Therapeutic drug monitoring of imatinib – how far are we in the leukemia setting?

ABSTRACT

Introduction

Tyrosine kinase inhibitors (TKIs) have revolutionized survival rates of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and replaced hematopoietic stem cell transplantation (hSCT) as the key treatment option for these patients. More recently, the so-called Philadelphia chromosome-like (Ph-like) ALL has similarly benefitted from TKIs. However, many patients shift from the first generation TKI, imatinib, due to treatment-related toxicities or lack of treatment efficacy. A more personalized approach to TKI treatment could counteract these challenges and potentially be more cost-effective. Therapeutic drug monitoring (TDM) has led to higher response rates and less treatment-related toxicity in adult CML but is rarely used in ALL or in childhood CML.

Areas covered

This review summarizes different antileukemic treatment indications for TKIs with focus on imatinib and its pharmacokinetic/-dynamic properties as well as opportunities and pitfalls of TDM for imatinib treatment in relation to pharmacogenetics and co-medication for pediatric and adult Ph+/Ph-like leukemias.

Expert opinion

TDM of imatinib adds value to standard monitoring of ABL-class leukemia by uncovering non-adherence and potentially mitigating adverse effects. Clinically implementable pharmacokinetic/-dynamic models adjusted for relevant pharmacogenetics could improve individual dosing. Prospective trials of TDM-based treatments, including both children and adults, are needed.

KEYWORDS:

• ABL-class leukemia
• acute lymphoblastic leukemia
• chronic myeloid leukemia
• imatinib
• Philadelphia chromosome-like
• Philadelphia chromosome positive
• therapeutic drug monitoring
• tyrosine kinase inhibitors

Article highlights

• Therapeutic drug monitoring (TDM) is a method to optimize dosing for an individual patient by monitoring and titrating the drug blood level, a discipline with immense yet unused potential in hemato-oncology.

• Development of tyrosine kinase inhibitors (TKIs) have revolutionized survival rates in BCR:ABL leukemia; still, as many as 40% of patients switch from the low cost first-generation TKI, imatinib, to newer TKIs due to toxicities or treatment failure.

• The pharmacokinetic interindividual variability and clear concentration–effect relationship render imatinib well suited for TDM.

• TDM of imatinib in adults with chronic myeloid leukemia (CML) has improved response rates; however, knowledge is sparse in acute lymphoblastic leukemia (ALL) and children.

• Clinically implementable pharmacokinetic/-dynamic (PK/PD) models adjusted for relevant pharmacogenetics could improve individual imatinib dosing.

• Prospective trials of TDM-based treatments including both children and adults with leukemia are needed.

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.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17512433.2024.2312256.

Additional information

Funding

This paper was funded by the Danish Childhood Cancer Foundation (2019–5934, 2020–5769, 2021–7410, and 2022–8178) and Engineer Otto Christensen’s Fond. This work is part of the Danish nation-wide research program Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) supported by the Danish Cancer Society [R-257–A14720] and the Danish Childhood Cancer Foundation [2019–5934 and 2020–5769]. The content of this manuscript is solely the responsibility of the authors.