Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib

ABSTRACT

Introduction: In spite of the proven efficacy of the tyrosine kinase inhibitor (TKI), imatinib, in chronic myeloid leukemia (CML), many patients develop intolerance and discontinue therapy in the long-term. Second-generation TKIs (dasatinib, nilotinib, bosutinib) and the third-generation TKI, ponatinib, have added opportunities but also complexity in the settings of CML treatment.

Areas covered: Different definitions of intolerance have been used through several clinical trials, making the published data non homogenous. In most cases, only the severity of acute adverse events (AEs), graded by conventional scales such as Common Terminology Criteria for Adverse Events, was reported. Limited attention to long-term events or more in general, to the impact of AEs on patient quality of life (QoL), remains a problem. Ponatinib is active against all BCR-ABL1 mutants, including T315I, and is widely used to treat patients who developed resistance to other TKIs in any CML phase; however, only limited data is available on the possible role of ponatinib for intolerant patients.

Expert opinion: We review the different definitions of intolerance used in sponsored trials and in clinical practice, and we discuss how such definitions impact on the management of AEs. We summarize how to evaluate QoL during treatment with TKIs and how to include ponatinib among possible option for intolerant patients.

KEYWORDS:

• Chronic myeloid leukemia
• tyrosine kinase inhibitors
• intolerance
• safety
• QoL

Article highlights

• Different definitions of intolerance have been used in sponsored clinical trials making difficult a single definition of tolerability.

• For each TKI, there has been a limited attention to specific long-term side effects that may impact on QoL.

• TKI-related toxicity is usually evaluated through CTCAE scale that does not take into consideration the persistence of low-grade adverse events that could have an effect on compliance to treatment.

• Ponatinib is widely used in resistant patients but it could also play a role in intolerant patients.

• The recent approval of lower-dose ponatinib may improve tolerability while also maintaining efficacy and reducing the risk of cardiovascular events and may therefore represent a possible option for patients intolerant to other TKIs.

This box summarizes key points contained in the article.

Declaration of interest

M. Breccia received honoraria for speaking by Novartis, BMS, Pfizer, Incyte. Dr Fabio Efficace declared consultancy by Incyte and BMS. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.