Pharmacology of tyrosine kinase inhibitors in chronic myeloid leukemia; a clinician’s perspective

Abstract

Objective In this review, we have summarized the pharmacokinetics, pharmacodynamics and adverse effects of imatinib, dasatinib, nilotinib, bosutinib, ponatinib and radotinib with focus on pharmacogenomic studies with clinical end points. We have discussed the key phase 3 trials of tyrosine kinase inhibitors (TKI) comparing with each other, treatment free remission (TFR) and selection of TKI. Upcoming concepts and related trials in the management of chronic myeloid leukemia (CML) along with future directions have been touched upon. Evidence acquisition PubMed, Embase, Google, Cochrane library and Medline were searched to identify relevant literature for the review. Clinicaltrial.gov was searched for upcoming data and trials. Results There are lot of gap in pharmacokinetics and pharmacodynamics of TKI. Imatinib appears to be the safest TKI. Newer TKI's achieve better achievement of therapeutic milestones, deeper molecular response and less chances of progression of CML compared to imatinib. Newer TKI appears to be better choice for achieving TFR. When the objective is survival, imatinib is still the TKI of choice. Primary prophylaxis with antiplatelet drugs for TKI having cardiovascular and thromboembolic side effects should be considered. Conclusion Pharmacogenetic data of TKI is still immature to guide in therapeutic decision making in clinical practice. There is need for further research in pharmacology and pharmacogenomics of newer TKI's. Randomized controlled trials are required to decide the optimum TKI for TFR. Safe and effective TKI for targeting T315I mutation, CML accelerated phase and blast crisis are an active area of research.

Quantitative chemometric phenotyping of three-dimensional liver organoids by Raman spectral imaging

“…Kernel-density probability estimates for unmixed deposit spectra revealed that each detectable xenobiotic exhibited unique drug-biomolecule complexes as determined by the relative abundance of lipid/protein in each voxel ( Figures 4 A–4D). This allowed us to elucidate xenobiotic-cell interactions in 3D iHLC, showing for example that amiodarone (a known lipophilic drug with a long half-life of >60 days 39 ) would faithfully accumulate in lipid-rich subcellular voxels, while the nilotinib spectra (also being lipophilic but having a considerably shorter half-life of 17 h 46 ) would be detected in protein-rich voxels, indicating metabolic processing. Neratinib spectra, in contrast, accumulated in voxels that are neither protein nor lipid rich.…”

State-transition Modeling of Blood Transcriptome Predicts Disease Evolution and Treatment Response in Chronic Myeloid Leukemia

“…?, reduced the effect of the treatment force. 37 The treatment force for TKI system, , and , were defined as the following, In the model, the transition from normal potential to CML potential was approximated using three critical points using c 1 , c 2 and c 5 as ∇ U p-CML = a ( x – c 1 )( x – c 2 )( x – c 5 ), and…”

A customized mass array panel for BCR::ABL1 tyrosine kinase domain mutation screening in chronic myeloid leukemia

“…Meanwhile, BCR::ABL1-independent mechanisms, including BCR :: ABL1 amplification and clonal evolution of CML clones, have been reported in CML with TKI resistance, albeit at lower frequencies [18] , [19] , [20] . BCR::ABL1-independent mechanisms can also consist of the impairment of specific TKI transporters (influx and efflux transporters), an inappropriate concentration of TKIs, dysregulation of alternative signaling pathways of CML cells, and epigenetics [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] . Recently, there has been evidence indicating that mutations in genes involved in the tumorigenesis of myeloid leukemia, such as DNMT3A and ASXL1 , IDH1 , and SETBP1, are associated with the resistance to TKIs therapy in CML without BCR :: ABL1 kinase domain mutations [29] , [30] .…”