Evaluating the Safety of Combining Tyrosine Kinase Inhibitors with Anticoagulants in Chronic Myeloid Leukemia : A Systematic Review

Introduction

Tyrosine kinase inhibitors (TKIs) constitute the standard of care for the management of chronic myeloid leukemia (CML). However, concomitant use of anticoagulants may complicate CML management and there is a lack of guidance on associated drug combinations and interactions. Cytochrome P450 enzyme(s) and p-glycoprotein transporters affect the metabolism of most TKIs and may also be inhibited or induced by anticoagulants. This systematic review investigated the potential drug interactions between different anticoagulants and TKIs in CML, and evaluated the safety of their use in combination.

Methods

A comprehensive search strategy was used, employing Medical Subject Headings (MeSH) and free text terms across databases such as PubMed, Scopus, Web of Science, EMBASE, and Web of Conferences via OVID. A team of independent reviewers screened the titles and abstracts for eligibility based on predefined inclusion and exclusion criteria. Data extraction was performed independently by a team of reviewers using a standardized form to record the studies' characteristics, the TKIs and anticoagulants used, and the outcomes related to safety. Two independent reviewers assessed each study's quality using Critical Appraisal Skills Program (CASP) checklists. The protocol for this systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. This protocol was registered in PROSPERO (CRD42024528737).

Results

The search yielded a total of 406 studies, of which 322 studies were excluded for duplication (n= 47) or irrelevance based on the title and abstract screening (n= 275). Upon full-text review, 74 articles were excluded due to the absence of outcomes of interest (n= 45), irrelevant interventions (n= 11), incorrect population (n= 4), language (n= 5), incomplete reporting of information (n= 3), unretrievable (n= 1), or incorrect study design (n = 5). Four additional studies were identified from grey literature. In total, 14 publications met the inclusion criteria for reporting real-world safety (n=11; 3 retrospective observational studies, 8 case reports) and pharmacokinetic data (n= 3) from adults receiving TKIs with anticoagulants. Of the 3 retrospective studies, 2 reported no bleeding or thrombotic events with the combinations of ponatinib and prophylactic apixaban (5 patients) or imatinib with warfarin (9 patients) in CML patients. The third study reported the incidence of 2 intramuscular hematoma events with the combinations of edoxaban with imatinib (with severe renal failure leading to edoxaban discontinuation) and rivaroxaban with nilotinib (with moderate renal failure leading to rivaroxaban dose reduction).

Five identified case reports (n_{(total cases)}= 8) did not identify any bleeding events with the combinations of apixaban with dasatinib or imatinib (n= 2), warfarin with nilotinib or dasatinib (n= 1), therapeutic heparin with imatinib (n= 1), and imatinib with the combination of rivaroxaban with ticagrelor (n= 1). One study reported worsening of disseminated intravascular coagulation with the combination of imatinib and prophylactic danaparoid in a patient in blast phase of CML that resolved with tranexamic acid, therapeutic heparin, and chemotherapy. Another case reported minor bleeding after dental extraction in a patient on ponatinib with therapeutic enoxaparin. The last study reported significant pulmonary hemorrhage with the combination of bosutinib and warfarin; however, the patient had other significant drug interactions for both medications that may have confounded the findings. Indications for anticoagulation included atrial fibrillation (n= 2), thrombosis treatment (n= 7), and prophylaxis (n= 2). No new thrombotic events were reported in any of these studies. The pharmacokinetic studies on healthy subjects reported no interactions between bosutinib and dabigatran (n= 1) and conflicting results between the two studies on the combination of nilotinib and warfarin.

Conclusion

This is the first systematic review that addresses a critical gap in the literature by systematically evaluating the safety profiles of various TKIs in combination with different anticoagulants. The findings from cohort studies highlighted the feasibility of concomitant use of anticoagulants and TKIs in CML patients, with close monitoring of potential adverse events and drug interactions.

No relevant conflicts of interest to declare.