Ardestani Majid Teremmahi, Kazemi Ahmad, Chahardouli Bahram, Mohammadi Saeed, Nikbakht Mohsen, Rostami Shahrbano, Jalili Mahdi, Vaezi Mohammad, Alimoghaddam Kamran, Ghavamzadeh Ardeshir
Iran University of Medical Sciences, School of Allied Medical Sciences, Department of Hematology, Tehran, Iran
Tehran University of Medical Sciences, Cell Therapy and Hematopoietic Stem Cell Transplantation Research Center; Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran, Iran
Turk J Haematol. 2018 Aug 3;35(3):158-167. doi: 10.4274/tjh.2018.0017. Epub 2018 May 22.
This study aimed to evaluate DNMT3A exon 23 mutations and their prognostic impacts in the presence of NPM1 and FLT3 mutations in acute myeloid leukemia (AML) patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT).
This study comprised 128 adult AML patients referred to the Hematology-Oncology and Stem Cell Research Center of Shariati Hospital. NPM1 and FLT3-ITD mutations were detected by fragment analysis. For DNMT3A exon 23 mutation analysis, we used Sanger sequencing. Overall survival (OS) and relapse-free survival (RFS) curves were estimated by the Kaplan-Meier method and the log-rank test was used to calculate differences between groups.
The prevalence of DNMT3A exon 23 mutations was 15.6% and hotspot region R882 mutations were prominent. RFS and OS were compared in patients with and without DNMT3A exon 23 mutations using univariate analysis and there was no significant difference between these groups of patients. On the contrary, the FLT3-ITD mutation significantly reduced the OS (p=0.009) and RFS (p=0.006) in AML patients after allogeneic HSCT. In the next step, patients with AML were divided into four groups regarding FLT3-ITD and DNMT3A mutations. Patients with DNMT3A R882mut/FLT3-ITDpos had the worst OS and RFS. These results indicate that DNMT3A mutations alone do not affect the clinical outcomes of AML patients undergoing allogeneic HSCT, but when accompanied by FLT3-ITD mutations, the OS was significantly reduced (5-year OS 0% for DNMT3A R882mut/FLT3-ITDpos patients vs. 62% DNMT3A R882wt/FLT3-ITDneg, p=0.025) and the relapse rate increased.
It can be deduced that DNMT3A R882mut/FLT3-ITDpos is an unfavorable prognostic factor in AML patients even after allogeneic HSCT.
本研究旨在评估接受异基因造血干细胞移植（HSCT）的急性髓系白血病（AML）患者中，DNMT3A外显子23突变及其在存在NPM1和FLT3突变情况下的预后影响。
本研究纳入了128例转诊至沙里亚蒂医院血液肿瘤与干细胞研究中心的成年AML患者。通过片段分析检测NPM1和FLT3-ITD突变。对于DNMT3A外显子23突变分析，我们使用了桑格测序法。采用Kaplan-Meier法估计总生存期（OS）和无复发生存期（RFS）曲线，并使用对数秩检验计算组间差异。
DNMT3A外显子23突变的发生率为15.6%，热点区域R882突变较为突出。使用单因素分析比较有和无DNMT3A外显子23突变患者的RFS和OS，这些患者组之间无显著差异。相反，FLT3-ITD突变显著降低了异基因HSCT后AML患者的OS（p=0.009）和RFS（p=0.006）。下一步，根据FLT3-ITD和DNMT3A突变将AML患者分为四组。DNMT3A R882mut/FLT3-ITDpos患者的OS和RFS最差。这些结果表明，单独的DNMT3A突变不影响接受异基因HSCT的AML患者的临床结局，但当伴有FLT3-ITD突变时，OS显著降低（DNMT3A R882mut/FLT3-ITDpos患者的5年OS为0%，而DNMT3A R882wt/FLT3-ITDneg患者为62%，p=0.025）且复发率增加。
可以推断，即使在异基因HSCT后，DNMT3A R882mut/FLT3-ITDpos也是AML患者的不良预后因素。
