CO-RELATION OF P-GLYCOPROTEIN AND PLASMA IMATINIB IN IMATINIB RESPONDERS AND NON-RESPONDERS PATIENTS WITH CHRONIC MYELOID LEUKAEMIA

LOKESH BAGARI NAGAPPA; ASHWATHY VARADARAJAN THUNDAKATTIL

doi:10.22159/ijap.2023v15i6.48819

Authors

LOKESH BAGARI NAGAPPA Department of Pharmacology, All India Institute of Medical Sciences, New Delhi-110608, India https://orcid.org/0000-0002-5756-3715
ASHWATHY VARADARAJAN THUNDAKATTIL Faculty of Medicine, Manipal University College Malaysia-75150 Melaka, Malaysia https://orcid.org/0000-0002-4212-1244

DOI:

https://doi.org/10.22159/ijap.2023v15i6.48819

Keywords:

Imatinib resistance, CML, Plasma trough levels, P-glycoprotein

Abstract

Objective: To measure and compare P-glycoprotein (P-gp) expressions in imatinib responders and non-responders with chronic myeloid leukemia-chronic phase (CML-CP) and correlate with plasma imatinib levels.

Methods: Patients were classified into two groups based on their haematological and cytogenetic responses to imatinib: responders and non-responders. Liquid chromatography-mass spectrometry was used to measure plasma imatinib levels, while flow cytometry was used to evaluate leucocyte P-gp expression.

Results: The median plasma imatinib trough levels in non-responders were 496 (217-3150) ng/ml compared to 2245 (454-4270) ng/ml in the responders, which was statistically significant (p=0.0003). The proportion of patients expressing P-gp in granulocytes was higher in the non-responder group than in the responder group (75% vs. 62.5%). The ratio of mean fluorescence intensity (RFI) revealed that non-responders had higher median P-gp expression than did respondents MFI (1.16(1.06-1.50) and 1.12(1.01-1.38), respectively; p = 0. 2307). In both groups, there was a negative correlation between P-gp expression and plasma imatinib trough levels (-0.4384 vs.-0.2848).

Conclusion: Imatinib median plasma trough levels in non-responders were considerably lower. This was highly supported by P-gp expression in granulocytes, which is inversely related to imatinib plasma trough levels; however, the difference was not statistically significant, which could be attributed to the small number of patients. This could be the cause of imatinib resistance in non-responder CML-CP patients, and P-gp levels should be evaluated to optimize treatment in patients who do not achieve hematologic or cytogenetic response.

Downloads

Download data is not yet available.

References

Cortes J, Pavlovsky C, Saußele S. Chronic myeloid leukaemia. Lancet. 2021;398(10314):1914-26. doi: 10.1016/S0140-6736(21)01204-6, PMID 34425075.

Baykal Kose S, Acikgoz E, Yavuz AS, Gonul Geyik O, Ateş H, Sezerman OU. Adaptive phenotypic modulations lead to therapy resistance in chronic myeloid leukemia cells. Plos One. 2020;15(2):e0229104. doi: 10.1371/journal.pone.0229104, PMID 32106243, PMCID PMC7046262.

Darji AA, Bharadia PD. Chronic myelogenous leukemia: a review and update of current and future therapy. Int J Pharm Pharm Sci. 2016;8:35-46.

Deininger MW, Shah NP, Altman JK, Berman E, Bhatia R, Bhatnagar B. Chronic myeloid leukemia. Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. 2020;18(10):1385-415. doi: 10.6004/jnccn.2020.0047, PMID 33022644.

Braun TP, Eide CA, Druker BJ. Response and resistance to BCR-ABL1-targeted therapies. Cancer Cell. 2020;37(4):530-42. doi: 10.1016/j.ccell.2020.03.006. PMID 32289275, PMCID PMC7722523.

Alves R, Gonçalves AC, Rutella S, Almeida AM, De Las Rivas J, Trougakos IP. Resistance to tyrosine kinase inhibitors in chronic myeloid leukemia-from molecular mechanisms to clinical relevance. Cancers (Basel). 2021;13(19):4820. doi: 10.3390/cancers13194820, PMID 34638304, PMCID PMC8508378.

Maia RC, Vasconcelos FC, Souza PS, Rumjanek VM. Towards comprehension of the ABCB1/P-glycoprotein role in chronic myeloid leukemia. Molecules. 2018;23(1):119. doi: 10.3390/molecules23010119, PMID 29316665, PMCID PMC6017716.

Ammar M, Louati N, Frikha I, Medhaffar M, Ghozzi H, Elloumi M. Overexpression of P-glycoprotein and resistance to imatinib in chronic myeloid leukemia patients. J Clin Lab Anal. 2020;34(9):e23374. doi: 10.1002/jcla.23374, PMID 32715517, PMCID PMC7521244.

Hoemberger M, Pitsawong W, Kern D. Cumulative mechanism of several major imatinib-resistant mutations in Abl kinase. Proc Natl Acad Sci USA. 2020;117(32):19221-7. doi: 10.1073/pnas.1919221117, PMID 32719139, PMCID PMC7431045.

Peng XX, Tiwari AK, Wu HC, Chen ZS. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells. Chin J Cancer. 2012;31(2):110-8. doi: 10.5732/cjc.011.10327, PMID 22098951, PMCID PMC3777469.

Ferrao PT, Frost MJ, Siah SP, Ashman LK. Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. Blood. 2003;102(13):4499-503. doi: 10.1182/blood-2003-01-0083, PMID 12881321.

Zong Y, Zhou S, Sorrentino BP. Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia. 2005;19(9):1590-6. doi: 10.1038/sj.leu.2403853, PMID 16001089.

Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966-84. doi: 10.1038/s41375-020-0776-2, PMID 32127639, PMCID PMC7214240.

Vasconcelos FC, Cavalcanti GB Jr, Silva KL, de Meis E, Kwee JK, Rumjanek VM. Contrasting features of MDR phenotype in leukemias by using two fluorochromes: implications for clinical practice. Leuk Res. 2007;31(4):445-54. doi: 10.1016/j.leukres.2006.07.016, PMID 16979236.

Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111(8):4022-8. doi: 10.1182/blood-2007-10-116475, PMID 18256322.

Pearce CM, Resmini M. Towards point of care systems for the therapeutic drug monitoring of imatinib. Anal Bioanal Chem. 2020;412(24):5925-33. doi: 10.1007/s00216-020-02545-4, PMID 32166445.

Natarajan H, Kumar L, Bakhshi S, Sharma A, Velpandian T, Kabra M. Imatinib trough levels: a potential biomarker to predict cytogenetic and molecular response in newly diagnosed patients with chronic myeloid leukemia. Leuk Lymphoma. 2019;60(2):418-25. doi: 10.1080/10428194.2018.1485907, PMID 30124353.

You JH, Chen J, Zhou L, Du SH, Lu HY, Sun SJ. Analysis of correlation between plasma trough level and response of generic imatinib in the treatment of Chinese patients with chronic myeloid leukemia. Zhonghua Xue Ye Xue Za Zhi. 2019;40(11):939-42. doi: 10.3760/cma.j.issn.0253-2727.2019.11.010, PMID 31856444, PMCID PMC7342369.

Prado Carrillo O, Arenas Ramirez A, Llaguno Munive M, Jurado R, Perez Rojas J, Cervera Ceballos E. Ketoconazole reverses imatinib resistance in human chronic myelogenous leukemia K562 cells. Int J Mol Sci. 2022;23(14):7715. doi: 10.3390/ijms23147715, PMID 35887063, PMCID PMC9317189.

Giles FJ, Kantarjian HM, Cortes J, Thomas DA, Talpaz M, Manshouri T. Multidrug resistance protein expression in chronic myeloid leukemia: associations and significance. Cancer. 1999 Sep 1;86(5):805-13. doi: 10.1002/(SICI)1097-0142(19990901)86:5<805::AID-CNCR16>3.0.CO;2-E, PMID 10463979.

Vasconcelos FC, Silva KL, Souza PS, Silva LF, Moellmann Coelho A, Klumb CE. Variation of MDR proteins expression and activity levels according to clinical status and evolution of CML patients. Cytometry B Clin Cytom. 2011;80(3):158-66. doi: 10.1002/cyto.b.20580, PMID 21520403.