The Levels of FoxO3a Predict the Failure of Imatinib Mesylate Therapy among Chronic Myeloid Leukemia Patients

Authors

  • Shinta Oktya Wardhani Doctoral Program in Medical Science, Division of Hematology and Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia
  • Hani Susanti Department of Clinical Pathology and Laboratory Medicine, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia
  • Puji Rahayu Department of Otorhinolaryngology, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia
  • Yuyun Yueniwati Department of Radiology, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia
  • Jonny Fajar Department of Internal Medicine, Brawijaya Internal Medicine Research Center, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia https://orcid.org/0000-0002-0309-5813

DOI:

https://doi.org/10.3889/oamjms.2021.5852

Keywords:

FoxO3a, Chronic myeloid leukemia, Treatment response, Treatment failure, Predictors

Abstract

INTRODUCTION: Forkhead Transcription Factor 3a (FoxO3a) has been proposed to have a high efficacy to predict the failure of imatinib mesylate (IM) therapy among Chronic Myeloid Leukemia (CML) patients. However, the limited evidence had made this marker remained controversy.

OBJECTIVES: We aimed to investigate the correlation between the levels of FoxO3a and the risk of treatment failure of IM therapy in CML patients.

METHODS: A prospective cohort study was carried out between February 2019 and February 2020 in Saiful Anwar Hospital, Malang, Indonesia. All CML patients treated with IM on our hospital during the study period were included. The levels of FoxO3a was determined using the Enzyme-linked immunosorbent assay (ELISA) using Cusabio Biotech Kit (Cusabio Biotech Co., New York, USA). The treatment response was assessed using the European Leukemia criteria. The correlation and effect estimate between the levels of FoxO3a and treatment response of CML patients was assessed using multiple logistic regression.

RESULTS: 53 CML patients receiving IM in our hospital were included, consisting of 29 patients with good response and 24 patients with non-response. Our study found that CML patients with lower levels of FoxO3a was associated with increased risk to develop treatment failure when treated with IM. Moreover, we also found that higher risk of treatment failure of IM therapy was also found in patients with increased levels of thrombocytes, basophils, and leukocytes, and lower levels of hemoglobin.

CONCLUSION: We reveal that FoxO3a is the prominent marker to predict the treatment response of CML patients treated with IM.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Flis S, Chojnacki T. Chronic myelogenous leukemia, a still unsolved problem: Pitfalls and new therapeutic possibilities. Drug Des Devel Ther. 2019;13:825-43. https://doi.org/10.2147/dddt.s191303 PMid:30880916

Hoglund M, Sandin F, Simonsson B. Epidemiology of chronic myeloid leukaemia: An update. Ann Hematol. 2015;94 Suppl 2:S241-7. https://doi.org/10.1007/s00277-015-2314-2 PMid:25814090

Granatowicz A, Piatek CI, Moschiano E, El-Hemaidi I, Armitage JD, Akhtari M. An overview and update of chronic myeloid leukemia for primary care physicians. Korean J Fam Med. 2015;36(5):197-202. https://doi.org/10.4082/kjfm.2015.36.5.197 PMid:26435808

Baccarani M, Pileri S, Steegmann JL, Muller M, Soverini S, Dreyling M, et al. Chronic myeloid leukemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23 Suppl 7:vii72-7. https://doi.org/10.1093/annonc/mds228 PMid:22997458

An X, Tiwari AK, Sun Y, Ding PR, Ashby CR Jr., Chen ZS. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review. Leuk Res. 2010;34(10):1255-68. https://doi.org/10.1016/j.leukres.2010.04.016 PMid:20537386

Bitencourt R, Zalcberg I, Louro ID. Imatinib resistance: A review of alternative inhibitors in chronic myeloid leukemia. Rev Bras Hematol Hemoter. 2011;33(6):470-5. https://doi.org/10.5581/1516-8484.20110124 PMid:23049365

Clark RE, Davies A, Pirmohamed M, Giannoudis A. Pharmacologic markers and predictors of responses to imatinib therapy in patients with chronic myeloid leukemia. Leuk Lymphoma. 2008;49(4):639-42. https://doi.org/10.1080/10428190701858823 PMid:18398725

Alonso-Dominguez JM, Casado LF, Anguita E, Gomez- Casares MT, Buño I, Ferrer-Marín F, et al. PTCH1 is a reliable marker for predicting imatinib response in chronic myeloid leukemia patients in chronic phase. PLoS One. 2017;12(7):e0181366. https://doi.org/10.1371/journal.pone.0181366 PMid:28704552

Stefanetti RJ, Voisin S, Russell A, Lamon S. Recent advances in understanding the role of FOXO3. F1000Res. 2018;7:F1000 Faculty Rev-1372. https://doi.org/10.12688/f1000research.15258.1 PMid:30228872

Schmitt-Ney M. The FOXO’s advantages of being a family: Considerations on function and evolution. Cells. 2020;9(3):787. https://doi.org/10.3390/cells9030787 PMid:32214027

Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17(1):104. https://doi.org/10.1186/s12943-018-0856-3 PMid:30045773

Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44(5):479-96. PMid:20370557

Corrado P, Mancini M, Brusa G, Petta S, Martinelli G, Barbieri E, et al. Acetylation of FOXO3a transcription factor in response to imatinib of chronic myeloid leukemia. Leukemia. 2009;23(2):405-6. https://doi.org/10.1038/leu.2008.186 PMid:18685617

Pellicano F, Scott MT, Helgason GV, Hopcroft LE, Allan EK, Aspinall-O’Dea M, et al. The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors. Stem Cells. 2014;32(9):2324-37. https://doi.org/10.1002/stem.1748 PMid:24806995

Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian J Psychol Med. 2013;35(2):121-6. https://doi.org/10.4103/0253-7176.116232 PMid:24049221

Haznedaroglu IC, Kuzu I, Ilhan O. WHO 2016 definition of chronic myeloid leukemia and tyrosine kinase inhibitors. Turk J Haematol. 2020;37(1):42-7. https://doi.org/10.4274/tjh.galenos.2019.2019.0241 PMid:31612694

Kantarjian HM, Larson RA, Guilhot F, O’Brien SG, Mone M, Rudoltz M, et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer. 2009;115(3):551-60. https://doi.org/10.1002/cncr.24066 PMid:19117345

Zhang S, Zhao Y, Xu M, Yu L, Zhao Y, Chen J, et al. FoxO3a modulates hypoxia stress induced oxidative stress and apoptosis in cardiac microvascular endothelial cells. PLoS One. 2013;8(11):e80342. https://doi.org/10.1371/journal.pone.0080342 PMid:24278276

Kalemci S, Edgunlu TG, Turkcu U, Çetin ES, Zeybek A, Candan H. FOXO3a gene polymorphism and serum FOXO3a levels in patients with chronic obstructive pulmonary disease and healthy controls: Effects of genetic polymorphism in chronic obstructive pulmonary disease. Smyrna Med J. 2014;1:1-5. https://doi.org/10.5114/kitp.2014.45682

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

Kim HY. Statistical notes for clinical researchers: Logistic regression. Restor Dent Endod. 2017;42(4):342-8. https://doi.org/10.5395/rde.2017.42.4.342 PMid:29142883

Wagle M, Eiring AM, Wongchenko M, Lu S, Guan Y, Wang Y, et al. A role for FOXO1 in BCR-ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia. Leukemia. 2016;30(7):1493-501. https://doi.org/10.1038/leu.2016.51 PMid:27044711

Komatsu N, Watanabe T, Uchida M, Mori M, Kirito K, Kikuchi S, et al. A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells. J Biol Chem. 2003;278(8):6411-9. https://doi.org/10.1074/jbc.m211562200 PMid:12456669

Essafi A, de Mattos SF, Hassen YA, Soeiro I, Mufti GJ, Thomas NS, et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene. 2005;24(14):2317-29. https://doi.org/10.1038/sj.onc.1208421 PMid:15688014

Yang JY, Hung MC. Deciphering the role of forkhead transcription factors in cancer therapy. Curr Drug Targets. 2011;12(9):1284-90. https://doi.org/10.2174/138945011796150299 PMid:21443462

Qin YZ, Jiang Q, Jiang H, Lai YY, Zhu HH, Liu YR, et al. Combination of white blood cell count at presentation with molecular response at 3 months better predicts deep molecular responses to imatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients. Medicine (Baltimore). 2016;95(2):e2486. https://doi.org/10.1097/md.0000000000002486 PMid:26765457

Assouline S, Lipton JH. Monitoring response and resistance to treatment in chronic myeloid leukemia. Curr Oncol. 2011;18(2):e71-83. https://doi.org/10.3747/co.v18i2.391 PMid:21505592

Cortes J, Quintas-Cardama A, Kantarjian HM. Monitoring molecular response in chronic myeloid leukemia. Cancer. 2011;117(6):1113-22. https://doi.org/10.1002/cncr.25527 PMid:20960522

El-Ghammaz AM, Hamed GM, Fattah MF, Attia MH. Basophil progenitor marker histamine and its relation to the treatment response in Egyptian chronic myeloid leukemia patients. Egypt J Haematol. 2015;40:30. https://doi.org/10.4103/1110-1067.155793

Valent P, Horny HP, Arock M. The underestimated role of basophils in Ph(+) chronic myeloid leukaemia. Eur J Clin Invest. 2018;48(10):e13000. https://doi.org/10.1111/eci.13000 PMid:30019447

Moura MS, Benevides TC, Delamain MT, Duarte GO, Percout PO, Dias MA, et al. Evaluation of anemia after long-term treatment with imatinib in chronic myeloid leukemia patients in chronic phase. Hematol Transfus Cell Ther. 2019;41(4):329-34. https://doi.org/10.1016/j.htct.2019.03.006 PMid:31395459

Jabbour E, le Coutre PD, Cortes J, Giles F, Bhalla KN, Pinilla- Ibarz J, et al. Prediction of outcomes in patients with Ph+ chronic myeloid leukemia in chronic phase treated with nilotinib after imatinib resistance/intolerance. Leukemia. 2013;27(4):907-13. https://doi.org/10.1038/leu.2012.305 PMid:23174881

Kabat GC, Wu JW, Moore SC, Morton LM, Park Y, Hollenbeck AR, et al. Lifestyle and dietary factors in relation to risk of chronic myeloid leukemia in the NIH-AARP diet and health study. Cancer Epidemiol Biomarkers Prev. 2013;22(5):848-54. https://doi.org/10.1158/1055-9965.epi-13-0093 PMid:23625904

Downloads

Published

2021-04-29

How to Cite

1.
Wardhani SO, Susanti H, Rahayu P, Yueniwati Y, Fajar J. The Levels of FoxO3a Predict the Failure of Imatinib Mesylate Therapy among Chronic Myeloid Leukemia Patients. Open Access Maced J Med Sci [Internet]. 2021 Apr. 29 [cited 2021 Dec. 4];9(B):255-9. Available from: https://oamjms.eu/index.php/mjms/article/view/5852

Most read articles by the same author(s)