Longer Hydroxyurea Administration Prior to Imatinib Mesylate is Risk Factor for Unsuccessful Major Molecular Response in Chronic-Phase Chronic Myeloid Leukemia: Possibility of P-Glycoprotein Role

Abstract

Objective: This study aimed to identify the association between duration of HU administration prior to IM treatment and MMR achievement in chronic-phase CML while evaluating the role of MDA, HIF-1α and P-gp. Methods: The study was conducted at Dr. Cipto Mangunkusumo National General Hospital and Dharmais Cancer Hospital, Jakarta using retrospective cohort design to analyse the association between the duration of HU before IM and its MMR achievement and cross-sectional design to analyse the association between MDA, HIF-1α and P-gp expressions with MMR achievement. Main subjects were chronic-phase CML patients treated by HU prior to IM for ≥ 12 months and HU only. The subjects were divided into four main groups: (1) chronic-phase CML patients treated with HU ≤ 6 months + IM ≥ 12 months and (2) HU > 6 months + IM ≥ 12 months (3) HU only (≤ 6 months), (4) HU only ( >6 months). Subjects were obtained from January 2015 to May 2016. Data were gathered through history taking, physical examination, medical record evaluation, and blood sample analysis. Bivariate analysis was conducted using chi square, independent T-test, and Mann-Whitney according to the variables. Results: Administration of HU for more than 6 months prior to IM was associated with unsuccessful MMR achievement (RR 1.60; 95%CI 1.29-2.00). MDA level, HIF-1α, P-glycoprotein expression were not associated with MMR achievement but the mean MDA level (0.63±0.31 vs 0.75±0.41 p=0.461) and median P-glycoprotein expressions {16,92 (0,04 -43,86) vs. 5,15 (0,02-39,64); p=0.311} were found to be higher in patients receiving HU for > 6 months group than in HU ≤ 6 months group consecutively. Conclusion: Administration of HU for more than 6 months prior to IM was associated with unsuccessful MMR achievement in chronic-phase CML. The study suggested that P-glycoprotein overexpression as the predictor for unsuccessful MMR achievement.

High STAT5A Expression is Associated with Major Molecular Response Achievement Failure of Chronic Phase Chronic Myeloid Leukemia Patients Receiving Hydroxyurea before Imatinib: A Cross-sectional Study

“…In the univariate analysis, longer hydroxyurea (>6 months) administration was associated with MMR achievement failure (prevalence ratio: 1.403; 95% CI: 1.156-1.704; p = 0.012) and longer IM (>24 months) administration was associated with successful MMR achievement (prevalence ratio: 0.724; 95% CI: 0.544-0.964; p = 0.022), as shown in Table 3. This result is inherent with previous study that showed hydroxyurea more than 6 months which was associated with MMR achievement failure as well [6].…”

“…Previously, we have conducted analysis of P-glycoprotein expressions, malondialdehyde, and hypoxia-inducible factor 1-alpha concentrations with MMR achievement in chronic CML patients who were previously given hydroxyurea [6]. Although the study showed the lack of association between those three markers with MMR achievement, the study revealed that long-term use of hydroxyurea before IM for at least 6 months can influence MMR achievement failure through IM resistance [6].…”

“…This study is a cross-sectional study that analyzed whole blood samples obtained from previous study [6]. Patients were categorized as either achieved the MMR and did not achieve the MMR.…”

“…In 1996, imatinib mesylate (IM) was discovered as the first tyrosine kinase inhibitor (TKI) and then become the first-line therapy for CML [5]. In Indonesia, IM is used for CML patients who were previously given hydroxyurea both less and more than 6 months [6].…”

“…Previously, we have conducted analysis of P-glycoprotein expressions, malondialdehyde, and hypoxia-inducible factor 1-alpha concentrations with MMR achievement in chronic CML patients who were previously given hydroxyurea [6]. Although the study showed the lack of association between those three markers with MMR achievement, the study revealed that long-term use of hydroxyurea before IM for at least 6 months can influence MMR achievement failure through IM resistance [6]. According to a study by Warsch et al, STAT5 activation protects leukemic cells from TKIs but does not prevent cytotoxicity effect from hydroxyurea treatment which may suggest potential different pathways of hydroxyurea-induced MMR achievement failure [11].…”