Therapy of acute myeloid leukemia: therapeutic targeting of tyrosine kinases

ABSTRACT

Introduction: Tyrosine kinases (TKs) drive cell survival and proliferation in many normal and malignant cell types. TKs are frequently mutated in acute myeloid leukemia (AML) and hence are increasingly targeted. The management of AML has dramatically improved because of TKI-targeted treatment.

Areas Covered: This review provides a biological background for TK inhibitors (TKIs) in AML and reviews their use in the clinic. TK expression and mutation in AML are explored with a focus on TKs associated with specific AML subsets and treatment outcomes. TKIs that specifically target FLT3, c-Kit, and Jak2 are discussed. TKI targeting of specific genes mutated in individual cases and general ‘untargeted’ use of these agents are highlighted. Lastly, the mechanisms TKI drug resistance in AML are explored.

Expert Opinion: The use of TKIs in the clinic is improving outcomes for many patients. An improved understanding of tyrosine kinase biology and the expanding use of TKIs are likely to dramatically improve outcomes in the coming decade. TKIs and other targeted agents could gradually supplant the use of cytotoxic chemotherapy for AML.

KEYWORDS:

• Acute myeloid leukemia
• FLT3
• targeted therapy
• tyrosine kinase

Article highlights

• Tyrosine kinases or tyrosine phosphatases are mutated in least 50% of AML cases. Even where no mutation is found, leukemia generally depends on TK signaling for growth or survival.

• FLT3 is mutated in up to 39% of AML cases and is now targetable by midostaurin and other TKIs. The use of these agents changes the adverse natural history of FLT3-mutated AML; it improves remission rates and long-term survivorship.

• c-Kit and Jak2 are mutated in certain AML subsets and may also be targeted for improved results.

• In AMLs with no TK mutation, the use of ‘multikinase’ inhibitors with broad TK inhibitory properties may produce improved progression-free survival.

• TKIs are finding increasing use in the multimodal management of AML.

This box summarizes key points contained in the article.

Declaration of interest

D Claxton has received research support for clinical studies conducted by the following organizations whose products are directly relevant to this work: Daiichi Sankyo Co. and Ambit Biosciences Corp, Astellas Pharma, Novartis Pharmaceuticals. In addition, he has received support for clinical studies from: Incyte Corporation, Incyte Corporation, Cyclacel Pharmaceuticals, Inc, Celegene Corporation, Medimmune, Inc, Merck Sharp & Dohme Corp., Gilead Sciences, Inc. 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. 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.

Additional information

Funding

This paper was not funded.