Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Department of Biostatistics and Clinical Research Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Clin Cancer Res. 2021 Jul 1;27(13):3683-3694. doi: 10.1158/1078-0432.CCR-20-4375. Epub 2021 Apr 23.
The current stratification system for acute promyelocytic leukemia (APL) is based on the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. However, the borderlines among different risk groups are sometimes ambiguous, and for some patients, early death and relapse remained challenges. Besides, with the evolving of the treatment strategy from all-trans-retinoic acid (ATRA) and chemotherapy to ATRA-arsenic trioxide-based synergistic targeted therapy, the precise risk stratification with molecular markers is needed.
This study performed a systematic analysis of APL genomics and transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial (NCT01987297) to illustrate the potential molecular background of Sanz score and further optimize it. The least absolute shrinkage and selection operator algorithm was used to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score).
Through combining mutations, APL9 score, and WBC, 321 cases can be stratified into two groups with significantly different outcomes. The estimated 5-year overall ( = 0.00031), event-free ( < 0.0001), and disease-free ( = 0.001) survival rates in the revised standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be validated using The Cancer Genome Atlas dataset.
We have proposed a two-category system for improving prognosis in patients with APL. Molecular markers identified in this study may also provide genomic insights into the disease mechanism for improved therapy.
过去二十年来，急性早幼粒细胞白血病（APL）的分层系统基于白细胞（WBC）和血小板计数（即 Sanz 评分）。然而，不同风险组之间的界限有时并不明确，对于某些患者，早期死亡和复发仍然是挑战。此外，随着治疗策略从全反式维甲酸（ATRA）和化疗发展到 ATRA-三氧化二砷联合靶向治疗，需要用分子标志物进行精确的风险分层。
本研究对 APL 的基因组和转录组进行了系统分析，以确定 348 名患者（主要来自 APL2012 试验（NCT01987297））的遗传异常，以说明 Sanz 评分的潜在分子背景，并进一步对其进行优化。最小绝对收缩和选择算子算法用于分析 323 例病例的基因表达，以建立评分系统（即 APL9 评分）。
通过结合突变、APL9 评分和 WBC，可将 321 例病例分为两组，两组的预后有显著差异。修订后的标准风险组（95.6%、93.8%和 98.1%）的估计 5 年总生存率（ = 0.00031）、无事件生存率（ < 0.0001）和无疾病生存率（ = 0.001）显著优于修订后的高危组（82.9%、77.4%和 88.4%），该结果可以使用癌症基因组图谱数据集进行验证。
我们提出了一种用于改善 APL 患者预后的两分类系统。本研究中鉴定的分子标志物也可能为疾病机制提供基因组见解，以改善治疗效果。
