Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML)

Active Ingredient: Bosutinib

Indication for Bosutinib

Population group: only adults (18 years old or older)

Bosutinib is indicated for the treatment of adult patients with:

  • newly-diagnosed chronic phase (CP) Philadelphia chromosome-positive chronic myelogenous leukaemia (Ph+ CML).
  • CP, accelerated phase (AP), and blast phase (BP) Ph+ CML previously treated with one or more tyrosine kinase inhibitor(s) [TKI] and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.

For this indication, competent medicine agencies globally authorize below treatments:

400-500 mg once daily

Route of admnistration

Oral

Defined daily dose

400 - 500 mg

Dosage regimen

From 400 To 500 mg once every day

Detailed description

Newly-diagnosed CP Ph+ CML

The recommended dose is 400 mg bosutinib once daily.

CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy

The recommended dose is 500 mg bosutinib once daily.

In clinical trials for both indications, treatment with bosutinib continued until disease progression or intolerance to therapy.

Dose adjustments

In the Phase ½ clinical study in patients with CML who were resistant or intolerant to prior therapy, dose escalations from 500 mg to 600 mg once daily with food were allowed in patients who failed to demonstrate complete haematological response (CHR) by Week 8 or complete cytogenetic response (CCyR) by Week 12 and did not have Grade 3 or higher adverse events possibly-related to the investigational product. Whereas, in the Phase 3 study in patients with newly-diagnosed CP CML treated with bosutinib 400 mg, dose escalations by 100 mg increments to a maximum of 600 mg once daily with food were permitted if the patient failed to demonstrate breakpoint cluster region-Abelson (BCR-ABL) transcripts ≤10% at Month 3, did not have a Grade 3 or 4 adverse reaction at the time of escalation, and all Grade 2 non-haematological toxicities were resolved to at least Grade 1.

In the Phase ½ clinical study in patients with CML who were resistant or intolerant to prior therapy who started treatment at ≤500 mg, 93 (93/558; 16.7%) patients had dose escalations to 600 mg daily.

In the Phase 3 study in patients with newly-diagnosed CP CML who started bosutinib treatment at 400 mg, a total of 46 patients (17.2%) received dose escalations to 500 mg. In addition, 5.6% of patients in the bosutinib treatment group had further dose escalations to 600 mg.

Doses greater than 600 mg/day have not been studied and, therefore, should not be given.

Dose adjustments for adverse reactions

Non-haematological adverse reactions

If clinically significant moderate or severe non-haematological toxicity develops, bosutinib should be interrupted, and may be resumed at a dose reduced by 100 mg taken once daily after the toxicity has resolved. If clinically appropriate, re-escalation to the dose prior to the dose reduction taken once daily should be considered. Doses less than 300 mg/day have been used in patients; however, efficacy has not been established.

Elevated liver transaminases: If elevations in liver transaminases >5 × institutional upper limit of normal (ULN) occur, bosutinib should be interrupted until recovery to ≤2.5 × ULN and may be resumed at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinuation of bosutinib should be considered. If transaminase elevations ≥3 × ULN occur concurrently with bilirubin elevations >2 × ULN and alkaline phosphatase <2 × ULN, bosutinib should be discontinued.

Diarrhoea: For NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade 3-4 diarrhoea, bosutinib should be interrupted and may be resumed at 400 mg once daily upon recovery to grade ≤1.

Haematological adverse reactions

Dose reductions are recommended for severe or persistent neutropenia and thrombocytopenia as described in the following table.

Dose adjustments for neutropenia and thrombocytopenia:

ANCa <1.0 × 109/LHold bosutinib until ANC ≥1.0 × 109/L and platelets ≥50 × 109/L.
and/or Platelets <50 × 109/LResume treatment with bosutinib at the same dose if recovery occurs within 2 weeks. If blood counts remain low for >2 weeks, upon recovery reduce dose by 100 mg and resume treatment. If cytopoenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment. Doses less than 300 mg/day have been used; however, efficacy has not been established.

a ANC = absolute neutrophil count

Dosage considerations

Bosutinib should be taken orally once daily with food. If a dose is missed by more than 12 hours, the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day.

Active ingredient

Bosutinib

Bosutinib belongs to a pharmacological class of medicinal products known as kinase inhibitors. Bosutinib inhibits the abnormal BCR-ABL kinase that promotes CML. Modeling studies indicate that bosutinib binds the kinase domain of BCR-ABL. Bosutinib is also an inhibitor of Src family kinases including Src, Lyn and Hck. Bosutinib minimally inhibits platelet-derived growth factor (PDGF) receptor and c-Kit. In in vitro studies, bosutinib inhibits proliferation and survival of established CML cell lines, Ph+ ALL cell lines, and patient-derived primary primitive CML cells.

Read more about Bosutinib

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