RESULTS OF THE PHASE 4 BYOND STUDY OF BOSUTINIB FOR PRETREATED CHRONIC PHASE CHRONIC MYELOID LEUKEMIA

Background:The tyrosine kinase inhibitor (TKI) bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP).Aims:The ongoing phase 4 BYOND study (NCT02228382) is further evaluating the efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs.Methods:Patients with CML and resistance/intolerance to previous TKI therapy were administered bosutinib at a starting dose 500 mg/d. Primary endpoint (not powered) in Ph+ CP CML cohorts is cumulative confirmed major cytogenetic response (MCyR) by 1 y.Results:Of 163 patients who received bosutinib, 156 had Ph+ CP CML (46, 61 and 49 after 1, 2 and 3 prior TKIs, respectively); 4 patients with accelerated phase CML and 3 with Ph–/BCR‐ABL+ CML were analyzed for efficacy separately. Across Ph+ CP CML cohorts, 51.9% of patients were male, and median age was 61 y. 53.2% of patients were resistant to ≥1 prior TKI and 46.8% intolerant to all. As of 1 y after last enrolled patient (median follow‐up 30.4 mo), 56.4% remained on bosutinib. Median treatment duration was 23.7 mo, and median dose intensity was 313 mg/d. Of 144 evaluable patients with a valid baseline assessment, cumulative confirmed MCyR by 1 y was 71.5% (95% confidence interval [CI] 63.4–78.7). Cumulative complete cytogenetic response rate anytime on treatment was 81.3% (95% CI 73.9–87.3). A substantial proportion of patients attained or maintained molecular responses (MRs) across lines of therapy (Table). Of 76 TKI‐resistant and 73 TKI‐intolerant patients evaluable for MR, respectively, cumulative major MR (MMR) rates were 61.8% (95% CI 50.0–72.8) and 82.2% (95% CI 71.5–90.2), MR4 rates were 46.1% (95% CI 34.5–57.9) and 68.5% (95% CI 56.6–78.9) and MR4.5 rates were 36.8% (95% CI 26.1–48.7) and 56.2% (95% CI 44.1–67.8). Among 48 TKI‐resistant and 31 TKI‐intolerant patients without baseline MMR, respectively, cumulative MMR rates were 45.8% (95% CI 31.4–60.8) and 80.6% (95% CI 62.5–92.5), MR4 rates were 22.9% (95% CI 12.0–37.3) and 61.3% (95% CI 42.2–78.2) and MR4.5 rates were 16.7% (95% CI 7.5–30.2) and 51.6% (95% CI 33.1–69.8). 10 deaths occurred (5 on treatment; 0 due to bosutinib toxicity); 1‐y overall survival rate was 98.0% (95% CI 94.0–99.4). No patient progressed to accelerated/blast phase on treatment. 25.0% discontinued bosutinib due to adverse events (AEs) and 5.1% due to insufficient response. Individual treatment‐emergent AEs (TEAEs) reported in >20% of patients across all cohorts (N = 163) were diarrhea (87.7%), nausea (39.9%), vomiting (32.5%), abdominal pain (28.2%), headache (27.6%), increased alanine aminotransferase (ALT; 25.8%), fatigue (23.9%), upper abdominal pain (22.1%), dyspnea (21.5%) and asthenia (20.2%). Grade 3/4 TEAEs in >10% of patients were diarrhea (16.0%) and increased ALT (14.1%). No individual TEAE led to discontinuation in >5% of patients. In all, 28.8% of patients had liver TEAEs (consisting of a cluster of predefined AEs), 14.7% had grade 3/4 liver TEAEs and 5.5% had liver TEAEs leading to bosutinib discontinuation.Summary/Conclusion:Most pretreated patients with Ph+ CP CML had confirmed MCyR by 1 y with bosutinib. MMRs and deep MRs were seen in TKI‐resistant and TKI‐intolerant patients and in all therapy lines, with >45% of TKI‐resistant and >80% of TKI‐intolerant patients achieving MMR or deeper MR with bosutinib. Results further support bosutinib use for patients with Ph+ CP CML resistant/intolerant to prior TKIs.image

Primary results of the phase 4 BYOND study of bosutinib (BOS) for pretreated chronic phase (CP) chronic myeloid leukemia (CML).

7012 Background: The tyrosine kinase inhibitor (TKI) BOS is approved for patients (pts) with Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed pts in CP. Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior TKIs. Primary endpoint (not powered) in Ph+ CP CML cohorts is cumulative confirmed major cytogenetic response (MCyR) by 1 y. Results: Of 163 pts who received BOS, 156 had Ph+ CP CML (46, 61 and 49 after 1, 2 and 3 prior TKIs, respectively). Across Ph+ CP CML cohorts, 51.9% of pts were male; median age was 61 y. As of 1 y after last enrolled pt (median follow-up 30.4 mo), 56.4% remained on BOS. Median BOS duration was 23.7 mo and median dose intensity after adjustment due to adverse events (AEs) 313 mg/d. Of 144 evaluable pts with a valid baseline assessment, cumulative confirmed MCyR by 1 y was 71.5% (95% confidence interval [CI] 63.4–78.7). Cumulative complete cytogenetic response rate anytime on treatment was 81.3% (95% CI 73.9–87.3). Cumulative molecular response (MR) rates were high across lines of therapy (Table). 10 deaths occurred (5 on treatment); 1-y overall survival rate was 98.0%. No pt progressed to accelerated/blast phase on treatment. 25.0% discontinued BOS due to AEs and 5.1% due to insufficient response. Most common treatment-emergent AEs (TEAEs) were diarrhea (87.8%) and nausea (41.0%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.7%) and increased alanine aminotransferase (ALT; 14.7%). The only TEAE leading to discontinuation in > 5% of pts was increased ALT (5.1%). Conclusions: Most pretreated pts with Ph+ CP CML had MCyR by 1 y with BOS; a substantial proportion achieved or preserved major MR (MMR) and deep MR in all therapy lines. Results further support BOS use for Ph+ CP CML resistant/intolerant to prior TKIs. Clinical trial information: NCT02228382. [Table: see text]

Russian Experience of Bosutinib Use in Chronic Myeloid Leukemia Patients in Routine Clinical Practice

Background. The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) have diminished death probability and have changed the disease course. Achievement of complete cytogenetic response (CCyR) and major molecular response (MMR) are serve as warranties for freedom of progression and death from CML. There are many of CML patients are needed to change of initial TKI therapy with choice of the most efficient and safe drug for continuous life-long therapy to reach the optimal results of CML treatment. The newest of registered TKI drug in Russia is Bosutinib which has dual BCR-ABL and SRC kinase inhibitory activity and had showed good tolerability and efficacy in case of other TKIs resistance or intolerance.Aim. To analyze of own Bosutinib experience in patients with chronic myeloid leukemia with other TKIs resistance or intolerance and to make comparison with clinical trial results.Materials and methods. Clinical trials results from peer-reviewed journals. Outpatients charts of 51 patients (25 male and 26 females) with CML. Disease phase at the moment of Bosutinib therapy initiation was as follows: chronic - 37; acceleration - 8, blastic - 6. Bosutinib was used in the next lines of TKI therapy: second - 10; third - 18; fourth - 23. The indications for Bosutinib therapy were: intolerance to previous TKI - 21; resistance to previous TKI - 30.Results. Median of therapy duration was 6 months (1-50 months). The adverse events and tolerability of Bosutinib were similar with clinical trials data. The treatment was withdrawn by the adverse event only in 5 (10%) patients. The rates of the responses in the whole group of patients were as follows: CHR - 88%, stable in 76%; CCyR - 39%, stable in 37%, MMR - 31% and was 25% at the last follow-up. The Bosutinib efficacy in real life settings was slightly higher than clinical trials data. The factors influencing treatment responses were: disease phase, cause of switching to Bosutinib, line of therapy and presence and kind of BCR-ABL mutations, Therapy was continued in 22 (43%) patients, most them achieved stable optimal treatment response (CCyR and MMR).Conclusions. Bosutinib is a real alternative to other tyrosine kinase inhibitors and has its own mechanism of action and adverse events profile. The use of Bosutinib in real life clinical practice settings showed its efficacy and tolerability and could serve as base for recommendation to apply Bosutinib in hematology practice in Russia. DisclosuresNo relevant conflicts of interest to declare.

Clinical Experience and Perspectives of Bosutinib Use in Patients with Chronic Myeloid Leukemia

Aim. To evaluate the clinical experience of bosutinib use for treatment of chronic myeloid leukemia (CML) patients with intolerance and resistance to other tyrosine kinase inhibitors (TKI), as well as to compare the obtained results with the data of clinical trials. Materials & Methods. The analysis was conducted on case history records of 51 CML patients (25 men and 26 women; median age was 56 years, range 28-86). By the beginning of bosutinib therapy 37 chronic phase, 8 acceleration phase, and 6 blast crisis patients were included in the study. Bosutinib was administered as second-line TKI treatment in 10 patients, as third-line treatment in 18 patients, and as fourth-line treatment in 23 patients. The causes for switching to bosutinib were poor tolerance of previous TKI therapy in 21 patients and resistance to previous TKI therapy in 30 patients. Results. The median duration of bosutinib treatment was 6 months (range 1-50). Bosutinib toxicity profile and its tolerance in common clinical practice corresponded to the data of clinical trials. Because of adverse events the therapy was discontinued only in 5 (10 %) patients. Complete hematological response was 88 % (persistent response was maintained in 76 % of patients); complete cytogenetic response (CCyR) was 39 %, (persistent response in 37 % of cases); major mo- lecular response (MMR) was 31 % (it was confirmed in 25 % of patients during the last follow-up visit). The efficacy of bosutinib in the real clinical setting was slightly higher compared to the results of clinical trials. This difference was associated with a disease phase, a reason for withdrawal of the previous TKI, line of treatment, BCR-ABL mutations, and the form of them. The therapy was continued in 22 (43 %) patients, most of them reached stable optimal response, both CCyR and MMR. Conclusion. Bosutinib appears to be an acceptable alternative to other TKIs having its specific mechanisms of action and adverse events. The efficacy and safety of bosutinib proved in routine clinical practice are sufficient to recommend it for use in national hematology.

The Real World Use of Bosutinib in Patients with Chronic Myeloid Leukaemia

Objectives.Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) indicated for patients with previously treated Philadelphia chromosome positive chronic myeloid leukaemia (CML) when imatinib, nilotinib and dasatinib are not appropriate. Data describing the use of bosutinib in patients with CML in the real world clinical setting are limited. The objective of this study was to describe the efficacy and safety of bosutinib in patients with CML used under routine clinical practice.Methods.An international, multi-centre, retrospective, non-interventional study in hospitals in the UK (n=7) and the Netherlands (n=2). Fifty-three patients (32 [60%] male) with CML, aged ≥18 years at bosutinib initiation and with ≥3 months data available post-initiation were recruited. Surviving patients provided written informed consent for data collection; data from deceased patients were collected by a member of the direct care team to preserve confidentiality. Data were analysed using descriptive statistics with no imputation of missing values (denominators presented where data are missing).Results.Median age at bosutinib initiation was 63.6 (range: 25.5 to 90.1) years; median time from CML diagnosis to bosutinib initiation was 7.1 (range: 0.5 to 35.7) years; 74% (39/53) of patients had one or more co-morbidities at initiation. Bosutinib was 3rd-line TKI in 32% (17/53) of patients and 4th-line TKI in 53% (28/53) of patients. Fifty-seven percent (30/53) of patients switched to bosutinib due to intolerance and 26% (14/53) due to resistance to a previous TKI. The most common bosutinib starting dose was 300 mg/day (28% [15/53] of patients). Median bosutinib treatment duration was 15.6 (range: 0.4 to 66.0) months. The proportions of patients with cumulative complete cytogenetic response (CCyR), major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) with bosutinib were 62%, 54%, 34% and 26%, respectively (see figure). At data collection (median follow-up 25.1 [range: 3.0 to 66.0] months), 38% (20/53) of patients had discontinued bosutinib; 2% (1/53) discontinued due to progression, 8% (4/53) due to treatment failure, 15% (8/53) due to adverse events (AE), 6% (3/53) due to loss of response, and 4% (2/53) due to patient request. Ninety-two percent (49/53) of patients experienced ≥1 AE, most commonly diarrhoea (55% [29/53] of patients); 26% (14/53) of patients had grade 3/4 AEs (diarrhoea grade 3/4: 4% [2/53] of patients).Conclusions.Bosutinib used in normal clinical practice in pre-treated patients with CML demonstrates high rates of cytogenetic and major molecular response similar to those seen in clinical trials. Bosutinib is generally well tolerated, with the majority of patients not experiencing grade 3/4 AEs, despite most patients having pre-existing co-morbidities. [Display omitted] DisclosuresApperley:Pfizer: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Byrne:Bristol Myers Squipp: Consultancy, Speakers Bureau. Smith:Pfizer: Honoraria, Other: Advisory boards and talks at regional sponsored meetings. Viqueira:Pfizer: Employment. Ferdinand:Pfizer: Employment. Carter:pH Associates: Employment. Nock:pH Associates: Employment. Milojkovic:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

Bosutinib: a SRC–ABL tyrosine kinase inhibitor for treatment of chronic myeloid leukemia

Bosutinib is one of five tyrosine kinase inhibitors commercially available in the United States for the treatment of chronic myeloid leukemia. This review of bosutinib summarizes the mode of action, pharmacokinetics, efficacy and safety data, as well as the patient-focused perspective through quality-of-life data. Bosutinib has shown considerable and sustained efficacy in chronic myeloid leukemia, especially in the chronic phase, with resistance or intolerance to prior tyrosine kinase inhibitors. Bosutinib has distinct but manageable adverse events. In the absence of T315I and V299L mutations, there are no absolute contraindications for the use of bosutinib in this patient population.