Bosutinib

BOSULIF is indicated for the treatment of:

• Adult and pediatric patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or intolerant to prior therapy [see Clinical Studies ( 14.1 , 14.2 , 14.3 )] .
• Adult patients with accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy [see Clinical Studies (14.2) ] . BOSULIF is a kinase inhibitor indicated for the treatment of
• adult and pediatric patients 1 year of age and older with chronic phase Ph+ chronic myelogenous leukemia (CML), newly-diagnosed or resistant or intolerant to prior therapy. ( 1 )
• adult patients with accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy. ( 1 )

Tablets:

• 100 mg: yellow, oval, biconvex, film-coated tablets debossed with "Pfizer" on one side and "100" on the other.
• 400 mg: orange, oval, biconvex, film-coated tablets debossed with "Pfizer" on one side and "400" on the other.
• 500 mg: red, oval, biconvex, film-coated tablets debossed with "Pfizer" on one side and "500" on the other. Capsules:
• 50 mg: white body/orange cap with “BOS 50” printed on the body and “Pfizer” printed on the cap in black ink.
• 100 mg: white body/brownish-red cap with “BOS 100” printed on the body and “Pfizer” printed on the cap in black ink.
• Tablets: 100 mg, 400 mg, and 500 mg. ( 3 )
• Capsules 50 mg, 100 mg. ( 3 )

BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis [see Adverse Reactions (6.1) ] . Hypersensitivity to BOSULIF. ( 4 )

• Gastrointestinal Toxicity: Monitor and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF. ( 2.3 , 5.1 )
• Myelosuppression: Monitor blood counts and manage as necessary. Withhold, dose reduce, or discontinue BOSULIF. ( 2.4 , 5.2 )
• Hepatic Toxicity: Monitor liver enzymes at least monthly for the first 3 months and as needed. Withhold, dose reduce, or discontinue BOSULIF. ( 2.3 , 5.3 )
• Cardiovascular Toxicity: Monitor and manage as necessary. Interrupt, dose reduce, or discontinue BOSULIF. ( 5.4 )
• Fluid Retention: Monitor patients and manage using standard of care treatment. Interrupt, dose reduce, or discontinue BOSULIF. ( 2.3 , 5.5 )
• Renal Toxicity: Monitor patients for renal function at baseline and during therapy with BOSULIF. ( 5.6 )
• Embryo-Fetal Toxicity: BOSULIF can cause fetal harm. Advise female patients of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.7 )

5.1 Gastrointestinal Toxicity Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement. In the randomized clinical trial in adult patients with newly-diagnosed Ph+ CML, the median time to onset for diarrhea (all grades) was 4 days and the median duration per event was 3 days. Among 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1–268). Among 49 pediatric patients with newly-diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the duration was 2 days. Among patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 2 (range 1 – 198). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .

5.2 Myelosuppression Thrombocytopenia, anemia and neutropenia occur with BOSULIF treatment. Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.4) and Adverse Reactions (6) ] .

5.3 Hepatic Toxicity Bosutinib may cause elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). Two cases consistent with drug induced liver injury (defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN with total bilirubin greater than 2×ULN and alkaline phosphatase less than 2×ULN) have occurred without alternative causes. This represented 2 out 1711 patients in BOSULIF clinical trials. In the 268 adult patients from the safety population in the randomized clinical trial in patients with newly-diagnosed CML in the BOSULIF treatment group, the incidence of ALT elevation was 68.3% and increased AST was 56%. Of patients who experienced increased transaminases of any grade, 73% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 29 and 56 days, respectively, and the median duration was 19 and 15 days, respectively. Among the 546 adult patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the incidence of increased ALT was 53.3% and AST elevation was 46.7%. Sixty percent of the patients experienced an increase in either ALT or AST. Most cases of transaminase elevations in this study occurred early in treatment; of patients who experienced increased transaminases of any grade, more than 81% experienced their first increase within the first 3 months. The median time to onset of increased ALT and AST was 22 and 29 days, respectively, and the median duration for each was 21 days. Among 49 pediatric patients with newly‑diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, the incidence based on laboratory data that worsened from baseline of increased ALT was 59% and of increased AST 51%. Seventy-six percent of the patients experienced an increase in either ALT or AST. Most cases of increased transaminases occurred early in treatment; of patients who experienced increased transaminases of any grade, 84% of patients experienced their first increases within the first 3 months. The median time to onset for adverse reactions of increased ALT and AST was 22 and 15 days, respectively. The median duration for adverse reactions of Grade 3 or 4 increased ALT or AST was 26 and 12 days, respectively. Perform hepatic enzyme tests monthly for the first 3 months of BOSULIF treatment and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .

5.4 Cardiovascular Toxicity BOSULIF can cause cardiovascular toxicity including cardiac failure, left ventricular dysfunction, and cardiac ischemic events. Cardiac failure events occurred more frequently in previously treated patients than in patients with newly diagnosed CML and were more frequent in patients with advanced age or risk factors, including previous medical history of cardiac failure. Cardiac ischemic events occurred in both previously treated patients and in patients with newly diagnosed CML and were more common in patients with coronary artery disease risk factors, including history of diabetes, body mass index greater than 30, hypertension, and vascular disorders. In a randomized study of adult patients with newly diagnosed CML, cardiac failure occurred in 1.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. Cardiac ischemic events occurred in 4.9% of patients treated with BOSULIF compared to 0.8% of patients treated with imatinib. In a single-arm study in adult patients with CML who were resistant or intolerant to prior therapy, cardiac failure was observed in 5.3% of patients and cardiac ischemic events were observed in 5.1% of patients treated with BOSULIF. Among 49 pediatric patients with newly diagnosed CP Ph+ CML or who had CP Ph+ CML that was resistant or intolerant to prior therapy, 4 (8%) patients had Grade 1-2 cardiac events, including tachycardia (n=2), angina pectoris, right bundle branch block, and sinus tachycardia (n=1 each). Monitor patients for signs and symptoms consistent with cardiac failure and cardiac ischemia and treat as clinically indicated. Interrupt, dose reduce, or discontinue BOSULIF as necessary [see Dosage and Administration (2.3) and Adverse Reactions (6) ] .

5.5 Fluid Retention Fluid retention occurs with BOSULIF and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. In the randomized clinical trial of 268 adult patients with newly-diagnosed CML in the bosutinib treatment group, 3 patients (1.1%) experienced severe fluid retention of Grade 3, 1 patient experienced Grade 3 pericardial effusion, and 2 patients experienced Grade 3 pleural effusion. Among 546 adult patients in a single-arm study in patients with Ph+ CML who were resistant or intolerant to prior therapy, Grade 3 or 4 fluid retention was reported in 30 patients (6%). Some patients experienced more than one fluid retention event. Specifically, 24 patients experienced Grade 3 or 4 pleural effusions, 9 patients experienced Grade 3 or Grade 4 pericardial effusions, and 6 patients experienced Grade 3 edema. […]

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Gastrointestinal toxicity [see Warnings and Precautions (5.1) ] .
• Myelosuppression [see Warnings and Precautions (5.2) ] .
• Hepatic toxicity [see Warnings and Precautions (5.3) ] .
• Cardiovascular toxicity [see Warnings and Precautions (5.4) ] .
• Fluid retention [see Warnings and Precautions (5.5) ] .
• Renal toxicity [see Warnings and Precautions (5.6) ] .
• Most common adverse reactions (≥20%), in adult and pediatric patients with CML are diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite respiratory tract infection, and constipation. The most common laboratory abnormalities (≥20%) in adult and pediatric patients are creatinine increased, hemoglobin decreased, lymphocyte count decreased, platelets decreased, ALT increased, calcium decreased, white blood cell count decreased, AST increased, absolute neutrophil count decreased, glucose increased, phosphorus decreased, urate increased, alkaline phosphatase increased, lipase increased, creatine kinase increased, and amylase increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions, in ≥20% of adults with newly diagnosed CP Ph+ CML or CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (N=814) were diarrhea (80%), rash (44%), nausea (44%), abdominal pain (43%), vomiting (33%), fatigue (33%), hepatic dysfunction (33%), respiratory tract infection (25%), pyrexia (24%), and headache (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of adults were creatinine increased (93%), hemoglobin decreased (90%), lymphocyte count decreased (72%), platelets decreased (69%), ALT increased (58%), calcium decreased (53%), white blood cell count decreased (52%), absolute neutrophils count decreased (50%), AST increased (50%), glucose increased (46%), phosphorus decreased (44%), urate increased (41%), alkaline phosphatase increased (40%), lipase increased (36%), creatine kinase increased (29%), and amylase increased (24%). The most common adverse reactions, in ≥20% of pediatric patients (N=49) were diarrhea (82%), abdominal pain (73%), vomiting (55%), nausea (49%), rash (49%), fatigue (37%), hepatic dysfunction (37%), headache (35%), pyrexia (31%), decreased appetite (27%), and constipation (20%). The most common laboratory abnormalities that worsened from baseline in ≥20% of pediatric patients were creatinine increased (92%), alanine aminotransferase increased (59%), white blood cell count decreased (53%), aspartate aminotransferase increased (51%), platelet count decreased (49%), glucose increased (41%), calcium decreased (31%), hemoglobin decreased (31%), neutrophil count decreased (31%), lymphocyte count decreased (29%), serum amylase increased (27%), and CPK increased (25%). Adverse Reactions in Adult Patients With Newly-Diagnosed CP CML The clinical trial randomized and treated 533 patients with newly-diagnosed CP CML to receive BOSULIF 400 mg daily or imatinib 400 mg daily as single agents (Newly-Diagnosed CP CML Study) [see Clinical Studies (14.1) ] . The safety population (received at least 1 dose of BOSULIF) included:

• two hundred sixty-eight (268) patients with newly-diagnosed CP CML had a median duration of BOSULIF treatment of 55 months (range: 0.3 to 60 months) and a median dose intensity of 394 mg/day. Serious adverse reactions occurred in 22% of patients with newly-diagnosed CP CML who received bosutinib. Serious adverse reactions reported in >2% of patients included hepatic dysfunction (4.1%), pneumonia (3.4%), coronary artery disease (3.4%), and gastroenteritis (2.2%). Fatal adverse reactions occurred in 3 patients (1.1%) due to coronary artery disease (0.4%), cardiac failure acute (0.4%), and renal failure (0.4%). Permanent discontinuation of bosutinib due to an adverse reaction occurred in 20% of patients with newly-diagnosed CP CML who received bosutinib. Adverse reactions which resulted in permanent discontinuation in > 2% of patients included hepatic dysfunction (9%). Dose modifications (dose interruption or reductions) of bosutinib due to an adverse reaction occurred in 68% of patients with newly-diagnosed CP CML. Adverse reactions which required dose interruptions or reductions in >5% of patients included hepatic dysfunction (27%), thrombocytopenia (16%), diarrhea (16%), lipase increased (10%), neutropenia (7%), abdominal pain (6%), rash (5%). The most common adverse reactions, in >20% of bosutinib-treated patients with newly-diagnosed CML (N=268) were diarrhea (75%), hepatic dysfunction (45%), rash (40%), abdominal pain (39%), nausea (37%), fatigue (33%), respiratory tract infection (27%), headache (22%), and vomiting (21%). The most common laboratory abnormalities that worsened from baseline in ≥20% of patients were creatinine increased (94%), hemoglobin decreased (89%), lymphocyte count decreased (84%), ALT increased (68%), platelet count decreased (68%), glucose increased (57%), AST increased (56%), calcium decreased (55%), phosphorus decreased (54%), lipase increased (53%), white blood cell count decreased (50%), absolute neutrophil count decreased (42%), alkaline phosphatase increased (41%), creatine kinase increased (36%), and amylase increased (32%). Table 7 identifies adverse reactions greater than or equal to 10% for All Grades and Grades 3 or 4 (3/4) for the Phase 3 CP CML safety population. Table 7: Adverse Reactions (10% or Greater) in Patients With Newly-Diagnosed CML in Bosutinib 400 mg Study Based on a Minimum of 57 Months of Follow-up. Adverse drug reactions are based on all-causality treatment-emergent adverse events. The commonality stratification is based on 'All Grades' under Total column. 'Grade 3', 'Grade 4' columns indicate maximum toxicity. Bosutinib 400 mg Chronic Phase CML (N=268) Imatinib 400 mg Chronic Phase CML (N=265) System Organ Class Preferred Term All Grades % Grade 3/4 % All Grades % Grade 3/4 % Gastrointestinal disorders Diarrhea 75 9 40 1 Abdominal pain Abdominal pain includes the following preferred terms: Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Dyspepsia, Epigastric discomfort, Gastrointestinal pain. 39 2 27 1 Nausea 37 0 42 0 Vomiting 21 1 20 0 Constipation 13 0 6 0 Hepatobiliary disorders Hepatic dysfunction Hepatic dysfunction includes the preferred terms: Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase increased, Bilirubin conjugated increased, Blood alkaline phosphatase increased, Blood bilirubin increased, Drug-induced liver injury, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Hepatic steatosis, Hepatitis, Hepatitis toxic, Hepatocellular injury, Hepatotoxicity, Hyperbilirubinemia, Jaundice, Liver disorder, Liver function test increased, Ocular icterus, Transaminases increased. […]

• Strong and Moderate CYP3A Inhibitors: Avoid concomitant use with BOSULIF. ( 7.1 )
• Strong CYP3A Inducers: Avoid concomitant use with BOSULIF. ( 7.1 )
• Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors. ( 7.1 )

7.1 Effect of Other Drugs on BOSULIF Strong or Moderate CYP3A Inhibitors Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF. Bosutinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor increases bosutinib C max and AUC [see Clinical Pharmacology (12.3) ] which may increase the risk of toxicities. Strong CYP3A Inducers Avoid the concomitant use of strong CYP3A inducers with BOSULIF. Bosutinib is a CYP3A substrate. Concomitant use with a strong CYP3A inducer decreases bosutinib C max and AUC [see Clinical Pharmacology (12.3) ] which may reduce BOSULIF efficacy. Proton Pump Inhibitors (PPI) As an alternative to PPIs, use short-acting antacids or H2 blockers and separate dosing by more than 2 hours from BOSULIF dosing. Bosutinib displays pH dependent aqueous solubility, Concomitant use with a PPI decreases bosutinib C max and AUC [see Clinical Pharmacology (12.3) ] which may reduce BOSULIF efficacy.

Lactation: Advise women not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, BOSULIF can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies conducted in rats and rabbits, oral administration of bosutinib during organogenesis caused adverse developmental outcomes, including structural abnormalities, embryo-fetal mortality, and alterations to growth at maternal exposures (AUC) as low as 1.2 times the human exposure at the dose of 500 mg/day ( see Data ). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2–4% and 15–20%, respectively. Data Animal Data In a rat fertility and early embryonic development study, bosutinib was administered orally to female rats for approximately 3 to 6 weeks, depending on day of mating (2 weeks prior to cohabitation with untreated breeder males until gestation day [GD] 7). Increased embryonic resorptions occurred at greater than or equal to 10 mg/kg/day of bosutinib (1.6 and 1.2 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and decreased implantations and reduced number of viable embryos at 30 mg/kg/day of bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively). In an embryo-fetal development study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and 2 fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 5.1 and 3.8 times the human exposures at the recommended doses of 400 and 500 mg/day, respectively. Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. In a rat pre- and postnatal development study, bosutinib was administered orally to pregnant animals during the period of organogenesis through lactation day 20 at doses of 10, 30, and 70 mg/kg/day. Reduced number of pups born occurred at greater than or equal to 30 mg/kg/day bosutinib (3.4 and 2.5 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively), and increased incidence of total litter loss and decreased growth of offspring after birth occurred at 70 mg/kg/day bosutinib (6.9 and 5.1 times the human exposure at the recommended doses of 400 or 500 mg/day, respectively).

8.2 Lactation Risk Summary No data are available regarding the presence of bosutinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, bosutinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a nursing child, breastfeeding is not recommended during treatment with BOSULIF and for 2 weeks after the last dose. Animal Data After a single radiolabeled bosutinib dose to lactating rats, radioactivity was present in the plasma of suckling offspring for 24 to 48 hours.

8.3 Females and Males of Reproductive Potential Based on findings from animal studies, BOSULIF can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Females of reproductive potential should have a pregnancy test prior to starting treatment with BOSULIF. Contraception Females Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with BOSULIF and for 2 weeks after the last dose. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. Based on findings from animal studies, BOSULIF may cause reduced fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of BOSULIF have been established in pediatric patients 1 year of age and older with newly-diagnosed CP Ph+ CML and CP Ph+ CML that is resistant or intolerant to prior therapy. Use of BOSULIF for these indications is based on data from BCHILD [NCT04258943]. The study included pediatric patients with newly diagnosed CP Ph+ CML in the following age groups: 2 patients 1 year of age to less than 6 years of age, 3 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age. The study also included pediatric patients with CP Ph+ CML that was resistant or intolerant to prior therapy in the following age groups: 4 patients 1 year of age to less than 6 years of age, 10 patients 6 years of age to less than 12 years of age, and 10 patients 12 years of age to less than 17 years of age [see Adverse Reactions (6.1) and Clinical Studies (14.3) ] . BSA-normalized apparent clearance in 27 pediatric patients aged 4 to <17 years (141.3 L/h/m 2 ) was 29% higher than BSA-normalized apparent clearance in adult patients with CP Ph+ CML (109.2 L/h/m 2 ) [see Clinical Pharmacology (12.3) ] . The recommended dosage of BOSULIF in pediatric patients is based on body surface area (BSA) [see Dosage and Administration (2.1) ]. The safety and effectiveness of BOSULIF in pediatric patients younger than 1 year of age with newly diagnosed CP Ph+ CML, pediatric patients younger than 1 year of age with CP Ph+ CML that is resistant or intolerant to prior therapy, and pediatric patients with AP Ph+ CML or BP Ph+ CML have not been established.

8.5 Geriatric Use In the single-arm study in patients with CML who were resistant or intolerant to prior therapy of BOSULIF in patients with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. Of the 268 patients who received bosutinib in the study for newly diagnosed CML, 20% were age 65 and over, 5% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment Reduce the BOSULIF starting dose in patients with moderate (creatinine clearance [CL cr ] 30 to 50 mL/min, estimated by Cockcroft-Gault (C-G)) and severe (CL cr less than 30 mL/min, C-G) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot tolerate the starting dose, follow dose adjustment recommendations for toxicity [see Dosage and Administration (2.3 , 2.5) and Clinical Pharmacology (12.3) ] . BOSULIF has not been studied in patients undergoing hemodialysis.

8.7 Hepatic Impairment Reduce the BOSULIF dosage in patients with hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.3 , 2.5) and Clinical Pharmacology (12.3) ].

Bosutinib is a TKI. Bosutinib inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src-family kinases including Src, Lyn, and Hck. Bosutinib inhibited 16 of 18 imatinib-resistant forms of BCR-ABL kinase expressed in murine myeloid cell lines. Bosutinib did not inhibit the T315I and V299L mutant cells.