An evaluation of ponatinib as a therapy in adult patients with resistant/intolerant chronic-phase chronic myeloid leukemia

ABSTRACT

Introduction

Chronic myeloid leukemia is now a highly treatable leukemia due to the availability of multiple tyrosine kinase inhibitors (TKIs) inhibiting the BCR-ABL1 oncogene. Some patients with CML can display resistance or intolerance to multiple TKIs, oftentimes due to the presence of mutations in BCR-ABL1, such as T315I, which limits effective treatment options. Ponatinib is a third-generation, rationally-designed TKI with clinically meaningful activity in this difficult-to-treat population. Ponatinib is associated with an increased risk of arterial occlusive events (AOEs) which has required a reexamination of its dosing in order to limit the risk of these events.

Areas covered

This review will provide an overview of the mechanism of action of ponatinib and the safety and efficacy data from clinical trials in chronic myeloid leukemia.

Expert opinion

Ponatinib is a potent pan-BCR-ABL1 TKI with substantial activity in patients with more resistant or advanced CML. Its efficacy needs to be balanced with the increased risk of vascular events, which seems to be at least partially diminished by the implementation of mitigation strategies aimed at modifying cardiovascular risk factors and adaptive dosing of the drug.

KEYWORDS:

• Arterial occlusive events
• BCR-ABL1
• chronic myeloid leukemia
• ponatinib
• tyrosine kinase inhibitors
• T315I

Article highlights

• Chronic myeloid leukemia (CML) is a cancer with excellent long-term outcomes in most patients utilizing treatment with tyrosine kinase inhibitors (TKIs).

• A minority of patients are intolerant or resistant to multiple TKIs and have a more guarded prognosis.

• CML with T315I mutation is resistant to all first and second-generation TKIs.

• Ponatinib is a third-generation TKI that was specifically designed and developed to overcome resistance due to the T315I mutation.

• Until very recently, ponatinib was the only FDA-approved TKI for the treatment of CML resistant/intolerant to multiple TKIs or with the T315I mutation.

• Ponatinib is associated with an increased risk of cardiovascular toxicity, particularly arterial occlusive events (AOEs), that is likely to be dose-dependent.

• Mitigation strategies to decrease the risk of ponatinib-associated AOEs are strongly encouraged.

• FDA-approved starting dose of ponatinib is 45 mg once daily with a recommendation to lower the dose to 15 mg once daily once BCR-ABL^IS ≤1% is achieved.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants,or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Takeda Pharmaceuticals provided a scientific accuracy review of this paper at the request of the journal editor.

Additional information

Funding

This paper was not funded.