Matsuo Hidemasa, Yoshida Kenichi, Nakatani Kana, Harata Yutarou, Higashitani Moe, Ito Yuri, Kamikubo Yasuhiko, Shiozawa Yusuke, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Okada Ai, Nannya Yasuhito, Takeda June, Ueno Hiroo, Kiyokawa Nobutaka, Tomizawa Daisuke, Taga Takashi, Tawa Akio, Miyano Satoru, Meggendorfer Manja, Haferlach Claudia, Ogawa Seishi, Adachi Souichi
Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
Blood Adv. 2020 Oct 13;4(19):4623-4631. doi: 10.1182/bloodadvances.2020002457.
Mixed-lineage leukemia (MLL) gene rearrangements are among the most frequent chromosomal abnormalities in acute myeloid leukemia (AML). MLL fusion patterns are associated with the patient's prognosis; however, their relationship with driver mutations is unclear. We conducted sequence analyses of 338 genes in pediatric patients with MLL-rearranged (MLL-r) AML (n = 56; JPLSG AML-05 study) alongside data from the TARGET study's pediatric cohorts with MLL-r AML (n = 104), non-MLL-r AML (n = 581), and adult MLL-r AML (n = 81). KRAS mutations were most frequent in pediatric patients with high-risk MLL fusions (MLL-MLLLT10, MLL-MLLT4, and MLL-MLLT1). Pediatric patients with MLL-r AML (n = 160) and a KRAS mutation (KRAS-MT) had a significantly worse prognosis than those without a KRAS mutation (KRAS-WT) (5-year event-free survival [EFS]: 51.8% vs 18.3%, P < .0001; 5-year overall survival [OS]: 67.3% vs 44.3%, P = .003). The adverse prognostic impact of KRAS mutations was confirmed in adult MLL-r AML. KRAS mutations were associated with adverse prognoses in pediatric patients with both high-risk (MLLT10+MLLT4+MLLT1; n = 60) and intermediate-to-low-risk (MLLT3+ELL+others; n = 100) MLL fusions. The prognosis did not differ significantly between patients with non-MLL-r AML with KRAS-WT or KRAS-MT. Multivariate analysis showed the presence of a KRAS mutation to be an independent prognostic factor for EFS (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.35-3.59; P = .002) and OS (HR, 1.85; 95% CI, 1.01-3.31; P = .045) in MLL-r AML. The mutation is a distinct adverse prognostic factor in MLL-r AML, regardless of risk subgroup, and is potentially useful for accurate treatment stratification. This trial was registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry (UMIN-CTR; http://www.umin.ac.jp/ctr/index.htm) as #UMIN000000511.
混合谱系白血病（MLL）基因重排是急性髓系白血病（AML）中最常见的染色体异常之一。MLL融合模式与患者预后相关；然而，它们与驱动突变的关系尚不清楚。我们对MLL重排（MLL-r）AML的儿科患者（n = 56；JPLSG AML-05研究）中的338个基因进行了序列分析，并结合了TARGET研究中MLL-r AML的儿科队列（n = 104）、非MLL-r AML（n = 581）和成人MLL-r AML（n = 81）的数据。KRAS突变在具有高危MLL融合（MLL-MLLLT10、MLL-MLLT4和MLL-MLLT1）的儿科患者中最为常见。患有MLL-r AML（n = 160）且有KRAS突变（KRAS-MT）的儿科患者的预后明显比没有KRAS突变（KRAS-WT）的患者差（5年无事件生存率[EFS]：51.8%对18.3%，P <.0001；5年总生存率[OS]：67.3%对44.3%，P =.003）。KRAS突变对成人MLL-r AML预后的不良影响得到了证实。KRAS突变与具有高危（MLLT10+MLLT4+MLLT1；n = 60）和中低危（MLLT3+ELL+其他；n = 100）MLL融合的儿科患者的不良预后相关。KRAS-WT或KRAS-MT的非MLL-r AML患者的预后没有显著差异。多变量分析显示，KRAS突变的存在是MLL-r AML患者EFS（风险比[HR]，2.21；95%置信区间[CI]，1.35 - 3.59；P =.002）和OS（HR，1.85；95%CI，1.01 - 3.31；P =.045）的独立预后因素。该突变是MLL-r AML中一个明显的不良预后因素，无论风险亚组如何，并且可能有助于准确的治疗分层。该试验已在UMIN（大学医院医学信息网络）临床试验注册中心（UMIN-CTR；http://www.umin.ac.jp/ctr/index.htm）注册，注册号为#UMIN000000511。
