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.

Rianto Setiabudy,Sri Widia Jusman,Alida Harahap,Ikhwan Rinaldi,Septelia Inawati Wanandi,Ary Harryanto Reksodiputro,Catharina Suharti,Karmel Tambunan

doi:10.31557/apjcp.2019.20.12.3689

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.

Highlights

Chronic myeloid leukemia (CML) is a myeloproliferative disorder marked by leukocytosis and the presence of myeloblast in various stages in the peripheral blood due to persistent activation of BCR-ABL gene, which encodes proteins involved in activation of tyrosine kinase transduction pathway (Hochhaus et al, 2009; Rao et al.,2010; Radich et al, 2016; Druker et al, 2001)
This study aimed to identify the association between duration of HU administration prior to imatinib mesylate (IM) treatment and major molecular response (MMR) achievement in chronic-phase CML while evaluating the role of MDA, HIF-1α and P-gp
Administration of HU for more than 6 months prior to IM was associated with unsuccessful MMR achievement in chronic-phase CML

Summary

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative disorder marked by leukocytosis and the presence of myeloblast in various stages in the peripheral blood due to persistent activation of BCR-ABL gene, which encodes proteins involved in activation of tyrosine kinase transduction pathway (Hochhaus et al, 2009; Rao et al.,2010; Radich et al, 2016; Druker et al, 2001). ROS production is induced by BCR-ABL protein through PI3K/AKT/mTOR pathway (Sattler et al, 2000; Kim et al, 2005). ROS restricts HIF-1α degradation which is part of hypoxia inducible factor-1 (HIF-1) These increase expression of HIF-1α dan HIF-1 which induce MDR1 gene to overly express P-glycoprotein (P-gp), an efflux protein that can reduce (IM) effectivity (Semenza, 2001; Nagy, 2011; Ullah, 2008). In vitro study by Mahon et al, (2003) shown that overexpression of P-gp reduced imatinib efficacy in cells with BCR-ABL positive. This study aimed to know the association between duration of HU administration prior to IM treatment and MMR achievement in chronic-phase CML, as well as role the of ROS, HIF-1α and P-gp in the process. ROS was represented by the level of malondialdehyde (MDA) as the result of ROS reaction with lipid inside cells (Sattler et al, 2000; Kim et al, 2005)

Materials and Methods

Results

Discussion