The development of agents targeting the BCR-ABL tyrosine kinase as Philadelphia chromosome-positive acute lymphoblastic leukemia treatment

ABSTRACT

Introduction: In Philadelphia chromosome-positive (Ph⁺) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event; consequently, it is targeted by ABL-tyrosine kinase inhibitors (TKIs), the first of which to be identified was imatinib mesylate. There are now four newer TKIs, three so-called second-generation inhibitors and one third generation inhibitor, all of which are more potent than imatinib in in vitro assays.

Areas covered: This paper reviews the current knowledge on the function of BCR-ABL. Furthermore, this paper highlights the impact of this knowledge on the development of a targeted therapy approach in Ph⁺ ALL and the obstacles for the successful treatment with these drugs.

Expert opinion: Identifying key components involved in disease pathogenesis may lead to new approaches that might overcome resistance mediated to the BCR-ABL TKIs. In a near future, the authors believe that monoclonal antibodies and immunotherapy should also be combined with TKIs and up-front chemotherapy for the successful treatment of ALL.

KEYWORDS:

• Acute lymphoblastic leukemia
• Philadelphia chromosome
• tyrosine kinase inhibitors
• chemotherapy
• resistance

Article highlights

• The outcome of patients with Ph⁺ ALL has substantially improved since the introduction of first- and second-generation TKIs.

• Rapid development of resistance during treatment remains a major problem in ALL.

• Although advance is being made towards the development of ponatinib, a pan BCR-ABL inhibitor (including the T315I mutation),further research efforts should explore the mechanisms of resistance to TKIs and the effectiveness of other targeted therapies, combination therapies, and inclusion of strategies for immune response modification.

• The determination of residual populations of quiescent Ph⁺ cells is important for evaluating response in treated patients.

• Although reduction in the number of LSCs by TKI therapy is feasible, new therapeutic strategies through targeting these cells should be developed.

This box summarizes key points contained in the article.

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.

Additional information

Funding

This manuscript has not been funded.