Effectiveness of Bosutinib in Chronic Myeloid Leukemia (CML) Who Have Received Multi Tyrosine Kinase Inhibitors (TKIs)
Authors: Cortes Jorge , Kantarjian Hagop M. , Richard-Carpentier Guillaume , Borthakur Gautam M. , Ravandi Farhad , Naqvi Kiran , Sasaki Koji , Kadia Tapan M. , Verstovsek Srdan , Garcia-Manero Guillermo , DiNardo Courtney D. , Pemmaraju Naveen , Daver Naval G. , Bose Prithviraj , Pierce Sherry A. , Dara Samuel , Jabbour Elias , Cortes Jorge E. 
Published: November 2019

Background: Despite the general efficacy of tyrosine kinase inhibitors (TKIs) in the treatment of patients (pts) with chronic myeloid leukemia patients (CML). Approximately 30-40% of CML pts need to switch to an alternative TKIs because of resistance or intolerance. Bosutinib is a Src/Abl TKI approved for treating adults with chronic phase (CP), accelerated (AP), or blast phase (BP) Philadelphia chromosome (Ph+) CML with resistance or intolerance to prior therapies, and as frontline therapy in CP-CML.
Methods: We reviewed the records of CML pts who received bosutinib in 2nd-9th line of therapy between 2006 and 2018. Response to therapy was assessed by standard criteria and overall (OS), failure-free (FFS), event-free (EFS), and transformation-free survival (TFS) were estimated by the Kaplan-Meier methods and 95% confidence intervals were calculated for 5-year survival estimates.
Results: Seventy pts were identified who received bosutinib for CML, 68 in chronic phase, 1 in accelerated phase and 1 in blast phase. We focus here on the 68 pts in CP. The median age was 52 years (range, 24 to 87). Fifty percent had received one prior TKI, 31% 2 prior TKIs, and 19% 3 or more prior TKIs. Three patients had received stem cell transplant and 7 had received interferon. The median follow-up was 126 months (range, 53 to 151) and the median duration of therapy was 24 months (range, 1 to 150). The median starting dose of bosutinib was 500 mg (range, 100 to 600). Forty four pts (65%) started at 500 mg and 14 pts (21%) started at 400 mg. At last follow-up 47 pts (69%) had discontinued therapy (9 pts due to AEs, 37pts due to resistance, one pt due to other reasons). Intermittent dose reductions were frequently required but 47 pts (69%) were still receiving their starting dose (including 75% of those starting at 500 and all those starting at 400 mg). The most common adverse event was diarrhea in 68% but it was mostly grade 1; 6 pts had grade 3 diarrhea (9%) and 2 of them had treatment discontinuation due to diarrhea. Two pts developed pulmonary hypertension and 2 cerebrovascular accidents while on therapy [table2]. Best response was major cytogenetic response 13 (19%), complete cytogenetic response (CCyR) in 1 (1.5% %), major molecular response (MMR) in 5 (7 %), MR 4.5 in 3 (4.4 %), sustained MR 4.5 in 10 (14.7 %) and complete molecular response (CMR, undetectable transcripts with at least 100,000 ABL copies) in 2 (3%) [table2]. Seven pts (10%) had CCyR before starting bosutinib, all maintained CCyR while they were taking bosutinib. The rates of 60 months OS, EFS, FFS, and TFS were 96% (95% CI 89.8%-100.0%), 85% (95% CI 76.3%-94.8%), 94% (95% CI 87.8%-100.0%), 56% (95% CI 42.9%-73.0%), respectively. Two patients with F317L mutation and both achieved CCyR and MMR. Baseline mutations before staring bosutinib are L248V, M244V, E463, M315T, and S359V.
Conclusions: Bosutinib is an effective treatment option for patients who have received multiple prior therapies, and associated with an acceptable toxicity.

Disclosures
Kantarjian: Amgen: Honoraria, Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding. Borthakur:Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agensys: Research Funding; PTC Therapeutics: Consultancy; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Arvinas: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Polaris: Research Funding; Tetralogic Pharmaceuticals: Research Funding; NKarta: Consultancy; BioTheryX: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Incyte: Research Funding; Strategia Therapeutics: Research Funding; Oncoceutics: Research Funding; Cantargia AB: Research Funding. Ravandi:Cyclacel LTD: Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Verstovsek:CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. DiNardo:agios: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; abbvie: Consultancy, Honoraria; medimmune: Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Daver:Celgene: Consultancy; Novartis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Otsuka: Consultancy; Novartis: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Astellas: Consultancy; Forty-Seven: Consultancy; BMS: Consultancy, Research Funding; Agios: Consultancy; Sunesis: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Sunesis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; NOHLA: Research Funding; Servier: Research Funding; NOHLA: Research Funding; Genentech: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Servier: Research Funding; Agios: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Glycomimetics: Research Funding; Incyte: Consultancy, Research Funding; Otsuka: Consultancy; Glycomimetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Forty-Seven: Consultancy; Astellas: Consultancy; BMS: Consultancy, Research Funding; Jazz: Consultancy; Immunogen: Consultancy, Research Funding; Jazz: Consultancy. Bose:Promedior: Research Funding; CTI BioPharma: Research Funding; NS Pharma: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Constellation: Research Funding; Kartos: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau. Jabbour:Takeda: Consultancy, Research Funding; Cyclacel LTD: Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.