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BOSU

Cancer Type: Hematologic, Leukemia - Chronic Myeloid (CML)  Intent: Palliative
Regimen Category: Evidence-Informed
Funding:
Exceptional Access Program
    bosutinib - For the treatment of patients with chronic, accelerated or blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML), according to specific criteria.
A - Regimen Name

BOSU Regimen
Bosutinib


Disease Site
Hematologic - Leukemia - Chronic Myeloid (CML)

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For the treatment of chronic, accelerated, or blast phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) with resistance or intolerance to prior TKI therapy, and for whom subsequent treatment with imatinib, nilotinib and dasatinib is not clinically appropriate.

 


Supplementary Public Funding

bosutinib
Exceptional Access Program (bosutinib - For the treatment of patients with chronic, accelerated or blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML), according to specific criteria.) (EAP Website)

 
B - Drug Regimen

bosutinib
500 mg PO Daily
(Outpatient prescription in 100 and 500 mg tablets)
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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity.

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

Other Supportive Care:

  • If high volume disease consider steroids and prophylaxis for tumour lysis
  • Patients should be tested for HBV infection prior to initiating treatment.  Carriers of HBV must be monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.

Also refer to CCO Antiemetic Recommendations.

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered. Pre-existing hypokalemia and hypomagnesemia must be corrected before starting treatment. Must be taken with food. Patients at risk of tumour lysis syndrome should be adequately hydrated prior to starting treatment and should be monitored closely.

Dose levels: 500 mg daily, 400 mg daily, 300 mg daily (doses less than 300 mg daily have not been studied)

 

 

 

In the phase 1/2 study, dose escalation to 600mg once daily was allowed in the following patients, but was expected to result in increased toxicity: 

  • Patients with ≤ grade 2 adverse effects

AND

  • who did not reach complete hematological response by 8 weeks OR
  • who did not reach complete cytogenetic response by 12 weeks.

Dosage with toxicity

Blood counts (x 109/L) / Toxicity while on Treatment
Action
Dose at restart
ANC < 1 and/or Platelets < 50 
If not related to leukemia, hold until ANC ≥ 1 and platelets ≥ 50.
 
 
If recovery < 2 weeks, restart at same dose. 
If recovery in > 2 weeks, restart with ↓ 1 dose level.
 
If cytopenia recurs, ↓ 1 dose level upon recovery.
Increased serum lipase + abdominal symptoms
Hold and investigate.  Discontinue if pancreatitis is confirmed.
 n/a
Liver transaminases >5 x ULN
Hold until recovery to ≤ 2.5 x ULN
↓ 1 dose level
Consider discontinuing if recovery takes > 4 weeks.
Liver transaminases ≥3 x ULN (ALP <2 x ULN) AND bilirubin >2 x ULN
Discontinue
n/a
Grade 3 or 4 Fluid retention
Hold until ≤grade 1,
or
Consider discontinuation depending on severity
↓ 1 dose level
or
n/a
Grade 3 or 4 Diarrhea (≥ 7 bowel movements over baseline)
Hold until ≤grade 1, manage with antidiarrheals and/or fluid replacement. 
↓ 1 dose level
Stevens-Johnson Syndrome Discontinued if suspected or confirmed N/A
Other clinically significant grade  3 or 4
Hold until ≤grade 1
↓ 1 dose level.  May consider ↑ dose by 1 dose level if clinically appropriate.
Falls in CrCl, renal failure See table under renal impairment See table under renal impairment



Hepatic Impairment

Bosutinib is contraindicated in patients with hepatic impairment at baseline, as higher risk of QT prolongation has been observed in these patients.  Clinical studies excluded patients with LFTs > 2.5 x ULN (or > 5 x ULN, if disease-related) and/or bilirubin > 1.5 x ULN.  Refer to dose modification above for hepatic toxicity during treatment.


Renal Impairment

Bosutinib exposure is increased in moderate to severe renal impairment; reduced starting doses are recommended. Patients with serum creatinine > 1.5 x ULN were excluded from clinical trials.

Creatinine Clearance (mL/min) Starting Dose
> 30 No change
30-50 400 mg daily
< 30 300 mg daily

Dosage in the Elderly

No dose adjustment is necessary.

 


 
F - Adverse Effects

Refer to bosutinib drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Diarrhea (may be severe)
  • Nausea, vomiting
  • Abdominal pain
  • Rash (may be severe)
  • Myelosuppression +/- infection (including atypical),
  • bleeding (may be severe, including CNS, GI hemorrhage)
  • Increased LFTs (may be severe)
  • Fatigue
  • Anorexia
  • Arrhythmia, QT prolongation
  • Venous thromboembolism
  • Arterial thromboembolism
  • Cardiotoxicity
  • Hypertension
  • Pericardial and pleural effusions
  • Edema
  • Increased amylase/lipase, pancreatitis
  • Tumour lysis syndrome
  • Hypersensitivity
  • Pneumonitis
  • Vasculitis
  • Fracture
  • Renal failure
  • Secondary malignancy
  • Atypical infections (including HBV reactivation)
 
G - Interactions

Refer to bosutinib drug monograph(s) for additional details


  • Bosutinib is primarily metabolized by CYP3A4 and is therefore susceptible to interactions with inducers and inhibitors of this enzyme.
  • Bosutinib is also an in vitro substrate for Pgp, BCRP and MRPs; interactions between bosutinib and substrates of these transporters may occur.
  • Proton-pump inhibitors may reduce bosutinib exposure. Consider using short-acting antacids instead and separate administration times.
  • Avoid drugs that may prolong the QT interval and/or disrupt electrolyte levels given additive risk of QT prolongation.
 
H - Drug Administration and Special Precautions

Refer to bosutinib drug monograph(s) for additional details


Administration:

  • Take once daily with food
  • Do not crush, cut or dissolve tablets in a liquid
  • If a dose is missed, skip this dose and take the next dose on the following day. Double dosing should be avoided.
  • Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment
  • Store at room temperature.

 

Contraindications:

  • Patients who have a hypersensitivity to this drug or to any of its components (includes PEG, povidone and polyoxamer 188)
  • Patients with a known history of long QT syndrome or with a persistent QT interval of >480ms
  • Patients with uncorrected hypokalemia or hypomagnesemia
  • Patients with hepatic impairment, as a higher risk of QT prolongation was observed in these patients

Other Warnings/Precautions:

  • Use with caution in patients with a history or predisposition for QTc prolongation, or who have uncontrolled or significant cardiac disease, or who are taking medications that are known to prolong the QT interval
  • Consultation with a liver disease expert is recommended prior to starting bosutinib in chronic HBV carriers (including those with active disease), and for patients who test positive for HBV infection while on treatment
  • Exercise caution in patients with recent or ongoing clinically significant GI disorders, pre-existing diarrhea or conditions that predispose to diarrhea, fluid retention or with previous history of pancreatitis
  • Patients with coagulation dysfunction/platelet disorders may be at higher risk of bleeding events.
  • Use with caution in patients with hyperparathyroidism or severe osteoporosis; monitor such patients closely
  • Use with caution in patients with pre-existing renal impairment or those with risk factors for renal dysfunction (see section E for dose modifications)

Pregnancy and lactation:

  • Bosutinib is not recommended for use in pregnancy.  For women of childbearing potential, adequate contraception should be used by both sexes during treatment (including vasectomized males), treatment interruptions and for at least 4 weeks after the last dose.
  • Breastfeeding is not recommended.
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • CBC; Baseline, weekly for the first month, and then monthly and as clinically indicated
  • Electrolytes, including magnesium, calcium, phosphorous, and as well as serum lipase/amylase; Baseline, monthly for the first 3 months and then as clinically indicated
  • Liver function tests; Baseline, then monthly for the first three months and then as clinically indicated.
  • Renal function tests; Baseline, then monthly and as clinically indicated (more frequent with renal failure)
  • ECG; Baseline and as clinically indicated
  • HBV infection status: Prior to starting treatment; consult infectious disease if positive
  • For carriers of HBV:  signs and symptoms of active HBV infection; At each visit during treatment and for several months after treatment discontinues
  • Clinical toxicity assessment for infection, bleeding, fluid retention (including weight monitoring), tumour lysis syndrome, GI, skin, pulmonary and cardiovascular effects, hypersensitivity; At each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Bone abnormalities (including bone density), in patients with endocrine abnormalities (e.g. hyperparathyroidism) or severe osteoporosis; Baseline and as clinically indicated

 


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J - Administrative Information

Outpatient prescription for home administration

 


 
K - References

BCR-ABL Tyrosine Kinase Inhibitors [GLEEVEC (imatinib mesylate), TASIGNA (nilotinib), BOSULIF (bosutinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib hydrochloride)] - Risk of Hepatitis B Reactivation. Health Canada, May 4, 2016. [Accessed May 13, 2016]. Available from: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/58222a-eng.php

Bosutinib drug monograph, Cancer Care Ontario.

Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 2011;118(17):4567-76.

Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012;119(15):3403-12.

May 2019 Updated emetic risk category


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.