Nadine Besson

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

Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinib-intolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier-estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

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

Bosutinib is an oral, dual SRC/ABL tyrosine kinase inhibitor (TKI) with clinical activity in Philadelphia chromosome-positive (Ph(+)) leukemia. We assessed the safety and tolerability of bosutinib 500 mg per day in a phase 1/2 study in chronic-phase (CP) chronic myeloid leukemia (CML) or advanced Ph(+) leukemia following resistance/intolerance to imatinib and possibly other TKIs. Patient cohorts included second-line CP CML (n = 286), third-/fourth-line CP CML (n = 118), and advanced leukemia (n = 166). Median bosutinib duration was 11.1 (range, 0.03-83.4) months. Treatment-emergent adverse events (TEAEs) in each cohort were primarily gastrointestinal (diarrhea [86%/83%/74%], nausea [46%/48%/48%], and vomiting [37%/38%/43%]). Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression TEAEs were reported in 41% of patients; among affected patients, 46% were managed with bosutinib interruption and 32% with dose reduction. Alanine aminotransferase elevation TEAEs occurred in 17% of patients (grade 3/4, 7%); among patients managed with dose interruption, bosutinib rechallenge was successful in 74%. Bosutinib demonstrated acceptable safety with manageable toxicities in Ph(+) leukemia. This trial (NCT00261846) was registered at www.ClinicalTrials.gov (this manuscript is based on a different data snapshot from that in ClinicalTrials.gov).

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. Am. J. Hematol. 89:732–742, 2014.

Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance

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. Am. J. Hematol. 89:732–742, 2014.

Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up: Bosutinib in Imatinib-treated CP CML: 24 Months

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. Am. J. Hematol. 89:732–742, 2014.

Health-related quality of life (HRQoL) of bosutinib (SKI-606) in imatinib-resistant (IM-R) or imatinib-intolerant (IM-I) chronic phase chronic myeloid leukemia (CP CML).

6620 Background: Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has demonstrated efficacy in a phase 1/2 single-arm study of patients (pts) with IM-R or IM-I CP CML. Given the potential for CP CML pts receiving 2nd-generation TKIs to be treated for significant durations, evaluation of concomitant HRQoL is important. The effect of bosutinib on HRQoL was assessed as an exploratory endpoint. METHODS In the phase 2 part of the trial, 253 pts with IM-R (n = 170) or IM-I (n = 83) CP CML were treated with bosutinib 500 mg/d. HRQoL was measured using the 44-item Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), which consists of 5 domains: Physical Well-being (PWB), Social/Family Well-being (SFWB), Emotional Well-being (EWB), Functional Well-being (FWB), and Leukemia Subscale (LeuS); and 3 summary scales: Treatment Outcome Index (TOI), FACT-General, and FACT-Leu Total. FACT-Leu items are rated on a scale of 0-4. Scores are obtained for each scale by summing item responses; higher scores reflect better HRQoL. The FACT-Leu was completed at baseline, wks 4, 8, and 12, every 12 wks thereafter, and at treatment completion. Within-cohort comparisons were assessed using paired t-tests. RESULTS In this interim analysis, median follow-up was 97 wks (range, 2-215 wks); 51% of pts were still receiving treatment. At 12 wks, IM-R pts reported significant improvements (P <0.05 to P <0.01) in the PWB, EWB, LeuS, Total, and TOI; IM-I pts reported improvement in the LeuS (P <0.05). At 24 wks, IM-R pts reported improvements from baseline in the EWB, LeuS, Total, and TOI; IM-I pts noted significant improvements (P <0.001 to P <0.05) in the PWB, EWB, LeuS, Total, and TOI. At 48 and 96 wks, the LeuS (P <0.01) and TOI (P <0.05) remained improved for IM-R pts, with additional improvements in PWB, Total (P <0.05), and EWB (P <0.01) observed at 96 wks. EWB, LeuS, Total, and TOI were improved for IM-I pts (P <0.001 to P <0.05) at 48 wks, although not at 96 wks. CONCLUSIONS When examined in the context of previously reported efficacy, these early HRQoL data suggest that bosutinib is associated with improved HRQoL among pts with IM-R or IM-I CP CML who remained on therapy.