A safety review of tyrosine kinase inhibitors for chronic myeloid leukemia

ABSTRACT

Introduction

Since the introduction of first tyrosine kinase inhibitor (TKI) imatinib, the treatment of chronic myeloid leukemia (CML) has reached excellent survival expectancies. Long survival rates bring about issues regarding TKI safety.

Areas covered

The aim of this review is to compare the side effects of current TKIs both in the first and later lines and outline a safety andprofile of CML treatment. Seminal studies on TKIs and other newer drugs and extended follow-up of these studies; real-life data of each drug were usedduring the course of this. PubMed was used as a search database and onlyarticles in English were included.

Expert opinion

With longer follow-up CML patients, resistant slowgrade adverse events seem to be the major obstacle in the way of treatmentefficacy. If efficacy is the priority, vigorous treatment of side effect and administration of full dose TKI are reasonable. But when treatment goals are reached, dose modifications or alternative treatment regimens may be acceptedpossible. More studies are needed on dose modification protocols and potential benefits and safety of treatment-free remission.

KEYWORDS:

• Adverse event
• chronic myeloid leukemia
• CML
• safety
• tyrosine kinase inhibitor
• TKI

Article highlights

• Since TFR is still not an option in most countries and in approximately 60% of the treated CML patients; a comprehensive knowledge and surveillance of the potential AEs of TKIs are mandatory.

• TKIs are generally regarded safe but each TKI has a distinct AE profile and recognizing significant side effects (CVEs, pancreatitis, PAH etc.) or any grade 3-4 AEs rapidly and treating them accordingly are major components of a successful treatment.

• As achieving deeper molecular responses at initial phase of treatment is crucial to reach optimal survival rates, temporary dose reductions or drug interruptions are reasonable during the period. But low-grade resistant adverse events have the potential to cause frequent or longer disruptions in treatment administration which will lead to treatment failure or diminished QoL scores.

• In patients with persistent low-level BCR::ABL1 transcripts (IS) 0.1–1%, the long-term treatment success rates have been proven to be excellent, so in or beyond 2nd line setting, especially in patients with prior toxicities, co-morbidities and in geriatric group lower doses is a reasonable option. Treatment switch may not be an ideal option all the time since data shows higher-than-expected cross-intolerance rates among TKIs (especially with bosutinib).

• Revisions in treatment goals in current guidelines (ELN, NCCN) are needed in risky populations for both minimizing toxicity profile and maintaining treatment goals. A more personalized approach will be the near-future aspect of TKI treatment in CML patients.

Declaration of interests

AE Eşkazan has received advisory board and speaker bureau honoraria from Novartis, Bristol-Myers Squibb, and Pfizer, outside the present study. 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

One reviewer is on the speakers bureaus for Bristol-Myers Squibb, Novartis Pharma K.K. another reviewer received honoraria and speaker fees from Bristol, Novartis, Pfizer, and Otsuka Pharmaceutical. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Author contribution statement

All the authors were involved in the study. D Özmen and AE Eşkazan contributed to the conception and study design. D Özmen, DD Alpaydın, and MA Saldoğan were responsible for data collection. D Özmen and AE Eşkazan were responsible for data analysis. D Özmen wrote the first draft of the manuscript, AE Eşkazan edited the manuscript, and all authors participated in the revision of the manuscript. All authors read and approved the final version.

Additional information

Funding

This paper was not funded.