Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma.
Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma.
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DOI：
10.3324/haematol.2021.280352
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发表时间：
2022-10-01
期刊：
影响因子：
10.1
通讯作者：
Ishida, Takashi
中科院分区：
文献类型：
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作者：
Tanaka, Norio;Mori, Seiichi;Kiyotani, Kazuma;Ota, Yuki;Gotoh, Osamu;Kusumoto, Shigeru;Nakano, Nobuaki;Suehiro, Youko;Ito, Asahi;Choi, Ilseung;Ohtsuka, Eiichi;Hidaka, Michihiro;Nosaka, Kisato;Yoshimitsu, Makoto;Imaizumi, Yoshitaka;Iida, Shinsuke;Utsunomiya, Atae;Noda, Tetsuo;Nishikawa, Hiroyoshi;Ueda, Ryuzo;Ishida, Takashi
为了寻找反映莫伽珠单抗治疗效果的基因组标志物，对莫伽珠单抗初治患者进行了成人T细胞白血病/淋巴瘤的分子综合分析。在驱动基因中，CCR4和CCR7分别有22%和11%的患者发生改变，均由C末端的单核苷酸变异(SNV)/插入-缺失(INDELs)组成。有CCR4改变和无CCR7改变的患者临床疗效较好(完全缓解率93%，13/14；P=0.024；CR率71%，40/56；P=0.036)。此外，在35%、16%和10%的患者中发现了TP53、CD28和CD274的改变。TP53改变包括SNV/Indels或拷贝数变异(CNV)，如纯合缺失；CD28改变包括SNV、CNV，如扩增或融合；CD274改变包括CNV，如扩增，或结构变异。单因素分析显示，Tp5 3、CD2 8或CD2 74基因突变与总生存率(OS)相关(危险比[HR]：2.330，95%可信区间[CI]：1.183~4.589；HR：3.191，95%CI：1.287~7.911；HR：3.301，95%CI：1.130~9.641)，但CCR4基因突变与OS改善相关(HR：0.286，95%CI：0.087~0.933)。多因素分析显示，除表现状态外，TP53、CCR4或CD274的改变(HR：2.467，95%CI：1.197~5.085；HR：0.155，95%CI：0.031~0.778；HR：14.393，95%CI：2.437~85.005)与OS独立显著相关。本研究有助于在ATL患者中应用莫伽慕珠单抗建立精确医学。
In order to identify genomic biomarkers for the outcome of mogamulizumab-containing treatment, an integrated molecular analysis of adult T-cell leukemia/lymphoma (ATL) was conducted on 64 mogamulizumab-naïve patients. Among driver genes, CCR4 and CCR7 alterations were observed in 22% and 11% of the patients, respectively, both consisting of single nucleotide variants (SNV)/insertion-deletions (indels) in the C-terminus. Patients with CCR4 alterations or without CCR7 alterations exhibited a more favorable clinical response (complete response [CR] rate 93%, 13/14; P=0.024, and CR rate 71%, 40/56; P=0.036, respectively). Additionally, TP53, CD28, and CD274 alterations were identified in 35%, 16%, and 10% of the patients, respectively. TP53 alterations included SNV/indels or copy number variations (CNV) such as homozygous deletion; CD28 alterations included SNV, CNV such as amplification, or fusion; CD274 alterations included CNV such as amplification, or structural variants. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS) (hazard ratio [HR]: 2.330, 95% confidence interval [CI]: 1.183-4.589; HR: 3.191, 95% CI: 1.287-7.911; HR: 3.301, 95% CI: 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR: 0.286, 95% CI: 0.087-0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR: 2.467, 95% CI: 1.197-5.085; HR: 0.155, 95% CI: 0.031-0.778; HR: 14.393, 95% CI: 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients.
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45.3
作者：
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Gensini GF