{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:30:04Z","timestamp":1794047404825,"version":"4.8.0"},"reference-count":50,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"10","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>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-na\u00efve 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.<\/jats:p>","DOI":"10.3324\/haematol.2021.280352","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T02:59:30Z","timestamp":1649905170000},"page":"2418-2431","source":"Crossref","is-referenced-by-count":19,"title":["Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia\/lymphoma"],"prefix":"10.3324","volume":"107","author":[{"given":"Norio","family":"Tanaka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiichi","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuma","family":"Kiyotani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Ota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Gotoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Kusumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuaki","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youko","family":"Suehiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asahi","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilseung","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiichi","family":"Ohtsuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michihiro","family":"Hidaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kisato","family":"Nosaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Yoshimitsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Imaizumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Iida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atae","family":"Utsunomiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Noda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyoshi","family":"Nishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuzo","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"40396","doi-asserted-by":"crossref","unstructured":"Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977; 50(3):481-492.","DOI":"10.1182\/blood.V50.3.481.bloodjournal503481"},{"key":"40397","doi-asserted-by":"crossref","unstructured":"Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukemia-lymphoma. A report from the Lymphoma Study Group (1984\u20131987). Br J Haematol. 1991; 79(3):428-437.","DOI":"10.1111\/j.1365-2141.1991.tb08051.x"},{"key":"40398","doi-asserted-by":"crossref","unstructured":"Cook LB, Fuji S, Hermine O. Revised adult T-cell leukemia-lymphoma international consensus meeting report. J Clin Oncol. 2019; 37(8):677-687.","DOI":"10.1200\/JCO.18.00501"},{"key":"40399","doi-asserted-by":"crossref","unstructured":"Utsunomiya A. Progress in allogeneic hematopoietic cell transplantation in adult T-cell leukemia-lymphoma. Front Microbiol. 2019; 10:2235.","DOI":"10.3389\/fmicb.2019.02235"},{"key":"40400","doi-asserted-by":"crossref","unstructured":"Nosaka K, Iwanaga M, Imaizumi Y. Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey. Cancer Sci. 2017; 108(12):2478-2486.","DOI":"10.1111\/cas.13398"},{"key":"40401","unstructured":"Ishida T, Utsunomiya A, Iida S. Clinical significance of CCR4 expression in adult T-cell leukemia\/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res. 2003; 9(10Pt1):3625-3634."},{"key":"40402","doi-asserted-by":"crossref","unstructured":"Ishida T, Iida S, Akatsuka Y. The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-Cell leukemia\/lymphoma. Clin Cancer Res. 2004; 10(22):7529-7539.","DOI":"10.1158\/1078-0432.CCR-04-0983"},{"key":"40403","doi-asserted-by":"crossref","unstructured":"Ishii T, Ishida T, Utsunomiya A. Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia\/lymphoma. Clin Cancer Res. 2010; 16(5):1520-1531.","DOI":"10.1158\/1078-0432.CCR-09-2697"},{"key":"40404","doi-asserted-by":"crossref","unstructured":"Ishida T, Joh T, Uike N. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol. 2012; 30(8):837-842.","DOI":"10.1200\/JCO.2011.37.3472"},{"key":"40405","doi-asserted-by":"crossref","unstructured":"Ishida T, Jo T, Takemoto S. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015; 169(5):672-682.","DOI":"10.1111\/bjh.13338"},{"key":"40406","doi-asserted-by":"crossref","unstructured":"Fuji S, Inoue Y, Utsunomiya A. Pretransplantation anti-CCR4 antibody mogamulizumab against adult T-cell leukemia\/lymphoma is associated with significantly increased risks of severe and corticosteroid-refractory graft-versus-host disease, nonrelapse mortality, and overall mortality. J Clin Oncol. 2016; 34(28):3426-3433.","DOI":"10.1200\/JCO.2016.67.8250"},{"key":"40407","doi-asserted-by":"crossref","unstructured":"Yonekura K, Kusumoto S, Choi I. Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study. Blood Adv. 2020; 4(20):5133-5145.","DOI":"10.1182\/bloodadvances.2020003053"},{"key":"40408","doi-asserted-by":"crossref","unstructured":"Kataoka K, Nagata Y, Kitanaka A. Integrated molecular analysis of adult T cell leukemia\/lymphoma. Nat Genet. 2015; 47(11):1304-1315.","DOI":"10.1038\/ng.3428"},{"key":"40409","doi-asserted-by":"crossref","unstructured":"Tsukasaki K, Hermine O, Bazarbachi A. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J Clin Oncol. 2009; 27(3):453-459.","DOI":"10.1200\/JCO.2008.18.2428"},{"key":"40410","doi-asserted-by":"crossref","unstructured":"Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12:323.","DOI":"10.1186\/1471-2105-12-323"},{"key":"40411","doi-asserted-by":"crossref","unstructured":"Koboldt DC, Zhang Q, Larson DE. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012; 22(3):568-576.","DOI":"10.1101\/gr.129684.111"},{"key":"40412","doi-asserted-by":"crossref","unstructured":"Cibulskis K, Lawrence MS, Carter SL. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013; 31(3):213-219.","DOI":"10.1038\/nbt.2514"},{"key":"40413","doi-asserted-by":"crossref","unstructured":"McKenna A, Hanna M, Banks E. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-1303.","DOI":"10.1101\/gr.107524.110"},{"key":"40414","doi-asserted-by":"crossref","unstructured":"Patch AM, Christie EL, Etemadmoghadam D. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015; 521(7553):489-494.","DOI":"10.1038\/nature14410"},{"key":"40415","doi-asserted-by":"crossref","unstructured":"Magi A, Tattini L, Cifola I. EXCAVATOR: detecting copy number variants from whole-exome sequencing data. Genome Biol. 2013; 14(19):R120.","DOI":"10.1186\/gb-2013-14-10-r120"},{"key":"40416","doi-asserted-by":"crossref","unstructured":"Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12(4):R41.","DOI":"10.1186\/gb-2011-12-4-r41"},{"key":"40417","doi-asserted-by":"crossref","unstructured":"McPherson A, Hormozdiari F, Zayed A. deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data. PLoS Comput Biol. 2011; 7(5):e1001138.","DOI":"10.1371\/journal.pcbi.1001138"},{"key":"40418","doi-asserted-by":"crossref","unstructured":"Kim D, Salzberg SL. TopHat-Fusion: an algorithm for discovery of novel fusion transcripts. Genome Biol. 2011; 12(8):R72.","DOI":"10.1186\/gb-2011-12-8-r72"},{"key":"40419","doi-asserted-by":"crossref","unstructured":"Kataoka K, Shiraishi Y, Takeda Y. Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature. 2016; 534(7607):402-406.","DOI":"10.1038\/nature18294"},{"key":"40420","doi-asserted-by":"crossref","unstructured":"Szolek A, Schubert B, Mohr C, Sturm M, Feldhahn M, Kohlbacher O. OptiType: precision HLA typing from next-generation sequencing data. Bioinformatics. 2014; 30(23):3310-3316.","DOI":"10.1093\/bioinformatics\/btu548"},{"key":"40421","doi-asserted-by":"crossref","unstructured":"Hayashi S, Yamaguchi R, Mizuno S. ALPHLARD: a Bayesian method for analyzing HLA genes from whole genome sequence data. BMC Genomics. 2018; 19(1):790.","DOI":"10.1186\/s12864-018-5169-9"},{"key":"40422","doi-asserted-by":"crossref","unstructured":"Sachet AS, Rooney MS, Rajasagi M. Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nat Biotechnol. 2015; 33(11):1152-1158.","DOI":"10.1038\/nbt.3344"},{"key":"40423","doi-asserted-by":"crossref","unstructured":"McGranahan N, Rosenthal R, Hiley CT. Allele-specific HLA loss and immune scape in lung cancer evolution. Cell. 2017; 171(6):1259-1271.","DOI":"10.1016\/j.cell.2017.10.001"},{"key":"40424","doi-asserted-by":"crossref","unstructured":"Monti S, Tamayo P, Mesirov J, Golub T. Consensus clustering: a resampling-based method for class discovery and visualization of gene expression microarray data. Machine Learning. 2003; 52:91-118.","DOI":"10.1023\/A:1023949509487"},{"key":"40425","doi-asserted-by":"crossref","unstructured":"Wilkerson MD, Hayes DN. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics. 2010; 26(12):1572-1573.","DOI":"10.1093\/bioinformatics\/btq170"},{"key":"40426","doi-asserted-by":"crossref","unstructured":"Tsukasaki K, Utsunomiya A, Fukuda H. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007; 25(34):5458-5464.","DOI":"10.1200\/JCO.2007.11.9958"},{"key":"40427","doi-asserted-by":"crossref","unstructured":"Sakamoto Y, Ishida T, Masaki A. Clinical significance of CD28 gene-related activating alterations in adult T-cell leukaemia\/lymphoma. Br J Haematol. 2021; 192(2):281-291.","DOI":"10.1111\/bjh.17211"},{"key":"40428","doi-asserted-by":"crossref","unstructured":"Forlenza CJ, Boudreau JE, Zheng J. KIR3DL1 allelic polymorphism and HLA-B epitopes modulate response to anti-GD2 monoclonal antibody in patients with neuroblastoma. J Clin Oncol. 2016; 34(21):2443-2451.","DOI":"10.1200\/JCO.2015.64.9558"},{"key":"40429","doi-asserted-by":"crossref","unstructured":"Wang L, Ni X, Covington KR. Genomic profiling of S\u00e9zary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat Genet. 2015; 47(12):1426-1434.","DOI":"10.1038\/ng.3444"},{"key":"40430","doi-asserted-by":"crossref","unstructured":"Katsuya H, Yamanaka T, Ishitsuka K. Prognostic index for acute- and lymphoma-type adult T-cell leukemia\/lymphoma. J Clin Oncol. 2012; 30(14):1635-1640.","DOI":"10.1200\/JCO.2011.38.2101"},{"key":"40431","doi-asserted-by":"crossref","unstructured":"Kataoka K, Iwanaga M, Yasunaga J. Prognostic relevance of integrated genetic profiling in adult T-cell leukemia\/lymphoma. Blood. 2018; 131(2):215-225.","DOI":"10.1182\/blood-2017-01-761874"},{"key":"40432","doi-asserted-by":"crossref","unstructured":"Sakamoto Y, Ishida T, Masaki A. Clinical significance of TP53 mutations in adult T-cell leukemia\/lymphoma. Br J Haematol. 2021; 195(4):571-584.","DOI":"10.1111\/bjh.17749"},{"key":"40433","doi-asserted-by":"crossref","unstructured":"Nakagawa M, Schmitz R, Xiao W. Gain-of-function CCR4 mutations in adult T cell leukemia\/lymphoma. J Exp Med. 2014; 211(13):2497-2505.","DOI":"10.1084\/jem.20140987"},{"key":"40434","doi-asserted-by":"crossref","unstructured":"Sakamoto Y, Ishida T, Masaki A. CCR4 mutations associated with superior outcome of adult T-cell leukemia\/lymphoma under mogamulizumab treatment. Blood. 2018; 132(7):758-761.","DOI":"10.1182\/blood-2018-02-835991"},{"key":"40435","doi-asserted-by":"crossref","unstructured":"Yesilkanal AE, Johnson GL, Ramos AF, Rosner MR. New strategies for targeting kinase networks in cancer. J Biol Chem. 2021; 297(4):101128.","DOI":"10.1016\/j.jbc.2021.101128"},{"key":"40436","doi-asserted-by":"crossref","unstructured":"Masaki A, Ishida T, Suzuki S. Human T-cell lymphotropic\/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals. Cancer Sci. 2018; 109(8):2383-2390.","DOI":"10.1111\/cas.13654"},{"key":"40437","doi-asserted-by":"crossref","unstructured":"Masaki A, Ishida T, Maeda Y. Prognostic significance of tryptophan catabolism in adult T-cell leukemia\/lymphoma. Clin Cancer Res. 2015; 21(12):2830-2839.","DOI":"10.1158\/1078-0432.CCR-14-2275"},{"key":"40438","doi-asserted-by":"crossref","unstructured":"Nosaka K, Kusumoto S, Nakano N. Clinical significance of the IgG heavy chain repertoire in PBMC of ATL patients receiving mogamulizumab. Br J Haematol. 2022; 196(3):629-638.","DOI":"10.1111\/bjh.17895"},{"key":"40439","doi-asserted-by":"crossref","unstructured":"Ratner L, Waldmann TA, Janakiram M, Brammer JE. Rapid progression of adult T-cell leukemia-lymphoma after PD-1 inhibitor therapy. N Engl J Med. 2018; 378(20):1947-1948.","DOI":"10.1056\/NEJMc1803181"},{"key":"40440","doi-asserted-by":"crossref","unstructured":"Yano H, Ishida T, Inagaki A. Regulatory T-cell function of adult T-cell leukemia\/lymphoma cells. Int J Cancer. 2007; 120(9):2052-2057.","DOI":"10.1002\/ijc.22536"},{"key":"40441","doi-asserted-by":"crossref","unstructured":"Ishida T, Ueda R. Immunopathogenesis of lymphoma: focus on CCR4. Cancer Sci. 2011; 102(1):44-50.","DOI":"10.1111\/j.1349-7006.2010.01767.x"},{"key":"40442","doi-asserted-by":"crossref","unstructured":"Kamada T, Togashi Y, Tay C. PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A. 2019; 116(20):9999-10008.","DOI":"10.1073\/pnas.1822001116"},{"key":"40443","doi-asserted-by":"crossref","unstructured":"Kumagai S, Togashi Y, Kamada T. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol. 2020; 21(11):1346-1358.","DOI":"10.1038\/s41590-020-0769-3"},{"key":"40444","doi-asserted-by":"crossref","unstructured":"Hatjiharissi E, Xu L, Santos DD. Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V\/V and V\/F polymorphism. Blood. 2007; 110(7):2561-2564.","DOI":"10.1182\/blood-2007-01-070656"},{"key":"40445","doi-asserted-by":"crossref","unstructured":"Niwa R, Hatanaka S, Shoji-Hosaka E. Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 Is independent of Fc\u03b3RIIIa functional polymorphism. Clin Cancer Res. 2004; 10(18Pt1):6248-6255.","DOI":"10.1158\/1078-0432.CCR-04-0850"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/haematol.2021.280352\/74357","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/haematol.2021.280352\/74886","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/10601\/74357","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:01:28Z","timestamp":1794045688000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/haematol.2021.280352"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,14]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2021.280352","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2022,4,14]]}}}