Table 2.

Practical management strategies for adverse events during bosutinib therapy [2, 19, 31]

Adverse event	Management strategy
Gastrointestinal Diarrhea GI upset Other	Assess all patients for signs of diarrhea (onset, duration, stool composition, episode frequency) and dehydration (thirst, infrequent urination, dark urine, dry skin, fatigue, dizziness); manage using standards of care, including diet changes, antidiarrheals, antiemetics, and/or fluid replacement Diarrhea: NCI CTCAE grade 3/4 diarrhea (increase of ≥7 stools/day over baseline/pretreatment), withhold bosutinib until recovery to grade ≤1, then resume at 400 mg QD Other nonhematologic clinically significant moderate/severe toxicity: withhold bosutinib until resolution, then consider resuming at 400 mg QD and consider escalating dose to 500 mg QD, if appropriate GI upset: take bosutinib with a meal and with a large glass of water Avoid alchohol, lactose-containing products, laxatives/stool softeners, raw fruits and vegetables, spicy or fatty foods, and caffeine PPIs should not be used because they may decrease bosutinib exposure
Myelosuppression Neutropenia Thrombocytopenia	Assess patients for signs of thrombocytopenia (easy bruising, unexpected bleeding, blood in urine or stool); neutropenia (fever, infection) In all patients receiving bosutinib, perform a complete blood count weekly for the first month and then monthly thereafter or as indicated clinically Neutropenia: grade 3/4 neutropenia (ANC <1 × 109 L–1): withhold bosutinib until ANC ≥1 × 109 L–1; resume bosutinib at same dose if recovery within 2 weeks; if >2 weeks, upon recovery, reduce dose by 100 mg and resume treatment Thrombocytopenia: grade 3/4 thrombocytopenia (platelet count <50 × 109 L–1): withhold bosutinib until platelet count ≥50 × 109 L–1; resume bosutinib at same dose if recovery within 2 weeks; if >2 weeks, upon recovery, reduce dose by 100 mg and resume treatment If cytopenia recurs, discontinue bosutinib. Upon recovery, reduce bosutinib dose by an additional 100 mg and resume treatment. Growth factors can be used concomitantly for resistant neutropenia and thrombocytopenia
Hepatic toxicity ALT/AST elevation	Assess patients for signs of AST/ALT elevations (jaundice, dark urine) In all patients receiving bosutinib, perform monthly hepatic enzyme tests for the first 3 months of treatment and as indicated clinically. In patients with transaminase elevations, perform hepatic enzyme tests more frequently Liver transaminases >5 × ULN: withhold bosutinib until ≤2.5 × ULN; resume at 400 mg QD thereafter (if recovery is >4 weeks, discontinue bosutinib) Liver transaminase elevations ≥3 × ULN concurrent with bilirubin elevations >2 × ULN and alkaline phosphatase <2 × ULN (Hy’s law case definition): discontinue bosutinib
Dermatologic Rash	Assess patients for skin irritation or signs of rash including red, flat blotches of varying size Treat with hypoallergenic moisturizing creams, topical steroids, antihistamines; in severe cases use systemic corticosteroids and/or antibiotics If grade ≤2, continue bosutinib at current dose and begin topical or oral steroid treatment and monitor; reduce bosutinib dose or temporarily discontinue bosutinib treatment if grade >2; resume/increase bosutinib dosing once the rash is resolved; permanently discontinue bosutinib if necessary
Fluid retention	Fluid retention events [e.g. edema (pulmonary and/or peripheral); pleural and pericardial effusion]: treat with diuretics and supportive care; interrupt, reduce dose, or discontinue bosutinib as necessary
Renal dysfunctiona	Assess patients for signs of renal dysfunction (changes in urinary frequency, polyuria, or oliguria) Monitor renal function status at baseline and during therapy, particularly for patients with preexisting renal impairment or risk factors for renal dysfunction For CrCL 30–50 ml/min, recommended starting dose: 400 mg/day For CrCL <30 ml/min, recommended starting dose: 300 mg/day

^aClassified using KDIGO based on eGFR (ml/min/1.73 m²): normal, ≥90; mild, 60 to <90; mild to moderate, 45 to <60; moderate to severe, 30 to <45; severe, 15 to <30; kidney failure, <15.

ANC, absolute neutrophil count; CrCL, creatinine clearance; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; KDIGO, Kidney Disease: Improving Global Outcomes; NCCN, National Comprehensive Cancer Network; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PPI, proton pump inhibitor; QD, once daily; ULN, upper limit of normal.