Table 3 Recommendations for the management of AEs before and during bosutinib treatment of CP-CML
AE | Before treatment | During treatment |
|---|---|---|
Diarrhea | • Ensure patients are aware that diarrhea is common, especially during the first few days or weeks of treatment • Patients should be given dietary guidance, as follows:  ◦ Avoid spicy or fatty food, caffeine, alcohol, dairy products, and raw fruit and vegetables (except for banana and apple)  ◦ Eat low-fiber starchy food and food that is high in sodium and potassium  ◦ Eat small meals, snack frequently, avoid very hot or cold food and drink  ◦ Re-introduce a balanced diet (high-fiber food, fruit, and vegetables) once diarrhea has resolved • Advise that diarrhea events are self-limiting and typically decrease over time. Patients should not stop taking bosutinib unless discussed with their doctor • Discuss discontinuation of medications that may exacerbate diarrhea (e.g., bulk laxatives, stool softeners, motility-promoting agents) • Advise patients to rehydrate orally (8–12 large glasses of water per day) and avoid supplements that increase gastrointestinal irritation during episodes of diarrhea | • Investigate non-bosutinib-related causes of diarrhea • Initial management strategies should include oral hydration (8–12 large glasses of clear liquid per day containing water, salt, and sugar), and dietary modification • Ensure elderly patients experiencing diarrhea are monitored carefully to ensure adequate hydration and electrolyte balance • Encourage patients to report abdominal pain and consider its underlying cause • For grade ≥ 3 diarrhea, fluid replacement therapy should continue and treatment should be interrupted • Appropriate anti-diarrheal medication should be administered for grade ≥ 3 diarrhea and may also be considered in some patients with lower-grade diarrhea • After grade ≥ 3 diarrhea, treatment may be resumed upon recovery to grade ≤ 1; if clinically appropriate, re-escalation of bosutinib should be considered when the diarrhea is resolved/improved |
Nausea and vomiting | • Patients should be advised that nausea and vomiting may occur during treatment and should be reported to physician • Remind patients that bosutinib should be taken with food | • Patients experiencing nausea or vomiting should be advised to try taking bosutinib at a different time of day (although still at a regular time each day, but a patient currently taking bosutinib in the morning may find afternoon or evening better tolerated) • Encourage patients to eat small meals and snack frequently, avoid mixing very hot or very cold food and drink together, and try to eat foods that are gentle on the stomach, possibly giving examples such as bananas, rice, applesauce, and toast • Patients should be encouraged to eat what appeals to them. They should not miss snacks or meals as nausea can worsen with an empty stomach • If nausea and vomiting cannot be managed conservatively, appropriate anti-emetic therapy should be prescribed and used per specific guidance |
Liver enzyme abnormalities | • Measure liver function before initiation of bosutinib • Advise patients that other hepatotoxic drugs should be avoided • Reducing alcohol intake may be recommended if a patient is drinking to excess | • Measure liver function every 2–4 weeks for the first 2–3 months after starting bosutinib, and weekly if practical during the first month as this is the period of greatest risk (in 1L treatment, the median time to onset of increased ALT was 32 days and AST was 43 days; in ≥ 2L, median time to onset of increased ALT was 35 days and AST was 33 days [1]). Subsequently, in patients without evidence of hepatotoxicity, measure liver function every 3 months for the first 2 years; in patients with evidence of hepatotoxicity, more frequent monitoring should be employed • Exclude non-bosutinib-related causes of liver function test elevation • Advise patients with liver transaminase elevations ≥ 2.5 × ULN to avoid hepatotoxic substances and alcohol • Interrupt treatment for liver transaminase levels > 5 × ULN. At recovery to ≤ 2.5 × ULN, treatment may be resumed at a lower dose and re-escalation considered if clinically appropriate. If re-escalation occurs, then frequent monitoring should be employed • When recovery takes > 4 weeks and liver function tests do not appear to be improving satisfactorily, discontinuation should be considered • Treatment should be discontinued for liver transaminase levels ≥ 3 × ULN concurrently with bilirubin elevations > 2 × ULN and alkaline phosphatase levels < 2 × ULN |
Myelosuppression | • Obtain complete blood counts prior to initiating treatment | • Complete blood counts should be performed weekly for the first month and then once per month thereafter, or as clinically indicated (for example, if patients are established on bosutinib and not returning regularly to the clinic, counts may be less frequent) • In patients with persisting cytopenia, consider:  ◦ Modifying starting dose  ◦ Using concomitant supportive care to enable continuation of treatment • In patients with advanced disease, treatment interruptions should be minimized and supportive care provided |
Skin disorders |  | • Assess possible causes of rash, e.g., contact with inflammatory substances, allergies, side effect of drugs other than bosutinib • Inform patients that adequate hydration (daily fluid intake of ≥ 2–3 l) will assist in the maintenance of healthy skin • Promote basic skin care, encourage patients to avoid factors that cause skin irritation, use pH-neutral soaps, and wear loose-fitting, lightweight cotton clothes • Manage BCR-ABL1 TKI-induced rashes with antihistamines and topical treatments • If a clinically significant moderate or severe rash develops, consider consultation with a dermatologist for the use of topical or systemic medical treatments |
Renal dysfunction | • Renal function status should be measured before initiation of treatment, particularly in patients with pre-existing renal impairment or risk factors for renal dysfunction | • Renal function status should continue to be measured • Patients with risk factors for grade ≥ 3b estimated glomerular filtration rate should be monitored closely • Adjust dose in patients with moderate to severe renal impairment, accompanied by close response monitoring at the reduced dose • Patients should be made aware of the possibility of developing renal problems and advised to immediately report changes in urinary frequency, polyuria, or oliguria |
Cardiac events | • Although cardiac events are not common, a patient starting any TKI should have their risk of cardiovascular events assessed • Assess risk factors for arterio-occlusive disease, including hypertension, hyperlipidemia, tobacco use, unhealthy diet, lack of physical activity, etc. and optimize management • Prior to initiating therapy, assessment for risk of QTc prolongation (medical history and use of concomitant medications) and a baseline electrocardiogram are recommended • Hypokalemia or hypomagnesemia must be corrected prior to treatment | • Potassium and magnesium levels should be monitored periodically during therapy • Heart failure was not commonly reported in bosutinib trials, and routine cardiac assessments are not required in all patients. Instead, patients with risk factors should be clinically assessed and additional tests (such as echocardiograms, electrocardiograms) performed as clinically indicated. In patients who develop heart failure, the cancer status should not affect how it is managed: current guidelines for management of heart failure should be followed |