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.

Background: The gene FOXO3a has been elucidated to govern the development of chronic granulocytic leukemia (CGL). Moreover, it has been suggested that the levels of FOXO3a in circulation are affected by the FOXO3a rs4946936 gene polymorphism. However, no study has assessed the correlation between the FOXO3a rs4946936 gene polymorphism and the levels of FOXO3a. The objective of this study was to assess the association between the FOXO3a rs4946936 gene polymorphism and the levels of FOXO3a in CGL patients treated with imatinib mesylate.  Methods: A cross-sectional study was conducted from February 2019 to February 2020. The genotyping of FOXO3a rs4946936 gene polymorphism was conducted using PCR-RFLP, and the levels of FOXO3a were assessed using ELISA. The association between the FOXO3a rs4946936 gene polymorphism and the levels of FOXO3a were assessed using multiple logistic regression.  Results: A total of 60 CGL patients were assessed in our study. Among them, the CC, CT, and TT genotypes of the FOXO3a rs4946936 gene polymorphism were 35.0%, 48.3%, and 16.7% respectively. Our calculation revealed that elevated levels of FOXO3a were found in CGL patients with the CC genotype of the FOXO3a rs4946936 gene polymorphism. While we failed to clarify the association between either the CT or the TT genotype of FOXO3a rs4946936 gene polymorphism and the levels of FOXO3a.  Conclusion: Our study identifies that the CC genotype of the FOXO3a rs4946936 gene polymorphism affects the elevated levels of FOXO3a in CGL patients treated with imatinib mesylate.

Background: The gene FOXO3a has been elucidated to govern the development of chronic granulocytic leukemia (CGL). Moreover, it has been suggested that the levels of FOXO3a in circulation are affected by the FOXO3a rs4946936 gene polymorphism. However, no study has assessed the correlation between the FOXO3a rs4946936 gene polymorphism and the levels of FOXO3a. The objective of this study was to assess the association between the FOXO3a rs4946936 gene polymorphism and the levels of FOXO3a in CGL patients treated with imatinib mesylate.  Methods: A cross-sectional study was conducted from February 2019 to February 2020. The genotyping of FOXO3a rs4946936 gene polymorphism was conducted using PCR-RFLP, and the levels of FOXO3a were assessed using ELISA. The association between the FOXO3a rs4946936 gene polymorphism and the levels of FOXO3a were assessed using multiple logistic regression.  Results: A total of 60 CGL patients were assessed in our study. Among them, the CC, CT, and TT genotypes of the FOXO3a rs4946936 gene polymorphism were 35.0%, 48.3%, and 16.7% respectively. Our calculation revealed that elevated levels of FOXO3a were found in CGL patients with the CC genotype of the FOXO3a rs4946936 gene polymorphism. While we failed to clarify the association between either the CT or the TT genotype of FOXO3a rs4946936 gene polymorphism and the levels of FOXO3a.  Conclusion: Our study identifies that the CC genotype of the FOXO3a rs4946936 gene polymorphism affects the elevated levels of FOXO3a in CGL patients treated with imatinib mesylate.

Genetic factors are known to play a role in the therapeutic response of several diseases, especially malignancy. In the process of apoptosis, Forkhead O transcription factor sub family 3a (Foxo3a) is involved in mitochondria-related and unrelated processes by triggering the expression of death receptor ligands such as Fas ligands, TNF apoptotic ligands and Bcl-xL, bNIP3, Bim from members of the Bcl2 family. In a study using a cell line, Foxo3a inactivation was shown due to a mutation in the FOXO3a gene, and this inactivation was associated with cancer progression. In addition, failure to induce apoptosis so that cancer cells continue to survive and spread is also the cause of failure to achieve a treatment response. This study aims to determine the role of genetic factors in the form of the FOXO3a rs4946936 gene polymorphism in response to imatinib mesylate therapy. This prospective cohort study was conducted at dr. Saiful Anwar General Hospital between February 2019 and February 2021. The method used for sampling was consecutive sampling. This study was approved by the ethic department of dr. Saiful Anwar General Hospital. Regression test were used to observe the effect of the FOXO3a rs 4946936 gene on the therapeutic response. Our results showed that the CC genotype was more common in the treatment response group, while the TT genotype was more common in the non-treated group. The TC genotype FOXO3a rs4946936 had a 6.96 (p=0.004) times risk of not achieving a major molecular response compared to the CC genotype. The TT genotype had a 17 times risk (p=0.003) of not achieving a major molecular response than the CC genotype. FOXO3a rs4946938 gene polymorphism influenced the response to imatinib mesylate therapy in CML patients. The CC genotype was more likely to achieve a therapeutic response than other genotypes and the T-allele was a susceptibility allele not to achieve a major molecular response.

Background: The failure of imatinib therapy in patients with chronic myeloid leukemia (CML) is associated with the presence of leukemic stem cell (LSC), and the altered LSC level was reported to occur earlier in the progression of CML. Objective: To assess the association between the level of LSC and treatment response among CML patients treated with imatinib mesylate. Methods: A cross-sectional study was conducted in Saiful Anwar Hospital. All participants were divided into two groups, response and non-response group. To assess the level of LSC, a flow cytometry was conducted conforming with BD Bioscience. The association and effect estimates were determined using multiple logistic regression. Results and Discussion: A total of 29 response and non-response CML patients treated with imatinib therapy was recruited for our study. After six months imatinib therapy, we found that elevated level of leukocytes, thrombocytes, basophils, and blast cells were associated with treatment failure among CML patients treated with imatinib. Moreover, we also found that LSC level was observed significantly higher in non-response group compared to response group among CML patients treated with imatinib. Conclusion: Our study reveals that elevated level of LSC is considered as an important factor to predict the failure of imatinib therapy among CML patients.