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Plasma imatinib levels and ABCB1 polymorphism influences early molecular response and failure-free survival in newly diagnosed chronic phase CML patients
Scientific Reports ( IF 3.8 ) Pub Date : 2020-11-26 , DOI: 10.1038/s41598-020-77140-9
Bharathi M Rajamani 1 , Esther Sathya Bama Benjamin 1 , Aby Abraham 1 , Sukanya Ganesan 1 , Kavitha M Lakshmi 1 , Senthamizhselvi Anandan 1 , Sreeja Karathedath 1 , Savitha Varatharajan 1 , Ezhilpavai Mohanan 1 , Nancy Beryl Janet 1 , Vivi M Srivastava 1 , Shaji Ramachandran Velayudhan 1 , Uday P Kulkarni 1 , Anup J Devasia 1 , N A Fouzia 1 , Anu Korula 1 , Biju George 1 , Alok Srivastava 1 , Vikram Mathews 1 , Poonkuzhali Balasubramanian 1
Affiliation  

Achieving early molecular response (EMR) has been shown to be associated with better event free survival in patients with chronic phase chronic myeloid leukemia (CP-CML) on Imatinib therapy. We prospectively evaluated the factors influencing the 2-year failure free survival (FFS) and EMR to imatinib therapy in these patients including day29 plasma Imatinib levels, genetic variants and the gene expression of target genes in imatinib transport and biotransformation. Patients with low and intermediate Sokal score had better 2-year FFS compared to those with high Sokal Score (p = 0.02). Patients carrying ABCB1-C1236T variants had high day29 plasma imatinib levels (P = 0.005), increased EMR at 3 months (P = 0.044) and a better 2 year FFS (P = 0.003) when compared to those with wild type genotype. This translates to patients with lower ABCB1 mRNA expression having a significantly higher intracellular imatinib levels (P = 0.029). Higher day29 plasma imatinib levels was found to be strongly associated with patients achieving EMR at 3 months (P = 0.022), MMR at 12 months (P = 0.041) which essentially resulted in better 2-year FFS (p = 0.05). Also, patients who achieved EMR at 3 months, 6 months and MMR at 12 months had better FFS when compared to those who did not. This study suggests the incorporation of these variables in to the imatinib dosing algorithm as predictive biomarkers of response to Imatinib therapy.



中文翻译:

血浆伊马替尼水平和ABCB1多态性影响新诊断的慢性期CML患者的早期分子反应和无衰竭生存

在伊马替尼治疗的慢性期慢性粒细胞白血病(CP-CML)患者中,实现早期分子应答(EMR)与更好的无事件生存率相关。我们前瞻性地评估了影响伊马替尼治疗2年无失败生存期(FFS)和EMR的因素,包括伊马替尼第29天血浆伊马替尼水平,遗传变异以及伊马替尼转运和生物转化中靶基因的基因表达。与Sokal评分较高的患者相比,Sokal评分较低和中等的患者具有更好的2年FFS(p = 0.02)。与野生型基因型患者相比,携带ABCB1-C1236T变体的患者29天血浆伊马替尼水平较高(P = 0.005),3个月时EMR升高(P = 0.044)和2年FFS较好(P = 0.003)。这转化为具有较低细胞内伊马替尼水平的ABCB1 mRNA表达较低的患者(P = 0.029)。发现较高的一天29血浆伊马替尼水平与3个月达到EMR(P = 0.022),12个月MMR(P = 0.041)的患者密切相关,这实质上导致2年FFS更好(p = 0.05)。此外,与未获得EMR的患者相比,在3个月,6个月获得EMR和12个月获得MMR的患者的FFS更好。这项研究建议将这些变量纳入伊马替尼给药算法中,作为对伊马替尼治疗反应的预测性生物标志物。041),这实际上导致了更好的2年FFS(p = 0.05)。此外,与未获得EMR的患者相比,在3个月,6个月获得EMR和12个月获得MMR的患者的FFS更好。这项研究建议将这些变量纳入伊马替尼给药算法中,作为对伊马替尼治疗反应的预测性生物标志物。041),这实际上导致了更好的2年FFS(p = 0.05)。此外,与未获得EMR的患者相比,在3个月,6个月获得EMR和12个月获得MMR的患者的FFS更好。这项研究表明将这些变量纳入伊马替尼给药算法中,作为对伊马替尼治疗反应的预测性生物标志物。

更新日期:2020-11-27
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